Morphofunctional characterisation of axonal damage in different rat models of chemotherapy-induced peripheral neurotoxicity: The role of nerve excitability testing.

BACKGROUND AND AIMS: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and long-lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage. METHODS: We tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density. RESULTS: NET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement. INTERPRETATION: NET after the first administration demonstrated the ongoing OHP-related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.

Effect of age on metabolomic changes in a model of paclitaxel-induced peripheral neurotoxicity.

BACKGROUND AND AIMS: Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most common dose-limiting side effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated. METHODS: Twenty-four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2-week follow-up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis. RESULTS: At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p < .05) in the caudal nerve of young PTX-animals, and in both the digital and caudal nerve of adult PTX-animals (p < .05). A significant decrease in the mechanical threshold was observed only in young PTX-animals (p < .001), but not in adult PTX-ones. Nevertheless, both young and adult PTX-rats had reduced IENF density (p < .0001), which persisted at the end of follow-up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX-animals developing peripheral neuropathy and age-matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration. INTERPRETATION: Our study identifies for the first time multiple related metabolic axes involved in PTX-induced peripheral neurotoxicity, and suggests age-related differences in CIPN manifestations and in the metabolic profile.

Considerations for establishing and maintaining international research collaboration: the example of chemotherapy-induced peripheral neurotoxicity (CIPN)-a white paper.

PURPOSE: This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. METHODS: An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. RESULTS: Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. CONCLUSION: Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. RELEVANCE TO INFORM RESEARCH POLICY: Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.

Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy.

The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood. Here, we report that the CIPN-causing drug bortezomib (Bort) promotes delta 2 tubulin (D2) accumulation while affecting microtubule stability and dynamics in sensory neurons in vitro and in vivo and that the accumulation of D2 is predominant in unmyelinated fibers and a hallmark of bortezomib-induced peripheral neuropathy (BIPN) in humans. Furthermore, while D2 overexpression was sufficient to cause axonopathy and inhibit mitochondria motility, reduction of D2 levels alleviated both axonal degeneration and the loss of mitochondria motility induced by Bort. Together, our data demonstrate that Bort, a compound structurally unrelated to tubulin poisons, affects the tubulin cytoskeleton in sensory neurons in vitro, in vivo, and in human tissue, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. The results reveal a previously unrecognized pathogenic role for D2 in BIPN that may occur through altered regulation of mitochondria motility.

Ion Channel and Transporter Involvement in Chemotherapy-Induced Peripheral Neurotoxicity.

The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN.

Axonal degeneration in chemotherapy-induced peripheral neurotoxicity: clinical and experimental evidence.

Multiple pathological mechanisms are involved in the development of chemotherapy-induced peripheral neurotoxicity (CIPN). Recent work has provided insights into the molecular mechanisms underlying chemotherapy-induced axonal degeneration. This review integrates evidence from preclinical and clinical work on the onset, progression and outcome of axonal degeneration in CIPN. We review likely triggers of axonal degeneration in CIPN and highlight evidence of molecular pathways involved in axonal degeneration and their relevance to CIPN, including SARM1-mediated axon degeneration pathway. We identify potential clinical markers of axonal dysfunction to provide early identification of toxicity as well as present potential treatment strategies to intervene in axonal degeneration pathways. A greater understanding of axonal degeneration processes in CIPN will provide important information regarding the development and progression of axonal dysfunction more broadly and will hopefully assist in the development of successful interventions for CIPN and other neurodegenerative disorders.

Toxic medications in Charcot-Marie-Tooth patients: A systematic review.

BACKGROUND AND AIMS: Several widely used medications, with a relevant efficacy profile, are toxic to the peripheral nervous system and an even larger number of agents are suspected to be neurotoxic. There are concerns about the use of these drugs in patients with Charcot-Marie-Tooth disease (CMT), a hereditary motor and sensory neuropathy. This review provides evidence-based updated recommendations on this clinically relevant topic. METHODS: A systematic review of the available studies/reports written in English was performed from July to September 2022 including in the search string all reported putative neurotoxic drugs. RESULTS: The results of our systematic review provide evidence-based support for the statement that use of vincristine, and possibly paclitaxel, can occasionally induce an atypical, and more severe, course of drug-related peripheral neurotoxicity in CMT patients. It is therefore reasonable to recommend caution in the use of these compounds in CMT patients. However, no convincing evidence for a similar recommendation could be found for all other drugs. INTERPRETATION: It is important that patients with CMT are not denied effective treatments that may prolong life expectancy for cancer or improve their health status if affected by non-oncological diseases. Accurate monitoring of peripheral nerve function in CMT patients treated with any neurotoxic agent remains mandatory to detect the earliest signs of neuropathy worsening and atypical clinical courses. Neurologists monitoring CMT patients as part of their normal care package or for natural history studies should keep detailed records of exposures to neurotoxic medications and support reporting of accelerated neuropathy progression if observed.

