Chemotherapy-Induced Peripheral Neuropathy

Frederick Hausheer

Stacey Bain

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and serious clinical problem that affects many patients receiving cancer treatment.¹^,²^,³^,⁴ This iatrogenic condition can pose diagnostic and management challenges for the clinician, particularly in patients with coexisting conditions or disorders resulting in damage or dysfunction of the peripheral nervous system.¹ The diagnosis and management of CIPN is further complicated by the fact that there is no universally accepted means to assess and quantify CIPN and there are currently no approved treatments for the prevention, mitigation, or management of the toxicity.

Many commonly used chemotherapeutic agents are associated with the induction of serious and dose-limiting CIPN that can adversely impact patients’ quality of life by direct interference with the patients’ activities of daily living (ADL) as well as affect the therapeutic outcomes of neurotoxic chemotherapy by necessitating treatment modifications as toxicity management measures (Table 22-1). There are numerous oncology medicaments central to the treatment of cancer commonly reported to induce neuropathy including taxanes¹^,²^,³^,⁵^,⁶^,⁷^,⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴ (docetaxel and all formulations/derivatives of paclitaxel), platinum agents¹^,²^,³^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷²^,⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹^,⁸²^,⁸³^,⁸⁴^,⁸⁵^,⁸⁶^,⁸⁷^,⁸⁸^,⁸⁹^,⁹⁰^,⁹¹^,⁹²^,⁹³^,⁹⁴^,⁹⁵^,⁹⁶^,⁹⁷^,⁹⁸^,⁹⁹^,¹⁰⁰^,¹⁰¹^,¹⁰²^,¹⁰³^,¹⁰⁴^,¹⁰⁵^,¹⁰⁶^,¹⁰⁷^,¹⁰⁸^,¹⁰⁹^,¹¹⁰^,¹¹¹^,¹¹²^,¹¹³^,¹¹⁴^,¹¹⁵^,¹¹⁶^,¹¹⁷^,¹¹⁸^,¹¹⁹ (cisplatin, carboplatin, and oxaliplatin), epothilones,¹^,²^,³^,¹²⁰ and vinca alkaloids¹^,²^,³^,¹²¹^,¹²² (vincristine, and less commonly vinblastine, vindesine, and vinorelbine). More recently, the use of thalidomide and bortezomib has been reported to have an association with the development of dose and treatment-limiting CIPN.¹^,²^,³^,¹²³^,¹²⁴^,¹²⁵^,¹²⁶

Owing to the absence of approved and effective treatment options for the prevention, mitigation, or management of CIPN, the development of this toxicity often results in treatment delays, dose modifications, and, in severe cases, cessation of a current form of treatment. Modification, delay, or cessation in a patient’s therapy may partially or completely alleviate the adverse symptoms of CIPN, but such maneuvers may adversely affect treatment of the primary tumor, especially if the patient’s malignancy is responding to treatment. The development and regulatory approval of safe and effective interventions to prevent and mitigate CIPN would be an important medical advancement for cancer patients.⁴^,¹²⁷^,¹²⁸^,¹²⁹^,¹³⁰^,¹³¹

The most important and challenging diagnostic assessment in patients with CIPN is to determine the degree of functional impairment in the patient’s ADL because these findings impact the key medical decision point for the potential need to modify, interrupt, or discontinue neurotoxic treatment. It is important to consider that the subjective nature of the patient symptoms and the degree of impairment by CIPN are analogous to patient symptoms of nausea, pain, and depression; the evaluation of the degree of severity and level of impairment of these symptoms requires patients’ cooperation and physicians’ skill in elucidation and detection.¹^,²^,³^,⁴

The clinical manifestations of CIPN are subjective and manifest as purely or predominantly neurosensory symptoms; CIPN symptoms are most commonly reported in the form of progressive distal symmetrically distributed symptoms of numbness, tingling, pins and needles, burning, decreased or altered sensation, or increased sensitivity that may be painful in the feet and hands.¹^,²^,³^,⁴^,¹²⁷^,¹²⁸^,¹²⁹^,¹³⁰^,¹³¹ The primary clinical objective is to determine the presence and severity of CIPN-associated symptoms that result in symptomatic interference with ADL, because such findings are critical for treatment decisions and to ensure quality of life for the patient. Symptoms of motor weakness because of CIPN are less commonly reported, and when present, tend to be observed in patients with more persistent and severe sensory findings.¹^,²^,³^,⁴^,¹²⁷^,¹²⁸^,¹²⁹^,¹³⁰^,¹³¹ Isolated motor weakness with the complete absence of sensory involvement because of CIPN has not been reported, and if such findings are observed in a patient, consideration should be given to other conditions that may produce pure motor weakness such as steroid myopathy, Eaton-Lambert syndrome, diabetic motor neuropathy, cachexia with decreased activity level, paraneoplastic motor neuropathy, and unmasked Charcot-Marie-Tooth (CMT) disease.¹^,²^,³^,⁴^,¹²⁷^,¹²⁸^,¹²⁹^,¹³⁰^,¹³¹ The diagnosis of CIPN must be approached with care in patients with potential coexisting or prior conditions that involve or predispose to peripheral neuropathy, and in these patients, who may pose a diagnostic dilemma, the neurologic evaluation should be directed at elucidation and differentiation of CIPN from other potential causes of peripheral neuropathy (Table 22-2).¹^,²^,³^,⁴^,¹²⁷^,¹²⁸^,¹²⁹^,¹³⁰^,¹³¹

