6.

28 Chemotherapy-Induced Peripheral Neuropathy

Adib Behrouzia and Jill C. Fehrenbachera,b, a Department of Pharmacology and Toxicology, Indiana University School of Medicine,
Indianapolis, IN, United States; and b Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN,
United States
© 2022 Elsevier Inc. All rights reserved.

6.28.1 Introduction 580

6.28.2 The clinical study of CIPN 581
6.28.2.1 CIPN: Clinical presentation and prevalence 581
6.28.2.2 CIPN: Obstacles to diagnosis and treatment 581
6.28.2.3 Risk factors that increase CIPN incidence and severity 582
6.28.3 The preclinical study of CIPN 583
6.28.3.1 Preclinical models of testing 583
6.28.3.1.1 In vivo models of CIPN 583
6.28.3.1.2 In vitro models of CIPN 584
6.28.3.2 Proposed pathological mechanisms and selected drug targets 585
6.28.3.3 Mechanisms for neurotoxicity from each chemotherapeutic class 586
6.28.3.3.1 Platin compounds 586
6.28.3.3.2 Microtubule agents 587
6.28.3.3.3 Protease inhibitors 588
6.28.3.3.4 Immunomodulatory agents 588
6.28.3.3.5 Non-pharmaceutical treatments 588
6.28.4 Summary 588
References 589

Glossary
Adducts and Crosslinks Specific types of DNA damage. An adduct is a covalent linkage between a DNA base and a chemical
moiety, such as a carcinogen or chemotherapeutic. Crosslinks are chemically-mediated linkages between strands of DNA that
are either linked in the same strand (intrastrand) or different strands (interstrand).
Allodynia Sensation of pain elicited from a stimulus that would not typically elicit pain. An example of this is pain in the hands
and feet upon covering with a blanket, as this type of mechanical stimulation is not normally considered a nociceptive
stimulus.
Biopsychosocial model of patient care Treating patients with the consideration of biological, social, and psychological factors,
that results in a multi-disciplinary approach to patient care.
Dysesthesia Spontaneous changes in sensation that are unpleasant and can lead to pain (spontaneous pain). An example of
this would be burning or shooting pain in the hands, in the absence of obvious nociceptive stimuli.
Hyperalgesia Increases in sensation of pain from a stimulus that normally does elicit responses of pain but at lower levels. An
example of this is an exaggerated pain response to a needle stick, as this type of mechanical stimulation is nociceptive but
usually does not elicit a very strong perception of pain.
Neurotoxicity/Neuropathy The effect of chemical, biological or physical agents on the peripheral or central nervous system
that results in direct or indirect damage to the neurons, leading to neuronal death in some cases. The resulting dysfunction to
the nerves can cause a sensory peripheral neuropathy, characterized by any combination of the following: dysesthesia,
allodynia, hyperalgesia, numbness and tingling, and proprioceptive deficits.
Nociceptive stimulus A stimulus that generally provokes painful perception. Stimulation modalities can include: thermal (hot
or cold), mechanical, electrical and chemical.

6.28.1 Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse side effect experienced by patients who receive neurotoxic
chemotherapeutics for the treatment of cancer. The symptoms of CIPN vary widely among patients, as some experience extreme
pain, while others experience only non-painful symptoms. Neuropathy can affect the quality of life of a patient, even in the absence
of pain. Difficulties with proprioception and light touch can hinder the ability of patients to perform activities of daily living, such as
dressing, grooming, and cooking. Hypersensitivity to temperature changes can negatively impact the performance of simple tasks,

580 Comprehensive Pharmacology, Volume 6 https://doi.org/10.1016/B978-0-12-820472-6.00109-2

 Chemotherapy-Induced Peripheral Neuropathy 581

such as touching a cold steering wheel to drive a car (Flatters et al., 2017). Severe neuropathy can force oncologists to alter or termi-
nate the administration of scheduled cancer treatments (Gordon-Williams and Farquhar-Smith, 2020), subsequently worsening the
patient’s prognosis for continued survival. Another consequence of CIPN is the financial liability (Berger et al., 2004). In general,
cancer patients are already economically burdened, but CIPN can require additional out of pocket costs for neuropathy medica-
tions, even for those who have private insurance. Because some patients have ongoing difficulties with sensory function caused
by CIPN, they are unable to return to the occupation they held prior to the cancer diagnosis, resulting in loss of work and further
economic burden not only to the patient but also to society at large (Pike et al., 2012; Zanville et al., 2016).

6.28.2 The clinical study of CIPN

6.28.2.1 CIPN: Clinical presentation and prevalence
The incidence and severity of CIPN varies widely among cancer patients. The treatment of multiple myeloma, breast, lung, gyne-
cological, pancreatic, and colorectal cancers is associated with the largest incidence of CIPN (Cavaletti et al., 2019), mainly due
to the classes and combinations of chemotherapeutic drugs that are efficacious in treating these aggressive cancers. CIPN is thought
to be driven primarily by changes in the activity and innervation patterns of the peripheral nervous system. The symptoms of CIPN
from different classes of chemotherapeutics vary, but patients can present with: numbness and tingling (paresthesia), abnormal
itching or burning pain (dysesthesia), mechanical and cold allodynia, and effects on fine motor ability (Kerckhove et al., 2017).
The severity of CIPN varies widely based on the chemotherapeutic agents and dosing strategies used to treat patients, with higher
individual doses and larger cumulative doses contributing to increased CIPN (International Collaborative Ovarian Neoplasm
Group, 2002; Roelofs et al., 1984). It has been suggested that the most common classes of drugs used in the clinic (taxanes, platins,
vinca alkaloids, proteasome inhibitors, immunomodulators) can affect neuronal function via different mechanisms (LaPointe et al.,
2013), possibly contributing to the wide array of clinical manifestations of CIPN in cancer patients. The changes in sensory nerve
function associated with CIPN can be physiologically categorized as increases or decreases in neuronal signaling. Increased neuronal
signaling underlies the allodynia and hyperalgesia in the presence of thermal or mechanical stimuli (hyperesthesia) and the spon-
taneous or cold-elicited abnormal and unpleasant sensation (dysesthesia or pain). In contrast, decreased neuronal signaling can
result in the diminished sensations experienced by patients, including numbness (hypoesthesia), loss of positional sense, loss of
reflexes, and decreased blood flow to extremities. In most patients, the first symptoms to present are loss of deep tendon reflexes
and ability to detect vibration (Cavaletti et al., 2019); these and other symptoms start in the outer extremities, such as the hands
and feet, and progress symmetrically in the distal to proximal direction (Finnerup et al., 2016; Di Stefano et al., 2020).
The symptoms of CIPN generally peak around 6 months following the initiation of chemotherapy treatment (Molassiotis et al.,
2019a,b) and can resolve following treatment cessation, but commonly persist for months to years, depending on the patient and
the class of drugs received (Kerckhove et al., 2017). Coasting is a phenomenon observed with platin drugs, where the symptoms of
CIPN continue to worsen after discontinuation of the platins, suggesting ongoing damage to the peripheral nerves. Coasting
complicates the diagnosis of CIPN and precludes dose reductions or a switch to a less neurotoxic chemotherapeutic to mitigate
neuronal damage in patients.
Altogether, the physical, emotional and economic effects of CIPN compromise the quality of life in cancer survivors. With
advances in cancer research, including increased early cancer detection and improvements in anticancer treatments, and subsequent
improvements in the survival of cancer patients, the incidence and prevalence of CIPN is increasing in adults (Shah et al., 2018) and
children (Kandula et al., 2016). Unfortunately, there are limited treatments available to prevent or treat CIPN; however, many scien-
tists are working towards understanding CIPN and developing therapeutics for neuropathy.

