Clin Transl Oncol (2010) 12:81-91
DOI 10.1007/S12094-010-0474-z
E D U C AT I O N A L S E R I E S Green Series
MOLECULAR TARGETS IN ONCOLOGY
Chemotherapy-induced peripheral neuropathy: clinical features,
diagnosis, prevention and treatment strategies
Gerardo Gutiérrez-Gutiérreza · María Serenoa · Ambrosio Miralles · Enrique Casado-Sáenz ·
Eduardo Gutiérrez-Rivas
Received: 31 December 2009 / Accepted: 23 January 2010
Abstract Chemotherapy-induced peripheral neuropathy
(CIN) is a common toxicity of anticancer treatment and its
incidence is growing. It significantly affects quality of life
and is a dose-limiting factor that interferes with treatment.
Its diagnosis can be established in clinical terms but some
complementary tests can help when the diagnosis is dif-
ficult. There is still no proven method to prevent it that has
become a standard of care in spite of the huge amount of
investigation carried out in recent years. There are prom-
ising strategies that could help reduce the burden of this
complication. This review will suggest an approach to the
diagnosis of these disorders and provide an update on new
therapies.
Keywords Chemotherapy · Neuropathy · Pain · Cancer ·
Polyneuropathy · Neuroprotection
a
Both authors have participated equally to this study
G. Gutiérrez-Gutiérrez · A. Miralles
Neurology Department
Infanta Sofía Hospital
San Sebastián de los Reyes, Madrid, Spain
M. Sereno (쾷) · E. Casado-Sáenz
Medical Oncology Department
Infanta Sofía Hospital
Paseo de Europa, 34
ES-28702 San Sebastián de los Reyes, Madrid, Spain
e-mail: mariasereno75@gmail.com
E. Gutiérrez-Rivas
Neuromuscular Unit
Neurology Department
Hospital Universitario 12 de Octubre
Madrid, Spain
Introduction
Chemotherapy-induced peripheral neuropathy (CIN) is
defined as the presence of signs or symptoms of periph-
eral nerve dysfunction, whether somatic or autonomic, as a
consequence of damage to the peripheral or the autonomic
nervous systems caused by chemotherapeutic agents [1].
The peripheral nervous system (PNS) is very sensitive
to the toxic effects of many antineoplastic agents. As the
survival of cancer patients increases, the prevalence of
secondary effects related to chemotherapy increases pro-
portionally. Unfortunately, the prevalence of CIN will grow
in the next decades.
The incidence of CIN is variable, but often ranges from
30 to 40% of patients receiving chemotherapy depending
on the definition of neuropathy. As has been stated previ-
ously, it is probable that these figures will grow in the near
future as treatments become more aggressive and patient
survival increases.
The importance of CIN lies in two factors: it impairs pa-
tients’ quality of life [2, 3] and it is a dose-limiting factor [4,
5]. Surprisingly, though, this issue has not yet been properly
investigated. However, one study has been completed and
another one is underway [6, 7]. CIN is for many patients a
cause of extreme pain, disabling dysfunctions and a signifi-
cant decrease in quality of life. For many patients the symp-
toms and functional limitations generated by CIN are the
most unpleasant and disabling of all the secondary effects
of chemotherapy. Some CIN are chronic and leave lifelong
sequelae. Besides, CIN is a major dose-limiting side ef-
fect of many commonly used chemotherapeutic agents and
therefore alters chemotherapy efficacy and survival.
In this article, we will discuss general concepts of CIN,
the clinical presentation of the CIN syndromes, the treat-
82
ment of established CIN and so-called neuroprotection,
where new evidence suggests that several strategies can
prevent our patients from suffering from this important
side effect.
Anatomy and physiology of the peripheral nervous
system
The PNS is an extension of the central nervous system
and it connects it to the limbs and the organs and systems.
It can be divided into the autonomic (ANS) and somatic
systems, which is normally named the PNS. It includes the
cranial nerves, the spinal nerves with their roots and rami,
and the peripheral components of the autonomic nervous
system [8]. The PNS, unlike the CNS, is not protected by
the haematoencephalic barrier and this makes it more vul-
nerable to the toxic effects of drugs [9]. Some of the neu-
rons in the PNS are the longest cells in the whole body.
