INTRODUCTION — Neurologic complications of anticancer therapy may result from direct toxic effects on the nervous system or indirectly from drug-induced metabolic derangements, cerebrovascular disorders, or in the case of checkpoint inhibitors, autoimmune disorders. A wide range of neurologic complications is associated with antineoplastic drug treatment (table 1). The most common indirect neurologic complication is chemotherapy-induced peripheral neuropathy (CIPN) (table 2) [1-4]. Early recognition of neurotoxicity is important because of potential confusion with metastatic disease, paraneoplastic syndromes, or comorbid neurologic disorders that do not require dose reduction or discontinuation. (See "Overview of paraneoplastic syndromes of the nervous system".)
The neurotoxicity associated with a variety of conventional cytotoxic chemotherapy agents will be reviewed here. The neurologic complications of platinum compounds (cisplatin, carboplatin, and oxaliplatin) and of biologic response modifiers and molecularly targeted agents (both orally administered and therapeutic monoclonal antibodies) are discussed elsewhere, as are strategies to prevent and manage CIPN. (See "Overview of neurologic complications of platinum-based chemotherapy" and "Neurologic complications of cancer treatment with molecularly targeted and biologic agents" and "Prevention and treatment of chemotherapy-induced peripheral neuropathy".)
RISK FACTORS — Risk factors that are best established for chemotherapy-induced peripheral neuropathy (CIPN) include dose, dose intensity, length of treatment, concurrent administration of other neurotoxic agents (especially platinum derivatives), age, and in the case of bortezomib, route of administration. (See 'Bortezomib' below.)
In addition, emerging data have linked an elevated risk of paclitaxel-related sensory neuropathy with vitamin D deficiency. (See 'Clinical features, incidence, and risk factors' below.)
The presence of a preexisting neuropathy may also be a risk factor for developing severe CIPN with a variety of neurotoxic agents. Compelling case reports describe severe neuropathy following single doses of potentially neurotoxic chemotherapeutic agents in patients with underlying neuropathic disease , including Charcot-Marie-Tooth, whether clinical or subclinical , other hereditary neuropathies [7,8], and recovered poliomyelitis . Whether diabetes with or without neuropathy or idiopathic peripheral neuropathy are significant risk factors remains controversial .
Genetic makeup may also be a significant risk factor for the development of neuropathy in patients receiving cancer therapy :
●The best established genetic risk factor is the presence of specific alleles that lead to diminished levels of dihydropyrimidine dehydrogenase (DPD), which can lead to severe neurotoxicity (as well as other toxicities) even at standard doses of fluorouracil . (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'DPD deficiency'.)
●Another study of 404 ovarian cancer patients receiving platinum/paclitaxel chemotherapy identified four single nucleotide polymorphisms (SOX10, BCL2, OPRM1, and TRVP1) that were risk factors for neurotoxicity . Neurotoxicity increased by a factor of 1.64 for every risk genotype and by 4.49 for patients with three risk variants.
●Others have reported a link between inherited variations in the Charcot-Marie-Tooth gene and susceptibility to paclitaxel-related neuropathy . (See 'Clinical features, incidence, and risk factors' below.)
●An association has also been reported between inherited polymorphisms in the CEP27 gene, which encodes a centrosomal protein involved in microtubule formation, and incidence and severity of vincristine-related neuropathy in children treated for acute lymphoblastic leukemia .
Although the available data are not sufficiently conclusive to recommend any molecular genetic test (including assay for DPD deficiency) to be used in the clinic to predict neurotoxicity, they provide promise for future individualization of cancer chemotherapy with respect to both efficacy and toxicity. Further discussions of specific genetic factors involved in neurotoxicity for individual drugs are discussed in the sections below.
METHOTREXATE — Methotrexate (MTX), a dihydrofolate reductase inhibitor, is used systemically for a wide range of cancers, both in conventional doses and in high doses with leucovorin rescue. It is also administered intrathecally (IT) to treat leptomeningeal metastases and in the treatment of certain hematologic malignancies. (See "Treatment of leptomeningeal disease from solid tumors" and "Secondary central nervous system lymphoma: Treatment and prognosis".)
Clinical manifestations — MTX can cause acute, subacute, and long-term neurotoxicities. Neurotoxicity can be manifested as aseptic meningitis, transverse myelopathy, acute and subacute encephalopathy, and leukoencephalopathy. The manifestations of MTX neurotoxicity are largely determined by its dose and route of administration:
●The administration of high doses of intravenous (IV) MTX (≥1000 mg/m2) permits high drug concentrations to be achieved within the central nervous system (CNS), which can be useful in the treatment of some types of leukemia, primary CNS lymphoma, and neoplastic meningitis. (See "Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults" and "Treatment of leptomeningeal disease from solid tumors" and "Primary central nervous system lymphoma: Treatment and prognosis".)
Systemic high-dose MTX can cause acute, subacute, or chronic neurotoxicity. The risk of neurotoxicity may be altered by drug excretion (which is related to renal function, hydration, and urinary alkalinization), the use of leucovorin rescue, coadministration of other antineoplastic agents, and pharmacogenetic factors . (See "Therapeutic use and toxicity of high-dose methotrexate" and "Overview of pharmacogenomics".)
●IT MTX is commonly associated with aseptic meningitis [17,18]. In addition, IT administration is rarely associated with posterior reversible leukoencephalopathy syndrome , seizures , subacute focal neurologic deficits , lumbosacral polyradiculopathy [22-24], noncardiogenic pulmonary edema , pneumonitis , and sudden death [1,2,25,27].
Leukoencephalopathy is a delayed complication of IT MTX, usually occurring after six months of therapy and when the cumulative IT dose of MTX exceeds 140 mg . It is more likely in patients who receive concurrent whole brain radiotherapy or have previously received chemotherapy with IV MTX.
The administration of intraventricular MTX through an Ommaya reservoir can cause leukoencephalopathy even at conventional doses if there is a block to egress of the drug from the ventricular system. Therefore, flow studies to assure normal CSF flow in patients with leptomeningeal metastases are important. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Pretreatment CSF flow study'.)
Aseptic meningitis — Aseptic meningitis is typically seen following IT administration of methotrexate and is indistinguishable clinically from other types of aseptic meningitis. (See "Aseptic meningitis in adults" and "Treatment of leptomeningeal disease from solid tumors", section on 'Methotrexate'.)
Aseptic meningitis is the most common neurotoxic effect of IT MTX [17,18]. Approximately 10 percent of patients are affected, but incidence rates as high as 50 percent have been reported. However, microfiltration of the methotrexate has considerably reduced this incidence. Characteristic symptoms include headache, nuchal rigidity, back pain, nausea, vomiting, fever, and lethargy. Symptoms usually begin two to four hours after the drug is injected (in contradistinction to an iatrogenic bacterial meningitis from a contaminated product that takes hours to days to develop), and they may last for 12 to 72 hours. Cerebrospinal fluid (CSF) analysis usually demonstrates a pleocytosis with an elevated protein content, but cultures are negative. (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states".)
Symptoms are usually self-limited, and treatment is usually not required. If headache and stiff neck are severe, a short course of corticosteroids may be helpful. Aseptic meningitis can be prevented to some extent by coadministering MTX with IT hydrocortisone or oral corticosteroids. Some patients who develop aseptic meningitis can be subsequently retreated with MTX without problems.
Transverse myelopathy — Transverse myelopathy is an uncommon complication of IT MTX manifested by the development of isolated spinal cord dysfunction over hours to days in the absence of a compressive lesion . Transverse myelopathy is most often associated with IT MTX and is generally seen in patients receiving concurrent craniospinal radiotherapy (RT) or frequent IT injections of MTX. (See "Complications of spinal cord irradiation" and "Treatment of leptomeningeal disease from solid tumors", section on 'Methotrexate'.)
Affected patients typically develop back or leg pain followed by paraplegia, sensory loss, and sphincter dysfunction. The onset is usually between 30 minutes and 48 hours after treatment but can occur up to two weeks later. Common imaging findings include abnormalities involving the dorsal column of the spinal cord seen on T2-weighted magnetic resonance imaging (MRI) .
Although the majority of cases show clinical improvement, the extent of recovery is variable .
Acute and subacute encephalopathy — Acute neurotoxicity is most frequently seen after high-dose MTX and is characterized by somnolence, confusion, and seizures within 24 hours of treatment. Symptoms usually resolve spontaneously without sequelae, and retreatment with methotrexate is often possible [1,17,31]. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Neurologic toxicity'.)
