Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) develops as a challenging nerve-damaging adverse effect of anticancer drugs used in chemotherapy. The disorder may require a chemotherapy dose reduction and a cessation of administration of chemotherapeutic drugs. Its principal sensory symptoms include, tingling, and numbness in the hands and feet. Severe pain can be encompassed among clinical manifestations. CIPN affects dramatically the patient’s quality of life (QoL). Pain and sensory symptoms may occur for months, or even years after the termination of chemotherapeutic drugs. Although many pharmacological and non-pharmacological therapeutic approaches have been tested to overcome these symptoms, there is currently no standardized treatment for CIPN. According to current guidelines, Duloxetine is the only recommended agent for painful neuropathic symptoms. Therefore, finding effective therapies for CIPN is mandatory. The aim of this review was to dissect CIPN, the target and immunotherapy-based approaches to this disorder, as well as to offer new insights for new therapeutic perspectives.
Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common side effect of cancer therapy, affecting approximately 40% of patients receiving active treatment (1). CIPN is mainly characterized by sensory symptoms in a typical distribution (i.e., ‘stocking and glove’) that first appear in the toes and fingers and then spread to the legs and arms. Patients suffering from a more severe form of CIPN, also show fatigue, pain, and gastrointestinal disorder. Interestingly, patient age, impaired renal function, exposure to other neurotoxic chemotherapeutic agents, or other disorders represent predisposing risk factors of CIPN (2). The pathophysiology of CIPN is very complex and relies on several processes depending on the type of chemotherapy used, although the underlying molecular mechanisms are still unknown (1-4). Many chemotherapy agents are associated with indirect or direct neurotoxicity and CIPN, including platinum derivates, taxanes, vinca alkaloids, proteasome inhibitors, Bortezomib, immunomodulatory agents and several classes of biological agents such as targeted therapies, multikinase inhibitors, immunotherapy, and antibody-drug conjugates (5). Moreover, cognitive impairment may arise from anticancer treatments.
The most common clinical manifestation of CIPN is sensory axonal neuropathy with motor and autonomic involvement. Specifically, depression, anxiety, and cognitive disorder, represent typical central symptoms. CIPN is a peripheral neurotoxicity. Cognitive impairment, commonly termed chemo-brain, affects cancer patients treated with chemotherapy agents (CNS toxicity) (6). A significant role of neuroinflammation, blood-brain barrier disruption, defective neurogenesis, and oxidative stress has been postulated in causing cognitive deficits (7).
Persistent CIPN symptoms are associated with an increased risk of falling, disability, and psychosocial distress (8). Moreover, as symptoms have been reported to be chemotherapy dose-dependent, prolonged treatment may reduce the survival rate of patients. To date, different clinical studies reported that CIPN arises predominately by the cumulative dose of the chemotherapy agent used in cancer therapies (9, 10). No biomarker has demonstrated clinical validity for diagnosing and monitoring CIPN, although serum determination of neurofilament light (NfL) appears to be a promising tool (11).
Currently, the main approach to prevention and treatment of iatrogenic peripheral neurotoxicity relies on dose modifications and the adaptation of schedules with a shorter treatment duration or premature cessation of the neurotoxic drug in case of severe symptoms. Despite several randomized trials conducted, no agent has been recommended for the prevention of CIPN. Many preventative interventions have been proposed including exercise, acupuncture, cryotherapy, and ganglioside monosialic acid. However, their use has no clinical indication (12). Furthermore, preventative strategies may have unanticipated consequences. The use of preventive acetyl-L-carnitine in patients treated with taxanes was associated with a paradoxical CIPN worsening. In a recent long-term follow-up analysis of a large double-blind randomized trial, 24 weeks of acetyl-L-carnitine therapy resulted in significantly worse CIPN, as measured by the Functional Assessment of Cancer Therapy-Neurotoxicity (FACT-Ntx) Questionnaire (13).