Trophic maintenance of neurons and their axons de-
pends on the axonal or axoplasmic flux, also called axo-
plasmic transport [10], a cellular process responsible for
movement of mitochondria, lipids, synaptic vesicles, pro-
teins and other cell parts (i.e., organelles) to and from a
neuron's cell body, through the axoplasm. This process is
essential for the correct working, growth and survival of
the nerve. It is also necessary for the degradation of toxic
substances or ruined proteins and organelles. The transport
can be as fast as 400 mm/day. In this process microtubules
play a crucial role.
The transmission of information is an electrochemical
process. PNS stroma is made up of Schwann cells, rolled
around some nerve fibres to form myelin, which protects
and helps to transmit the nervous impulse at greater speed.
These differences are also important in diagnosis, since
conventional neurophysiological studies can only explore
the fastest fibres.
Most toxic, metabolic and nutritional neuropathies are
axonal in nature (axonopathies), while some others, like
the paraprotein-associated neuropathy anti-MAG of the
multiple myeloma, are demyelinating (myelinopathies).
This means that the site of lesion is primarily the axon or
the Schwann cell, although some can secondarily damage
the other part of the nerve. Platin compounds damage the
neuron soma and they produce what is called a ganglioneu-
ronopathy or a neuronopathy. It is undistinguishable from
an axonopathy from a clinical or a neurophysiological
point of view.
Within the peripheral nerve there is a variety of nerve
fibres, with different morphology, myelination, functions
and chemical features. These fibres differ in their resistance
to the toxic effects of the chemotherapeutical agents. In
general, the longer the nerve, the more vulnerable it is (Fig.
1). Because of this, sometimes the polyneuropathy is called
length-dependent. Sensory fibres are generally more vul-
nerable to the toxic effects of anticancer drugs.
Clin Transl Oncol (2010) 12:81-91
Motor Sensory Autonomic
Thinly Un- Thinly
Myelinated Myelinated Myelinated myelinated Myelinated Unmyelinated
A Alpha A
A delta C C
Alpha-Beta
LARGE
SMALL
SLOW
FAST
Touch Heart rate,
Muscle vibration, Cold Warm Blood pressure,
position perception, perception, Sweating, GIT,
control
perception pain pain GUT function
Fig. 1 Scheme of peripheral nervous system
Clinical manifestations
There are several patterns of peripheral nerve disease [11]:
radiculopathy, plexopathy, polyradiculoneuropathy, monon-
europathy, either cranial or not, multiple mononeuropathy,
also called mononeuritis multiplex, and symmetrical poly-
neuropathy.
Each pattern reflects the part of the PNS damaged and
has a typical clinical pattern. Chemotherapeutic agents can
harm any part of the PNS, the muscle, some even the CNS.
But the most predictable pattern is the polyneuropathic, so
when we say CIN we normally refer to a symmetrical dis-
tal polyneuropathy.
The deficits can be sensory, motor and autonomic.
Symptoms and signs can be classified as positive or nega-
tive [12] (Table 1). Most polyneuropathies are purely sen-
sory, manifesting as initial distal paraesthesias and sensory
loss in a stocking distribution affecting large or small fibre
modalities or both, and lesser and later onset of distal mo-
tor impairment. Some cases never progress to demonstrable
motor changes or have purely or predominantly sensory
manifestations. Autonomic involvement is common in most
neuropathies but pure autonomic neuropathy is rare [11].
Some manifestations are sometimes difficult to relate
to peripheral nerve dysfunction, such as cramps caused by
motor neuropathy, diarrhoea or autonomic constipation,
frequently attributed to concomitant opiate use, the dizzi-
ness of hypotension caused by autonomic dysfunction, neu-
ropathic pain, often associated to other nociceptive pains,
or distal tremor caused by the alteration of proprioception.
Sensory symptoms present as paraesthesia, numbness
and pain in the feet and hands, with symptoms generally
appearing in the toes and then in the fingers. Paraesthesia
occurs in distal lower extremities with a classical glove-
and-stocking distribution and is most severe on plantar
surfaces. Allodynia is feeling pain in response to non-no-
ciceptive stimuli [12]. It can sometimes be felt in response
to selective cold or hot stimuli. Impairment of fine motor
Clin Transl Oncol (2010) 12:81-91
Table 1 Positive and negative symptoms in peripheral nerve disease (adapted from Ref. [90])
Damaged fibre Negative manifestations
Motor fibre Weakness
Fatigue
Hyporeflexia
Large sensitive fibre Hypoaesthesia
Vibratory sensory alteration
Arthrokinetic sensory alteration
Hyporeflexia
Small sensitive fibre Hypoalgesia
Thermal sensitivity alteration
Autonomic fibre Hypotension
Constipation
Hypohydrosis
Impotence
Urinary collapse
skills (e.g., buttoning a shirt or putting on earrings), as well
as sensory ataxia, which worsens in low light or with the
eyes closed (i.e., Romberg sign), may be present as symp-
toms of proprioceptive sensory disturbance.