Weekly or biweekly administration of high-dose MTX, prolonged low-dose oral treatment, and IT administration may produce a subacute "stroke-like" syndrome, characterized by transient focal neurologic deficits, confusion, and occasionally seizures . Symptoms develop approximately 2 to 14 (average 6) days after drug administration, last from 15 minutes to 72 hours, and then resolve spontaneously without sequelae. Neuroimaging studies are usually normal, although changes have been described on MRI, including areas of restricted diffusion on diffusion-weighted imaging and non-enhancing T2 hyperintense lesions in the white matter [33,34]. CSF analysis is usually normal, but the electroencephalogram (EEG) may show diffuse slowing, and diffusion-weighted images may be abnormal.
The magnitude of risk is not well described. In a report of 369 children treated for acute lymphoblastic leukemia with both high-dose IV MTX and IT MTX, subacute encephalopathy developed in 14 (3.8 percent) . Symptoms consisted of seizures in eight patients, a stroke-like picture in six, and ataxia in one. Most episodes were brief, but the one patient had persistent ataxia for four weeks. All 12 patients with MRIs available at the time of the event had leukoencephalopathy; seven persisted through the end of therapy. Thirteen patients were rechallenged with high-dose MTX or IT MTX, and only one experienced recurrence with severe headache and confusion.
The pathogenesis is unclear, although several hypotheses have been proposed, including homocysteine toxicity, altered folate homeostasis, and/or direct neuronal damage [36-40].
Leukoencephalopathy — Clinical symptoms of MTX-induced neurotoxicity are often associated with leukoencephalopathy, typically seen as white matter hyperintensities on T2-weighted MRI. However, leukoencephalopathy can also develop in asymptomatic individuals . Leukoencephalopathy is dependent on MTX dose and route of administration [17,42,43]. Although this syndrome may be produced by MTX alone, it is more common in the setting of concurrent or past RT. (See "Delayed complications of cranial irradiation".)
The magnitude of risk and natural history were addressed in a report of 369 children treated for acute lymphoblastic leukemia with both high-dose MTX and IT MTX, in whom brain MRIs were obtained at four time points during therapy: postinduction (between days 33 and 46), postconsolidation (week 1 of reinduction I), continuation week 48, and continuation week 120 (the "off-therapy" MRI) . Overall, 86 (23 percent) had evidence of leukoencephalopathy on at least one screening MRI; this included 73 of the 355 asymptomatic patients (21 percent) and 13 of the 14 patients with clinical neurotoxicity (93 percent). Of the 62 patients who developed leukoencephalopathy at any time during therapy and for whom an off-study MRI was available, leukoencephalopathy persisted in 46 (74 percent). The presence of leukoencephalopathy on one of the first two screening MRIs indicated clinical neurotoxicity with 50 and 100 percent sensitivity, respectively, but the positive predictive value was low at both time points (15 and 13 percent, respectively). Over time, leukoencephalopathy improved in 41 percent (resolving completely in 23 percent), it remained stable in 47 percent, and worsened in 15 percent. In multivariate analysis, higher MTX levels at 42 hours after the first course of high-dose MTX was the only significant risk factor for leukoencephalopathy. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Prevention and management of high-dose methotrexate toxicity'.)
The mechanism of MTX-related leukoencephalopathy is not fully understood. It is possible that cranial irradiation either potentiates the toxic effects of MTX or disrupts the blood-brain barrier, allowing high concentrations of MTX to reach the brain. Studies in mouse models and human autopsy specimens suggest that MTX activates microglia and depletes oligodendrocyte precursor cells, resulting in persistent deficits in myelination .
The characteristic clinical feature of leukoencephalopathy is a gradual impairment of cognitive function months to years following treatment with MTX. Clinical manifestations range from mild learning disability to severe progressive dementia accompanied by somnolence, seizures, ataxia, and hemiparesis.
The diagnosis is supported by cranial computed tomography (CT) and MRI, which typically show cerebral atrophy and diffuse white matter lesions. On CT, these are characteristically hypodense nonenhancing lesions, while on MRI, areas of high signal intensity are noted on T2-weighted images.
The clinical course is also variable. Many patients stabilize or improve following discontinuation of MTX, but the course is progressive in others. Disseminated necrotizing leukoencephalopathy, a rare manifestation of methotrexate leukoencephalopathy, is irreversible and may be fatal [45,46]. No effective treatment is available.
Management — There is no standard treatment for any of these acute and subacute neurotoxicities from IT or IV MTX. Case reports suggest that MTX-induced neurotoxicity can be relieved by aminophylline, but this is not considered a standard treatment .
Benefit for dextromethorphan was reported in a retrospective series of 18 patients with subacute encephalopathy (16 following IT therapy and two after IV therapy) . The patients were drawn from a cohort of 501 patients who received IT therapy (encephalopathy risk 3.2 percent) and 191 patients who received high-dose IV MTX (encephalopathy risk 1.9 percent) . Nine of 10 patients treated with 1 to 3 mg/kg dextromethorphan within 7.6 hours after the onset of the neurologic symptoms had resolution of symptoms within 3.5 hours. Those who received the drug more than 24 hours after the onset of symptoms recovered in 13.9 hours. The rationale for the use of dextromethorphan is that homocysteine is an agonist of N-methyl-D-aspartate (NMDA) receptors and dextromethorphan is an antagonist.
There is no standard treatment after development of IT MTX-induced transverse myelopathy, although rapid neurologic improvement has been reported following administration of high doses of the key metabolites of the methyl-transfer pathway including S-adenosylmethionine, folinate, cyanocobalamin, and methionine . Further administration of MTX is contraindicated.
Whether the drug should be discontinued for any of the other neurologic toxicities associated with MTX is not a settled matter. Many physicians would discontinue the drug permanently for lumbosacral polyradiculopathy that is not a symptom of aseptic meningitis because of concern for a MTX-induced myelitis. Discontinuation of the MTX in the setting of leukoencephalopathy is not an absolute necessity; multiple factors must be considered. These include whether there is an identifiable reason why the person is at higher risk for toxicity (eg, is there hydrocephalus that is disrupting absorption of the MTX and causing delayed excretion), whether leukoencephalopathy is symptomatic or not, how extensive it is, and how much the patient is benefiting from the IT MTX.
If there is untreated hydrocephalus evolving in a patient receiving IT MTX, treatment should be temporarily discontinued, and consideration given to addressing the hydrocephalus with a shunt. The administration of intraventricular MTX through an Ommaya reservoir can cause leukoencephalopathy even at conventional doses if there is a block to egress of the drug from the ventricular system. Therefore, flow studies to assure normal CSF flow in patients with leptomeningeal metastases are important. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Pretreatment CSF flow study'.)
For other patients, if the changes are mild and not overtly symptomatic, and the person seems to be responding to treatment, then treatment continuation is an option. For highly symptomatic patients with no identifiable reversible cause of leukoencephalopathy, treatment discontinuation, at least temporarily, is advisable.
The presence of disseminated necrotizing leukoencephalopathy should prompt immediate and permanent discontinuation of the drug.
Accidental overdose of intrathecal methotrexate — Significant overdosage with IT MTX, particularly a dose >500 mg compared with the usual dose of 10 or 12 mg, must be treated vigorously since it can lead to acute myelopathy, encephalopathy, seizures, and death . Patients with such overdoses are treated with the combination of IT administration of glucarpidase (carboxypeptidase G2, CPDG2) to metabolize the MTX [52,53], rapid CSF drainage by lumbar puncture, CSF exchange, ventriculolumbar perfusion to reduce the amount of MTX in the CSF, systemic leucovorin rescue (using either the d,l-racemic mixture of leucovorin or l-leucovorin [LEVOleucovorin], the biologically active isomer), plus alkaline diuresis [2,53-55]. (See "Enhanced elimination of poisons", section on 'Urinary alkalinization'.)
The success of these approaches can be illustrated by a report of seven patients who accidentally received 155 to 600 mg of IT MTX . Symptoms included seizures, coma, severe cardiopulmonary compromise, confusion, tachycardia, hypertension, severe headache, intense back pain, and nausea and vomiting. All were treated with glucarpidase (2000 units reconstituted in 12 mL of normal saline), administered IT over a period of five minutes immediately after reconstitution. In addition, all received concurrent IV leucovorin (100 mg every six hours for four doses) and dexamethasone (4 mg every six hours for four doses). In four of the seven patients, a ventricular catheter was inserted and ventriculolumbar perfusion was performed to remove MTX via CSF exchange. CSF concentrations of MTX were reduced by 99 percent in all patients, with the levels being lowest in those who received both glucarpidase and CSF exchange. All patients recovered, although two suffered memory loss.
Benefit was also suggested in a single case study of a patient with primary central nervous system lymphoma who received 10 times the intended dose of IT methotrexate and who received 2000 units of IT glucarpidase approximately 11 hours after the overdose; the patient was back to baseline within 72 hours, and discharged without any neurologic deficit . The authors caution that while the reported cases support the positive benefit-risk balance in the use of IT glucarpidase when given up to 11 hours after IT methotrexate overdose, the precise role of glucarpidase cannot be determined. They advise immediate CSF withdrawal along with systemic administration of glucocorticoids (preferably dexamethasone for its penetration through the blood-brain barrier), and leucovorin, to circumvent potential arachnoiditis and systemic effects of methotrexate, respectively, alongside any glucarpidase administration.