An increasing amount of medical evidence strongly suggests that the incidence of CIPN is substantially underreported in clinical trials because of the subjective nature of CIPN, the lack of diagnostic standards, and important limitations in the available grading scales that are commonly used to assess CIPN.¹^,²^,³^,⁴ Underreporting may also be a consequence of two other factors: (1) the physician fails to elucidate symptoms or observe diagnostic findings of CIPN in a given patient or (2) there can be a degree of nihilism about the presence of CIPN because of the absence of an approved effective treatment for this complication of chemotherapy. The challenges in diagnosing and assessing the extent of patients’ functional impairment in a reliable and reproducible manner is a critical consideration for the clinician in practice for medical decision making as well as in designing and implementing controlled clinical trials involving prospective evaluation of neurotoxic chemotherapy or interventions aimed at the prevention and mitigation of CIPN.¹^,²^,³^,⁴

Table 22-1
Agents Reported to Cause Peripheral Neuropathy: Classification by Predominant Clinical and Pathologic Findings

Sensory	Motor	Sensory and Motor	Demyelinating	Demyelinating and Axonopathy
Atorvastatin	β-Bungarotoxin	Acrylamide	Buckthorn	Amiodarone
Bortezomib	Botulism	Alcohol (ethanol)	Chloroquine	Ethylene glycol
Cadmium	Gangliosides	Allopurinol	Diphtheria	1,1′-Ethylidinebis
Carboplatin	Latrotoxin	Allyl chloride	FK506 (tacrolimus)	[tryptophan]
Chloramphenicol	Lead	Arsenic	Hexachlorophene	Gold
Cisplatin	Mercury	Ara-C, Ara-A, Ara-G^a	Muzolimine	n-Hexane
Dioxin	Misoprostol	Cadmium	Perhexiline	Methyl n-butyl ketone
Didanosine	Tetanus	Captopril	Procainamide	Na⁺ cyanate
Ethambutol	Tick paralysis	Carbon disulfide	Tellurium	Suramin^b
Ethionamide		Chlorphenoxyl	Zimeldine	Toluene
Etoposide^a		Ciguatoxin
Flecanide		Colchicine
Gemcitabine		Cyanide
Glutethimide		Dapsone
Hydralazine		Disulfiram
Ifosfamide^a		Docetaxel
Interferon-α^a		DMAPN
Isoniazid		Epothilones^b
Lamuvidine		Enalopril
Lead		Ergots
Leflunomide		Ethylene oxide
Metronidazole		Hexamethylmelamine
Misonidazole		Indomethacin
Nitrous oxide		Lithium
Oxaliplatin		Methyl bromide
Phenytoin		Nitrofurantoin
Procarbazine		Organophosphates
Propafenone		Penicillamine
Pyridoxine		Paralytic shellfish
		poisoning
Stavudine		Podophyllin
Suramin^b		PCBs
Thalidomide		Saxitoxin
Zalcitabine		Spanish toxic oil
		Paclitaxel
		(all formulations)
		Tetrodotoxin
		Thallium
		Trichloroethylene
		TOCP
		Vacor (PNU)
		Vincristine
		Vinblastine
		Vinorelbine
		Vindesine^b
DMAPN, N, N’-dimethylaminopropionitrile; PCBs, polychlorinated biphenyls; TOCP, tri-o-cresyl phosphate; PNU, N’-p-nitrophenyl urea.
Bold indicates chemotherapeutic or radiation therapy agents.
^aChemotherapeutic agents with uncommon or rarely reported association. ^bInvestigational.