The first sign of sensory neuropathy is an elevated vi-
bratory perception threshold in feet and hands and is often
associated with loss of pain and temperature sensation. The
sense of position is usually lost in grade 3 or 4 neuropathy
(see below).
Motor neuropathy can present as weakness, muscle
wasting, cramps or fasciculation. This weakness is typi-
cally distal in its onset. Proximal weakness is exceptional
and should cause suspicion of a different condition.
Both motor and sensory neuropathies are manifested by
decreased deep-tendon and ankle reflexes. Small fibre neu-
ropathy can occur with deep-tendon reflexes preserved.
Pain, as a sensory positive symptom, deserves special
attention, since it affects quality of life in a singular man-
ner and can respond to specific treatment. Pain caused by
peripheral nerve dysfunction is called neuropathic pain
and has some particular features. It is usually difficult for
the patient to describe and is associated with depression
more frequently than somatic pain. Its treatment will be
explained below.
Associations are easiest with acute or subacute symp-
toms beginning soon after exposure to a new medication
or dosage increase and subsequent improvement after ces-
sation; however, some symptoms and signs may appear or
progress for up to 2 months after cessation of the chemo-
therapeutic agent. This phenomenon is called the “coasting
phenomenon”. It could be explained by slow drug clear-
ance or slow physiopathology.
There is a specific type of polyneuropathy that is partic-
ularly difficult to diagnose: small fibre neuropathy. Patients
affected by this have predominantly pain and distal impair-
ment of temperature and pinprick due to damage to the
smallest unmyelinated fibres, the A-delta and the C fibres,
which carry dull pain and temperature sensations. In fact,
neuropathic pain intensity is usually more severe in small
83
Positive manifestations
Fasciculations
Cramps
Myokymias
Paraesthesias
Dysaesthesias
Burning dysaesthesias
Allodynia
Hypertension
Diarrhoea
Hyperhydrosis
Priapism
fibre neuropathy that in large fibre neuropathy. These pa-
tients often have normal deep tendon reflexes and vibration
perception, making the diagnosis difficult. They usually
present allodynia to light touch, warm or cold stimulus.
Clinical signs of autonomic dysfunction, such as hypoan-
hydrosis, flushing or abnormal temperature and cutaneous
blood flow are frequent [13]. This is not surprising as au-
tonomic fibres are also non-myelinated small fibres. How-
ever, it is important to remember that most CIN are mixed
fibre neuropathies, affecting both large and small fibres.
Diagnosis
Diagnosis of CIN is usually established within clinical
terms. A number of scales are used to grade the severity of
the clinical symptoms (Table 2). The search is still on for
the perfect scale and some initiatives to improve existing
scales are underway. The examination of clinical signs is
probably the easiest and most cost-effective way to diag-
nose an early ongoing neuropathy. As has been said, loss of
reflexes and vibratory sensation are the first clinical signs to
appear, often preceding clinical symptoms. Motor testing
should include extensor hallucis longus, as it is usually one
of the first muscles to show weakness [14]. However, not all
oncologists are comfortable with neuroexamination. Clini-
cal examination is rapid, cheap, reproducible, easy to learn
and predictive of neurophysiological alterations [15–17].
Nerve function studies
Conventional nerve conduction studies are the best repro-
ducible tests and they are available in almost any hospital.
