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Chemotherapy-induced neuropathy: A comprehensive survey

Cancer Treatment Reviews, 7, 40, pages 872 - 882

Abstract

Chemotherapy induced peripheral neuropathy (CIPN) is a potentially dose limiting side effect of commonly used chemotherapeutic agents like taxanes, vinca-alkaloids, platinum compounds, bortezomib and thalidomide.

Supposed pathogenetic mechanisms of CIPN are axonopathy through dying back axon damage and neuronopathy in which the cell bodies of the dorsal root ganglia are involved. The exact pathophysiology however is not clear and different underlying mechanisms have been proposed for different classes of anti-cancer drugs.

Sensory symptoms, like pain, numbness and tingling are most common, but motor weakness, autonomic dysfunction and even cranial nerve involvement may occur. CIPN can be painful and/or disabling, causing significant loss of functional abilities and decreasing quality of life. This can lead to dose reductions, discontinuation of treatment and may thus, ultimately, affect survival.

Risk factors for CIPN include dose per cycle, cumulative dose, treatment schedule, duration of infusion, administration of other chemotherapeutics, comorbidity and pre-existing peripheral neuropathy.

The exploration of polymorphisms in genes associated with incidence or severity of neuropathy might result in identifying individuals being at higher risk of neurotoxicity. An update on genes possibly associated with CIPN is given.

CIPN may be reversible or be more or less permanent. Many preventive and treatment strategies have been explored, without significant efficacy up till now.

In this review we describe the different drug-related characteristics of CIPN, pharmacogenomic studies, neurophysiological findings, treatment and outcome, and neuroprotective strategies.

Keywords: Neuropathy, Chemotherapy, CIPN, Neurotoxicity, Platinum-compounds, Taxanes, Vinca-alkaloids.

Introduction

Chemotherapy induced peripheral neuropathy (CIPN) is a common and potentially debilitating side-effect of cancer treatment. Because of better treatment options like new anti-emetics and hematopoietic colony stimulating factors for other serious side-effects CIPN becomes more often a dose limiting factor. Despite its clinical relevance and common occurrence, the pathophysiology of CIPN in the different groups of chemotherapy is still largely unknown. Mechanisms of CIPN are axonopathy through axon damage and neuronopathy in which the cell bodies of the dorsal root ganglia are involved. The primary axon damage starts at the most vulnerable part of the nerve, i.e. the end of the longest nerves, after which it spreads centrally (dying back neuropathy). The exact pathophysiology however is not elucidated and different underlying mechanisms have been proposed for the different classes of anti-cancer drugs.

Symptoms are predominantly sensory, like pain, numbness and tingling. Sometimes there are motor symptoms like weakness, autonomic neuropathy and incidentally cranial nerve involvement. CIPN can be painful and/or disabling, causing significant loss of functional abilities and decreasing quality of life. This can lead to dose reductions, discontinuation of treatment, and may thus, ultimately, affect overall survival. In routine practice CIPN is evaluated using clinical parameters. Usually objective assessment of neuropathic signs is performed with bedside clinical examinations, sometimes with additional electrophysiological studies. There are several scales to evaluate CIPN; commonly used are the common toxicity criteria of the national cancer institute (NCI-CTC) and the total neuropathy score (TNS). TNSc, mISS, NCI-CTC and the EORTC QLQ-C30 questionnaire with its CIPN20 module are the most reliable tools for accurately grading CIPN [1] .

Electromyography and nerve conduction studies have only limited usefulness in the clinical setting. Compared to clinical examination nerve conduction studies in patients treated with cisplatin showed no diagnostic advantage [2] . Semi-quantitative assessment of sensory threshold or of muscle strength has been advocated, but standardization of the instruments and of the methods have never been achieved.

In this review we summarize the characteristics and management of CIPN caused by different chemotherapeutic agents.

Taxanes

Taxanes include paclitaxel (Taxol) and docetaxel (Taxotere). These chemotherapeutic agents inhibit the disassembly of microtubules by binding to the beta-tubulin subunit in the microtubules. The principal function of microtubules is the formation of the mitotic spindle during cell division. Consequently, microtubules become extraordinarily stable and dysfunctional, leading to death of the cell by disrupting the normal tubule dynamics required for cell division and vital interphase processes [3] . Paclitaxel is used in the treatment of ovarian-, breast- and non small cell lung cancer. Docetaxel is used in the treatment of breast-, non small cell lung-, prostate-, gastric and head- and neck cancer. Main toxicities of these microtubule-stabilizing agents are haematologic toxicity, especially in docetaxel and peripheral neuropathy.

Pathogenesis of the neuropathy

The exact mechanism of taxane induced neuropathy is not elucidated. Axonal microtubules are important for the development and maintenance of neurons. Microtubule elongation contributes toward the growth and structure of neurites. They form the major participating elements mediating axonal anterograde and retrograde transport of for example neurofilaments, degradative organelles and endosomes containing signaling platforms [4] .

Neurotoxicity by taxanes may be caused by disruption of microtubule structure leading to impairment of axoplasmic transport and dying back neuropathy. In vitro studies demonstrated large abnormal microtubule arrays in spinal cord-sensory ganglia following exposure to paclitaxel [5] , and addition of paclitaxel to dorsal root ganglia cell cultures inhibited anterograde axonal transport [6] .

Another hypothesized mechanism is a toxic effect on mitochondria in primary afferent neurons leading to a deficit in axonal energy supply and chronic sensory neuropathy [7] . In the rat, paclitaxel neuropathy is associated with significant increase of swollen and vacuolated mitochondria in the axons [8] . Paclitaxel opens the mitochondrial permeability transition pore (mPTP), which is a multimolecular complex containing the voltage dependent anion channel. Paclitaxel evoked opening of the mPTP causes the calcium release from the mitochondria. This calcium mediated neuronal excitability is suggested to play a role in neurotoxicity [8] . Bennet et al. [9] described a deficient oxygen consumption in the dorsal root sensory axons from animals treated with paclitaxel, with increased amounts of ATP produced by both respiratory complex I and II. The above explained mechanisms involved in neuropathy may be interrelated.