6.28.2.2 CIPN: Obstacles to diagnosis and treatment

Recognizing CIPN during and following chemotherapeutic treatment is important to ensure proper patient care (Wasilewski and
Mohile, 2021). Empowering patients to report their symptoms is critical to establish an accurate assessment of their CIPN, as
medical providers frequently underestimate CIPN in patients (Shimozuma et al., 2009). In addition, patients who have pre-
existing conditions, such as diabetes or HIV, might develop more severe neuropathy with chemotherapy. Such pre-existing condi-
tions highlight the importance of obtaining a full medical history and testing for neuropathy prior to the first chemotherapy
administration so that the least neurotoxic treatment option might be considered for those patients with pre-existing neuropa-
thies (Wasilewski and Mohile, 2021). Regardless of various pre-existing conditions, proper patient care is imperative in allowing
successful and timely diagnosis of CIPN.
There is ongoing debate on how best to assess CIPN in the community health setting and within clinical trials. One of the chal-
lenges in clinical CIPN research is the number of assessment options to grade neuropathy in patients on clinical trials. The most
common clinician-reported assessment used for grading CIPN is the NCI Common Terminology Criteria for Adverse Events
(CTCAE), which is based upon patient symptoms. The drawbacks of this assessment are that it lacks standardization across admin-
istrators, has low sensitivity for sensory neuropathy symptoms, and may overestimate motor neuropathy due to confounding
factors (Frigeni et al., 2011; Postma et al., 1998). While this lack of uniformity likely does not affect CIPN treatment for individuals
within the community hospital setting, it complicates the use of the CTCAE for clinical trials, where accurate grading of CIPN with
minimal subjectivity is essential for experimental reproducibility and interpreting the effects of putative therapeutics on neuropathy.
582 Chemotherapy-Induced Peripheral Neuropathy

The three most utilized patient-reported outcome measures include the European Organization for Research and Treatment of
Cancer Quality of Life Questionaire-CIPN20 (Postma et al., 2005), the Functional Assessment of Cancer Therapy/Gynecologic
Oncology Group-Neurotoxicity (FACT/GOG-NTX) (Calhoun et al., 2003), and the Patient Neurotoxicity Questionnaire (PNQ)
(Shimozuma et al., 2009), which score varying criteria to assess the physical symptoms of cancer patients. The Total Neuropathy
Score (TNS) involves similar patient-reported information; however, it also includes endpoints of neurophysiological function
as objective measures of neuropathy. These neurophysiological assessments include: vibration thresholds, sensitivity to sharp tactile
stimuli, muscle strength and reflexes, overall mobility, and muscular and neuronal action potential outputs in patients (Cavaletti
et al., 2007). Quantitative sensory testing (QST) is based solely upon neurophysiological assessments, evaluating tolerance thresh-
olds to noxious and non-noxious mechanical, thermal and vibratory stimuli (Argyriou et al., 2019). There are other tests that focus
purely on objective changes in neurophysiological function and form in patients with CIPN, such as nerve conduction studies
(NCS) and studies to determine the density of intraepidermal nerve fibers (IENF). Nerve conduction studies paired with electromy-
ography are popular methods for determining neurological and muscular function (Fuglsang-Frederiksen and Pugdahl, 2011).
Measurements of velocities of action potentials in the proximal and distal sural nerve have shown that different chemotherapeutics
elicit changes in action potential conduction patterns (Mileshkin et al., 2006). IENF studies require patient skin biopsies and focus
on changes in distal axonal degeneration (Bennett et al., 2011; Han and Smith, 2013; Zheng et al., 2012). Unfortunately, NCS and
IENF can be painful for patients.
The use of such a variety of diagnostic tools, without a clear frontrunner that has been validated to be the best assessment for
CIPN, provides a challenge to oncologists and other clinicians in the patient care team to choose the most appropriate and efficient
tool to monitor patients throughout their treatment. Painful neuropathy is prevalent in a subset of CIPN patients, but not all of the
assessments described above identify pain as a component of the disease (Kanzawa-Lee et al., 2019). Furthermore, the lack of
a single comprehensive assessment tool for CIPN has hindered our ability to compare the relative efficacies of putative therapeutics
across clinical trials, as not all measures have historically assessed all of the different sensory modalities in patients. Potential
discrepancies between patient-reported and clinician-reported assessments of painful CIPN can occur (Timmins et al., 2020), which
adds to the exigency of developing or adopting a single comprehensive assessment. The subjective nature of patient-reported
outcomes is always concerning within a clinical trial, therefore objective neurophysiological endpoints (NCV and IENF) have
also been proposed as clinical trial endpoints. While NCV and IENF studies can demonstrate ongoing dysfunction and denervation
in some patients following chemotherapy treatment; these deficits do not always translate to symptoms reported by the patients
(Kalliomaki et al., 2011). Furthermore, other confounding diseases can skew the baseline levels of epidermal innervation in patients
(Lauria et al., 1998; Polydefkis et al., 2002). Patient-reported outcomes are the most clinically relevant endpoints that we have, as
the patients’ quality of life will be affected to the extent that they experience symptoms. As researchers learn more about the natural
history of CIPN in patients, there is hope that better objective measures in patients will be identified as biomarkers for the severity of
the neuropathy. Delayed recognition of symptoms of CIPN in patients, along with a lack of drugs to treat CIPN, can lead to poor
patient quality of life. One recommendation would be for cancer care providers and primary care physicians to align protocols for
various assessments of CIPN, in order to ensure standardized patient care (Banach et al., 2017).