Nevertheless they are clearly insufficient as the only com-
plementary test because they only examine large myelinat-
ed fast conducting fibres. For many years they have been
used to identify patients at risk. They are essential for the
84 Clin Transl Oncol (2010) 12:81-91

Table 2 Description of the main scales involved in CIN grading

Scores 0 1 2 3 4

Total Neuropathy Scores (TNS)*

A. Sensory symptoms None
B. Motor symptoms
C. Autonomic symptoms, n
D. Pin sensitivity
E. Vibration sensitivity
F. Strength
G. DTR
ECOG
Ajani (sensory)
NCI-CTC 2.0, revised
1 June 1999 (neurosensory)
Symptoms limited Symptoms extend Symptoms extend to knee Symptoms above knee
to fingers or toes to ankle or wrist or elbow or elbow or functionally
disabling
None Slight difficulty Moderate difficulty Require help/assistance Paralysis
0 1 2 3 4 or 5
Normal Reduced in fingers/toes Reduced up to wrist/ankle Reduced up to elbow/knee Reduced to above elbow/
knee
Normal Reduced in fingers/toes Reduced up to wrist/ankle Reduced up to elbow/knee Reduced to above elbow/
knee
Normal Mild weakness Moderate weakness Severe weakness Paralysis (MRS 0–1)
(MRC 4) (MRC 3) (MRC 2)
Normal Ankle reflex reduced Ankle reflex absent Ankle reflex absent, All reflexes absent
others reduced
None Decreased DTR, mild Absent DTR, severe Disabling sensory loss, Respiratory dysfunction
paraesthesias, mild paraesthesias, severe severe neuropathic pain, secondary to weakness,
constipation constipation, mild severe weakness, bladder constipation requiring
weakness dysfunction, constipation surgery, paralysis (chair/
bedbound)
None Paraesthesias, Mild objective Severe paraesthesias, Complete sensory loss,
decreased DTR abnormalities, absent moderate objective loss of function
DTR, mild to moderate abnormality, severe
functional abnormality functional abnormality
None Loss of DTR or Objective sensory loss Sensory loss or Permanent sensory
paraesthesias but not or paraesthesias paraesthesias interfering loss that interferes
interfering interfering with function, with activities of daily with function
with function but not interfering with living
activities of daily living

diagnosis of focal neuropathies or plexopathies, but cannot
differentiate different toxicities.
Nowadays they are still being used as the gold standard
in some ongoing clinical trials. They can be helpful in de-
ciding when to stop treatment [18]. They allow quantifica-
tion of the damage in the nerve and can also characterise
the specific site of the lesion, i.e., differentiating a demyeli-
nating neuropathy from an axonal neuropathy. In practice
though, all CIN are axonal in nature and indistinguishable
from a neurophysiological point of view.
However, they are not the perfect instrument, being
neither sensitive [19] nor specific enough (i.e., a patient can
have a polyneuropathy with a normal neurophysiological
study or a patient can have a diabetic neuropathy undistin-
guishable from a CIN). Furthermore, alterations in neuro-
physiological markers do not change until late in the course
of treatment [20, 21]. Probably, electrophysiological testing
is rarely needed for the diagnosis of the polyneuropathy [22]
except in situations where the clinical features are atypical.
Simple clinical tests should be enough in most cases.
Quantitative sensory testing (QST)
Quantitative sensory testing (QST) is a group of techniques
designed to study those fibres that conventional conduction
studies cannot assess. It allows the study of so-called small
fibres, responsible for carrying pain and temperature. The
results are highly dependent on methodology and the full
cooperation of the subject. As has been said, some chemo-
therapy agents preferentially damage these types of fibres.
Unfortunately these techniques are not available in all
hospitals [23]. Axonal excitability techniques are relatively
new and promising neurophysiological tests used to study
sensory and motor axonal excitability. Some studies have
detected changes after oxaliplatin infusions. They could
identify at-risk patients prior to the development of irrevers-
ible oxaliplatin neuropathy. They also seem more sensitive
and specific than conventional conduction studies [21, 24].
These techniques are also helping us to look more closely at
the pathophysiology of neurotoxicity and point us in the di-
rection of better treatments [25]. Another interesting assess-
ment method for CIN is skin biopsy [26–29]. It allows the
unmyelinated small nervous fibres that lie in the epidermis
to be seen and quantified in vivo. It is now being used as the
gold standard in some studies evaluating neuroprotection.
As with other techniques, it requires the service of highly
motivated pathologists. A trial is ongoing [30] to determine
the clinical usefulness of these techniques in CIN.
So far, no serum markers of PNS damage have been
identified to predict those patients more susceptible to this
complication. It has been suggested that pharmacogenom-
Clin Transl Oncol (2010) 12:81-91
ics could help detect patients at risk [31]. A trial is ongoing
[32]. There is still no role for this in clinical practice but
there will be soon. Further investigations are needed to find
prognostic factors associated to a higher risk of CIN.
Classical chemotherapy agents involved in CIN
Microtubule-stabilising agents (MTSAs)
Microtubule-stabilising agents (MTSAs), including taxanes
and epothilones, are effective chemotherapeutic agents for
the treatment of many type of cancers.