IT administration represents an off-label use for glucarpidase given that there is no labeled indication for IT use in the United States Prescribing Information for IV glucarpidase. A specific formulation of glucarpidase intended for IT use is not commercially available, and it is no longer being supplied for single-patient investigational use by the manufacturer (BTG Medical).
TAXANES — Paclitaxel and docetaxel are antimicrotubule agents that are used to treat a variety of tumors. Both are associated with a predominantly sensory neuropathy, although paclitaxel appears to be more neurotoxic than docetaxel (overall incidence of any grade neuropathy 60 versus 15 percent) (table 2) [57-60]. In addition, severe (grade 3 or 4) sensory neuropathy is much more common with paclitaxel than with docetaxel . Motor neuropathy is uncommon with both agents, and if it is significant, should prompt investigation of another possible cause. The peripheral neuropathy associated with these drugs may sometimes be confused with hand-foot syndrome (acral erythema). (See "Toxic erythema of chemotherapy (hand-foot syndrome)", section on 'Hand-foot syndrome'.)
The mechanism of taxane-induced peripheral neuropathy appears to be related to disrupted microtubules of the mitotic spindle, which interferes with axonal transport, macrophage activation in both the dorsal root ganglia and peripheral nerve, as well as microglial activation within the spinal cord [62-64]. In addition, taxanes evoke a "dying back" process starting from distal nerve endings followed by effects on Schwann cells and other neuronal cells, which is an essential microtubule-based process that moves cellular components over long distances between neuronal cell bodies and nerve terminals .
Clinical features, incidence, and risk factors — The most common neuropathy caused by paclitaxel involves sensory nerve fibers. The major manifestations are burning paresthesias of the hands and feet and loss of reflexes.
The predominant risk factor is cumulative dose over time; the neurotoxic threshold is approximately 1000 mg/m2 . However, the frequency and time to onset are also proportional to dose. Patients treated with higher doses (≥250 mg/m2) may develop symptoms after the first cycle . (See 'Dose and schedule' below.)
Other risk factors for sensory neuropathy are concurrent use of a platinum agent, older age, history of diabetes mellitus [65,66], vitamin D insufficiency [67,68], and possibly, obesity and a lower activity level . The best data linking vitamin D deficiency with a higher risk of paclitaxel related sensory neuropathy come from a retrospective analysis of data from the phase III SWOG0221 trial which compared different paclitaxel-containing regimens in patients with early stage breast cancer . In a preliminary report presented at the 2022 annual ASCO meeting, of the 1116 patients in the analysis, 169 (15.1 percent) experienced peripheral neuropathy and 376 (33.7 percent) had vitamin D deficiency (defined as a level ≤20 ng/mL). In the entire population, vitamin D deficiency was associated with a higher neuropathy risk (19.3 versus 13.0 percent, OR 1.62. p = 0.005). Compared with White Americans, Black Americans were more likely to have vitamin D deficiency (78 versus 29 percent), less likely to take supplements during adjuvant therapy, and they also had a more than twofold higher risk of peripheral sensory neuropathy (29.3 versus 13.3 percent, OR 2.66, p <0.001). Adjusting for vitamin D deficiency decreased but did not eliminate the higher neuropathy risk in Black Americans (OR 2.33, p = 0.002). Although prospective trials are needed to test whether vitamin D supplementation lessens paclitaxel-related peripheral neuropathy, these data suggest that patients initiating treatment with paclitaxel should be screened for vitamin D deficiency, and repleted if levels are low. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Paclitaxel'.)
It should be noted that the lack of consensus regarding optimal outcome measures and the significant discordance between patient- and clinician-reported neurotoxicity complicate the assessment of risk factors for paclitaxel-related neuropathy .
Other, less common manifestations of paclitaxel neurotoxicity include:
●Autonomic neuropathies (rare) .
●Taxane-associated acute pain syndrome, which is characterized by severe arthralgias and myalgias accompanied by numbness and tingling, beginning within one to two days after treatment and lasting a median of four to five days . Newer data support the view that this is a form of an acute neuropathy, as opposed to a disorder of joints and/or muscles [73-75]. The incidence in patients treated with unbound paclitaxel varies widely; in a systematic review of 26 published studies, the incidence ranged from 0.9 to 86 percent (median 13.1 percent) . Variability was related to schedule (higher with three-hour versus 96-hour infusions and with administration every three weeks rather than weekly) and disease stage (higher incidence in the metastatic as compared with adjuvant therapy setting).
●Transient encephalopathies [77,78].
●Phantom limb pain .
Nerve conduction studies reveal a decrease of sensory nerve action potentials (SNAP) or absence of sensory responses, consistent with axonal loss from sensory nerves; the sural nerve is particularly affected [80,81].
The neurotoxicity of paclitaxel is synergistic with that of concomitant platinum administration [82,83]. Other risk factors include preexisting peripheral neuropathy and duration of infusion (1 to 3 versus 24-hour infusions). Risk appears unrelated to older age . (See 'Dose and schedule' below.)
There is substantial interindividual variability in prevalence, severity, and onset of peripheral neuropathy related to paclitaxel, and there is some suggestion that inherited polymorphisms or mutations in some genes, including those associated with Charcot-Marie-Tooth disease, and beta-tubulin; CYP3A4 variants may also contribute [14,85-92]. (See 'Risk factors' above and "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis".)
Dose and schedule — The risk of sensory neuropathy is proportional to dose. Grade 3 or 4 sensory neurotoxicity (table 3) occurs in 20 to 35 percent of patients receiving 250 mg/m2 every three weeks compared with 5 to 12 percent in large series using doses ≤200 mg/m2 every three weeks .
The time to onset was illustrated in a phase III trial of patients with metastatic breast cancer treated with paclitaxel (135 or 175 mg/m2) every three weeks; the mean total dose at the onset of grade 2 neurotoxicity was 715 mg/m2 .
Weekly paclitaxel is less myelosuppressive than an every three-week schedule, thereby allowing increased dose intensity. Whether the weekly schedule is associated with worse neurotoxicity is unclear as evidenced by the following conflicting reports:
●Two separate phase III randomized trials have randomly assigned women with breast cancer to paclitaxel weekly (80 mg/m2) or every three weeks (175 mg/m2); both demonstrated more frequent neurotoxicity with weekly therapy [94,95].
•In the other study comparing weekly versus every three week paclitaxel dosing for adjuvant treatment of breast cancer following standard doxorubicin-cyclophosphamide, grade 2, 3, or 4 neuropathy (table 3) occurred more frequently with weekly paclitaxel (27 percent versus 20 percent with treatment every three weeks) .
●On the other hand, a meta-analysis of seven trials comparing weekly versus every three-week paclitaxel or docetaxel for advanced breast cancer does not support this view, concluding that the incidence of serious adverse effects, including peripheral neuropathy, was significantly lower with a weekly taxane schedules .
The effect of infusion duration on the incidence of severe neurotoxicity is uncertain . Extending the duration of infusion from 3 to 24 hours has given conflicting results:
●In a randomized trial in women with metastatic breast cancer treated with 250 mg/m2, the longer infusion was associated with a lower incidence of severe chronic neurotoxicity (13 versus 22 percent) .
●By contrast, in women with ovarian cancer treated with a lower dose of paclitaxel (135 or 175 mg/m2), no significant differences were observed between infusion rates of 3 versus 24 hours (0.6 versus 0.7 percent) .
On the other hand, at least some data suggest that the incidence of paclitaxel-associated acute pain syndrome (arthralgias and myalgias with numbness and tingling two to three days after chemotherapy) is higher with 3 versus 96 hour infusion duration (25 versus 2 percent) .
Nanoparticle albumin-bound paclitaxel versus unbound drug — The nanoparticle albumin-bound form of paclitaxel was originally formulated to enable lower doses and reduce toxicity, but peripheral neuropathy still remains a significant treatment-limiting toxicity.
Clinical experience with the nanoparticle albumin-bound nanoparticle formulation of paclitaxel (nabpaclitaxel, Abraxane) suggests that while the overall toxicity profile is better as compared with conventional paclitaxel, the incidence of transient sensory neurotoxicity may be slightly higher, although with a shorter recovery duration [99,100]. Grade 3 neuropathy is reversible to grade ≤1 in approximately one-half of patients who receive nabpaclitaxel, most of which improve within one month of treatment discontinuation .