6.28.2.3 Risk factors that increase CIPN incidence and severity

A biopsychosocial approach to clinical CIPN research might help identify risk factors to serve as predictive biomarkers for CIPN
incidence and severity. Ideally, these risk factors also could help clinicians personalize chemotherapeutic approaches to minimize
toxicities. The two main groups of risk factors that will be discussed are biological and behavioral factors. Biological factors include
ancestry, genetics, pre-existing neuropathies, diabetes, age, and diet-related nutrient deficiencies. Behavioral risk factors include low
physical exercise levels, eating disorders, and smoking.
It is widely acknowledged that African ancestry is a risk factor for increased CIPN. There are likely multiple underlying causes for
this disparity, and researchers are identifying genetic polymorphisms that might contribute to different sensitivities to chemother-
apeutics. Variations in the gene, SBF2, predict higher CIPN in African American patients following treatments with paclitaxel
(Schneider et al., 2016). Variations in SCN9A, the gene that encodes the alpha subunit of the Nav1.7 voltage-gated sodium channel,
have been associated with higher grade CIPN in Japanese populations (Tanabe et al., 2020). Whether this polymorphism contrib-
utes to CIPN in other populations, where the variant alleles for SCN9A (homozygous variants, TT) are less rare (NCBI, 2021), has
not been investigated. Finding more genetic polymorphisms that underlie ancestry-associated risks of CIPN would provide an addi-
tional facet of CIPN prevention and understanding of CIPN mechanisms that could be beneficial in the clinic (Baldwin et al., 2012).
Genetic variations, independent of race, also appear to increase the risk for greater CIPN in patients treated with vincristine, plat-
ins, and taxanes (Cliff et al., 2017). Variations in genes encoding a variety of proteins, including ion channels and signaling proteins,
contribute to CIPN: a mutation in sodium channel Nav1.4 (rs2302237) increases the risk for platin-induced peripheral neuropathy
(Argyriou et al., 2013), whereas a mutation in FGD4 (rs10771973), an actin-binding protein integral for maintaining cell structure,
increases the risk for paclitaxel-induced peripheral neuropathy (Lam et al., 2016). Genetic mutations that underlie the Charcot
Marie Tooth (CMT) syndromes of inherited neuropathies also predict the incidence and severity of CIPN, suggesting some overlap
for the mechanisms of chemotherapy-induced and inherited neuropathies. Polymorphisms in several genes that underlie CMT
disease were shown to increase CIPN (Boora et al., 2015; Shah et al., 2018; Baldwin et al., 2012; Beutler et al., 2014); however,
only two of these, FZD3 and EPHA5, were replicated in an independent patient cohort (Chen et al., 2020).
 Chemotherapy-Induced Peripheral Neuropathy 583

Cancer patients often present with comorbidities that predispose them to neuropathy; however, most prospective CIPN clinical
trials have excluded patients with preexisting neuropathies. Diabetic peripheral neuropathy (DPN) can contribute to greater
neuropathy after treatment with chemotherapeutics (Hershman et al., 2016; Visovsky et al., 2008). Chronic inflammatory demye-
linating polyneuropathy (CIDP) and other autoimmune neuropathies, as well as treatments for HIV, could affect the incidence and
severity of CIPN. Therefore in patients with a predisposition to neuropathy, baseline neurological function should be conducted
through patient interviews and/or electrophysiological evaluation to be able to assess the patient risk for CIPN (Banach et al.,
2017). Future studies are warranted to determine whether mechanisms underlying neuropathies from different etiologies parallel
each other and to determine whether these patients would benefit from increased monitoring and the selection of less neurotoxic
chemotherapeutics (Gewandter et al., 2017).
The importance of addressing CIPN is underscored by the enhanced survival of pediatric patients, as a consequence of increas-
ingly successful chemotherapy treatments (Kandula et al., 2016). The sluggish development of patient-reported measures designed
explicitly for pediatric patients exacerbated the difficult task of identifying CIPN in this population (Johnston et al., 2016). Just
recently, researchers constructed a patient-reported outcome measure for the pediatric population, known as the electronic Pediatric
Chemotherapy-Induced Neuropathy assessment (P-CIN) (Smith et al., 2020). As with adult populations, viable treatment options
for neuropathy in pediatric patients are scarce. Scrambler therapy, a novel treatment that applies therapeutic cutaneous electrical
current to purportedly alleviate the activity of c-fibers, and the anticonvulsant pregabalin, an analog of gabapentin, have undergone
Phase 1 studies for CIPN in the pediatric population with promising results (Tomasello et al., 2018; Vondracek et al., 2009);
however, further use of these drugs in Phase 3 trials would strengthen confidence in the efficacy of these treatments. Greater
CIPN persistence is associated with older patient populations (Bulls et al., 2019), and older patients also are more likely to have
pre-existing autonomic neuropathy. Although older age has not been shown to affect the severity of CIPN, older patients seem
to suffer difficulties with CIPN at a greater rate (Argyriou et al., 2006).
Different diets and subsequent nutritional profiles for patients might also result in variability in CIPN. Diet deficiencies in vita-
mins and macromolecules, including thiamine (vitamin B1), pyridoxine (vitamin B6), cobalamin (vitamin B12), calciferol
(vitamin D), and fatty acids, have been correlated with greater development and severity of CIPN in patients (Grim et al., 2017;
Mongiovi et al., 2018). Even in the absence of chemotherapy treatment, diets lacking vitamin B12 can cause neuropathy (Ekabe
et al., 2017; McCombe and McLeod, 1984). Many studies have been performed to explore whether exogenous vitamin B could
prevent or treat CIPN, however, the results of those trials were disappointing (Schloss et al., 2017). While dietary deficiencies
are obviously biological risk factors, it is also important to appreciate that these deficiencies could be attributed to patient behavior
(Morse, 2006). Eating disorders such as anorexia and bulimia could potentially contribute to the diet deficiencies that are present in
patients exhibiting CIPN. Treatments, such as cannabis, might be suitable to enhance caloric intake and avoid diet deficiencies
(Abrams and Guzman, 2015; Abrams, 2016).
Patient lifestyle choices can also predict CIPN, as a lack of physical activity or exercise, increased obesity or body mass index
(BMI), and a history of smoking all increase the risk for greater CIPN (Wirtz and Baumann, 2018; Greenlee et al., 2017; Molassiotis
et al., 2019a,b). Exercise has been suggested to help alleviate the symptoms of CIPN (McCrary et al., 2019; Duregon et al., 2018),
and is an encouraging area of ongoing research. As mentioned previously, the identification of risk factors that increase the incidence
and severity of CIPN may help to shape treatment decisions for patients, but they also provide clues into the mechanisms by which
chemotherapeutic drugs cause neurotoxicity.