Framework to leverage physical therapists for the assessment and treatment of chemotherapy-induced peripheral neurotoxicity (CIPN).

PURPOSE: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a highly prevalent, dose-limiting, costly, and tough-to-treat adverse effect of several chemotherapy agents, presenting as sensory and motor dysfunction in the distal extremities. Due to limited effective treatments, CIPN can permanently reduce patient function, independence, and quality of life. One of the most promising interventions for CIPN is physical therapy which includes exercise, stretching, balance, and manual therapy interventions. Currently, there are no physical therapy guidelines for CIPN, thus limiting its uptake and potential effectiveness. METHODS: Utilizing the authors' collective expertise spanning physical therapy, symptom management research, oncology, neurology, and treating patients with CIPN, we propose a comprehensive clinical workflow for physical therapists to assess and treat CIPN. This workflow is based on (1) physical therapy guidelines for treating neurologic symptoms like those of CIPN, (2) results of clinical research on physical therapy and exercise, and (3) physical therapy clinical judgement. RESULTS: We present detailed tables of pertinent physical therapy assessment and treatment methods that can be used in clinical settings. CIPN assessment should include detailed sensory assessment, objective strength assessments of involved extremities, and validated physical performance measures incorporating static and dynamic balance, gait, and functional mobility components. CIPN treatment should involve sensorimotor, strength, balance, and endurance-focused interventions, alongside a home-based exercise prescription that includes aerobic training. We conclude with action items for oncology teams, physical therapists, patients, and researchers to best apply this framework to address CIPN. CONCLUSIONS: Physical therapists are in a unique position to help assess, prevent, and treat CIPN given their training and prevalence, yet there are no physical therapy clinical practice guidelines for CIPN. Our preliminary suggestions for CIPN assessments and treatments can catalyze the development of guidelines to assess and treat CIPN. We urge oncology teams, physical therapists, patients, and researchers to develop, adapt, and disseminate this framework to help alleviate the burden of chemotherapy on patients with cancer.

Patient perceptions of altering chemotherapy treatment due to peripheral neuropathy.

PURPOSE: Clinical practice guidelines recommend altering neurotoxic chemotherapy treatment in patients experiencing intolerable chemotherapy-induced peripheral neuropathy (CIPN). The primary objective of this survey was to understand patient's perspectives on altering neurotoxic chemotherapy treatment, including their perceptions of the benefits of preventing irreversible CIPN and the risks of reducing treatment efficacy. METHODS: A cross-sectional online survey was distributed via social networks to patients who were currently receiving or had previously received neurotoxic chemotherapy for cancer. Survey results were analyzed using descriptive statistics and qualitative analysis. RESULTS: Following data cleaning, 447 participants were included in the analysis. The median age was 57 years, 93% were white, and most were from the UK (53%) or USA (38%). Most participants who were currently or recently treated expected some CIPN symptom resolution (86%), but 45% of those who had completed treatment more than a year ago reported experiencing no symptom resolution. Participants reported that they would discontinue chemotherapy treatment for less severe CIPN if they knew their symptoms would be permanent than if symptoms would disappear after treatment. Most patients stated that the decision to alter chemotherapy or not was usually made collaboratively between the patient and their treating clinician (61%). The most common reason participants were reluctant to talk with their clinician about CIPN was fear that treatment would be altered. Participants noted a need for improved understanding of CIPN symptoms and their permanence, better patient education relating to CIPN prior to and after treatment, and greater clinician understanding and empathy around CIPN. CONCLUSIONS: This survey highlights the importance of shared decision-making, including a consideration of both the long-term benefits and risks of altering neurotoxic chemotherapy treatment due to CIPN. Additional work is needed to develop decision aids and other communication tools that can be used to improve shared decision making and help patients with cancer achieve their treatment goals.

Morpho-Functional Characterisation of the Rat Ventral Caudal Nerve in a Model of Axonal Peripheral Neuropathy.