On the other hand, the incidence of sensory neurotoxicity may be similar with nabpaclitaxel and docetaxel. This was demonstrated in a phase II study of women with metastatic breast cancer who were randomly assigned to docetaxel 100 mg/m2 every three weeks, nabpaclitaxel 300 mg/m2 every three weeks, nabpaclitaxel 100 mg/m2 weekly, or nabpaclitaxel 150 mg/m2 weekly . The frequency and severity of peripheral neuropathy was similar in all groups, although sensory neuropathy resolved more rapidly in the nabpaclitaxel arms compared with docetaxel, a finding that has been confirmed by others . (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Taxanes'.)
It is unclear whether taxane-acute pain syndrome is more or less common with nabpaclitaxel as compared with unbound paclitaxel or docetaxel. In a systematic review of eight studies, the incidence of taxane-acute pain syndrome with nabpaclitaxel ranged from 13 to 43 percent (median 26 percent), and it did not differ substantially when given in the metastatic disease setting as compared with the adjuvant or neoadjuvant setting . By contrast, the incidence with unbound paclitaxel ranged from 0.9 to 86 percent (median 13 percent), and for docetaxel, it ranged from 3.6 to 70 percent (median 10.5 percent).
Docetaxel — Like paclitaxel, docetaxel causes both sensory and motor neuropathies, although both of these occur less frequently than with paclitaxel . Grade 3 or 4 neuropathies (table 3) occur in 10 percent or less [58,103]. Treatment with docetaxel has also been associated with the development of Lhermitte's sign, a nonpainful but unpleasant electric shock-like sensation that shoots down the spine during neck flexion .
Like paclitaxel, the incidence of docetaxel neurotoxicity is proportional to the cumulative dose; the neurotoxic threshold is approximately 400 mg/m2 . The time to onset was illustrated in a phase III trial of women with metastatic breast cancer treated with docetaxel (100 mg/m2 every three weeks); the onset of grade 2 or greater neuropathy (table 3) occurred at a median cumulative dose of 371 mg/m2 .
Unlike paclitaxel, the effect of administration schedule on the incidence of severe neurotoxicity is uncertain; phase III studies randomizing patients to weekly versus every three-week docetaxel have yielded conflicting results:
●In a trial directly comparing docetaxel 75 mg/m2 every three weeks versus 35 mg/m2 weekly in patients with metastatic breast cancer, the rate of grade 3 or 4 neuropathy (table 3) was higher with every three-week therapy (10 versus 5 percent) .
●On the other hand, a meta-analysis of all randomized trials comparing the two regimens in patients with advanced non-small cell lung cancer yielded similar rates of grade 3 or 4 neurotoxicity (2.5 versus 3 percent for the every three-week and weekly regimens, respectively) .
Docetaxel has also been associated with an acute pain syndrome similar to that observed with paclitaxel [107-112]. The overall incidence, clinical pattern, and time course appear to be the same. In a systematic review of 27 published studies, the incidence of taxane-acute pain syndrome ranged from 3.6 to 70 percent (median 10.5 percent), and the variability was attributable to dosing, the specific chemotherapy regimen used, and disease stage (higher incidence in the adjuvant setting than in the metastatic disease setting) . By contrast, the incidence with unbound paclitaxel ranged from 0.9 to 86 percent (median 13 percent), and the incidence was higher in patients treated in the metastatic disease setting.
Cabazitaxel — Cabazitaxel is a semisynthetic taxane that is approved for treatment of advanced prostate cancer. It appears to be less neurotoxic than either paclitaxel or docetaxel. Peripheral neuropathy of any grade is reported in 13 to 17 percent of treated patients, but fewer than 1 percent are severe [113,114]. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Men who have received prior docetaxel'.)
Outcomes, prevention, and treatment — The neuropathies caused by taxanes often do not progress even if treatment is continued, and there are reports of symptomatic improvement despite continued therapy. After completing treatment, approximately 50 to 60 percent of patients improve over a period of months [60,115-119]. However, severe neuropathy can persist:
●In one study, up to 80 percent of patients still had neuropathic symptoms up to two years after completing treatment; approximately 25 percent reported severe symptoms of numbness and/or discomfort in their hands and feet .
Some suggest that if neuropathy persists, it is mild and does not interfere with function or quality of life . However, on the other hand, other data support the view that symptoms of neurotoxicity remain clinically meaningful for up to two years in approximately 30 percent of breast cancer patients treated with adjuvant taxane-based therapy .
There are no established agents that can be recommended for the prevention of chemotherapy-induced peripheral neuropathy (CIPN) in patients with cancer undergoing treatment with neurotoxic agents, including taxanes. However, as noted above, low vitamin D levels appear to be a risk factor for paclitaxel-related neuropathy, and although prospective trials are needed to test whether vitamin D supplementation lessens paclitaxel-related peripheral neuropathy, these data suggest that patients receiving taxanes should be screened for vitamin D deficiency, and repleted if levels are low. (See 'Clinical features, incidence, and risk factors' above and "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Preventive approaches'.)
Dose reduction guidelines for neuropathy during treatment with some docetaxel-containing regimens are available in the US Food and Drug Administration (FDA)-approved manufacturer's drug information for docetaxel. Recommendations are also provided for patients receiving nabpaclitaxel but not unbound paclitaxel.
Amelioration of symptoms from the CIPN, including pain, may be achieved through use of antidepressants such as duloxetine. For symptomatic patients with chronic neuropathy who fail to respond to duloxetine, other adjuvant analgesics (eg, tricyclic antidepressants, anticonvulsants), opioids, physical modalities such as cutaneous electrical stimulation, and/or interventional procedures may be indicated. Symptomatic treatment for chemotherapy-induced neuropathy is discussed in detail elsewhere. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Duloxetine' and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with neuropathic pain' and "Rehabilitative and integrative therapies for pain in patients with cancer", section on 'Other modalities' and "Cancer pain management: Interventional therapies".)
Few trials have addressed therapy for taxane-induced acute pain syndrome, and optimal therapy has not been established . (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Acute neurotoxicity'.)
VINCA ALKALOIDS — The vinca alkaloids are plant-derived cytotoxic agents whose mechanism of action involves antimicrotubule activity. The drugs in this class have a different toxicity profile; vincristine is the most neurotoxic (table 2).
Vincristine — Vincristine is a useful agent for many cancers. The dose-limiting toxicity is an axonal neuropathy resulting from disruption of the microtubules within axons and interference with axonal transport [122,123]. The neuropathy involves both sensory and motor fibers, although small sensory fibers are especially affected.
Virtually all patients receiving vincristine have some degree of neuropathy. The earliest symptoms are usually paresthesias in the fingertips and feet, with or without pain, muscle cramps, and/or mild distal weakness (table 2). These symptoms often develop after several weeks of treatment and after cumulative doses between 30 and 50 mg , but they may occur after the first dose. Furthermore, symptoms may appear even after the drug has been discontinued and progress for several months before improving . (See 'Outcomes, options for neuroprotection, and treatment' below.)
Initially, objective sensory findings tend to be relatively minor compared with the subjective complaints, but loss of deep tendon reflexes, especially ankle jerks, is common and develops early. Vibration perception is rarely more than mildly affected . Occasionally there may be profound weakness, with bilateral foot drop, wrist drop, and loss of all sensory modalities. Neurophysiologic studies are compatible with a symmetric primarily axonal neuropathy [127,128].
Severity is dose-related. Severe neuropathies are also particularly likely to develop in older or cachectic patients, those who have received prior irradiation to the peripheral nerves or concomitant hematopoietic colony-stimulating factors , concurrent use of azole antifungal agents, and other inhibitors of CYP3A4 drug metabolizing enzyme [130,131], and those who have preexisting neurologic conditions such as Charcot-Marie-Tooth [132,133]. Vincristine is generally contraindicated in patients with demyelinating conditions like Charcot-Marie-Tooth. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis" and "Pharmacology of azoles" and "Pharmacology of azoles", section on 'Major drug interactions'.)
Autonomic neuropathies are common in patients receiving vincristine, and may precede paresthesias or loss of deep tendon reflexes. Colicky abdominal pain and constipation occur in almost 50 percent of patients, and rarely, a paralytic ileus may result . Less commonly, patients may develop erectile impotence , postural hypotension, or an atonic bladder. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Vinca alkaloids'.)
Vincristine may also cause focal mononeuropathies, sometimes involving the cranial nerves [1,135]; the most commonly involved is the oculomotor nerve. Other nerves that may be involved include recurrent laryngeal nerve, optic nerve, facial nerve, and auditory nerve. Vincristine may also cause retinal damage and night blindness, and some patients may experience jaw and parotid pain during treatment. (See "Third cranial nerve (oculomotor nerve) palsy in adults".)