6.28.3 The preclinical study of CIPN

6.28.3.1 Preclinical models of testing
In an attempt to better understand the mechanisms by which chemotherapeutics alter neuronal function and to validate the efficacy
of putative therapeutics prior to administration to patients, scientists have developed experimental models of CIPN: in vivo
(animal-level) and in vitro (tissue-level). In vivo studies allow the field to examine CIPN in an intact system, whereas in vitro exper-
iments are helpful in elucidating the mechanisms of the various chemotherapeutics.

6.28.3.1.1 In vivo models of CIPN

Within the published literature, there is very little discussion regarding the validity of animal models of CIPN. A systematic anal-
ysis of animal models of CIPN show that they are wide and numerous, using a wide range of doses and routes of administration
for the different chemotherapeutics examined, using multiple species and strains of animals for testing, and assessing a variety of
behavioral, neurophysiological and biochemical endpoints to assess CIPN (Gadgil et al., 2019). Chemotherapeutics from all
classes have been administered to animals to study CIPN, including: platins, taxanes, immunomodulators, epothilones, protea-
some inhibitors, and vinca alkaloids. Different methods of chemotherapeutic administration are significant, as they can impact
drug absorption, metabolism, and excretion (Benet, 1978). The distribution of the drug to peripheral sites of action is also depen-
dent upon availability of the drug in the bloodstream. The two main routes of chemotherapy administration in rodents are via
intraperitoneal and intravenous injection. Drugs administered into the peritoneal cavity are subject to hepatic first pass elimina-
tion, whereas drugs administered intravenously avoid first-pass elimination, resulting in higher concentrations of the drugs in the
systemic circulation. Earlier models of CIPN generally used very high doses of chemotherapeutics that do not emulate current
dosing protocols for patients. High doses of the drugs elicit large levels of sensory neuronal death, which is inconsistent with
584 Chemotherapy-Induced Peripheral Neuropathy

what is observed in patients, therefore these dosing protocols are now rarely used to study CIPN (Forsyth et al., 1997; Lipton
et al., 1989). More contemporary animal models use dosages that more closely replicate clinical dosing paradigms with lower
doses and intermittent exposure (Polomano et al., 2001; Authier et al., 2003). Sex of species has not been a particular focus
for many animal studies, as most studies have used males; however, there is increasing evidence showing the importance of
sex-differences in CIPN in animals (Gadgil et al., 2019; Naji-Esfahani et al., 2016). Similar to the challenges faced with clinical
assessment of CIPN, preclinical testing for neuropathic symptoms has been challenged with the use of many different behavioral
assessments of the animals, including observations of spontaneous nociception, reflex withdrawal upon thermal and mechanical
stimulation, and multiple operant-like models to assess spontaneous pain or allodynia and hyperalgesia. All of these assays
contribute to inter-laboratory variability and, depending on the assays used, maybe have low predictive therapeutic value, likely
leading to low bench to bedside translation.
The effects of combination treatments on CIPN have received little attention in preclinical models. Combination treatments are
typically used as interventions for specific aggressive cancers; FOLFOX (oxaliplatin and fluorouracil) (Neugut et al., 2019), XELOX
(oxaliplatin and fluoropyrimidines) (Wang et al., 2018; Schmoll et al., 2015), and FOLFIRI (oxaliplatin and irinotecan) (Neugut
et al., 2019) are used clinically, but the effects of these combinations on CIPN have not been discussed. Additionally, promising
combinations of classical chemotherapeutics with immunotherapeutics are being used clinically, therefore there is a need to start
examining combination therapies in animal models to ascertain the mechanisms for interactions between these treatments on
neuronal function.
Another underexplored research area pertains to the use of tumor-bearing animals. Few studies have used treatment of tumor-
bearing animals to model CIPN (Zhu et al., 2019). Although it is clear that chemotherapeutics cause neuropathy in naive animals,
the contribution of the tumor alone or in combination with treatment towards the development of CIPN has not been deeply inves-
tigated. The last few years have seen an increased interest in the role of the nervous system in oncology (Monje et al., 2020);
however, an increased emphasis on understanding the tumor effects towards neuropathy is warranted. The rationale for using
tumor-bearing animals extends beyond the mechanisms for CIPN, as it is essential to validate that putative therapeutics for
CIPN do not compromise the anti-tumor efficacy of the chemotherapy drugs, and consequently the survival of the patients. In
summary, although there have been advances in the understanding of CIPN through the use of animal models, there is room
for improvement that will hopefully increase the translatability of preclinical findings.