Therapeutic options for patients with CIPN are very limited. Topical local interventions such as the use of 1% menthol cream, Topical baclofen, amitriptyline, ketamine, and Capsaicin 8%-containing patches, in absence of safety concerns, have been introduced in clinical practice based on limited data (14-16). According to current guidelines, the selective serotonin and norepinephrine reuptake inhibitor antidepressant (SSNRI) duloxetine is the only recommended agent for painful neuropathic symptoms. A large, randomized trial demonstrated a moderate clinical benefit in patients with painful CIPN treated with this drug versus placebo, with a higher rate of pain reduction (59% versus 38%) (17). Alternatively, a small, randomized trial supports the use of another SSNRI, venlafaxine (18). In addition, membrane-stabilizing agents such as Pregabalin, Amitriptyline, and rarely opioids, should be used as salvage therapy (19, 20). Non-pharmacological approaches such as scrambler therapy, acupuncture, and exercise may reduce established CIPN symptoms and appear to be reasonably safe (21). Limited data are available, and more research is needed to determine the clinical utility of these approaches. The ceramide-to-S1P rheostat is emerging as a critical regulator of the pain pathway. The functional significance of genetic variations within the ceramide-to-S1P rheostat is an object of further investigation to gain a better understanding of neuropathic pain pathogenesis. In this context, FTY720 (fingolimod, Gilenya®), an S1P receptor modulator, the first FDA-approved orally bioavailable medicine for treating relapsing forms of multiple sclerosis, has raised hopes for treating neuropathic pain disorders. Fingolimod, is currently being investigated in several trials for the management of CIPN (22). Future trials should adopt a multimodal methodological approach, with the implementation of subjective (patient-reported) outcomes as primary endpoints and objective (neurophysiological; imaging) outcomes as secondary endpoints, to reveal the full extent of CIPN abnormalities, their impact on patient’s function, and quality of life and to dive insights into the pathophysiology of symptomatic CIPN. Therefore, finding effective therapies for CIPN is mandatory.
The purpose of this review is to dissect CIPN pathophysiology, and to offer new insights for novel therapeutic perspectives.
Mechanisms of Chemotherapy-induced Peripheral Neuropathy
Multifactorial mechanisms induced by chemotherapy-based cancer therapy are causative of CIPN and involve mitochondrial damage and oxidative stress, microtubule disruption, impaired ion channel activity, myelin sheath damage, DNA damage, neuroinflammation, and immunological processes (23) (Table I). Accumulated pre-clinical and clinical studies, demonstrated that platinum-based chemotherapeutic drugs (cisplatin, oxaliplatin, and carboplatin) mainly used for the treatment of various types of solid tumors, induce CIPN by neuro-inflammation resulting from glia cell activation or by alteration of excitability of trigeminal ganglion (TG) and dorsal root ganglion (DRG) neurons, due to the change of voltage-gated channels (24-26). Moreover, cisplatin, can induce peripheral neuropathy (CisIPN) in a dose-dependent manner, and may cause different types of toxicity (i.e., nephrotoxicity, myelotoxicity, ototoxicity) (27, 28). Similarly, oxaliplatin may induce side effects leading to peripheral neuropathy (OIPN, oxaliplatin-induced), such as myelotoxicity and entero-toxicity. Differently from CisIPN, OIPN induces cold neurotoxicity (29). The neurotoxic effect induced by platinum-based chemotherapeutic agents is strictly associated with their different anticancer mechanisms (affecting mainly mitochondria), which impair the functions and the structure of glial and neuronal cells (29-31). As reported by Was et al. (32), the mechanism by which platinum compounds induced neuropathy is mainly due to the DNA adducts formed in the nucleus of the neurons, which are not completely removed by the nucleotide excision repair pathway (NER), thus leading to an aberrant ribosomal RNA synthesis, and causing the death of DRG neurons. Additionally, several studies reported that platinum-based substances impaired mitochondrial DNA (mtDNA) replication and altered the morphology and function of mitochondria. This results in an increase in ROS levels (reactive oxygen species) and oxidative stress. Consequently, a complex cascade of events leads to the degeneration of DRG neurons causing neuropathy (33-35). Moreover, studies showed that oxaliplatin increased the levels of chemokines, C-X3-C motif chemokine ligand 1 (CX3CL1) and C-X3-C motif chemokine ligand 12 (CXCL12), and their ligands, chemokine ligands (CCLs), in DRG neurons thus enhancing peripheral neuropathy. Animal studies demonstrated that oxaliplatin induces peripheral neuropathy by altering the potential action of different ion channels: transient receptor potential (TRP) channels, sodium channels (NaV), and potassium channels (KV) (36-43).