Table 22-2
Differential Diagnosis of Disorders Involving Peripheral Neuropathy

Acquired
Abnormal metabolic conditions
	Diabetes mellitus
	Neuropathy secondary to renal disease
	Hypothyroidism
	Primary biliary cirrhosis
	Vitamin deficiency states (deficiencies of vitamin B₁, B₆, pantothenic acid, α-tocopherol or B₁₂)
		Excessive doses of pyridoxine (B6)
		Primary (and familial) amyloidosis
		Acromegaly
	Immune-mediated
		Myasthenia gravis
		Guillain-Barré syndrome
		Chronic inflammatory demyelinating polyneuropathy
		Vasculitis (polyarteritis nodosa; Churg-Strauss syndrome)
	Systemic vasculitis associated with connective tissue diseases: rheumatoid arthritis, lupus erythematosus, Sjögren syndrome
	Monoclonal antibody neuropathy: Waldenström macroglobulinemia, myeloma
		Plexitis-cervical and lumbosacral
		Multifocal motor neuropathy
	Infectious
		Herpes Zoster (sensory)
		Cytomegalovirus (motor)
		HIV
		Sarcoid
		Lyme disease
		Mycobacterium leprae
		Camphylobacter jejuni
		Polio (motor)
		Hepatitis B or C (vasculitic)
Cancer-related
		Eaton-Lambert myasthenic syndrome
		Lymphoma, carcinoma-related
		Paraneoplastic sensory neuropathy
		Horner syndrome
		Paraneoplastic motor neuropathy (rare)
Drug or toxins (see Table 22-1)
		Chemotherapy induced
		Other medications
		Alcohol (ethanol)
		Heavy metal and industrial toxins
		Shellfish, marine, arthropod toxins and venoms
Mechanical/compressive/physical
	Radiculopathy
	Mononeuropathy
	Ionizing radiation
Unknown etiology
	Cryptogenic sensory and sensorimotor neuropathy
	Amyotrophic lateral sclerosis
Hereditary
CMT disease
Riley-Day syndrome
Familial amyotrophic lateral sclerosis
X-linked spinobulbar muscular atrophy
Gower distal myopathy
Hereditary motor sensory neuropathy
Hereditary neuropathy with predisposition to pressure palsies
Familial brachial plexopathy
Familial amyloidosis
Acute porphyria
Other peripheral neuropathies (rare)
Fabry, metachromatic leukodystrophy, adrenoleukodystrophy, Refsum disease

In some patients, it may be challenging to differentiate CIPN from the symmetrical, distal neurosensory manifestations that are associated with paraneoplastic sensory neuropathy, diabetic neuropathy, or toxic/metabolic neuropathies. Diagnostic elucidation of the underlying neuropathic disorder can be approached by careful evaluation of history and comparison with baseline findings and the temporal onset of new neurosensory findings, recognizing that asymmetric, focal or proximal involvement, or complete loss of sensation are strongly indicative of other etiologies.¹^,²^,³^,⁴^,¹²⁷^,¹²⁸^,¹²⁸^,¹³⁰^,¹³¹ The most common coexisting condition that may pose a diagnostic dilemma is diabetic neuropathy, which can be asymmetric or symmetric, focal or diffuse, or manifest as mononeuritis multiplex and has many different clinical presentations and patterns. The most common form of diabetic neuropathy, the distal symmetric polyneuropathic form, has clinical symptoms and findings that may be similar to CIPN, which can be further elucidated by a careful evaluation.¹

Accordingly, a clinical approach must be taken that enables reliable, convenient, and noninvasive elicitation and assessment of the diagnostic symptoms of CIPN for the day-to-day management of the patient, as well as to apply such methods in clinical trials of interventions for the prevention or mitigation of CIPN. When sensory symptoms of CIPN are more severe, the patient commonly expresses symptoms of functional impairment of important ADL such as being unable to walk, button clothing, drive, use a keyboard, or write.¹^,²^,³^,⁴^,¹²⁷^,¹²⁸^,¹²⁹^,¹³⁰^,¹³¹ It may be challenging to elicit such information from some patients, and to address this consideration, there is an increased requirement for monitoring and following up on potential patient symptoms that may be because of CIPN by nursing and medical staff.

PATHOGENESIS AND PATHOPHYSIOLOGY OF CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY

The underlying pathophysiologic mechanisms for the development of CIPN have not been fully elucidated. Various proposed mechanisms are reported, and it is apparent that a high degree of similarity exists in the pattern and spectrum of clinical manifestations of CIPN associated with the administration of different chemotherapeutic agents (e.g., vinca alkaloids, platinum agents, thalidomide, bortezomib, and taxanes). CIPN is generally thought to arise as a consequence of disruption of axoplasmic microtubule-mediated transport, distal axonal (Wallerian) degeneration, and direct damage to the sensory nerve cell bodies of the dorsal root ganglia (DRG).¹^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷²^,⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹^,⁸²^,⁸³^,⁸⁶^,⁸⁷^,⁸⁸^,⁸⁹^,⁹⁰^,⁹¹^,⁹² Demyelination (diffuse or segmental) secondary to chemotherapy is uncommonly reported (but occasionally observed with cisplatin, and reported for suramin, an investigational agent), and when observed, it is typically a secondary and isolated finding relative to the extent of axonal and DRG-associated pathologic findings. It is important to note that CIPN is associated with the administration of chemotherapeutic agents that cannot appreciably distribute across the blood-brain barrier (e.g., taxanes, platinum agents, vinca alkaloids, thalidomide, and bortezomib).¹ Terminal axonal degeneration and axonal microtubule disruption are the most common pathologic processes observed in CIPN and have been reported in association with exposure to vinca alkaloids, platinum agents, taxanes, thalidomide, suramin, and others. Peripheral myelin degeneration (diffuse or segmental) has been reported in association with other agents such as perhexiline, hexanes, and amiodarone. Demyelination is far less commonly observed in CIPN, and myelin damage appears to be a secondary finding as compared with damage to the terminal axon or disruption of the axonal microtubulin architecture.1,64-83,86-92