6.28.3.1.2 In vitro models of CIPN

In addition to animal models of CIPN, in vitro preparations of primary sensory neurons or neuron-like cells have also been
utilized to model changes in neuronal structure and function secondary to exposure to chemotherapeutics. Obvious limita-
tions of using in vitro models are that the neurons are removed from their natural microenvironment and from the organism,
at large, so that cell to cell interactions and the effects of local and circulating neuronal modulators cannot be studied in vitro.
Despite these constraints, in vitro models provide optimal models for examining the neuron autonomous intracellular
signaling pathways perturbed by chemotherapeutics, as it is easier to manipulate protein expression and function via pharma-
cological and genetic tools in culture compared to in the intact animal. Primary cultures derived from human tissues best reca-
pitulate the complement of proteins, lipids, and nucleic acids present in patients (Chang et al., 2018; Rostock et al., 2018);
however, there are limitations to the availability of those tissues to enable all preclinical research to take place in human
DRG cultures.
Primary cultures of sensory neurons can be obtained from rodents at varying developmental stages (Burkey et al., 2004; Owen
and Egerton, 2012). Although DRG cultures derived from rodent embryos are dependent upon NGF for survival, adult DRG cultures
are independent of NGF for survival (Zhu et al., 2004). This NGF independence of adult cultures allows for the manipulation of
NGF signaling, since several publications suggest that a loss of NGF mediates, in part, the neuronal changes associated with
CIPN (Youk et al., 2017; Cavaletti et al., 2004). The neuronal endpoints used in in vitro studies usually include an assessment
of function and/or morphology. Functional endpoints include neurotransmission by the neurons (glutamate or peptide release),
changes in intracellular calcium levels within the neurons, or changes in the excitability of the neurons. Neuronal morphology
has been a major endpoint for the in vitro study of chemotherapeutics, as the drugs elicit a stark decrease in neuronal outgrowth
and branching as is observed in vivo with decreases in intraepidermal nerve fibers (Boyette-Davis and Dougherty, 2011; Melli et al.,
2006; Siau et al., 2006; Xiao et al., 2009; Zheng et al., 2012).
The in vitro effects of the various classes of chemotherapeutics on neuronal sensitivity and morphology are quite similar, despite
the distinctive intracellular mechanisms of action for the drugs. Similar morphological changes in sensory neurons have been
observed with bortezomib, cisplatin, oxaliplatin, paclitaxel, and vincristine (Ale et al., 2015; Lopez-Gonzalez et al., 2018; Maggioni
et al., 2010; Malgrange et al., 1994; Pittman et al., 2016), where the chemotherapeutics reduce the total outgrowth and the branch-
ing or complexity of the neurites. Paclitaxel, cisplatin, and oxaliplatin all cause a concentration-dependent change in neuropeptide
release, with lower concentrations of the drugs increasing and higher concentrations diminishing the stimulated release of neuro-
transmitter (Jiang et al., 2008; Kelley et al., 2014; Pittman et al., 2014). Some reports even suggest that the drugs can directly elicit
the release of neuropeptides (He and Wang, 2015; Miyano et al., 2009). One obvious mechanism by which neurotransmitter release
is altered is via a change in intracellular calcium levels. Indeed, changes in intracellular calcium levels have been observed with pacli-
taxel (Boehmerle et al., 2006; Li et al., 2015) and the platinum drugs (Leo et al., 2020), and would be expected with bortezomib
treatment since the drug is known to alter T-type calcium current in sensory neurons (Tomita et al., 2019). Even though the effects of
the different chemotherapeutics on integrated neuronal functions are similar, it is not surprising that these effects are mediated by
 Chemotherapy-Induced Peripheral Neuropathy 585

a varied array of membrane and cytosolic targets, including: ion channels, membrane receptors, mitochondrial proteins, DNA
damage, cytoskeletal filaments, calcium-binding proteins, and proteasome components, which will be detailed in the following
sections.
As mentioned previously, data interpretation can be limited with primary cultures, as the neurons under investigation have been
removed from their in vivo milieu and have undergone axotomy during excision from the animals. To facilitate the study of inter-
actions between the sensory neurons and non-neuronal cells that exist in vivo, the nerve-on-a-chip has been developed by Kramer
and colleagues, whereby a DRG explant is placed on a specialized coated slide, allowing for electrophysiology, different types of
microscopy and protein localization and expression analysis on the same specimen (Kramer et al., 2020). These types of assays
should facilitate the study of interactions between Schwann cells and the sensory neurons. Attributing the effects of chemothera-
peutic drugs to direct effects on sensory neurons has been limited, because DRG cultures are generally a heterogeneous mixture
of neurons and non-neuronal cells, including glial cells and fibroblasts. To overcome this limitation, Park and colleagues purified
primary cultures by utilizing a bovine serum albumin gradient centrifugation method and found that similar effects of paclitaxel on
neuronal outgrowth were observed in cultures with dramatically fewer non-neuronal cells (Park et al., 2021), suggesting that the
effects of the drugs on neurite length, at least, are due to neuron autonomous effects.
Multiple other cell types have been used to study the effects of chemotherapeutics, since the primary culture of sensory neurons is
animal- and labor-intensive. These include 50B11 cells, generated by immortalizing rat dorsal root ganglion sensory neurons (Chen
et al., 2007); F11 cells, a fusion product of a mouse neuroblastoma cell line with embryonic rat DRG (Fan et al., 1992); and multiple
other nerve-like cells derived from murine or human nerve/adrenal-based tumors (Biedler et al., 1978; Greene and Tischler, 1976;
Klebe and Ruddle, 1969). While these cells have been useful to examine the changes in cellular form and function following drug
exposure, data interpretation is limited by the knowledge that immortalization likely alters the genotype/phenotypes of the cells
compared to dissociated primary sensory neurons.
Humans are not rodents, therefore the expression of some proteins in mice might not be found in the same relative abundance
in humans and vice versa. Indeed, Chang and colleagues found differential expression of key sensory neuron sodium channels
between humans and mice (Chang et al., 2018). Human DRG cultures can be derived from tissues donated by patients undergoing
surgical ganglionectomy or from cadavers (Valtcheva et al., 2016; Li et al., 2017). Although it is not practical every in vitro exper-
iment in human DRG cultures, the establishment of resources demonstrating relative protein expression of key neuronal proteins in
humans and rodents (Ray et al., 2018) will help to focus our studies on targets that are known to be relevant in the cancer patient
and increase the likelihood of developing novel therapeutics.
Human pluripotent stem cells (iPSC) may play a role in filling the gap between the patients and rodent in vitro models, as they
are human cells derived from patient skin or blood reprogrammed back towards an embryonic-like pluripotent state. The iPSC can
then, with the assistance of several different growth factors, be differentiated into sensory neuron-like cells that express many similar
important functional channels found in primary neurons (Wheeler et al., 2015) to model CIPN (Rana et al., 2017; Xiong et al.,
2021). Treatment with vincristine and paclitaxel alters cellular morphology (Wheeler et al., 2015) and treatment with oxaliplatin
alters electrophysiological endpoints similar to those observed in primary cultures derived from rodents (Wainger et al., 2015). In
addition to their wide availability, another advantage of iPSCs is that they retain the genetic diversity of the donor patients. There-
fore, mechanistic in vitro studies in human sensory neuron-like cells can be performed to understand the correlation between clin-
ical CIPN and neuron autonomous changes in protein expression and function. However, there are also limitations with the use of
iPSCs. Depending on the protocol used to reprogram the cells, the expression of genes generally thought to be expressed in sensory
neurons changes (Cai et al., 2017; Chambers et al., 2012; Wainger et al., 2015; Cao et al., 2016), contributing to possible variations
in function and sensitivity between different types of iPSCs generated in different laboratories. Additionally, this model would be
unable to recapitulate potential epigenetic changes induced by chemotherapeutic drugs in sensory neurons, since the cells are
derived from non-neuronal cells.
Both in vivo and in vitro models of CIPN are informative and valuable, but depending on the question being investigated one
might be more preferential over the other. In vitro models can be more precisely controlled and manipulated to study specific
signaling mechanisms by which the drugs alter form and function and thus eliminate some of the variability that is inherent in
animal models. In vivo models allow for the maintenance of the entire microenvironment in the animal and monitor translational
behaviors that are more closely related to effects of the drugs observed in the clinic. Using these models in a complementary fashion
will likely provide novel drug targets that have a higher chance for translation to therapeutics for CIPN.