The mechanisms of chemotherapeutic agent-induced chemotherapy-induced peripheral neuropathy (CIPN).
Similarly, oxaliplatin, by activating the pro-inflammatory cytokines tumor necrosis factor alfa (TNF-α), interleukin-β (IL-1), interleukin-6 (IL-6) and the related receptors, interfered with the activity of the neurotransmitter gamma-aminobutyric acid (GABA) and induced allodynia (44). Interestingly, as reported by Shen et al. (45, 46), the microbiota is responsible for OIPNs and hypersensitivity development by acting on TNF-α, IL-6 and lipopolysaccharide (LPS)-Toll-like receptor 4 (TLR4) pathways. Accumulating evidence highlighted that the immunomodulatory drugs, particularly, thalidomide, induced CIPN by altering the excitability of peripheral neurons through the inhibition of nuclear factor kappa beta (NF-kB) and the deregulation of TNF-α pathways, leading to increased cell death (47-50). Similarly to platinum drugs, vinca alkaloids (vinblastine, vinorelbine, vincristine, vindesine), used mainly in the treatment of different types of lymphoma, cause CIPN. As reported by Lobert et al. (51), vinca alkaloids are responsible for inducing sensory-motor neuropathy, and vincristine induced a more severe neurotoxicity compared to other alkaloids. Two different processes mediate vinca alkaloid-induced CIPN. The first is the neuroinflammation caused by an increased release of pro-inflammatory cytokines (interleukins and chemokines) and the second is the hyperexcitability of peripheral neurons induced by the inhibition of polymerization of microtubules, Wallerian degeneration, and an alteration in the activity of ion channels (52, 53). Taxanes (i.e., paclitaxel, docetaxel, and cabazitaxel) mainly used for the treatment of breast, ovarian, and prostate tumors, induce CIPN through a complex dose-depending mechanism involving the disruption of microtubules leading to Wallerian degeneration, the altered activity of ion channels and the altered excitability of peripheral neurons. Neuroinflammation results because of nociceptor sensitization due to damage of mitochondrial DNA transcription, release of reactive oxygen species (ROS), and demyelination of peripheral neurons (54-57). Importantly, different pre-clinical studies showed that paclitaxel (PCTX) treatment, also induced macrophage infiltration in the DRG and mechanical hypersensitivity by acting on different molecular pathways (i.e., TNF-α, NF-kβ, CXCL1). Again, protease inhibitors, particularly bortezomib, used for the management of lymphoma and myeloma, can induce CIPN by a complex process involving different mechanisms. Specifically, bortezomib provokes an upregulation of interleukin-1β (IL-1β) and TNF-α, which in turn impairs sphingolipid metabolism in astrocytes, and alters excitability of peripheral neurons (58-60). Similarly, bortezomib increases ROS production and provokes an apoptotic change at the level of peripheral neurons by damaging the mitochondria. Contemporarily, by activating monocytes and T-lymphocytes and by increasing the ROS production, bortezomib treatment results in the release of pro-inflammatory cytokines, leading to neuroinflammation (61). Epothilones, mainly used in the treatment of breast cancer, induce CIPN through mechanisms similar to those described for bortezomib (62, 63). Growing evidence supports a role of 5-fluorouracil (5-FU) in CIPN induction, probably due to its ability to inhibit DNA synthesis and repair, to cause cell death and to cross blood brain barrier (BBB) (64, 65). More studies are necessary, to shed a light on the different mechanisms underlying CIPN and to set up appropriate strategies of prevention and treatments.