Rarely, vincristine may cause inappropriate secretion of antidiuretic hormone (SIADH), resulting in hyponatremia, confusion, and seizures . Other rare central nervous system (CNS) complications that are unrelated to SIADH include seizures, encephalopathy, transient cortical blindness, ataxia, athetosis (slow, writhing movements of the limbs), and parkinsonism . (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Drugs'.)
Outcomes, options for neuroprotection, and treatment — Patients with mild neuropathy can usually continue to receive full doses of vincristine, but when symptoms increase in severity and interfere with neurologic function, dose reduction or discontinuation of the drug may be necessary. Dose reduction guidelines for neuropathy are not provided in the US Food and Drug Administration (FDA)-approved manufacturer's drug information for unencapsulated vincristine.
Vincristine neuropathy is usually reversible but improvement is gradual and may take many months [124,138-142]. Furthermore, symptoms may progress for several months before improving . Children tend to recover more quickly than adults. Although most deep tendon reflexes reappear, recovery of ankle reflexes is uncommon . Because of the high incidence of constipation, patients receiving vincristine should take prophylactic stool softeners and/or laxatives.
To minimize the potential neurotoxic effects of vincristine, the usual recommended vincristine dose is 1.4 mg/m2 per single dose, and many (but not all) protocols recommend an upper limit of 2 mg on single doses, regardless of body surface area. (See "Treatment protocols for lymphoma".)
There are no established agents that can be specifically recommended for the prevention of vincristine-induced peripheral neuropathy. Two small placebo-controlled trials addressing the use of prophylactic glutamic acid in patients receiving vincristine suggest some benefit in reducing neurotoxicity. However, the benefits are modest, and whether this translates to improved long-term neurologic outcomes or better disease control because of fewer patients requiring dose reduction is unclear.
A larger trial of oral glutamine supplementation in young patients receiving vincristine for a variety of tumors has been completed but not yet reported . An updated 2020 American Society for Clinical Oncology (ASCO) systematic review of neuroprotectants for prevention of chemotherapy-induced peripheral neuropathy (CIPN) concluded that until larger definitive studies are available, clinicians should not offer glutamate for prevention of CIPN to patients receiving treatment with any neurotoxic agent, including vincristine . (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Vitamins, minerals, and dietary supplements'.)
For patients with established painful neuropathy from vincristine, there are no evidence-based recommendations. A small placebo-controlled trial of gabapentin was negative . The updated 2020 ASCO guideline concluded that no recommendations could be made as to the use of gabapentinoids for treatment of CIPN caused by any drug . (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Gabapentinoids'.)
Amelioration of symptoms from established vincristine-related peripheral neuropathy, including pain, might be achieved through use of antidepressants such as duloxetine , although the available data are limited to patients with taxane- or platinum-related chronic neuropathy. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Duloxetine'.)
For symptomatic patients with chronic neuropathy who fail to respond to duloxetine, a trial of another adjuvant analgesic (eg, tricyclic antidepressants, anticonvulsants), opioids, physical modalities such as cutaneous electrical stimulation, and/or interventional procedures may be indicated. Symptomatic treatment for chemotherapy-induced neuropathy is discussed in detail elsewhere. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with neuropathic pain' and "Rehabilitative and integrative therapies for pain in patients with cancer", section on 'Other modalities' and "Cancer pain management: Interventional therapies".)
Other vinca alkaloids — The related vinca alkaloids vindesine, vinblastine, and vinorelbine tend to be associated with less neurotoxicity, possibly related to differences in lipid solubility, plasma clearance, and affinity for neural tissue (table 2) [1,137].
●Vinblastine-induced peripheral neuropathy is qualitatively similar to that of vincristine, but less severe. Hematologic toxicity rather than neurotoxicity represents the main dose limiting adverse effect.
●Vinorelbine is associated with mild distal neuropathy, mainly manifested with paresthesias in only approximately 20 percent of patients . Severe neuropathy is rare, occurring most often in patients with prior paclitaxel exposure [147,148]. The neuropathy is dose-dependent and reversible after treatment discontinuation.
EPOTHILONES — Epothilones are non-taxane tubulin polymerizing agents that induce peripheral neuropathy by causing damage to the ganglion soma cells and peripheral nerve axons through the disruption of microtubules of the mitotic spindle and by interfering with axonal transport and cytoplasmic flow in affected neurons [63,149].
Ixabepilone — Ixabepilone is used for treatment of advanced breast cancer.
The neuropathy associated with ixabepilone is a dose-dependent predominantly sensory distal peripheral neuropathy, although motor (and rarely autonomic) neuropathies have also been reported (table 2)  Overall, up to 71 percent of patients exposed to ixabepilone manifest a sensory neuropathy of any grade, which is severe (grade 3 or 4 (table 3)) in 6 to 21 percent . In a randomized phase III clinical trial of capecitabine with or without ixabepilone for metastatic breast cancer, the rate of grade 3 or 4 sensory neuropathy (table 3) was 21 percent with combination therapy (versus zero with capecitabine alone) . Neurotoxicity was cumulative, and the median time to onset of grade 3 or 4 peripheral neuropathy was four cycles. Symptoms were reversible and typically resolved within six weeks after dose reduction.
There are no established agents that can be recommended for the prevention of chemotherapy-induced peripheral neuropathy (CIPN) in patients with cancer undergoing treatment with ixabepilone. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Preventive approaches'.)
The US Food and Drug Administration (FDA)-approved manufacturer's drug information recommends a 20 percent decrease in dose for patients with grade 2 neuropathy persisting more than seven days or grade 3 neuropathy of less than seven days duration . More severe or persistent neuropathy should result in discontinuation of therapy. Symptoms are generally reversible within weeks of treatment discontinuation. Special care is warranted in patients with diabetes or preexisting neuropathy, because of the increased risk of severe neuropathy.
Eribulin — Eribulin mesylate, a synthetic analogue of halichondrin B, a substance derived from a marine sponge, inhibits the polymerization of tubulin and microtubules. In a randomized trial in patients with metastatic breast cancer, peripheral neuropathy (sensory or motor neuropathy, polyneuropathy, or paresthesias) developed in 35 percent of the 508 patients who were randomly assigned to eribulin; it was severe (grade 3 or 4) in 8 percent [154,155]. Neuropathy was the most common drug toxicity leading to treatment discontinuation. Although symptoms are generally reversible, neuropathy can last beyond a year in approximately 5 percent of patients.
Treatment — Amelioration of symptoms from epothilone-related CIPN, including pain, might be achieved through use of antidepressants such as duloxetine , but the available data on efficacy are limited to patients receiving taxanes or platinum agents. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Duloxetine'.).
For symptomatic patients with chronic neuropathy who fail to respond to duloxetine, other adjuvant analgesics (eg, tricyclic antidepressants, anticonvulsants), opioids, physical modalities such as cutaneous electrical stimulation, and/or interventional procedures might be tried. Symptomatic treatment for chemotherapy-induced neuropathy is discussed in detail elsewhere. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with neuropathic pain' and "Rehabilitative and integrative therapies for pain in patients with cancer", section on 'Other modalities' and "Cancer pain management: Interventional therapies".)
THALIDOMIDE AND RELATED AGENTS
Thalidomide — The potent antiangiogenic activity of thalidomide has led to its use in plasma cell dyscrasias. (See "Multiple myeloma: Initial treatment" and "Multiple myeloma: Management in resource-limited settings".)
Initial studies of thalidomide in patients with multiple myeloma reported severe (grade 3 or 4) peripheral neurotoxicity in approximately one-third of patients who received daily thalidomide doses of >200 mg . With the recognition that effects are dose-dependent and cumulative over time, efforts were made to reduce the dose and duration of thalidomide [157-162]. With modern treatment protocols (starting dose of thalidomide at 200 mg per day for patients <75 years of age, and 100 mg per day for those 75 and older), peripheral neuropathy develops in approximately 50 percent of patients receiving first-line thalidomide for multiple myeloma, but fewer than 10 percent are severe [163-165].
The clinical presentation is typically that of symmetric distal paresthesias or dysesthesias with or without sensory loss; motor peripheral neuropathy can complicate treatment in 30 to 40 percent of patients (table 2) [158-160,163,166-168]. The pathogenesis of thalidomide-induced peripheral neuropathy is unknown. Data from nerve conduction studies suggest that the underlying pathophysiology is a dying-back degeneration of sensory and motor nerves, indicative of a toxic axonopathy . Dysregulation of neurotrophin activity may also play a significant role in the pathogenesis of neurotoxicity .
Neuropathy is the reason for dose reduction or cessation of treatment in up to 60 percent of patients. Toxicity due to thalidomide needs to be distinguished from a neuropathy due to the malignancy (particularly myeloma) or to antecedent chemotherapy with other neurotoxic agents such as the vinca alkaloids.