6.28.3.2 Proposed pathological mechanisms and selected drug targets

Multiple types of preventative and therapeutic interventions have been tried in the clinic to alleviate the burden of CIPN, including
both pharmacological and non-pharmacological treatments. Currently, there are no approved pharmacological agents for the
prevention of CIPN and the selective serotonin-norepinephrine reuptake inhibitor (SSNRI), duloxetine, is the only FDA-
approved agent to treat existing CIPN in the United States. The different types of agents that have been evaluated as potential preven-
tatives or treatments for CIPN include: chemoprotectants, anticonvulsants, antidepressants, nutrient repletion strategies herbal
supplements, and non-pharmaceutical methods of treatment such as acupuncture, cryotherapy, exercise therapy, and physical
therapy. A pilot and subsequent follow up trial for acupuncture shows promise for alleviating CIPN (Lu et al., 2020; Molassiotis
et al., 2019c). Studies conducted to evaluate the effects of exercise should be continued, however show potential promise for
lowering the painful effects of CIPN (Dhawan et al., 2020).
586 Chemotherapy-Induced Peripheral Neuropathy

The pharmacological treatment of neuropathy has always been challenging, as patients with neuropathic pain generally do not
respond reliably to conventional analgesics (Kingery, 1997). Early work by researchers studying neuropathy secondary to overt
nerve damage or diabetes provided the early putative therapeutics for CIPN. These drugs include tricyclic antidepressants SSNRIs,
and tend to target general neuronal activation and stress responses or modulate the integration of inputs in the dorsal horn of the
spinal cord (Marks et al., 2009). Indeed, the SSNRI duloxetine is thought to have a central action via the enhancement of descending
modulation to dampen painful inputs into the spinal cord and is FDA-approved for CIPN. Duloxetine and venlafaxine, another
SSNRI, demonstrate the ability to lessen severe CIPN in patients (Salehifar et al., 2020; Farshchian et al., 2018). In addition, several
other therapeutics have recently shown promise. Pregabalin, an anticonvulsant analog of gabapentin which has had mixed results in
trials in the past (Rao et al., 2007; Hincker et al., 2019), has recently been demonstrated to have superior efficacy compared to dulox-
etine against painful neuropathy induced by taxanes in breast cancer patients (Salehifar et al., 2020). Scrambler therapy, which
recently concluded a phase II trial for CIPN (Loprinzi et al., 2020b; Childs et al., 2020), is a novel treatment that applies therapeutic
cutaneous electrical current to purportedly alleviate the activity of c-fibers, resulting in less pain for patients (Childs et al., 2020).
The paucity of options for CIPN prevention or treatment is not due to lack of effort in testing, as over 73 randomized controlled
trials have been performed to test CIPN preventatives and treatments (Hershman et al., 2014; Loprinzi et al., 2020a). Although
many of these putative therapeutics have targeted general stress responses of the sensory neurons (antioxidants) and spinal integra-
tion of primary afferent inputs within the dorsal horn of the spinal cord (anticonvulsants and SSNRIs), and therefore could be effi-
cacious in CIPN induced by any class of chemotherapeutic, researchers are also investigating whether prophylactics or therapeutics
can be designed to target neuropathy via mechanisms that are specific for each of the different chemotherapeutic classes. The ratio-
nale for this approach is to prevent or mitigate damage to the sensory neurons to prevent the downstream neuronal stress response;
however, the challenge with this approach is to find discrete targetable differences between the neurons and cancer cells to protect
the neurons without compromising anti-cancer efficacy of the chemotherapeutics. To advance this line of research, it is essential that
we understand the primary effects of each of the drugs on sensory neuron function and morphology.

6.28.3.3 Mechanisms for neurotoxicity from each chemotherapeutic class

Prototype drugs from each of the different chemotherapeutic classes have been studied preclinically to enhance our understanding
of the mechanisms by which the drugs affect neuronal function. A summary diagram of the neuron autonomous signaling elicited
by each of these drugs is presented in Fig. 1.