Symptoms and risk factors

Paclitaxel induces a bilateral, distal, symmetrical axonal neuropathy that is predominantly characterized by sensory symptoms like numbness, tingling and burning pain in a stocking-and-glove distribution. There is often symmetrical loss of sensation carried by both large fibers (proprioception, vibration) and small ones (temperature, pinprick). Achilles tendon reflexes are low or absent. Motor and autonomic dysfunction are rare [10] . The incidence of taxane-induced neuropathy has been variously reported and depends on risk factors including dose per cycle, cumulative dose, treatment schedule, duration of infusion, concurrent administration of other neurotoxic drugs and comorbidity such as diabetes [5] and [11].

Neuropathic symptoms may begin 24–72 h after paclitaxel treatment with higher dose (250 mg/m2) but usually occur only after multiple courses at conventional dose (<200 mg/m2). Severe neurotoxicity precludes the administration of paclitaxel doses above 250 mg/m2[3], [11], and [12]. Grade 3 or 4 sensory neurotoxicity occurs in 20–35% of patients receiving 250 mg/m2 every three weeks compared to 5–12% in large series using doses ⩽200 mg/m2 every 3 weeks [11] . The weekly schedule is associated with increased neurotoxicity [12] . CTC grade 2/3 neurotoxicity occurs from a cumulative dose of about 1400–1500 mg/m2[3], [5], [10], and [13].

A higher rate of CIPN occurs when paclitaxel is infused over 3 h instead of 24 h, suggesting that neurotoxicity is related to peak plasma concentration [14] . Weekly administration (80 mg/m2) was associated with a higher incidence of grade 3/4 sensory neuropathy compared to 3 weekly administration (175 mg/m2) [15] . On the contrary, a more recent meta-analysis stated that in weekly paclitaxel regimens the incidence of grade 3/4 peripheral neuropathy was lower than in 3-week regimens [16] .

At high dose (>250 mg/m2) proximal weakness can develop with severe muscle aches, for which dose reduction is necessary [17] . Transient mild myalgias can occur at doses of >170 mg/m2, which start 2 or 3 days following treatment and resolve within 6 days [3] .

Symptoms of docetaxel induced neuropathy are similar but usually milder and disappear spontaneously after discontinuation probably because of lower dosing of docetaxel due to more profound hematological toxicity. In patients treated with docetaxel, grade 3/4 neuropathy occurs in 10% or less [11] , proportional to the cumulative dose. Hilkens reported severe docetaxel neuropathy following cumulative dosages over 600 mg/m2 in 4 out of 15 patients [18] . Docetaxel treatment has been associated with Lhermitte’s sign, a non-painful electric shock-like sensation that shoots down the spine during neck flexion, indicating involvement of the central dendrites of the dorsal root ganglia in the dorsal columns [19] .

Neurophysiological examination

In paclitaxel induced neuropathy, sensory nerve potentials (SNAPs) amplitudes are reduced or absent, in particular of the sural nerve. Compound muscle action potential amplitude can also be reduced. Nerve conduction velocities can be decreased [20] . Likewise, in docetaxel induced neuropathy, low amplitude sensory and motor potentials are measured but conduction velocities are generally normal [11] .

Genetic studies

The role of genetic markers to predict CIPN is investigated. Multiple single nucleotide polymorphisms (SNP’s) were evaluated in relation to neurotoxicity, and genome wide association studies as well as studies with selected target genes have been performed.

Polymorphisms in genes encoding paclitaxel metabolizing enzymes and transporters may contribute to interindividual toxicity and response.

Polymorphisms in the CYP 2C8 and CYP 3A5 genes encoding paclitaxel metabolizing enzymes were described to be associated with CIPN. A twofold risk of neuropathy in patients with the CYPC2C8∗3 variant was reported [21] and [22]. In addition, an association between polymorphisms in the ABCB1 gene, that encodes ATP binding cassette proteins, which transport various molecules across cellular membranes and CIPN was described [22] . Furthermore, a twofold increased risk of CIPN was described for FANCD2, that plays a role in DNA repair pathways [23] . However, data are inconclusive and should be replicated in larger studies.

Outcome

Mild symptoms usually improve with reduction of the dose, but paclitaxel induced neuropathic pain and sensory abnormalities may persist for months or years after paclitaxel therapy. After completing therapy, half of patients improve over a period of months [12] .

In a study on taxane-induced neuropathy 10 patients received paclitaxel (mean cumulative dose 597 ± 296 mg/m2,150 mg/m2 by cycle), 56 patients docetaxel (mean cumulative dose 400 ± 205 mg/m2, 75–100 mg/m2 by cycle) and 3 patients both (mean cumulative docetaxel dose 530 ± 319 mg/m2 and paclitaxel dose 962 ± 437 mg/m2). Sensory neuropathy occurred in 64% of patients and totally disappeared within months in only 14% of patients after cessation of treatment. However symptoms were then considered as minor by almost all patients, with no interference with daily life activities (grade 2). 3 patients experienced grade 3 neuropathy (2 received docetaxel, 1 paclitaxel) [24] .

Specific treatment

Symptomatic treatment of painful neuropathy includes various opioids, tricyclic antidepressants, anticonvulsants, serotonin–norepinephrine reuptake inhibitors (SSRI’s) and non-steroidal anti-inflammatory agents. Neuropathic pain is often treated with anti-epileptic agents but RCT’s of gabapentin (2700 mg/day) for CIPN, and of lamotrigine (300 mg/day) did not show efficacy [25] . Tricyclic antidepressiva, like amitriptyline and nortriptyline are often used for neuropathic pain and dysesthesias in CIPN. In a RCT of duloxetine, a SSRI, in patients with taxanes or oxaliplatin neuropathy moderate efficacy was observed (decrease of pain in 59% vs 38% for placebo) [26] .

Multiple strategies to prevent CIPN have been investigated, but without proven efficacy. Alternative dosing regimens and treatment modification (see above) may limit neurotoxicity. Acetyl-l carnitine is presumed to play a role in neural protection by acetylating intracellular tubulin, ensuring availability of acetylcoA in the mitochondria and enhancing availability of nerve growth factor. In a small non-randomized study oral ALC was shown to improve grade 2 or higher neuropathy caused by taxanes or cisplatin. Sensory neuropathy improved in 60% of patients, motor neuropathy in 79% [27] . However, in a recent RCT including 401 patients treated with taxanes, there was no evidence that ALC affected CIPN at 12 weeks and ALC even significantly increased CIPN by 24 weeks [28] . Therefore ALC should not be used in the prevention of chemotherapy induced neuropathy.