Treatments of Chemotherapy-induced Peripheral Neuropathy
Many pharmacological and non-pharmacological therapeutic approaches have been evaluated for their efficacy in CIPN treatment (Figure 1).
Treatments of chemotherapy-induced peripheral neuropathy (CIPN). The cartoon recapitulates the pharmacological and non-pharmacological therapeutic approaches tested for their efficacy in CIPN treatment.
Ion channels-target therapy. Ion channels play a significant role in the pathogenesis of CIPN, since their expression is altered in sensory neurons. Thus, ion channel-targeted therapy represents a promising therapeutic approach in the treatment of CIPN. Lidocaine can block sodium channels. Pre-clinical studies conducted on animal models showed that lidocaine reversed allodynia induced by vincristine and oxaliplatin (66, 67). Moreover, clinical studies demonstrated that intravenous lidocaine possessed an analgesic effect (transient or persistent) in patients suffering of CIPN (68) and neuro-pathic pain (69) although these findings should be confirmed by additional studies. Promising findings were obtained from the clinical studies conducted with the anticonvulsant medications Gabapentin and Pregabalin (70, 71), while infusion with calcium magnesium or sodium gave discouraging data (72, 73). Pregabalin and Gabapentin can bind to the alpha2-delta protein inhibiting calcium influx and releasing excitatory neurotransmitters, although Pregabalin is notably preferred to Gabapentin due to its better pharmacokinetic profile (74). On the contrary, as reported by de Andrade et al. in a randomized Phase III clinical trial, no improvement in chronic pain and life quality of patients pre-treated with Pregabalin before oxaliplatin infusion was observed (75). Finally, more studies are necessary to examine the varying efficacy of these medications for CIPN treatment.
Anti-inflammatory therapies. Chemotherapeutic substances activate inflammatory cascades and cause the release of many inflammatory mediators (i.e., chemokines, cytokines), which are involved in nerve damaging induced by neurotoxic drugs. Particularly, growth factors (TNF-α), interleukins (IL-6, IL-8, IL-1β) and chemokines C-C motif ligand 2 (CCL2), are associated with CIPN. Thus, non-steroidal anti-inflammatory drug (NSAID)-based therapy should be applied to patients suffering of CIPN. Pre-clinical studies conducted on animal models with neuropathy induced by chemotherapeutic agents (i.e., bortezomib, paclitaxel) showed that treatment with anti-TNF-α and anti-CCL2 antibodies (76), improved drug-induced neuropathy. Despite these encouraging results, the efficacy of against NSAIDs must be further confirmed.
Neurotransmitter-based interventions. The neurotransmitters norepinephrine and serotonin exert an anti-nociceptive effect; thus, neurotransmitter-based therapy could represent a valid strategy in CIPN treatment (77). According to current guidelines, Duloxetine, a selective serotonin and norpholedrine reuptake inhibitor (SNRI), is the only recommended agent for painful neuropathic symptoms, as confirmed by many studies (78, 79). A large, randomized trial demonstrated a moderate clinical benefit in patients with painful CIPN treated with duloxetine versus placebo, with a higher rate of pain reduction (59% versus 38%) (17). In addition, a small, randomized trial supports the use of Venlafaxine (18). Tricyclic antidepressants (TCAs, i.e., ami-triptyline, nortriptyline, desipramine) can block the reuptake of norepinephrine and serotonin (80). Pre-clinical studies demonstrated that amitriptyline administration reduced only mechanical allodynia in rats treated with oxaliplatin, but, unfortunately, no successful clinical studies revealed its efficacy in the treatment of pain associated with CIPN (81). Moreover, TCAs possess many side effects and thus they should be avoided because they would put the patient’s life at risk (82).