6.28.3.3.1 Platin compounds

The platin compounds, including cisplatin, oxaliplatin and carboplatin, comprise one of the most utilized classes of anti-cancer
drugs; cisplatin and oxaliplatin elicit severe neurotoxicity in some patients, but neurotoxicity from carboplatin is not observed
unless very high doses of the drug are administered (Kelley et al., 2014). The chemical structures of cisplatin/oxaliplatin and car-
boplatin differ, in that cisplatin and oxaliplatin have efficient leaving groups (chlorine and oxalate respectively). With the increased
tendency towards aquation, cisplatin and oxaliplatin can more efficiently generate free radicals (Zhu et al., 2005) and oxidize intra-
cellular components, such as DNA, lipids and proteins. In contrast, carboplatin has a cyclobutanedicarboxylate leaving group,
which is a less efficient leaving group, resulting in less reactive oxygen species generated. Due to higher binding affinity for blood-
stream components such as albumin, transferrin and g-globulin, cisplatin and oxaliplatin remain in the bloodstream far longer than
carboplatin (Gullo et al., 1980).
The general mechanism for the platin drugs can be segmented into four primary parts. The first step in this proposed mechanism
is the cellular uptake of the molecule which can be done either by simple passive diffusion or the active transport via the Organic
Cation/Carnitine or Copper transporters (OCTN2/CTR1; (Hucke and Ciarimboli, 2016; Hall et al., 2008)). The second step of the
mechanism, after entering the cell, is the activation of the platin compounds where the primary leaving group (chloride, oxalate, or
cyclobutanedicarboxylate) is replaced by water molecules. Immediately after, a nucleophilic attack reaction occurs where the elec-
tron rich purine bases attack the platin compounds resulting in DNA cross-links between different purine bases and adduct forma-
tion (Faivre et al., 2003). These cross-links can occur both in nuclear and mitochondrial DNA which allow for a maintained
presence of the drugs well after administration. Platin-DNA (Pt-DNA) crosslinks have been detected up to 25 years following
discontinuation of platin chemotherapy (Kerckhove et al., 2017), suggesting that there is a depot of aquated platins in the neuronal
soma. Finally, multiple DNA repair processes exist to mitigate the Pt-DNA lesions, and can lead to either cellular survival or
apoptosis, depending on the cell type. In addition, platins can be attacked by cytoplasmic cysteine-containing nucleophiles, which
can result in abundant reactive oxygen species (ROS) formation and subsequent oxidative damage of lipids, proteins, and DNA
(Kelley et al., 2014).
Due to the known generation of enhanced ROS associated with platin treatment, early attempts to reverse CIPN were focused on
the administration of antioxidants. Preclinical evidence for the efficacy of antioxidants, specifically glutathione, demonstrated
a protective effect against neuropathy; however, glutathione treatment did not protect against neuropathy in clinical trials (Leal
et al., 2014). Another putative therapeutic tested specifically for oxaliplatin-induced neurotoxicity included calcium/magnesium
infusions to replenish calcium and magnesium levels which are thought to be reduced by chelation with oxalate; however, no effect
of the infusions was seen in multiple clinical trials (Grothey et al., 2011; Loprinzi et al., 2014).
As the platins are well-known to form DNA crosslinks, DNA damage induced by the platins is recognized as an important mech-
anism for platin-induced neurotoxicity. Adduct formation by the platin drugs can be repaired by nucleotide excision repair
 Chemotherapy-Induced Peripheral Neuropathy 587

Fig. 1 Putative mechanisms for neurotoxicity in the sensory neuron. Figure created with BioRender.com.

(Dzagnidze et al., 2007), but when that repair process is overwhelmed, nuclear and mitochondrial adducts can lead to inhibition of
transcription and subsequent apoptosis of the sensory neurons (Yan et al., 2015a; Podratz et al., 2011). Interestingly, cisplatin and
carboplatin initiate similar intrastrand crosslinks, whereas oxaliplatin elicits largely interstrand crosslinks (Kelley and Fehrenbacher,
2017), leading researchers to question whether the platin adducts are the primary source of neurotoxicity. Recent preclinical
research has identified a putative role for oxidative DNA damage in the neurotoxicity of sensory neurons. By increasing the repair
of oxidative DNA damage via the base excision repair pathway and increases in the enzyme, APE1, neurotoxicity induced by
cisplatin and oxaliplatin was reduced (Kelley et al., 2014). Cisplatin can also change mitochondrial movement along axons; the
underlying cause of transport deficits remains unknown, but could be a consequence of depleted ATP levels or elevated intracellular
calcium levels (Podratz et al., 2017). Cisplatin can also change the morphology and number of mitochondria, further contributing
to a diminished capacity for ATP generation in the axons (Bobylev et al., 2018). Oxaliplatin has been shown to elicit channelopathy,
which is thought to underlie some of the cold hypersensitivity induced by the drug (Descoeur et al., 2011).

6.28.3.3.2 Microtubule agents

The microtubule altering drugs comprise another class of chemotherapeutics, which can be subdivided into either microtubule
stabilizers or destabilizers. The stabilizers include the taxanes and epothilones, and the anti-cancer effects of these drugs are medi-
ated by the inhibition of tubulin breakdown, preventing depolymerization. The taxanes include paclitaxel, docetaxel, and cabazi-
taxel, whereas ixabepilone is the only US-approved epothilone. In neuronal axons, microtubules are highly dynamic, undergoing
rapid phases of assembly and disassembly. Interference with those processes can contribute to deficits in axonal transport and
peripheral nerve functionality. Taxanes have also been shown to induce neuroinflammation (Makker et al., 2017), change ion
channel activity (Li et al., 2015, 2018) and disrupt mitochondrial DNA transcription (Kober et al., 2018). Because of the mitochon-
drial disruption caused by taxanes, resulting in ROS generation, one potential therapeutic that was tested against taxane-induced
neuropathy was acetyl-l carnitine, known to be a protective antioxidant (Callander et al., 2014; Fritz and Yue, 1963). However,
acetyl-l carnitine actually worsened CIPN when tested in a phase 2 clinical trial (Hershman et al., 2013) for taxane-induced periph-
eral neuropathy. In addition to binding to microtubules to elicit neuronal effects, paclitaxel has also been shown to bind to toll-like
receptors (TLR; (Byrd-Leifer et al., 2001)). Paclitaxel binding to TLR4 on sensory neurons results in the sensitization of TRPV1 (Yan
et al., 2015b); whereas binding to microglia and astrocytes can elicit activation of those cell types to indirectly alter neuronal
588 Chemotherapy-Induced Peripheral Neuropathy