Amifostine, an anti-oxidant, gave some neuroprotection in a RCT including 187 patients [29] , however other studies demonstrated no efficacy [30] and [31].

In a phase II trial the anti-oxidant Vitamin E, seemed neuroprotective when given during treatment with paclitaxel (incidence of neurotoxicity 19% vs 63% for controls) [32] . However a large phase III trial [33] reported no difference in neuropathy.

Two pilot studies suggested a neuroprotective effect [34] and [35], but another study showed no difference [36] (see Table 1 ).

Table 1 Taxanes and characteristics of the induced neuropathy.

  Clinical manifestations Outcome Risk factors
  Sensory Motor Autonomic    
Paclitaxel (Taxol) Distal loss of sensation to all modalities Rare

At high dose >250 mg/m2 sometimes proximal weakness with pain
Rare Half of the patients improve over a period of months Onset dose > 250 mg/m2

Cumulative dose >1500 mg/m2

Infusion in 3 h (instead of 24 h)

Comorbidity causing neuropathy, like diabetes
 
Docetaxel (Taxotere) Mild distal loss of sensation to all modalities.

Lhermitte’s sign
Rare Rare Symptoms disappear spontaneously after discontinuation Onset dose 75–100 mg/m2

Cumulative dose >600 mg/m2

1 h infusion
  SNP Symptomatic treatment Specific treatment
Paclitaxel (Taxol) CYPC28

CYP3A5

ABCB1

FANCD2
Anticonvulsants (gabapentin or pregabalin)

Tricyclic antidepressants, serotonin–norepinephrine reuptake inhibitors

Opioids

Non-steroidal anti-inflammatory agents
Vitamin E

Amifostine

Glutamine

Not:Acetyl-l-carnitine
 
Docetaxel (Taxotere)   Idem  

Vinca-alkaloids

Antitubulin vinca alkaloids prevent tubulin polymerization from soluble dimers into microtubules. The affinity for tubulin differs among vinca-alkaloid compounds (decreasing in order vincristine, vinblastine, vinorelbine), which might explain the distinct neurotoxic profiles of these drugs [37] . Vincristine is the most neurotoxic one, vinblastine, and vinorelbine are less neurotoxic. Vincristine is used in the treatment of hematologic tumors and for pediatric sarcomas. Vincristine has low bone marrow suppressive effects and its use is limited by neurotoxicity. Vinblastine is used for Hodgkin lymphoma and testicular cancer, and vinorelbine, a semisynthetic analogue of vinblastine, for breast and non small cell lung cancer.

Pathogenesis of the neuropathy

Vinca alkaloids affect tubulin dimers and produce a loss of axonal microtubules and alterations in their length, arrangement and orientation. These alterations in the neuronal cytoskeleton lead to impaired axonal transport and axonal degeneration. Sensory fibers are effected earlier and more severe than motor fibers.

Symptoms and risk factors

Virtually all patients receiving vincristine develop some degree of neuropathy, a mixed sensorimotor neuropathy [38] . Early symptoms include numbness and tingling of hands and feet. Initially, objective sensory findings tend to be relatively minor compared to the subjective complaints, but loss of ankle jerks is an early finding [10] ; pain and temperature sensation are lost more often than vibration sensation. These symptoms often develop after several weeks of treatment, but sporadically occur after the first dose. Occasionally muscle pain in jaws and legs occurs acutely after injection of vincristine. Vincristine induced neuropathy is mainly cumulative and dose dependent [38] , with onset usually at a dose of 4–10 mg. Dose per gift is 1.6 mg/m2 but should not exceed 2 mg, and the interval between gifts must be at least 1 week. Severe neuropathy occurs at cumulative doses of 15–20 mg and may lead to muscle weakness, especially in hands and feet [39] . More than a third of patients develop autonomic neuropathy, characterized by orthostatic hypotension, constipation, paralytic ileus, bladder dysfunction and impotence [10] . After discontinuation of vincristine symptoms sometimes worsen for a few months before improving [40] , a phenomenon called coasting.

Severe painful neuropathy was reported with concomitant use of hematopoietic colony-stimulating factors [41] . Exacerbation of neuropathy occurs in patients with preexisting neuropathy (diabetic, Charcot–Marie Tooth disease) [39] .

Vincristine may also cause mononeuropathies, sometimes involving the cranial nerves. The oculomotor nerve is most commonly involved. Other mononeuropathies include the recurrent laryngeal nerve, optic nerve, trigeminal nerve, facial nerve, auditory nerve, glossopharyngeal nerve, tibial nerve and peroneal nerve.

Vinblastine rarely causes some sensory neuropathy, and vinorelbine is associated with mild paresthesias in only 20% of patients; severe neuropathy is rare, occurring mostly after prior paclitaxel exposure [42] .

Neurophysiological examination

Nerve conduction studies show prolonged mean distal latencies, decreased amplitudes of compound muscle action potentials (CMAPs) and sensory action potentials (SNAPs), with almost unchanged conduction velocities. H-reflex can be absent. Electromyography can show denervation [43] and [44].

Genetic studies

An association was reported between vincristine neuropathy and polymorphisms in genes involved in absorption, distribution, metabolism and excretion, like DPYD and ABCC1 [45] and CYP2C9, CYP2C8. Also described are ADRB2, NFATC2, ID3, SLC10A2 and CAMKK1 (expressed in neurons resistant to oxidative stress) [46] . However these findings should be confirmed in larger data sets.

Outcome

Vincristine neuropathy is frequently dose limiting and sometimes worsens for a few months after discontinuation (“coasting”) [40] . However, vincristine neuropathy has a fairly good prognosis on the long term; it is usually reversible. Recovery can last for many months [10] . Vinorelbine neuropathy usually recovers after discontinuation.