Taxanes
Taxanes include polyoxyethylated castor oil-based pacli-
taxel, docetaxel and ABI-007 and are effective chemo-
therapeutic agents for various cancers. ABI-007 is a new
polyoxyethylated castor oil-free formulation of paclitaxel
with good antitumour activity in phase III clinical trials
of breast cancer. Epothilones are newly emerged MTSAs
in active clinical trials and include ixabepilone (BMS-
247550), BMS-310705, patupilone (EPO906), epothilone
D (KOS-862) and ZK-EPO.
Neuropathy is a major adverse effect of MTSA-based
chemotherapy, with severe peripheral neuropathy (grade 3
or 4) occurring in as many as 30% of patients treated with
a MTSA. This CIN presents as axonopathy or axonopathy
plus myelinopathy. The mechanism of MTSA-induced neu-
ropathy is unclear but it is thought to be related to distur-
bance of axoplasmic transport. The incidence of this neu-
ropathy depends on risk factors including dose per cycle,
treatment schedule, duration of infusion, cumulative dose
and comorbidity such as diabetes. Other risk factors may
include concurrent administration of cisplatin, or age with
limited data. Associations between these risk factors and
the incidence of CIN have been confirmed in clinical tri-
als. Although the clinical response of tumours to a specific
MTSA is the most important reason to select a chemother-
apy regimen, it is also prudent to evaluate the risk of devel-
oping CIN associated with each chemotherapy regimen,
especially for patients already at high risk of neuropathy.
The clinical picture includes sensory and motor symptoms.
Acute tingling in fingertips and toes may occur within 24
h of paclitaxel infusion. Motor neuropathy is usually mild
and presents as muscle weakness such as foot drop.
There is a clinical picture associated with acute pain
secondary to paclitaxel consisting of subacute aches and
pains following paclitaxel, which were studied using struc-
tured interviews to characterise symptoms. This work re-
vealed that the pain symptoms typically began 1–2 days af-
ter the patients received paclitaxel and lasted for a median
of 4–5 days. Pain was most commonly located in the back,
hips, shoulders, thighs, legs and feet, with the most com-
mon descriptors used being “aching” or “deep pain”. Some
patients described increased pain with weight bearing,
85
walking or tactile contact. This acute paclitaxel syndrome
has been proposed as a form of acute motor CIN [33].
No specific treatments for MTSA-induced neuropathy
are available. MTSA-induced CIN generally improves
when MTSA dose is reduced or MTSA therapy is delayed
or completed. Approximately half of the patients with CIN
by polyoxyethylated castor oil-based paclitaxel experi-
enced improvement of CIN within 9 months of cessation
of paclitaxel treatment. Several types of neuroprotective
agents have been tested for MTSA-induced neuropathy
in animal models and clinical trials: AM424, amifostine,
disodium 2,20-dithio-bisethanol, lamotrigine, dimesna and
BNP7787 are being evaluated in phase II or III clinical tri-
als of MTSA-containing chemotherapy regimens for the
prevention of chemotherapy-induced neuropathy [34].
Epothilones
Epothilones are a group of MTSAs, including epothilone
A, epothilone B and epothilone D. They are MTSAs simi-
lar to taxanes. They have the advantage of being more wa-
ter soluble. Ixabepalone is an analogue that was approved
in October 2007 by the FDA. Distal sensory and motor
neuropathy, similar to taxanes, has been reported from
phase III clinical trials [35, 36].
Platinum compounds
Platinum compounds have been used for treating cancer for
40 years and their use is increasing. The chemotherapeutic
mechanism of platinum compounds is thought to be similar
to that of alkylating agents that bind to DNA. Pure sensory
involvement is a unique feature of CIN associated with the
platinum drugs. Selective vulnerability of sensory neurons
depends, in part, on their fenestrated capillary blood sup-
ply [37]. It has subsequently been demonstrated both in
vitro and in vivo that platinum binds avidly to neuronal
DNA during treatment with both cis- and oxaliplatin [38].
The amount of platinum binding to DNA is comparable to
or exceeds levels known to be cytotoxic to tumour cells.
Platinum compounds produce neuronal death inducing an
aberrant re-entry into the cell cycle and apoptosis. They
induce aberrant re-entry into the cell cycle and apoptosis
[39]. Binding of platinum to mitochondrial DNA has been
proposed as a potential mechanism underlying delayed
neuronal death.