Peripheral Neuropathies (PN) are common conditions whose treatment is still lacking in most cases. Animal models are crucial, but experimental procedures should be refined in some cases. We performed a detailed characterization of the ventral caudal nerve to contribute to a more effective assessment of axonal damage in future PN studies. PN was induced via weekly systemic injection of a neurotoxic drug (paclitaxel); we compared the control and PN-affected rats, performing serial neurophysiological evaluations of the caudal nerve for its entire length. On the same nerve portions, we performed light microscopy and ultrastructural pathological observations to assess the severity of damage and verify the integrity of the surrounding structures. Neurophysiological and morphological analyses confirmed that a severe axonopathy had ensued in the PN group, with a length-dependent modality, matching morphological observations. The site of neurophysiological recording (e.g., distance from the base of the tail) was critical for achieving useful data. A flexible experimental paradigm should be considered in animal studies investigating axonal PN, particularly if the expected severity is relevant; the mid-portion of the tail might be the most appropriate site: there damage might be remarkable but neither as extreme as at the tip of the tail nor as mild as at the base of the tail.

Prospectively assessing serum neurofilament light chain levels as a biomarker of paclitaxel-induced peripheral neurotoxicity in breast cancer patients.

Our aim was to assess the significance of measuring serum neurofilament light chain (sNfL) levels as a biomarker of paclitaxel-induced peripheral neurotoxicity (PIPN). We longitudinally measured sNfL in breast cancer patients, scheduled to receive the 12-weekly paclitaxel-based regimen. Patients were clinically examined by means of the Total Neuropathy Score-clinical version (TNSc), while sNfL were quantified, using the highly sensitive Simoa technique, before starting chemotherapy (baseline), after 2 (week 2) and 3 (week 3) weekly courses, and at the end of chemotherapy (week 12). Among 59 included patients (mean age: 53.1 ± 11.5 years), 33 (56%) developed grade 0-1 and 26 (44%) grade 2-3 PIPN at week 12. A significant longitudinal increase of sNfL levels from baseline to week-12 was determined, whereas patients with TNSc grade 2-3 PIPN had significantly increased sNfL levels at week 12, compared to those with grade 0-1. receiver-operated characteristics (ROC) analysis defined a value of NfL of >85 pg/mL at week 3 as the best discriminative determination to predict the development of grade 2-3 PIPN at week 12 (sensitivity 46.2%, specificity 84.8%). The logistic binary regression analysis revealed that age > 50 years and the cutoff of >85 pg/mL of sNfL levels at week 3 independently predicted the development of grade 2-3 PIPN at week 12 with a sensitivity of 46%, a specificity of 91%, and a positive and negative predictive values of 75% and 67%, respectively. sNfL levels seem to be a valuable biomarker of neuro-axonal injury in PIPN. An early increase of this biomarker after a 3-weekly chemotherapy course can be a predictive marker of final PIPN severity.

Sodium-Calcium Exchanger 2: A Pivotal Role in Oxaliplatin Induced Peripheral Neurotoxicity and Axonal Damage?

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a frequent adverse event of colorectal cancer treatment. OIPN encompasses a chronic and an acute syndrome. The latter consists of transient axonal hyperexcitability, due to unbalance in Na+ voltage-operated channels (Na+VOC). This leads to sustained depolarisation which can activate the reverse mode of the Na+/Ca2+ exchanger 2 (NCX2), resulting in toxic Ca2+ accumulation and axonal damage (ADa). We explored the role of NCX2 in in vitro and in vivo settings. Embryonic rat Dorsal Root Ganglia (DRG) organotypic cultures treated with SEA0400 (SEA), a NCX inhibitor, were used to assess neuroprotection in a proof-of-concept and pilot study to exploit NCX modulation to prevent ADa. In vivo, OHP treated mice (7 mg/Kg, i.v., once a week for 8 weeks) were compared with a vehicle-treated group (n = 12 each). Neurophysiological and behavioural testing were performed to characterise acute and chronic OIPN, and morphological analyses were performed to detect ADa. Immunohistochemistry, immunofluorescence, and western blotting (WB) analyses were also performed to demonstrate changes in NCX2 immunoreactivity and protein expression. In vitro, NCX inhibition was matched by ADa mitigation. In the in vivo part, after verifyingboth acute and chronic OIPN had ensued, we confirmed via immunohistochemistry, immunofluorescence, and WB that a significant NCX2 alteration had ensued in the OHP group. Our data suggest NCX2 involvement in ADa development, paving the way to a new line of research to prevent OIPN.

Human Intravenous Immunoglobulin Alleviates Neuropathic Symptoms in a Rat Model of Paclitaxel-Induced Peripheral Neurotoxicity.