Specific treatment

Glutamine or pyridoxine plus pyridostigmine might be of some benefit [47] , but efficacy has not been proven for any intervention in a randomized trial. Painful neuropathy can be treated with opioids, tricyclic antidepressivants or anticonvulsatives. Patients with mild neuropathy can usually continue to receive full doses of vincristine, but at interference with neurologic function, dose reduction or discontinuation may be necessary [48] (see Table 2 ).

Table 2 Vinca-alkaloids and characteristics of the induced neuropathy.

  Clinical manifestations Outcome Risk factors
  Sensory Motor Autonomic    
Vincristine Distal paresthesias and dysesthesias

Can also cause focal neuropathies, including cranial nerves
When severe, muscle weakness can appear, especially in the distal muscles of the hand and feet More than a third of patients develop signs of autonomic nervous system dysfunction (orthostatic hypotension constipation, paralytic ileus, bladder dysfunction, impotence) Usually reversible after discontinuation.

Symptoms may worsen or appear after the drug has been discontinued and progress for several months before improving in 30% of patients
Onset dose 4–10 mg/m2

Cumulative dose 15–20 mg/m2

Charcot Marie Tooth syndrome

Concomitant hematopoietic colony-stimulating factors
 
Vinorelbine Mild paresthesias, severe neuropathy is rare     Reversible after discontinuation  
  SNP Symptomatic treatment Specific treatment
Vincristine ADRB2

CAMKK1

CYP2C9

NFATC2

ID3

SLC10A2

CYP2C8
Anticonvulsants (gabapentin or pregabalin)

Opioids

Tricyclic antidepressants serotonin–norepinephrine reuptake inhibitors

Non-steroidal anti-inflammatory agents
Glutamine

Pyridoxine plus pyridostigmine
 
Vinorelbine   Idem  

Ixabepilone

Epothilones constitute a novel class of microtubule targeting agents. Ixabepilone is an epothilone derivate and a macrolide antibiotic. It is used in the treatment of breast cancer. Similar to the taxanes, ixabepilone binds to tubulin and enhances microtubule stability, inducing G2–M cell-cycle arrest and apoptosis. However, ixabepilone has a distinct tubulin binding site and therefore has activity in taxane-resistant disease. Main toxicities are neuropathy and neutropenia.

Pathogenesis of the neuropathy

The mechanism of epothilone neuropathy is unclear but probably, alike taxane neuropathy disruption of microtubule structure interferes with axonal transport.

Symptoms and risk factors

Ixabepilone neuropathy is primarily sensory and is characterized by (painful) paresthesias and burning sensation in hands and feet. Motor or autonomic involvement is rare [10] and [49]. Neuropathy appears early during treatment (75% of new-onset or worsening neuropathy occurs during the first 3 cycles of treatment). The ixabepilone dose of onset for neuropathy of any grade ranges from 40–120 mg/m2. With an ixabepilone dosage of 40 mg/m2 the incidence of neuropathy (any grade) ranged from 20% in treatment naïve breast cancer to 63% in taxane resistant metastatic breast cancer. The incidence of grade 3/4 neuropathy increased from 12% at a cumulative dose of 120 mg/m2 to 23% at 206 mg/m2[50] and [51].

Outcome

In several studies up to one-quarter of patients discontinued the drug because of neuropathy. Fortunately, symptoms typically improve substantially within 1–2 months of discontinuation or even with dose reduction [50] and [51]. It is recommended to decrease the ixabepilone dose at sensory neuropathy grade 2 and withhold it at grade 3 neuropathy [50] .

Platinum derivatives

Cisplatin was the first member of a class of platinum-containing anti-cancer drugs, which now also includes carboplatin and oxaliplatin. These compounds contain platinum complexes that inhibit DNA synthesis by forming cross linking of DNA molecules. Cisplatin is used to treat lung, ovary, bladder, head and neck, cervical and testicular cancer. Main toxicities of cisplatin are nephrotoxicity, severe nausea, vomiting, neuropathy and ototoxicity. Peripheral neurotoxicity is the most common dose-limiting factor [52] .

Carboplatin is a second generation platinum drug and is used for lung and ovary cancer. Hematologic toxicity is dose-limiting for carboplatin [53] . Carboplatin is clearly less neurotoxic than cisplatin and relatively free from peripheral neurotoxicity [52] and [53].

Oxaliplatin is a third generation platinum compound used for colorectal cancer. Oxaliplatin frequently causes neutropenia, but sensory neuropathy is often dose-limiting [52] .

Pathogenesis of the neuropathy

The dorsal root ganglion appears to be the primary site of neural damage. For cisplatin, post mortem studies showed that platinum was retained in the dorsal root ganglion cells with reduction in nuclear size [54] and [55].

In experimental studies chronic cisplatin administration caused severe damage of the spinal dorsal root ganglia. Changes also occurred in the sciatic and peroneal nerves with the features of axonopathy [56] . In cultured rat embryo dorsal root ganglion models, [57] , cisplatin reproducibly inhibited axonal growth in a dose-dependent manner in concentrations similar to those known to produce toxicity in man.

Oxaliplatin causes two clinical types of neuropathy; an acute and reversible neuropathy and a chronic type. It is supposed that the acute neuropathy is caused by transient activation of the voltage-gated sodium channels of the peripheral nerves as a result of chelation of calcium by oxaliplatin, causing hyperexcitability of the peripheral nerve membrane [58], [59], and [60].

There are multiple hypothesized mechanisms for the pathophysiology of chronic oxaliplatin neuropathy; experimental studies show accumulation of platinum compounds in the cell body of the dorsal root ganglia alike cisplatin gangliopathy [59] and [61] resulting in decreased cellular metabolism and axoplasmic transport. Besides, repeated episodes of acute hyperexcitability might eventually lead to structural damage of the neurons [60] .

In rats, oxaliplatin caused loss of intraepidermal nerve fibers in the plantar hind paw skin. Furthermore, oxaliplatin caused a significant increase in swollen and vacuolated mitochondria in peripheral nerve axons, but not in their Schwann cells. Mitochondrial toxicity with subsequent energy deficiency may play a role in neurotoxicity [7] and [9].