Neurotoxicity is a dose-limiting side effect for all the
platinum compounds that are involved in sensory symp-
toms. It is necessary to distinguish between the different
platinum drugs and their effects on sensory nerves:
Cisplatin
Cisplatin was first described in 1980 [40]. The develop-
ment of neuropathy is closely related to total cumulative
drug dose [41]. Significant peripheral neurotoxicity is ap-
parent in the majority of adult patients who receive more
than 400–500 mg/m2 of cisplatin, typically 3–6 months
86
after treatment starts. It is predominantly sensory, with
initial complaints of paraesthesias in the distal extremities.
All sensory modalities are involved, but loss of large fibre
sensory function is often prominent. This may progress to
severe sensory ataxia. Lhermitte’s symptom is quite com-
mon. Autonomic affectation is infrequent and can produce
dizziness, palpitations or impotence [42].
Oxaliplatin
Neurotoxicity is the most frequent dose-limiting toxic-
ity, developing in 60–80% of patients. It includes a stereo-
typical cold-induced acute toxicity that involves reversible
paraesthesias in the throat, mouth, face and hands, occur-
ring within 30–60 min and usually during the second or
third course. Paraesthesias are described as an unpleasant
tingling or burning induced by contact with cold surfaces
or liquids and they are acute and intermittent. They typi-
cally remit 2–3 days after infusion is completed. However,
20–30% of patients develop fixed sensory loss that is simi-
lar to that induced by cisplatin [43].
Carboplatin
Carboplatin is less neurotoxic, however in high doses it
produces the same type of neuropathy as cisplatin. Espe-
cially when it is combined with paclitaxel, around 20% of
patients develop moderate or severe neuropathy [44].
Coasting phenomenon has been described. When cis-
or oxaliplatin are discontinued, neuropathic symptoms and
signs may progress for up to 2 months. Because of this, it
is important that treatment be discontinued at the first signs
of fixed sensory impairment. Once a plateau is reached,
there may be gradual improvement. However, because the
underlying pathology is a ganglionopathy, recovery may be
incomplete, especially in more severe cases. Many patients
experience residual pain after some improvement in their
neuropathy. This may last for several years after discon-
tinuation of therapy.
Vinca alkaloids
The vinca alkaloids are derived form the Madagascar
periwinkle (Catharanthus roseus), a common ground cover
plant. In this group, four subtypes are described: vinblas-
tine, vincristine, and the semisynthetic derivatives, vin-
desine [45] and vinorelbine. Vinca alkaloids act by inhibit-
ing assembly and promoting disassembly of microtubules,
which interferes with axonal transport. They do not cross
the blood–brain barrier but they do enter peripheral nerves,
where they act locally rather than at the level of the cell
body [46]. All the drugs of this family produce a dose-re-
lated sensorimotor neuropathy. The most severe neurotox-
icity is associated with vincristine and vindesine, whereas
vinorelbine and vinblastine cause less neurotoxicity. CIN
is usually presented around the first three months of treat-
ment. Early symptoms include paraesthesias and pain in
the hands and in the feet and distally accentuated hyperaes-
Clin Transl Oncol (2010) 12:81-91
thesia. Muscle weakness and muscle cramps are frequent.
Weakness can occur in wrist extensors and dorsiflexors of
the toes. Mononeuropathies (femoral, peroneal), cranial
nerve lesions, diplopia, vocal cord paralysis, facial nerve
palsy and sensoneural hearing loss have been described in
individual case reports. Autonomic changes can occur [47].
Reducing dose level and frequency may ameliorate the de-
velopment of neuropathy. Coasting phenomenon is possible
[48]. Lifelong sequelae are common in survivors [49].
Proteasome inhibitors
Bortezomib is a polycyclic derivative of boronic acid
that inhibits the mammalian 26S proteasome. The pro-
teasome degrades the intracellular inhibitor of NFKbeta
(IkB). Bortezomib thus increases the level of the inhibi-
tor and decreases the activity of NFKbeta. This, in turn
downregulates the expression of proteins that promote cell
division and proliferation. The neuropathy is dose related
and cumulative, with a frequency of minor symptoms in
31%; more severe neuropathy was predominantly sensory,
distal and length dependent. In most cases, motor func-
tion remained normal. Sensory “neuropathy” was of small
fibre type and often involved significant neuropathic pain
that required modification or cessation of the drug therapy.