The onset of chemotherapy-induced peripheral neurotoxicity (CIPN) is a leading cause of the dose reduction or discontinuation of cancer treatment due to sensory symptoms. Paclitaxel (PTX) can cause painful peripheral neuropathy, with a negative impact on cancer survivors' quality of life. While recent studies have shown that neuroinflammation is involved in PTX-induced peripheral neurotoxicity (PIPN), the pathophysiology of this disabling side effect remains largely unclear and no effective therapies are available. Therefore, here we investigated the effects of human intravenous immunoglobulin (IVIg) on a PIPN rat model. PTX-treated rats showed mechanical allodynia and neurophysiological alterations consistent with a severe sensory axonal polyneuropathy. In addition, morphological evaluation showed a reduction of intra-epidermal nerve fiber (IENF) density and evidenced axonopathy with macrophage infiltration, which was more prominent in the distal segment of caudal nerves. Three weeks after the last PTX injection, mechanical allodynia was still present in PTX-treated rats, while the full recovery in the group of animals co-treated with IVIg was observed. At the pathological level, this behavioral result was paralleled by prevention of the reduction in IENF density induced by PTX in IVIg co-treated rats. These results suggest that the immunomodulating effect of IVIg co-treatment can alleviate PIPN neurotoxic manifestations, probably through a partial reduction of neuroinflammation.

Neurofilament light chain: a specific serum biomarker of axonal damage severity in rat models of Chemotherapy-Induced Peripheral Neurotoxicity.

Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a severe and long-lasting side effect of anticancer therapy, which can severely impair patients' quality of life. It is a sensory and length-dependent neuropathy, which predominantly affects large myelinated fibers. Easy and reliable monitoring of CIPN in patients is still an unmet clinical need. Since increasing clinical evidence supports the potential use of neurofilament light chain (NfL) as a biomarker of axonal injury, in this study we measured serum NfL levels in animals chronically treated with cisplatin (CDDP) and paclitaxel (PTX), two antineoplastic drugs with different neuronal targets. Wistar rats were treated with CDDP (2 mg/kg i.p. twice/week for 4 weeks) or PTX (10 mg/kg i.v. once/week for 4 weeks). Repeated serum NfL quantification was obtained using the Single Molecule Array (Simoa) technology. The onset and progression of peripheral neurotoxicity were evaluated through neurophysiology, morphological assessments and intraepidermal nerve fibers density quantification. Our results showed that serum NfL measurements correlated with the severity of axonal damage. In fact, both treatments induced serum NfL increase, but higher levels were evidenced in PTX-treated animals, compared with CDDP-treated rats, affected by a milder neurotoxicity. Notably, also the timing of the NfL level increase was associated with the severity of morphological and functional alterations of axonal structure. Therefore, NfL could be a useful biomarker for axonal damage in order to follow the onset and severity of axonal degeneration and possibly limit the occurrence of serious PNS disease.

Toxic neuropathies: Chemotherapy Induced Peripheral Neurotoxicity.

PURPOSE OF REVIEW: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and distressing side-effect of many chemotherapy regimens. Currently, aside from symptomatic treatments for neuropathic pain, there are no treatments to prevent CIPN or treat established CIPN. We discuss recent articles addressing clinimetric issues and treatment of CIPN. RECENT FINDINGS: There are important clinimetric issues that need to be addressed so that robust clinical trials in CIPN can be performed. There are new compounds in early development that may treat CIPN, but larger studies are needed. SUMMARY: A multidisciplinary, international approach is needed to unravel CIPN; the Toxic Neuropathy Consortium (TNC) of the Peripheral Nerve Society may be the home for such efforts.

Neurophysiological, nerve imaging and other techniques to assess chemotherapy-induced peripheral neurotoxicity in the clinical and research settings.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common dose-limiting side effect of several anticancer medications. CIPN may involve multiple areas of the peripheral nervous system from the autonomic and dorsal root ganglia (DRG) to the axon and any peripheral nerve fibre type. Large diameter sensory myelinated (Aß) fibres are more frequently involved, but motor, small myelinated (Aδ), unmyelinated (C) or autonomic fibres may also be affected. Here, we review the current evidence on techniques for the CIPN assessment in the clinical and experimental settings. Nerve conduction studies (NCS) may be used at the subclinical and early CIPN stage, to assess the extent of large nerve fibre damage and to monitor long-term outcomes, with the sural or dorsal sural nerve as the most informative. The quantitative sensory neurological examination provides valuable data alongside NCS. Quantitative sensory testing and nerve excitability studies add information regarding pathophysiology. Nerve MRI and ultrasound may provide information on enlarged nerve, increased nerve signal intensity and DRG or spinal cord changes. Skin biopsy, corneal confocal microscopy, laser-evoked potentials, contact heat-related potentials and microneurography may reveal the extent of damage to small unmyelinated nerve fibres that go undetected by NCS. The information on the role of these latter techniques is preliminary. Hence, the use of multimodal testing is recommended as the optimal CIPN assessment strategy, employing objective NCS and other specialised techniques together with subjective patient-reported outcome measures.