Antioxidant interventions. Chemotherapeutic agents induced cancer cells apoptosis via oxidative stress leading to the production of reactive oxygen species (ROS) (83). Specifically, in the spinal and peripheral nervous system, oxidative stress mediated a complex neurodegenerative process that could be associated to CIPN. Thus, antioxidant-based therapy could be used for CIPN treatment. Different clinical studies showed that premedication of cancer patients treated with chemotherapeutic drugs with Amifostine protected against neuropathy induced by carboplatin, paclitaxel, and cisplatin in different type of cancers (84). Unfortunately, patients treated with Amifostine developed side effects; therefore, its use in the treatment of CIPN is not recommended (85). Other clinical studies demonstrated that another antioxidant, Mangafodipir (intravenously administered), was able to reduce the neuropathy caused by oxaliplatin (86), thus suggesting its possible role in CIPN treatment. However, Mangafodipir is not used clinically, due to the toxicity of manganese. Interestingly, Calmangafodipir (PledOx) a low molecular weight superoxide dismutase mimetic (LowMEM) compound derived from Mangafodipir has shown preliminary activity in CIPN prevention. Calman-gafodipir showed a protective effect against OHP-induced small fiber neuropathy in a BALB/c murine model. Interestingly, a U-shaped effect was observed with higher doses, which were less effective than the lower doses. In a phase I-II trial, Calmangafodipir at a dose of 5 mmol/kg reduced the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumor outcomes (87, 88).
Cannabinoids and glutamine. Opioids can be used as salvage therapy for CIPN (89, 90). Other clinical studies have shown that cannabinoids (i.e., nabiximols), could be used as therapeutic approach for CIPN (91, 92) although additional studies are necessary to determine not only their efficacy, but also their safety for patients. Finally, several studies demonstrated that the natural amino acid glutamine ameliorated CIPN symptoms, although its efficacy should be demonstrated with more accurate (i.e., large sample size, controls) clinical trials (93).
Topical combined treatments. Different clinical studies examined combined topical therapies in CIPN treatment. Particularly, as reported by Barton et al. (94) a topical mixture of baclofen, amitriptyline, and ketamine in the form of gel, applied to patients with CIPN symptoms for four weeks, improved pain symptoms compared to patients treated with placebo. Subsequently in a phase III clinical trial, as reported Gewandter et al. (95) a topically applied mixture of amitriptyline and ketamine to patients suffering of pain had discouraging effects, although no toxicity was observed. Again, Fallon et al. (96) in a proof-of-concept study, demonstrated that topical intervention with 1% menthol, a potential melastatin 8 (TRPM8) antagonist, ameliorated CIPN symptoms, but the study lacked of consistency (i.e., no-blinded study). Finally, different studies (97, 98) highlighted a potential role of topical capsaicin, a component of chili peppers and a transient receptor potential vanilloid receptor TRPV1 antagonist, in CIPN treatment.
Non-pharmacological interventions. Despite several pharmacological agents have been studied for CIPN prevention, no agent has demonstrated efficacy and no positive recommendation exists in this setting. Different studies (i.e., meta-analysis, systematic review) demonstrated the efficacy of non-pharmacological treatments of CIPN (i.e., massage, acupuncture, physical therapy, foot bath, scrambled therapy) (99, 100). Moreover, recent studies demonstrated that neurofeedback therapy (NF), a type of treatment targeting brain activity, alleviates the symptoms of chronic pain, thus, representing a putative therapeutic choice for CIPN treatment (101). Unfortunately, limited data is available, and more studies are necessary to determine the clinical utility of these approaches in the treatment of established CIPN.