Symptoms and risk factors

Cisplatin produces an axonal neuropathy that predominantly affects large myelinated sensory fibers (neuronopathy) [62] . Symptoms include unpleasant distal paresthesias, numbness and occasionally pain. Lhermitte’s sign (an electric shock-like sensation on bending the neck) caused by involvement of the central dendrites of the dorsal root ganglion cells in the posterior columns may occur [63] . On examination there is large fibre sensory impairment (reduced vibration and joint position sensations) and above a cumulative dose of 300 mg/m2 diminished or absent distal tendon reflexes [64] and [65]. Sensory ataxia develops in patients who have severe neuropathy. Small fiber sensation is spared or mildly diminished (decreased pain and temperature sensation). Strength is generally normal [63] . Symptoms begin in toes and fingers, spreading proximally.

Cisplatin neuropathy may present or increase after discontinuation of the drug (coasting) [66] and [67]. Worsening of neuropathy may last 3–6 months after discontinuation of cisplatin administration. Most patients completing a full course of cisplatin chemotherapy (usual cumulative dose 300–450 mg/m2) develop symptomatic sensory neuropathy [63] . High cisplatin dose intensity does not enhance the severity of the neuropathy [68] . Cisplatin neuropathy usually becomes evident at a cumulative dose of 300 mg/m2[63] and [64], but occasionally patients, especially those with combination neurotoxic chemotherapy may develop symptoms after lower cumulative doses [57] and [64]. From a cumulative dose of 600 mg/m2 a debilitating sensory ataxia develops [69] .

Neurotoxicity from carboplatin administration is less frequent (4–6%) and is typically less severe. Risk of carboplatin sensory neuropathy increased in patients older than 65 years and in patients previously treated with other neurotoxic agents [52] . However, outcome of cisplatin neuropathy appeared not influenced by subsequent treatment with carboplatin (Boogerd, unpublished data).

Acute oxaliplatin neuropathy can appear during, or shortly after the first few infusions and occurs in nearly all patients. Symptoms are often induced by cold and include paresthesias in hands and feet and the perioral region. It can be accompanied by muscle cramps, jaw tightness and fasciculations. This usually lasts less than 7 days. [59], [60], and [70].

Chronic oxaliplatin neuropathy is comparable to that observed with cisplatin i.e. a symmetric, distal, axonal sensory neuropathy. There is usually no motor involvement. Lhermitte’s sign may also occur. Grade ⩾2 neuropathy occurs in 40–50% of patients receiving standard treatment regimens of oxaliplatin, with grade ⩾3 neuropathy in 10–20% of patients [59] and [60].

After a cumulative dose of 750–850 mg/m2 82–93% of patients experience symptoms of neuropathy including 12–34% with grade 3/4 neuropathy [70] and [71].

Neurophysiological examination

Nerve conduction studies in cisplatin neuropathy show prolonged distal sensory latencies [64] , reduction of SNAP amplitudes and little or no change in motor nerve conduction or needle electromyography. Reduction of the SNAP amplitude occurs early in the course of cisplatin neuropathy, often before clinical signs or symptoms of sensory neuropathy [63] .

Sensory nerve conduction velocities are reduced by 10–15% at cumulative doses of 450–700 mg/m2, consistent with loss of large myelinated fibers [65] . SEP’s of the tibial nerve showed slowing of central conduction velocity at cumulative doses of 200–400 mg/m2 [2] .

Electromyography after oxaliplatin infusion reveals spontaneous high frequency bursts of muscle fiber action potentials. During voluntary contraction a repetitive discharge of motor units is evident, characteristic of excessive nerve excitability. Reduction in SNAP amplitudes, in combination with clinical assessment of acute neuropathic symptoms predicted the development of severe oxaliplatin neuropathy with high accuracy [72] . In chronic oxaliplatin neuropathy findings are alike changes in cisplatin neuropathy.

Genetic studies

Multiple polymorphisms in genes have been suggested to be associated with a higher risk of developing a neuropathy following treatment with a platinum compound.

In a recent review Cavaletti et al. [22] summarized the most important genes that are investigated. Gene targets were identified in genome wide association studies or on the basis of mechanistic hypotheses relevant mainly to cancer cells.

Many studies were focused on the GSTP1 gene, coding gluthatione S-transferase, supposed to play a role in detoxification [22] and [73]. The GSTP1 Ile105Val SNP has been studied for its relation to peripheral neuropathy and platinum drugs but with conflicting results [22] and [73], Other genes that have been related to neuropathy are GSTM1 and GSTM3 genes, encoding a subclass of glutathione S-transferase; ITGB3, coding for integrin B3, involved in cell adhesion and cell-surface-mediated signaling; AGXT, coding for alanine glyoxylate aminotransferase that prevents accumulation of glyoxylate in the cytosol; and ERCC involved in DNA repair [22] .

Although pharmacogenetic profiling may hold some promise for identifying patients at a greater risk for severe neurotoxicity, the data so far are insufficient to draw conclusions and to justify routine genetic testing.

Outcome

Even if cisplatin is discontinued neuropathy continues to worsen for several months in 30% of patients (coasting). Neuropathy may even begin after therapy is discontinued. It eventually improves in most patients, although recovery can take more than a year and is usually incomplete [63] and [74].

Chronic oxaliplatin neuropathy is less well characterised. It has been stated that recovery from oxaliplatin neuropathy is faster and more complete than recovery from cisplatin neuropathy. In many cases however, often in the face of responding disease, neuropathy forces discontinuation of oxaliplatin. In the MOSAIC trial, 1123 patients with colon cancer were treated with oxaliplatin (85 mg/m2 every other week for 24 weeks) and peripheral neuropathy developed in 92% of patients, including grade 2 in 31.6% and grade 3 in 12.4%. One month after treatment 15.9% of patients had neuropathy grade 2 and 5.0% grade 3, and 12 months after treatment 4.8% grade 2 and 1.1% grade 3 [75] . In another trial with oxaliplatin 85 mg/m2 as a 2-h infusion with a median of 12 cycles, sensory neurotoxicity was observed in 68% of the patients and reached grade 3 in 18%. Cold-related dysesthesia was reported in 67.5% and pharyngolaryngeal dysesthesia in 22.5%; 1% had a laryngospasm like syndrome. Cramps were present in 5.7% and Lhermitte’s sign in 3.3%. Reversibility of grade 3 neuropathy was observed in 25 (74%) of 34 patients with median time to improvement of 13 weeks [76] .