Bortezomib and other proteosome inhibitors-induced peripheral neurotoxicity: From pathogenesis to treatment.

Proteasome inhibitors (PIs), especially bortezomib (BTZ), have come to the forefront over the last years because of their unprecedented efficacy mainly against multiple myeloma (MM). Unfortunately, peripheral neuropathy (PN) secondary to treatment of MM with PIs has emerged as a clinically relevant complication, which negatively impacts the quality of life of MM survivors. Bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, which develops in 30% to 60% of patients during treatment. Typically, BIPN is a length-dependent sensory axonopathy characterized by numbness, tingling, and severe neuropathic pain in stocking and glove distribution. BIPN mechanisms have not yet been fully elucidated. Experimental studies suggest that aggresome formation, endoplasmic reticulum stress, myotoxicity, microtubule stabilization, inflammatory response, and DNA damage could contribute to this neurotoxicity. A new generation of structurally distinct PIs has been developed, being increasingly used in clinical settings. Carfilzomib exhibits a much lower neurotoxicity profile, with a significantly lower incidence of PN compared to BTZ. Pre-existing PN increases the risk of developing BIPN. Besides, BIPN is related to dose, schedule and mode of administration and modifications of these factors have lowered the incidence of PN. However, to date there is no cure for PIs-induced PN (PIIPN), and a careful neurological monitoring and dose adjustment is a key strategy for preserving quality of life. This review critically looks at the pathogenesis, incidence, risk factors, both clinical and pharmacogenetics, clinical phenotype and management of PIIPN. We also make recommendations for further elucidating the whole clinical spectrum of PIIPN.

Vinca alkaloids, thalidomide and eribulin-induced peripheral neurotoxicity: From pathogenesis to treatment.

Vinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy-induced peripheral neurotoxicity (CIPN) emerged as their main non-hematological and among dose-limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length-dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre-existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin.

Chemotherapy-induced peripheral neurotoxicity: A multifaceted, still unsolved issue.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a potentially dose-limiting side effect of several commonly used cytotoxic chemotherapy agents. The main pharmacological classes that may cause CIPN include classical anticancer drugs, as well as the recently introduced immune checkpoint inhibitors and antibody drug conjugates. The absence of a complete knowledge of CIPN pathophysiology is only one of the several unsolved issues related to CIPN. Among some of the most relevant aspects of CIPN deserving further attention include the real number of patients exposed to the risk of CIPN, the long-term impact on cancer survivors' quality of life due to incomplete recovery from CIPN, the economic burden related to acute and chronic CIPN, and the different perspective and education of the healthcare specialists in charge of managing patients with CIPN. Overall, CIPN remains a very challenging area of research as there are still several unresolved issues to be addressed in the future. In this special issue, the multifaceted profile of CIPN will be presented, with particular emphasis on bolstering the need to develop more optimized outcome measures than the existing ones to accurately evaluate the extent of CIPN, but also to ascertain the differences in the incidence, risk factors, clinical phenotype, and management of CIPN, according to the most commonly used neurotoxic chemotherapy classes. Perspectives for future research to pursue in order to cover the gaps in knowledge in the CIPN field will also be discussed.

Taxane and epothilone-induced peripheral neurotoxicity: From pathogenesis to treatment.

Taxane-induced peripheral neurotoxicity (TIPN) is the most common non-hematological side effect of taxane-based chemotherapy, and may result in dose reductions and discontinuations, having as such a detrimental effect on patients' overall survival. Epothilones share similar mechanism of action with taxanes. The typical TIPN clinical presentation is mainly comprised of numbness and paresthesia, in a stocking-and-glove distribution and may progress more proximally over time, with paclitaxel being more neurotoxic than docetaxel. Motor and autonomic involvement is less common, whereas an acute taxane-induced acute pain syndrome is frequent. Patient reported outcomes questionnaires, clinical evaluation, and instrumental tools offer complementary information in TIPN. Its electrodiagnostic features include reduced/abolished sensory action potentials, and less prominent motor involvement, in keeping with a length-dependent, axonal dying back predominately sensory neuropathy. TIPN is dose-dependent and may be reversible within months after the end of chemotherapy. The single and cumulative delivered dose of taxanes is considered the main risk factor of TIPN development. Apart from the cumulative dose, other risk factors for TIPN include demographic, clinical, and pharmacogenetic features with several single-nucleotide polymorphisms potentially linked with increased susceptibility of TIPN. There are currently no neuroprotective strategies to reduce the risk of TIPN, and symptomatic treatments are very limited. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of TIPN.