Future Therapeutic Perspectives
The ceramide-to-S1P rheostat is emerging as a critical regulator of the pain pathway. The functional significance of genetic variations within the ceramide-to-S1P rheostat is subject of further investigations to gain a better understanding of neuropathic pain pathogenesis. In this context, FTY720 (fingolimod, Gilenya®), an S1P receptor modulator, the first FDA-approved orally bioavailable medicine for treating relapsing forms of multiple sclerosis, has raised hopes for treating neuropathic pain disorders. Fingolimod, is currently being investigated in several trials for management of CIPN (22). Erythropoiet-in-producing hepatoma receptor A (EPHA) genes encode for receptors associated with neural development and nervous system repair. Gene variants in EPHA 5, 6, and 8 have been associated with increased risk for taxane-induced CIPN. In addition, single nucleotide polymorphisms (SNPs) in VAC14, a neurodevelopmental protein, have been associated with docetaxel induced CIPN. Recent data show that the Sigma-1 receptor plays a key role in neuroprotection against chemotherapy-induced peripheral neuropathy. S1R is a transmembrane protein in the endoplasmic reticulum and the mitochondria-associated endoplasmic reticulum membrane. MR309, a novel selective sigma-1 receptor ligand previously developed as E-52862 was tested in a phase II, randomized placebo-controlled trial. Treatment with MR309 was associated with significantly lower severe chronic neuropathy and with a higher Oxaliplatin cumulative dose (102-104). Future trials should adopt a multi-modal methodological approach, with the implementation of subjective (patient-reported) outcomes as primary endpoints and objective (neuro-physiological; imaging) outcome as secondary endpoints, to reveal the full extent of CIPN, their impact on patient’s function and quality of life and to provide insights into the pathophysiology of CIPN (Figure 2).
Multimodal methodological approaches for chemotherapy-induced peripheral neuropathy (CIPN). The multimodal methodological approach should provide the implementation of subjective (patient-reported) outcomes as primary endpoints and objective (neuro-physiological; imaging) outcomes as secondary endpoints, to reveal the full extent of CIPN, its impact on patient’s function and quality of life and to provide insights into the pathophysiology of symptomatic CIPN.
Conclusion
CIPN arises as a challenging nerve-damaging adverse effect of chemotherapy used for cancer treatment. The pathophysiology of CIPN is quite complex and relies on several processes depending on the type of chemotherapy used, although the underlying molecular mechanisms are still not completely elucidated. Chemotherapy agents commonly used for treatment of different types of cancers are associated with indirect or direct neurotoxicity. They are represented by platinum derivates, taxanes, vinca alkaloids, proteasome inhibitors, bortezomib, immunomodulatory agents and several classes of biological agents such as targeted therapies, multikinase inhibitors, immunotherapy, and antibody-drug conjugates. Among them, more neurotoxicity has been observed for taxanes, platinum-based agents, and thalidomide, while less neurotoxicity was associated to vinca alkaloids and bortezomib. CIPN may require a chemotherapy dose reduction and is accompanied by multiple sensory symptoms, thus affecting dramatically the patient’s quality of life (QoL). Moreover, CIPN is difficult to be assessed and diagnosed. Many pharmacological and non-pharmacological therapeutic approaches have been tested in pre-clinical and clinical studies, to overcome CIPN symptoms, via inhibiting ion channels, reducing oxidative stress, and targeting inflammatory cytokines. Substances such as duloxetine and mangafodipir are effective for CIPN treatment, while venlafaxine, tricyclic anti-depressants, and Gabapentin do not prevent or ameliorate CIPN with consistent efficacy. Moreover, some agents (i.e., menthol, erythropoietin, amifostine) should be avoided because of their ability to cause side effects. Thus, no standardized cure, except those based on duloxetine, is available to prevent or treat CIPN. Despite encouraging results obtained using different therapeutic approaches (i.e., cannabinoids, fingolimod, physical therapy, etc.), further clinical studies are needed to test not only the efficacy but also the safety of drugs used for CIPN. Future strategies should be based on a multimodal methodological approach with the implementation of subjective and objective outcomes, to define better CIPN, their impact on patient’s function and quality of life, and provide insights into CIPN pathophysiology.
Acknowledgements
The Authors are grateful to Dr. Alessandra Trocino and Mrs. Mariacristina Romano from Istituto Nazionale Tumori IRCCS Fondazione Pascale for providing excellent bibliographic service and assistance. This research received no external funding.
Footnotes
Authors’ Contributions
A. Cuomo: writing — original draft preparation; S. Bimonte and M. Cascella: conceptualization, writing—review and editing; A. Avallone, C. Cardone: supervision. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to disclose in relation to this study.
- Received July 20, 2022.
- Revision received August 2, 2022.
- Accepted August 6, 2022.
- Copyright © 2022 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