Specific treatment

Once established, there is no effective treatment. Patients with mild neuropathy can continue to receive full cisplatin doses, but physicians should be aware of coasting. Alternative strategies include dose reduction or replacement of cisplatin with a less neurotoxic agent such as carboplatin.

In some patients with platinum-induced neuropathy, pain is a prominent symptom. Neuropathic pain is usually treated with anti-epileptic agents or with antidepressiva. A study with cisplatin neuropathy, however was unable to demonstrate significant improvement for nortriptyline (maximum dose 100 mg/day) compared to placebo [77] . However, the SSRI venlafaxine (50 mg prior to oxaliplatin infusion and 37.5 mg b.i.d. from day 2 to day 11) was investigated in preventing oxaliplatin induced neuropathy and showed less acute neurotoxicity (31% vs 5%) and less grade 3 toxicity after 3 months (0% vs 33%) [78] . Duloxetine (30 mg bid for 5 weeks during oxaliplatin treatment), an other SSRI, showed a moderate but significant relief of pain (59% vs 38%) [26] .

Attempts to modulate cisplatin dose schedules did not influence the intensity of neurotoxicity [68] . Although the precise mechanism of cisplatin-induced neurotoxicity is unknown, various potentially chemoprotective agents were investigated including vitamin E, amifostine, acetyl-l-carnitine, glutathione, the ACTH analog Org 2766 and diethyldithiocarbamate. A Cochrane Database review [63] concluded that there are no agents that prevent or limit neurotoxicity of platinum drugs in man. The review did not include the use of intravenous calcium and magnesium for oxaliplatin-induced sensory neuropathy.

Multiple approaches were used to minimize oxaliplatin neuropathy. These include interrupting and reintroducing oxaliplatin therapy, lengthening duration of infusion, and various pharmacologic agents. A small RCT suggested that oxcarbazepine may protect against oxaliplatin neuropathy [93] .

Several trials evaluated the stop-and-go strategy. In the OPTIMOX1 trial, half of the patients temporarily stopped oxaliplatin after 6 cycles. No significant difference was found in grade 3 neurotoxicity (13% in intermittent FOLFOX-7 vs 18% in FOLFOX4) [79] . In the CONCEPT trial (FOLFOX 7 and bevacizumab in both arms) grade 3 neurotoxicity was significantly reduced in the intermittent oxaliplatin arm versus the continuous arm (8% vs 22%) [59] .

In the COIN trial (oxaliplatin with or without cetuximab) grade 3 or worse neuropathy was more frequent on continuous than on intermittent treatment (27% vs 5%). Intermittent chemotherapy had no influence on survival [80] .

So, stop-and-go oxaliplatin use is as efficacious as continuous oxaliplatin (with 5FU/LV or bevacizumab as maintenance) and possibly results in reduced neurotoxicity. Timing for reintroduction of oxaliplatin is uncertain and the optimum oxaliplatin-based regimen is unknown [59] .

Calcium and magnesium infusions are used for acute oxaliplatin neuropathy, but have also been suggested as prophylactic therapy for chronic oxaliplatin neuropathy. It is supposed that they decrease oxaliplatin induced hyperexcitability of peripheral neurons [60] and [81].

In a retrospective study of patients treated with oxaliplatin (85, 100 or 130 mg/m2) patients receiving calcium (1 g) and magnesium (1 g) infusions before and after oxaliplatin had less frequent and severe acute symptoms, and pseudolaryngospasm did not occur. The percentage of patients with grade 3 neuropathy was lower in Ca/Mg group (7% vs 26%) and only 4% of patients withdrew because of neurotoxicity versus 31% in the control group. The tumor response was similar in both groups [82] .

Patients from the CONcePT trial received placebo or Calcium and Magnesium before and after oxaliplatin treatment. Because of a suggested decreased tumor response in the Ca/Mg arm, this trial was prematurely closed. However subsequent analysis demonstrated no significant difference in response. Ca/Mg infusions did not induce significant reduction in grade ⩾3 late neuropathy neither in the continuous oxaliplatin arm (23% vs 24%) nor in the intermittent arm (11% vs 8%) [111] . Review of the effect of Ca/Mg infusions on neuropathy from the CAIRO study also reported no reduction of neuropathy [81] .

In contrast, a RCT of continuous FOLFOX with or without Ca/Mg reported significant lower grade ⩾2 neuropathy in the Ca/Mg arm (22% vs 41%). For acute oxaliplatin neuropathy Ca/Mg did not decrease cold sensitivity toxicity but reduced muscle cramping [60] .

Although still controversial, calcium and magnesium infusions are often recommended for the management of acute oxaliplatin neuropathy [70] (see Table 3 ).

Table 3 Platinum compounds and characteristics of the induced neuropathy.

  Clinical manifestations Outcome Risk factors
  Sensory Motor Autonomic    
Cisplatin Distal paresthesias, numbness and sometimes pain. Reduced vibration and joint position sensations

Lhermitte
None Rare Worsen for several (3–6) months after discontinuation in 30% of patients

Eventually improves, but can take more than a year and is often incomplete
Cumulative dose >300 mg/m2
 
Oxaliplatin (acute) Cold induced paresthesias/dysesthesias distal extremities and perioral Cramps, jaw tightness None Lasts less than 7 days Any
 
Oxaliplatin (chronisch) Symmetrical distal loss of sensation and dysesthesias Rare Rare Improves gradually Cumulative dose > 750–850 mg/m2
 
Carboplatin          
  SNP Symptomatic treatment Specific treatment
Cisplatin GSTP1

GSTM1

GSTM3

ITGB3

AGXT

ERCC
Anticonvulsants (gabapentin or pregabalin)

Opioids

Tricyclic antidepressants serotonin–norepinephrine reuptake inhibitors

Non-steroidal anti-inflammatory agents
 
 
Oxaliplatin (acute)   Idem Ca/Mg infusions
 
Oxaliplatin (chronisch)     Stop-and-go strategy

Ca/Mg infusions may be preventive
 
Carboplatin      

Bortezomib

Bortezomib is a proteasome inhibitor blocking the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. It is used in the treatment of myeloma. Peripheral neuropathy is the main dose-limiting toxicity associated with bortezomib therapy [45] .