Another common side effect of thalidomide treatment is somnolence, affecting 43 to 55 percent of patients. The somnolence decreases in many patients after two or three weeks of continued therapy. Constipation is also common, particularly in elderly patients , and has been attributed to an autonomic nerve fiber injury. Other signs of thalidomide-induced autonomic peripheral neuropathy, which may be unrecognized, include impotence and bradycardia .
Other reported manifestations of neurotoxicity include a mild to moderate tremor in up to one-third of patients [163,167], dizziness , rarely seizures , progressive multifocal leukoencephalopathy (PML) , and at least one case of severe encephalopathy with prolonged thalidomide monotherapy .
Natural history, prevention, and management — The long-term course and final outcome of thalidomide-induced peripheral neuropathy has not been extensively investigated . Neuropathy frequently improves, although it may be only partially reversible with treatment discontinuation [161,175].
There are no established pharmacologic agents that can be recommended for the prevention of chemotherapy-induced peripheral neuropathy (CIPN) in patients with cancer undergoing treatment with neurotoxic agents, including thalidomide. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Preventive approaches'.)
Dose reduction guidelines for neuropathy are not provided in the US Food and Drug Administration (FDA)-approved manufacturer's drug information or from the EMA (European Medicines Agency); suggested guidelines have been proposed by a group of European myeloma experts .
Amelioration of symptoms from the CIPN, including pain, might be achieved through use of antidepressants such as duloxetine , although the available data are limited to patients who received taxanes or a platinum drug. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Duloxetine'.)
For symptomatic patients with chronic neuropathy who fail to respond to duloxetine, other adjuvant analgesics (eg, tricyclic antidepressants, anticonvulsants), opioids, physical modalities such as cutaneous electrical stimulation, and/or interventional procedures may be tried. Symptomatic treatment for chemotherapy-induced neuropathy is discussed in detail elsewhere. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with neuropathic pain' and "Rehabilitative and integrative therapies for pain in patients with cancer", section on 'Other modalities' and "Cancer pain management: Interventional therapies".)
Lenalidomide — Lenalidomide, a second-generation thalidomide derivative with more potent antiangiogenic properties, appears to be substantially less neurotoxic, even when it is given to patients with preexisting CIPN . Most cases are mild (grade 1 or 2). In a long-term follow-up study of 704 patients enrolled in two multicenter, randomized phase III trials of dexamethasone plus either lenalidomide or placebo for relapsed or refractory multiple myeloma , the rate of grade 3 peripheral neuropathy (table 3) was only 1.4 percent among patients treated with lenalidomide versus 0.6 percent in the dexamethasone alone group.
Pomalidomide — Pomalidomide is approved for patients with multiple myeloma who have received at least two prior agents, including bortezomib and lenalidomide. Mild to moderate (grade 1 or 2 (table 3)) neuropathy can occasionally be seen (up to 9 percent of patients) but no cases of severe neuropathy were seen in large randomized trials testing the efficacy of this agent [179,180]. Rare cases of PML have been described .
Bortezomib — Peripheral nerve damage is one of the most significant nonhematologic toxicities of bortezomib. When it occurs, the painful sensory neuropathy can interfere with quality of life and with performance of activities of daily living, and it may force dose modification and/or treatment discontinuation [181-183].
●Incidence, severity and risk factors – Treatment-emergent neuropathy of any grade (ie, developing or worsening neuropathy or pain during treatment) is reported in up to 75 and 60 percent of patients treated with twice weekly therapy for recurrent and newly diagnosed disease, respectively [181,182,184-188]. It is severe (grade 3 or 4) in approximately 15 percent of patients treated with the twice weekly schedule. The risk of severe neuropathy appears to be significantly lower (5 percent or less) with once weekly dosing, which appears to be feasible without compromising efficacy, as long as a rapid disease response is not needed [189-191]. Risk is also lower with subcutaneous rather than intravenous (IV) administration, and possibly with concomitant use of dexamethasone . (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Bortezomib'.)
Both the incidence and severity of neurotoxicity appear to be higher in patients with preexisting baseline neuropathy, in those who receive a higher cumulative dose amount during the first five therapy courses, and in heavily pretreated patients [181,183,193]. The available data suggest a neurotoxic dose threshold rather than a classic cumulative dose effect [176,183]. Genetic factors may also contribute [194,195]. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors'.)
●Clinical manifestations – The predominant feature is a painful sensory neuropathy in a stocking glove distribution with burning dysesthesias of the fingers and toes (table 2). Symptoms typically occur after the first few courses of treatment, usually by cycle 5 (corresponding to a cumulative dose of approximately 26 mg/m2) [181,196,197]. The neurologic examination reveals distal sensory loss to all modalities and changes in proprioception, while deep tendon reflexes are either suppressed or absent [182,198]. The mechanism is thought to be mainly a direct toxic effect on the dorsal root ganglion , with axonopathy to a lesser extent.
Motor neuropathy, consisting of mild to severe distal weakness in the lower extremities, develops in up to 10 percent of patients with the twice weekly schedule and may be immune-mediated. A single report describes five patients with a peripheral neuropathy associated with severe motor involvement . Electrodiagnostic studies indicated either a demyelinated or a mixed axonal-demyelinated neuropathy. The protein concentration in the cerebrospinal fluid was elevated, and magnetic resonance imaging (MRI) of the lumbar spine revealed enhancement of nerve roots in two patients. Four of the five patients responded to IV immunoglobulin or glucocorticoids.
Gastrointestinal side effects (diarrhea or constipation) and orthostatic hypotension complicate therapy in approximately 10 to 15 percent of patients who receive bortezomib [184,188,201]. These are thought to be mainly caused by autonomic peripheral neuropathy.
In addition, bortezomib has been associated with posterior reversible encephalopathy syndrome and cerebellar toxicity [202-204]. (See "Reversible posterior leukoencephalopathy syndrome".)
●Natural history, prevention, and treatment – For patients who develop neuropathy during treatment, discontinuation or dose modification leads to improvement or complete resolution in the majority of patients [181,184,197,205]. Reversal usually occurs after a median interval of three months following treatment discontinuation, but it may persist for up to two years or indefinitely in some cases [183,197,206].
A dose adjustment algorithm for patients who develop treatment-related neuropathy is available in the US Food and Drug Administration (FDA)-approved manufacturer's drug information (table 4). In a subanalysis of patients receiving bortezomib for treatment of relapsed myeloma in a phase III clinical trial, dose modification using this algorithm improved peripheral neuropathy management without adversely affecting outcome . Of 91 patients with ≥grade 2 peripheral neuropathy during treatment, 58 (64 percent) experienced improvement or resolution to baseline at a median of 110 days. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors'.)
Slightly different dose modification guidelines have been proposed by a group of European myeloma experts .
There are no established pharmacologic agents that can be recommended for the prevention of chemotherapy-induced peripheral neuropathy (CIPN) in patients with cancer undergoing treatment with neurotoxic agents, including bortezomib. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Preventive approaches'.)
In general, the best way to reduce the incidence of bortezomib-induced neurotoxicity appears to be use of a once weekly as opposed to a twice weekly schedule (where clinically appropriate), and subcutaneous rather than IV administration. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Bortezomib'.)
A single case report describes symptomatic improvement (neuropathy as well as pain) using twice daily application of topical menthol (0.5 percent in calamine lotion) , an approach that has been useful for the treatment of postherpetic neuralgia. Whether bortezomib could then be resumed at a lower dose was not addressed. In addition, limited data suggest the possibility that bortezomib may cause an immune-mediated neuropathy with both motor and sensory involvement in addition to the usual neurotoxicity (a predominantly sensory neuropathy) and that this may be responsive to immunotherapy. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Topical menthol' and "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Patients treated with bortezomib'.)
Amelioration of symptoms from the chronic neuropathy, including pain, might be achieved through use of antidepressants such as duloxetine , although the available data are limited to patients who received taxanes or a platinum drug. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Duloxetine'.)
For symptomatic patients with chronic neuropathy who fail to respond to duloxetine, other adjuvant analgesics (eg, tricyclic antidepressants, anticonvulsants), opioids, physical modalities such as cutaneous electrical stimulation, and/or interventional procedures may be tried. Symptomatic treatment for chemotherapy-induced neuropathy is discussed in detail elsewhere. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with neuropathic pain' and "Rehabilitative and integrative therapies for pain in patients with cancer", section on 'Other modalities' and "Cancer pain management: Interventional therapies".)
Carfilzomib — Peripheral neuropathy appears to be less common and less severe with the second generation proteasome inhibitor carfilzomib. In phase II studies (in which most of the patients had been previously exposed to bortezomib), the incidence of treatment-emergent peripheral neuropathy was 12 to 23 percent overall, and it was severe (grade 3 or 4) in ≤1 percent [208-211]. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors' and "Multiple myeloma: Treatment of first or second relapse", section on 'Carfilzomib, lenalidomide, dexamethasone (KRd)'.)