function. Paclitaxel also can bind to neuronal calcium sensor-1 (NCS-1), resulting in changes in calcium signaling (Blachford et al.,
2009), subsequent calpain activation, and neurotoxicity. Paclitaxel also prevents translation of a specific member of the Bcl2 family,
Bclw, which typically binds to receptor IP3R1 to prevent axon degeneration (Pease-Raissi et al., 2017).
Microtubule destabilizers are comprised of vinca alkaloids, including vinblastine, vincristine, vinflunine, and vinorelbine; the
halichondrins, and immunomodulators, and they inhibit microtubule formation by preventing tubulin polymerization. Treatment
with vinca alkaloids results in poor axonal transport and axonal process degeneration, mediated by sterile a-motif-containing and
armadillo-motif-1 (SARM1), a nicotinamide adenine dinucleotide hydrolase, which can affect the excitability of peripheral neurons
(Gerdts et al., 2013). Vinca alkaloids can also cause disruption of calcium homeostasis (Tari et al., 1986), mitochondrial toxicity
(Chiu et al., 2012), and neuroinflammatory activity (Altinoz et al., 2018). Compared to vincristine, newer drugs in this class
such as vinflunine and vinorelbine have less reported cases of CIPN (Islam et al., 2019). Eribulin, the only approved halichondrin,
has a similar mechanism to vinca alkaloids, affecting microtubule activity through microtubule degradation (within (LaPointe et al.,
2013)).

6.28.3.3.3 Protease inhibitors

Protease inhibitors, including carfilzomib and bortezomib, are another class of drugs that elicit neuropathy. Protease inhibitors
cause disruption of axonal transport, axonal degeneration and functional alterations in sensory nerve fibers (Carozzi et al.,
2013; Ale et al., 2015; Meregalli et al., 2010). The proposed mechanisms of action by which protease inhibitors elicit neurotoxicity
include: the transient release of calcium from intracellular stores that leads to mitochondrial disruption and ROS generation (Zheng
et al., 2012); the effects of proteotoxic stress, including DNA damage, adaptive increases in the number and size of nucleoli and the
number of Cajal bodies (Palanca et al., 2014a,b); and enhanced microtubule polymerization, that can modulate neuronal function
in a manner similar to paclitaxel (discussed above; (Staff et al., 2013; Meregalli et al., 2014)). Bortezomib can also promote neuro-
inflammation through increases in the expression of IL-6, IL-6R, TGF-b1, TNFa, and IL-1b within the sensory ganglia and TNFa and
IL-1b in the spinal cord (Liu et al., 2019; Ale et al., 2014). It is unclear whether increases in cytokine signaling are secondary to
bortezomib-induced alterations in NFkB signaling (Ale et al., 2016), mitotoxicity, or microtubule stabilization; however, ongoing
research is certain to elucidate the relationships between these effects of the proteasome inhibitor.

6.28.3.3.4 Immunomodulatory agents

Immunomodulatory agents include thalidomide, lenalidomide, and several new checkpoint inhibitors. While the mechanisms of
neurotoxicity for thalidomide are not known, peripheral neurons might be affected by this drug through activation of Transient
Receptor Potential Cation Channel Subfamily A Member (TRPA) 1 and TRPV4 (De Logu et al., 2020). Antibodies against checkpoint
inhibitors have been developed and tested over the past 10 years to further engage the immune system in combating aggressive
cancers. These drugs include antibodies against: programmed death receptor-1 (PD-1), programmed death receptor-ligand 1
(PD-L1), and cytotoxic T-lymphocyte associated antigen 4 (CTLA-4). Fortunately, the use of these drugs results in low severity of
CIPN; however, when these drugs are co-administered with chemotherapeutics, the incidence and severity of CIPN increases (Si
et al., 2019). In addition to neuropathy, the checkpoint inhibitors have been shown to elicit musculoskeletal pain in patients.
Thus, combining the risk of CIPN via classical chemotherapeutics and musculoskeletal pain via the checkpoint inhibitors warrants
further research into how these drugs alter neuronal function and to determine how to diminish those effects (Kao et al., 2017).

6.28.3.3.5 Non-pharmaceutical treatments

There are also non-pharmaceutical manipulations and treatments that are being investigated, such as physical therapy, cryotherapy,
photobiomodulation, acupuncture, electro-acupuncture, exercise therapy, and massage therapy, all of which have the potential to
treat patients with CIPN. However, there is a lack of robust research to validate the methodologies for these interventions and to
accurately assess the efficacy of these potential interventions (Lodewijckx et al., 2020; Andersen Hammond et al., 2020; Hwang
et al., 2020; Kanzawa-Lee et al., 2020). The use of herbal supplements for the treatment of CIPN, such as ashwagandha, curcumin,
and resveratrol has been viewed skeptically; however, additional preclinical research to demonstrate the pharmacological targets of
these substances and clinical research to demonstrate clinical efficacy would increase the enthusiasm for these alternative treatments
(Noh et al., 2018). Stringent studies are needed to completely understand the effects of these non-traditional interventions on
managing and potentially alleviating CIPN. With the many potential pharmacological and non-pharmacological treatment inter-
ventions that have been introduced in this work, we remain hopeful for more FDA approved treatments for CIPN in the coming
future.

6.28.4 Summary

The outcomes of clinical trials testing putative preventatives or therapeutics for CIPN have seen limited success, reinforcing the need
to understand the signaling mechanisms by which chemotherapeutic drugs can affect neuronal form and function. There is a dire
need for therapeutics to not only increase the quality of life for survivors, but also to increase survivorship of cancer. A stark example
of the impact of CIPN is illustrated within the African American breast cancer population. Cancer survival rates for breast cancer
among African Americans are lower than that in Americans with European ancestry (Schneider et al., 2017). While there are likely
numerous factors that contribute to this disparity, one important contributor is likely the higher incidence of CIPN in African
 Chemotherapy-Induced Peripheral Neuropathy 589

American patients (Schneider et al., 2015). A larger incidence of CIPN results in more dose reductions and treatment discontinu-
ations than in patients without CIPN (Griggs et al., 2003), suggesting that CIPN does affect the survival of patients and providing
strong rationale for distinguishing risk factors for increased CIPN and identifying the mechanisms of CIPN.

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