Pathogenesis of the neuropathy

The mechanism of bortezomib-associated peripheral neuropathy is unknown. Dorsal root ganglia neuronal cell bodies seem the primary target of proteasome inhibition, with peripheral nerve degeneration occurring later. Experimental studies reveal that proteasome inhibition results in accumulation of cytoplasmic aggregates, including neurofilaments, in neuronal cells [49] and [83].

Dysregulation of mitochondrial calcium homoeostasis [84] , autoimmune factors and inflammation [85] , and blockade of nerve-growth-factor-mediated neuronal survival through inhibition of nuclear factor κB (NFκB) [86] might contribute to bortezomib-induced neuropathy.

Notably, baseline neuropathy is present in 15–20% of patients with newly diagnosed myeloma, which might be of both axonal and demyelinating subtypes [45] .

Symptoms and risk factors

Bortezomib induced neuropathy is a small fiber, axonal neuropathy with sensory loss or paresthesias affecting feet and hands. Neuropathic pain is de predominant feature [49] and [87]. Sensory examination can show distal loss of sensation to pain and temperature. Vibration sense and ankle jerks are often preserved unless the neuropathy is severe. Muscle weakness is uncommon. Approximately 10% of patients develop autonomic dysfunction.

Grade 1 and 2 bortezomib peripheral neuropathy occurs in 25–33% of patients with newly diagnosed multiple myeloma and in 27–75% with recurrent multiple myeloma. Grade 3 and 4 neuropathy might affect up to 18% of patients with newly diagnosed disease and 30% with recurrent disease [45] and [88]. In a phase III trial comparing bortezomib with dexamethasone in relapsed multiple myeloma [86] and [89] 37% of patients developed peripheral neuropathy, including 9% with grade 3 neuropathy; 2% had motor involvement. Peripheral neuropathy generally occurred at the fifth cycle of bortezomib, at a cumulative dose of approximately 26 mg/m2. Neuropathy symptoms plateaued at the eighth cycle (cumulative dose approximately 42 mg/m2).

Baseline neuropathy and comorbidities that evoke peripheral nerve damage, like diabetes, may potentiate bortezomib neuropathy [86] and [88].

Furthermore, in a randomized phase 3, non-inferiority study, subcutaneous administration of bortezomib was associated with a decrease in neurotoxicity. Peripheral neuropathy of any grade (38% vs 53%), grade 2 or worse (24% vs 41%) and grade 3 or worse (6% vs 16%) was significantly less common with subcutaneous than with intravenous administration [90] .

Neurophysiological examination

Nerve conduction studies reveal low amplitude of sensory action potentials (SNAP), and loss of H-reflexes. Amplitude of compound muscle action potential can be reduced. Mild distal slowing of sensory and motor conduction velocities may also occur. Electromyography may show active denervation in distal muscles of the lower limbs [57], [87], and [88].

SNP’S

An association was reported between bortezomib neuropathy and SNP’s in SOD2 and MYO5A genes, involved in development and function of the nervous system, in inflammatory genes MBL2 and PPARD and DNA repair genes ERCC4 and ERCC3 [45] .

Outcome

Following dose reduction or drug discontinuation, neuropathy is reversible in the majority of patients (64–85%), resolving within 3–4 months [49], [86], and [87].

Treatment

There is no effective prophylactic therapy against bortezomib neuropathy and treatment is merely symptomatic.

A once weekly schedule with dose reductions, instead of a standard twice weekly schedule, reduces bortezomib neurotoxicity. Subanalysis of a phase III trial showed that schedule and dose modification improved peripheral neuropathy without affecting anti-tumor effect [91] . Among 91 patients with ⩾grade 2 neuropathy 58 (64%) experienced improvement or resolution at a median of 110 days.

Thalidomide and lenalidomide

Thalidomide is a glutamic acid derivative that induces production of interferon-γ and interleukin 2, inhibits tumor necrosis factor-α production and angiogenesis. It is used in the treatment of multiple myeloma.

Lenalidomide is a thalidomide analog, used for multiple myeloma and myelodysplastic syndrome. It carries a higher risk of myelosuppression than thalidomide, but peripheral neuropathy is exceptional and mild [92] .

Pathogenesis of the neuropathy

Peripheral neuropathy is the principal neurotoxic effect of thalidomide. The exact anti-cancer and neurotoxicity mechanisms of thalidomide are not known. Immunomodulation plays a role [93] .

Symptoms and risk factors

The neuropathy is mostly sensory; motor involvement is distinctly uncommon. The classic presentation is numbness and paresthesias in hands and feet, and tingling at tapping the fingertips. At examination there is diminution of light touch and pinprick in these areas but slight impairment of vibratory sensation and deep tendon reflexes. Autonomic neuropathy manifesting as constipation affects 80–90% of patients (grade 3 or more in 16%) [94] . Pain is rarely a prominent symptom [49] and [93]. Several prospective studies have explored risk factors for thalidomide neuropathy, including age, daily dose, duration of drug exposure, cumulative dose, and preexisting neuropathy [95] .

At low dosages of 25–50 mg daily, half of patients developed detectable sensory neuropathy by 14 months [96] . With doses from 200 to 400 mg daily, the incidence of neuropathy was 83% after 1 year [97] .

From a cumulative dose above 15–20 g symptoms of neuropathy may develop. Paresthesias are initially usually mild and become more severe above 100 g [49], [95], and [97]. Lenalidomide rarely causes peripheral neuropathy [98] . Some trials combined thalidomide, bortezomib and dexamethasone (sometimes with melphalan as well) in myeloma. Unsurprisingly, the maximum tolerated doses of thalidomide combined with bortezomib are significantly lower than single-agent doses, with peripheral neuropathy as a key dose-limiting toxicity [99] .

Neurophysiological examination

Nerve conduction studies demonstrate reduced SNAP amplitudes with relatively preserved conduction velocities, in keeping with a sensory axonal neuropathy [95] .

Genetic studies

Thalidomide neuropathy has been associated with genes governing repair mechanisms and inflammation in the peripheral nervous system like ABCA1, ICAM1, PPARD, SERPINB2 and SLC12A6 [46] .