Rare cases of posterior reversible leukoencephalopathy syndrome (RPLS) [212,213] and progressive multifocal leukoencephalopathy (PML), which can be fatal, have been reported with carfilzomib. If either is suspected, the drug should be discontinued and an evaluation initiated. (See "Reversible posterior leukoencephalopathy syndrome" and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)
Ixazomib — In contrast to bortezomib and carfilzomib, ixazomib is an orally active proteasome inhibitor. It is approved, in combination with lenalidomide and dexamethasone, for treatment of relapsed multiple myeloma. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors' and "Multiple myeloma: Treatment of first or second relapse", section on 'Ixazomib, lenalidomide, dexamethasone (IRd)'.)
●In a phase II trial of ixazomib monotherapy in patients with relapsed myeloma not refractory to bortezomib, peripheral neuropathy developed in approximately 40 percent; there were no cases of severe (grade 3 or 4) neuropathy .
●In a preliminary report of a trial comparing lenalidomide and dexamethasone with and without ixazomib, rates of all-grade neuropathy were slightly higher in the ixazomib arm (28 versus 21 percent), but rates of severe peripheral neuropathy were similar (2 percent in each group) .
The United States Prescribing Information contains dose modification recommendations in the event of peripheral neuropathy.
NELARABINE — Nelarabine, a purine analog used for T-cell acute lymphoblastic leukemia, is associated with peripheral neuropathy that can mimic Guillain-Barré syndrome (progressive, fairly symmetric muscle weakness accompanied by absent or depressed deep tendon reflexes) . Reduced consciousness, headache, and seizures have also been reported. In phase II studies, 40 to 72 percent of patients have had neurotoxicity of any grade attributed to nelarabine, 15 to 20 percent of which are grade 3 or 4 (table 5) [216-218]. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'Clinical features'.)
Full recovery has not always occurred with treatment discontinuation. As a result, the US Food and Drug Administration (FDA)-approved drug information suggests that treatment be discontinued for any neurologic toxicity grade 2 or higher (table 5).
OTHER AGENTS CAUSING NEUROTOXICITY
Asparaginase — Asparaginase is used mainly to treat acute lymphoblastic leukemia. Although direct neurotoxicity is uncommon, asparaginase is associated with a coagulopathy with hemorrhagic and thrombotic complications, including sagittal sinus thrombosis and cerebral infarction . These complications typically occur after several weeks of treatment. At high doses, asparaginase may also produce a reversible encephalopathy. The related pegylated Escherichia coli (PEG)-asparaginase (pegaspargase) has similar neurotoxicity; fatigue and disorientation are reported in approximately 10 percent. (See "Cancer-associated hypercoagulable state: Causes and mechanisms", section on 'Therapy-related factors'.)
Cytarabine — Cytarabine (cytosine arabinoside) is a pyrimidine analog that is used for the treatment of leukemias, lymphomas, and intrathecally for neoplastic meningitis. Conventional doses are associated with little neurotoxicity. However, high doses (≥3 g/m2 every 12 hours) cause an acute cerebellar syndrome in 10 to 25 percent of patients [220-223]. Patients over the age of 40 who have abnormal liver or renal function, underlying neurologic dysfunction, or who receive a total dose of >30 g are particularly likely to develop cerebellar toxicity. The pathogenesis of this syndrome is unknown, but there is widespread loss of Purkinje cells in the cerebellum.
The characteristic syndrome begins with somnolence and occasionally an encephalopathy that develops two to five days after beginning treatment. Immediately thereafter, cerebellar signs are noted on physical examination. Symptoms range in severity from mild ataxia to an inability to sit or walk unassisted. Rarely, seizures develop.
No specific treatment or preventive measure is available, but cytarabine should be discontinued immediately. In some patients, the syndrome resolves spontaneously, but it is permanent in others . Avoidance of very high doses of the drug, especially in patients with renal impairment, has led to a decrease in the incidence of this syndrome .
High-dose cytarabine infrequently causes peripheral neuropathies resembling Guillain-Barré syndrome, brachial plexopathy, encephalopathy, lateral rectus palsy, optic neuropathy, or an extrapyramidal syndrome [222,225-231].
Intrathecal cytarabine — Intrathecal (IT) administration of cytarabine in patients with leptomeningeal metastases produces high drug levels in the cerebrospinal fluid (CSF) for at least 24 hours. Uncommonly, IT cytarabine can cause a transverse myelopathy that is similar to that seen with IT methotrexate (see 'Transverse myelopathy' above) . Rarely, it has been associated with aseptic meningitis, encephalopathy, headaches, and seizures . (See "Treatment of leptomeningeal disease from solid tumors".)
Fluorouracil — Fluorouracil (FU) is a fluorinated pyrimidine that impairs DNA synthesis by inhibiting thymidylate synthetase. It is a component of multi-drug treatment for many cancers, including colon and breast cancer.
An acute cerebellar syndrome occurs rarely in patients receiving FU [232,233]. The characteristic syndrome is an acute onset of ataxia, dysmetria, dysarthria, and nystagmus that develops weeks to months after beginning treatment. FU should be discontinued in any patient who develops cerebellar toxicity; with time, symptoms usually resolve completely. The development of a cerebellar syndrome may be partly explained by the fact that FU readily crosses the blood-brain barrier, and the highest concentrations are found in the cerebellum.
Multiple reports have described an encephalopathy with FU chemotherapy [234-237]. This has been associated with markedly elevated serum ammonia levels in the absence of decompensated liver disease. Factors that may contribute to this complication include renal dysfunction, weight loss, and constipation . Other rarer neurologic side effects include an optic neuropathy , eye movement abnormalities , focal dystonia , cerebrovascular disorders , a parkinsonian syndrome , peripheral neuropathy , or seizures . The FU derivatives doxifluridine, carmofur, and ftorafur (which is combined with uracil to slow degradation; the combination is called UFT) have also been reported to rarely cause encephalopathies and cerebellar syndromes [245-247].
Patients treated with fluoropyrimidines who lack the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD) are at increased risk for severe neurologic toxicity, including cerebellar toxicity . This is often (but not inevitably ) accompanied by severe diarrhea, mucositis, myelosuppression, and cardiotoxicity. In such cases, prompt administration of the specific antidote uridine triacetate may be lifesaving. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Risk with conventional cytotoxic agents' and "Management of acute chemotherapy-related diarrhea", section on 'Uridine triacetate' and "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management", section on 'Is there an antidote?'.)
Capecitabine — Capecitabine is an orally active fluorinated pyrimidine; it is metabolized to the active moiety, FU, by the enzyme thymidine phosphorylase. Neurologic complications are uncommon; fewer than 10 percent of treated patients experience paresthesias, headaches, dizziness, or insomnia. Like FU, cerebellar toxicity has also been reported .
In addition, a subacute encephalopathy, manifested by confusion, short-term memory loss, and white-matter changes on magnetic resonance imaging (MRI), has been described that develops shortly after starting capecitabine [251,252]. Symptoms resolved over several days following cessation of treatment.
Ifosfamide — Ifosfamide is an analog of cyclophosphamide; in general, its systemic toxicities are similar. However, unlike cyclophosphamide, approximately 10 to 30 percent of patients treated with ifosfamide develop an encephalopathy [253-256]. Patients at increased risk for this complication include those with a prior history of ifosfamide-related encephalopathy, renal dysfunction, low serum albumin, concomitant use of aprepitant as an antiemetic, or prior cisplatin treatment [253,254,257-261].
Symptoms begin hours or days after drug administration and usually resolve completely several days later. This encephalopathy is thought to result from accumulation of chloroacetaldehyde, one of the breakdown products of ifosfamide.
Other neurologic toxicities associated with ifosfamide are rare and are usually described in the context of encephalopathy. They include seizures, nonconvulsive (complex partial) status epilepticus , ataxia , weakness, cranial nerve dysfunction , neuropathies , or an extrapyramidal syndrome [265,266]. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis".)
A report of 400 patients treated with ifosfamide identified 52 with central nervous system (CNS) toxicity, of whom 11 developed an encephalopathy . Seven patients suffered movement disorders including postural tremor and myoclonus; four also had encephalopathy. Hemiballismic limb movements have also been reported .
●Prevention and treatment – Some reports suggest that dexmedetomidine (a sympathetic blocker), thiamine, or methylene blue (an inhibitor of monoamine oxidase) with or without thiamine may be useful for the treatment and/or prevention of ifosfamide encephalopathy [268-272]. However, other reports do not support benefit from methylene blue and thiamine , and the possibility of spontaneous resolution must be taken into account.