Tubulin, a ubiquitous cellular protein that is present in high cellular concentrations, plays an important role in numerous critical cellular processes and functions, including a critical role in normal physiologic functions of peripheral nerves. Anterograde and retrograde axoplasmic transport is mediated by tubulin.¹^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹ Taxanes and epothilones are known to induce abnormal tubulin aggregation by preventing tubulin depolymerization, whereas the vinca alkaloids depolymerize tubulin; all of these agents are known for their ability to disrupt cellular microtubulin structure and function. Monohydrated platinum has been demonstrated to directly disrupt the ability of tubulin to polymerize, which is most likely because of denaturation of tubulin by the formation of platinum-tubulin adducts involving the accessible cysteine residues on tubulin.⁷⁸^,⁷⁹^,⁸⁰^,⁸¹ These observations suggest that tubulin may be an essential target in
the pathogenesis of CIPN. Because of the high degree of similarity in the clinical symptoms and signs of CIPN observed in association with the administration of different chemical classes of neurotoxic chemotherapeutic drugs, a common underlying mechanism is suggested involving a potential toxic effect of taxanes, platinum agents, vinca alkaloids, and other neurotoxic chemotherapeutic agents that is mediated by drug interactions with neuronal tubulin.¹

One of the important anatomic targets for neurotoxic chemotherapeutic agents is the DRG and the larger anatomic portions of afferent and efferent axons, which are located outside of the CNS.¹ In contrast to the blood-brain barrier in the CNS, the DRG and peripheral axons lack an efficient neurovascular barrier, thereby allowing facile diffusion of large molecular weight compounds in the interstitium surrounding the DRG and along the axon filaments. In addition to capillary fenestrations in the vascular supply to the DRG and axons, there are open junctions between adjoining endothelial cells of the peripheral epineural blood vessels that allow proteins and drugs to pass readily from the blood into the extracellular space.¹ This absence of a vascular barrier in the DRG may play an important role in CIPN development, by allowing the relatively unimpeded exposure of the DRG and the peripheral axons to neurotoxic agents directly from the plasma. Protein-bound and unbound forms of drugs can gain direct access to the local epineurium and can readily diffuse along the nerve fascicles, a process that is facilitated by the hydrostatic capillary pressure gradient. The endoneural fascicles also lack lymphatics, which limit removal of toxic substances in the endoneural fluid, thereby allowing local accumulation of neurotoxic agents. Consistent with the foregoing considerations, autopsy and experimental studies have shown high concentrations of platinum in the DRG and high concentrations of taxanes in the peripheral axons as compared with significantly lower levels of these substances in the brain and spinal cord.¹^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷²^,⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷

Cisplatin and carboplatin exposure leads to direct damage of the DRG in animal models.⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷²^,⁷³^,⁷⁴ Cisplatin has been demonstrated to substantially interfere with and disrupt axonal microtubule assembly, vesicular axonal transport, and inhibit neurite outgrowth from neurons.⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷²^,⁷³^,⁷⁴^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹^,⁸²^,⁸³^,⁸⁷^,⁸⁸^,⁸⁹^,⁹⁰^,⁹¹^,⁹² DRG neurons exposed to cisplatin in vitro demonstrated nuclear condensation, cell shrinkage, and fragmentation with maintenance of plasma membrane and intracellular organelle integrity. These studies demonstrate that cisplatin-treated DRG neurons continue to enter the cell cycle before any detectable morphologic measure of cell death is observed. Cisplatin exposure appears to directly cause tubulin dysfunction and axonal degeneration, thereby interfering with the supply of nutrients to distal axons mediated by fast anterograde axoplasmic transport; tubulin and microtubulin function are critical for normal axoplasmic transport. In animal models, carboplatin induces a highly similar pattern of histopathologic (DRG and axonopathy with evidence of Wallerian degeneration) damage that appears indistinguishable from cisplatin-induced toxicopathologic findings, suggesting that cisplatin and carboplatin act upon a common intracellular target.⁶⁴^,⁷⁴^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹^,⁸²^,⁸³^,⁸⁷^,⁸⁸^,⁸⁹^,⁹⁰^,⁹¹^,⁹²

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