Outcome

Thalidomide neuropathy is usually reversible with dose reductions or cessation of therapy [95] and [100]. However, after drug discontinuation neuropathy sometimes worsens for several months, and recovery can be slow and incomplete [49] .

Specific treatment

The general recommendation is to discontinue the drug when more severe neuropathy develops. However, the risks of serious neuropathy need to be balanced with the risk of discontinuing effective therapy for a fatal disease. Therefore, when no satisfactory alternatives exist in a patient with grade 2 or 3 neuropathy, it is reasonable to withhold thalidomide, wait until neuropathy decreases to grade 1, and then reduce the dose.

Other agents

Eribulin

Eribulin mesilate is a non-taxane inhibitor of microtubule dynamics. Eribulin inhibits the microtubule growth phase without affecting the shortening phase and causing tubulin sequestration into non-productive aggregates [101] .

Eribulin is a new drug for breast cancer. In a recent RCT peripheral neuropathy developed in 35% of the 508 patients who were randomly assigned to eribulin; it was severe (grade 3/4) in 8%. Peripheral neuropathy was the most common adverse event leading to discontinuation from eribulin, occurring in 5% of the patients. In patients with grade 3/4 neuropathy who continued treatment, neuropathy improved to grade 2 or lower in later cycles after delays and dose reductions. The incidence of grade 3/4 neuropathy was similar in patients with pre-existing grade 1 or 2 neuropathy (13%) as in those without pre-existing neuropathy (8%) [101] .

Nelarabine

Nelarabine is a prodrug of ara-C and toxic to T-lymphoblasts. It is used for T-cell leukemia and lymphoma and has prominent neurotoxicity. The mechanism of neurotoxicity is unknown. Phase II studies showed that 40% of patients suffered neurotoxicity (including neuropathy, tremors, weakness, and seizures), with 20% of patients experiencing grade 3 or 4 toxicity [102] and [103]. A poorly characterized peripheral neuropathy with leg weakness and paresthesias is common in patients being treated with nelarabine; on rare occasions these effects are severe and mimic Guillain–Barré syndrome. Cumulative nelarabine dose is related to neuropathy [49] and [102]. As nelarabine has not been studied extensively, an accurate appraisal of the risk and reversibility of neurotoxicity, and the role of total drug dose, await further studies.

Cytarabine

Cytarabine (cytosine arabinoside, Ara-C) 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. Immunosuppression could trigger an immune-mediated neuropathy. A direct neurotoxic effect on Schwann cells has also been postulated. High-dose cytarabine infrequently (1%) causes demyelinating peripheral neuropathy resembling Guillain–Barré syndrome and produces severe motor disability. Furthermore, cytarabine can cause brachial plexopathy or optic neuropathy [104] .

Procarbazine

Procarbazine is an alkylating agent. It is used to for Hodgkin lymphoma and primary brain tumors. At conventional doses (100 mg/m2 daily for 14 of every 28 days) procarbazine can cause a mild reversible neuropathy [105] .

Etoposide

Etoposide is a topoisomerase II inhibitor that is used extensively for lung cancer, germ cell tumors, and refractory lymphomas. Although neurotoxicity is uncommon, in high doses, peripheral neuropathy (less than 2%) has been reported [110] .

Capecitabine and 5-fluorouracil

5-FU and capecitabine, a pro-drug of 5-FU are used in colorectal cancer. Hand-foot syndrome is a common side-effect of capecitabine and is associated with pain, paresthesias and temperature intolerance. Peripheral neuropathy associated with capecitabine has seldomly been reported [106] and [107]. The etiology of neurotoxicity remains unclear; however, as capecitabine is rapidly metabolized to 5-FU in patients with normal liver function, it is likely that 5-FU or its active metabolites (fluoro-beta-alanine) are contributing factors [107] . Neuropathy of 5-FU has also rarely been reported and occurs most often with intermittent high dose 5-FU as bolus injection or 24- to 48-h infusions [108] and [109]. Discontinuation of 5-FU therapy results in gradual resolution of neuropathy [108] and [109] (see Table 4 ).

Table 4 Other chemotherapeutic compounds and characteristics of the induced neuropathy.

  Clinical manifestations Outcome Risk factors
  Sensory Motor Autonomic    
Bortezomib Neuropathic pain

Distal sensory loss and paresthesias. Loss of sensation to pain and temperature.
Uncommon In 10% Reversible in the majority of patients (64–85%), resolving within 3–4 months Cumulative dose 26 mg/m2

Iv administration compared to sc
Thalidomide Distal paresthesias   In 80–90% Usually reversible with dose reductions or cessation of therapy. However, after drug discontinuation, neuropathy can worsen for several months, and recovery can be slow and incomplete Onset dose 25–50 mg/m2

Cumulative dose 15–20 gr
Lenalidomide
Ixabepilone Primarily sensory; (painful) paresthesias and burning of the hands and feet Rare Rare Symptoms typically improve substantially within 1–2 months of discontinuation or even with dose reduction Onset dose 40 mg/m2

Cumulative dose 120–260 mg/m2

single dose (40–50 mg/m2) every 21-day administration schedule
Eribulin          
Nelarabine          
Cytarabine          
Procarbazine          
Etoposide          

Conclusion

Many chemotherapeutic drugs, extensively used to treat common malignancies including lung-, breast-, colorectal- and ovarian cancer can cause peripheral neuropathy that may limit the use of higher effective doses of the drug. Chemotherapy induced peripheral neuropathy (CIPN) affects the quality of life in the early stage of treatment, but with increasing survival also results in more long lasting morbidity. There is yet no established effective treatment for CIPN, so knowledge of preventive measures and recognition of imminent serious neurotoxicity are critical. Better insight in the different mechanisms of CIPN including the relationship with genetic polymorphisms will help to develop neuroprotective drugs and to refine cytostatic treatment in the individual cancer patient.

Conflict of interest

All authors are aware of and agree to the submission of this article and they have both contributed to the work described sufficiently to be named as authors. There are no competing financial interests or other conflicts of interest.

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Footnotes

Department of Neuro-oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands

lowast Corresponding author. Tel.: +31 20 5122570; fax: +31 20 5122572.


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