Joint guidelines from the European Society for Medical Oncology/European Oncology Nursing Society/European Association of Neuro-Oncology specifically recommend against the use of methylene blue and/or thiamine for the prevention or treatment of ifosfamide encephalopathy .
Nitrosoureas — The nitrosoureas (carmustine [BCNU], lomustine [CCNU], PCNU, and nimustine [ACNU]) are lipid-soluble alkylating agents that rapidly cross the blood-brain barrier; they are used to treat brain tumors, melanoma, and lymphomas. The nitrosoureas are associated with little neurotoxicity at conventional doses. By contrast, high-dose IV BCNU, as used in the setting of high-dose therapy with hematopoietic cell transplantation, can cause an encephalomyelopathy and seizures. Typically, these symptoms develop over a period of weeks to months following drug administration . (See "Preparative regimens for hematopoietic cell transplantation".)
Intra-arterial administration of BCNU produces ocular toxicity and neurotoxicity in 30 to 48 percent of patients [276-278]. Patients often complain of headache, eye, and facial pain, and retinopathy and blindness may occur. Other neurotoxic effects include confusion, seizures, and progressive neurologic deficits. Imaging and pathologic studies show similarities to radiation necrosis, confined to the vascular territory perfused by the BCNU [276,279]. Concurrent radiotherapy increases the neurotoxicity of intracarotid BCNU. Injection of the drug above the origin of the ophthalmic artery (supraophthalmic injection) reduces the incidence of ocular toxicity but increases other neurotoxicities.
Although generally well tolerated, the adjuvant use of Gliadel wafers (carmustine) has been associated with potentially fatal cerebral edema. In addition, the use of Gliadel wafers has been associated with infection and poor wound healing .
Procarbazine — Procarbazine is a weak monoamine oxidase inhibitor that probably acts as an alkylating agent. It is orally active and is used to treat Hodgkin lymphoma and brain tumors. At conventional doses (100 mg/m2 daily for 14 of every 28 days), procarbazine can cause a mild reversible encephalopathy and neuropathy, and rarely psychosis and stupor [1,137,281]. The incidence of encephalopathy may be higher in patients receiving higher doses of procarbazine in chemotherapy regimens for malignant gliomas . Procarbazine also potentiates the sedative effects of opiates, phenothiazines, and barbiturates.
RARE CAUSES OF NEUROTOXICITY
Anthracyclines — Apart from accidental intrathecal injection, which can cause myelopathy, encephalopathy and death, anthracyclines and their derivatives (doxorubicin, daunorubicin, mitoxantrone, epirubicin) cause little neurotoxicity . Patients who receive doxorubicin in combination with cyclosporine can develop a coma, which may be fatal . In addition, doxorubicin can cause arrhythmias and a dose-related cardiomyopathy, which in turn can result in cerebrovascular complications .
Busulfan — Busulfan is associated with little neurotoxicity at conventional doses, but high-dose therapy, commonly used in the setting of hematopoietic stem cell transplantation, can cause seizures (table 3) . (See "Preparative regimens for hematopoietic cell transplantation", section on 'Chemotherapy without RT'.)
Chlorambucil — Chlorambucil is an uncommon cause of neurotoxicity, but encephalopathy, myoclonus , and seizures have been reported with high doses, particularly in children with the nephrotic syndrome .
Etoposide — Etoposide (VP-16) is a topoisomerase II inhibitor that is used extensively in the treatment of lung cancer, germ cell tumors, and refractory lymphomas. Although neurotoxicity is uncommon, even in high doses, peripheral neuropathy (less than 2 percent), mild disorientation, seizures, transient cortical blindness, and optic neuritis have been reported .
Gemcitabine — Gemcitabine is a deoxycytidine analogue that is used for the treatment of pancreatic, bladder, and lung cancer. Up to 10 percent of patients experience mild paresthesias during treatment, although occasionally, more severe peripheral and autonomic neuropathies are described .
An acute, inflammatory myopathy has been reported following chemotherapy with gemcitabine and docetaxel, presenting as a symmetrical, painful, proximal muscle weakness . Gemcitabine has also been implicated in a painful, focal myositis when the drug is given during or after radiation therapy (radiation recall phenomenon) . Rarely, gemcitabine may cause acute confusion and seizures , and reversible posterior leukoencephalopathy .
Hydroxyurea — Hydroxyurea is used to treat chronic myeloid leukemia and head and neck cancers. It is also used for the treatment of sickle cell disease (to stimulate production of hemoglobin F) and polycythemia vera. Sedation is common with high doses, and rare adverse effects including headaches, hallucinations, confusion, and seizures may occur .
Irinotecan — Irinotecan (CPT-11) is a topoisomerase inhibitor that is useful in the treatment of colon cancer. Some patients experience transient visual disturbances and symptoms suggestive of cholinergic overactivity . Transient dysarthria, during or immediately after treatment, has also been described; the dysarthria can recur with subsequent irinotecan infusions .
Mechlorethamine — Mechlorethamine (nitrogen mustard) is an alkylating agent. Rarely, it causes somnolence, headaches, and weakness. At high doses such as those used in the past for high-dose therapy and hematopoietic cell transplantation, it has been reported to cause confusion and seizures .
Mitomycin — Mitomycin is an alkylating agent used to treat carcinomas of the gastrointestinal tract, breast cancer, and head and neck malignancies. Although it does not cause direct neurotoxicity, an associated encephalopathy may be caused by a thrombotic microangiopathy that resembles hemolytic uremic syndrome . (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)
Purine analogs — Fludarabine, an inhibitor of DNA polymerase and ribonucleotide reductase, is used to treat chronic lymphocytic leukemia (CLL) and indolent lymphomas. Neurotoxicity is uncommon, but fludarabine can cause headache, somnolence, confusion, and paresthesias at low doses [1,296]. A delayed progressive encephalopathy with seizures, cortical blindness, paralysis, and coma is more common at high doses; the incidence is 36 percent with doses >96 mg/m2 for five to seven days, compared with <0.2 percent for doses <125 mg/m2 per cycle. Rarely, progressive multifocal leukoencephalopathy has been reported . The onset of neurologic symptoms may be delayed for three to four weeks [296,298].
Cladribine (2-chlordeoxyadenosine), a related drug used for hairy cell leukemia, CLL, and Waldenstrom macroglobulinemia, is associated with little neurotoxicity at conventional doses but can produce a paraparesis or quadriplegia at high doses .
Pentostatin, an inhibitor of adenosine deaminase, is used for the treatment of a variety of leukemias, including hairy cell leukemia and cutaneous T-cell lymphomas. At low doses, lethargy and fatigue are common. Higher doses can cause a severe encephalopathy, seizures, and coma .
Retinoic acid — All-trans-retinoic acid, which is used to treat acute promyelocytic leukemia, can rarely cause pseudotumor cerebri  and multiple mononeuropathies . By contrast, headache and fatigue are common during treatment.
Temozolomide — Temozolomide is an alkylating agent used predominantly for treatment of malignant gliomas. Drug-induced headaches are experienced by 40 percent of patients, although serious neurologic complications are rare. As temozolomide is used mainly for malignant gliomas, many of the "toxicities" attributable to this drug may in fact be due to the underlying disease.
Thioguanine — Thioguanine is used to treat various leukemias. Rarely, it causes loss of vibratory sense and ataxia.
Thiotepa — Thiotepa is an alkylating agent occasionally used to treat leptomeningeal metastases and in high-dose regimens in the setting of hematopoietic cell transplantation (table 3). High intravenous doses of thiotepa can produce an encephalopathy that can be fatal . Rarely, intrathecal (IT) use of thiotepa has been associated with a myelopathy .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathic pain".)
●Etiology – Neurologic complications of anticancer therapy may result from direct toxic effects on the nervous system or indirectly from drug-induced metabolic derangements or cerebrovascular disorders (table 1). (See 'Introduction' above.)
●Risk factors – Risk factors that are best established for chemotherapy-induced peripheral neuropathy (CIPN)include the specific drug, dose, dose intensity, length of treatment, concurrent administration of other neurotoxic agents (especially platinum derivatives), age, and in the case of bortezomib, route of administration. (See 'Risk factors' above.)
In addition, emerging data have linked vitamin D deficiency with an elevated risk of paclitaxel-related sensory neuropathy. (See 'Clinical features, incidence, and risk factors' above.)
●Specific agents – Among the non-platinum chemotherapy agents, neurotoxicity is most frequently seen with the following drugs:
•Nelarabine (peripheral neuropathy that can mimic Guillain-Barré syndrome, with progressive, symmetric muscle weakness accompanied by absent or depressed deep tendon reflexes). (See 'Nelarabine' above.)
ACKNOWLEDGMENT — We are saddened by the death of Jay Loeffler, MD, who passed away in June 2023. UpToDate acknowledges Dr. Loeffler's past work as a section editor for this topic.
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