Electrophysiological changes demonstrated axonal loss. In
patients with previous treatment like thalidomide, severe
cases of neuropathy were developed as well as anecdotal
reports of serious motor damage associated to bortezomib
treatment. This kind of neuropathy is reversible and symp-
toms generally improve and return to baseline after termi-
nation of treatment [50].
Other chemotherapeutic agents
Thalidomide
Thalidomide was introduced in Europe around 1950 as an
antiemetic for use during pregnancy. It was teratogenic,
causing amelia or focomelia, and was withdrawn from use.
More recently, it has been used in the treatment of a variety
of disorders including multiple myeloma. After introduc-
tion of thalidomide in the 1960, it was recognised that the
drug frequently caused peripheral neuropathy, which usual-
ly occurs in 20–40% of patients. Frequently the neuropathy
increases with age and cumulative dose of length of treat-
ment. Early symptoms include numbness and paraesthesias
in hands and feet and leg cramps. Distal loss of all sensory
modalities is the predominant feature, although motor in-
volvement is usually mild. There are increasing reports of
more severe neuropathy as the drug is more widely used
for the treatment for myeloma [51, 52].
Lenalidomide
Lenalidomide is an analogue of thalidomide and it is no-
tably more potent compared to thalidomide, inhibiting the
Clin Transl Oncol (2010) 12:81-91
production of TNF-. It appears that it is less toxic than
thalidomide regarding somnolence and neuropathy [53].
Cytosine arabinoside
High doses of cytosine arabinoside (Ara C) cause a demy-
elinating polyneuropathy in approximately 1% of cases
[54]. This follows a progressive monophasic course, start-
ing 2–3 weeks after initiation of the therapy, and produces
severe motor weakness, even quadriparesis requiring venti-
latory support. However, predominantly sensorimotor neu-
ropathy is seen with low doses of Ara C. Also, an acute and
severe autonomic neuropathy has been described [55].
Etoposide (VP16)
Etoposide (VP16) produces a mild, occasionally moderate
length-dependent sensorimotor neuropathy. Its occurrence
is related to both total dose and dosing intervals. Increased
age of the patient, pronounced weight loss and pre-existing
neuropathy may be predisposing factors for the develop-
ment of neuropathic toxicity [56].
Gemcitabine
Up to 10% of patients experience mild paraesthesias during
treatment, although occasionally more severe peripheral
and autonomic neuropathies are described [57].
New biological treatments
Bevacizumab
Recently, a case report has been described with a new be-
vacizumab toxicity: optic neuropathy. Bevacizumab has
become a treatment option for recurrent glioblastoma.
Sherman et al. have reported 6 recent patients who devel-
oped severe optic neuropathy after bevacizumab treatment.
While not seen in patients treated for non-brain tumour
indications, this association appears to require dose-inde-
pendent radiation to the optic apparatus, suggesting a prim-
ing effect for optic nerve injury. The patients in the report
received standard chemoradiation, with radiation to the op-
tic apparatus generally considered within tolerance levels.
Ophthalmologic assessment in all patients confirmed optic
neuropathy of unknown aetiology. Proposed mechanisms
may involve arterial thrombosis or upregulation of VEGF
and subsequent neovascularisation after radiotherapy with
delayed ischaemia following bevacizumab. Until the mech-
anistic basis for these findings is better understood, patients
receiving bevacizumab should be followed closely [58].
Tipifarnib
Tipifarnib is an oral non-peptidomimetic farnesyl trans-
ferase inhibitor, used in both solid tumours and haemato-
logical malignancies. Although toxicity is predominantly
haematologic, a mild neuropathy has been reported [59].
ZD6474
ZD6474 (Zactima, a selective inhibitor of VEGFR and
EGFR tyrosine kinase) has demonstrated activity in pa-
87
tients with relapsed multiple myeloma, colon and lung
cancer. In a phase II trial of ZD6474 for multiple myeloma,
the most common drug-related adverse events were nausea,
vomiting, fatigue, rash, pruritus, headache, diarrhoea and
dizziness. But around 20% of patients developed a sensory
neuropathy, all of which were grade I–II in severity and not
related to myeloma neuropathy [60].
Prospidium chloride
Prospidium chloride was an antineoplastic dispiropipera-
zine derivative used against Kaposi’s sarcoma. It produced
a dose-dependent sensory neuropathy [61].
Prevention: neuroprotection
Neuroprotection is still a utopia. It could be defined as a
group of strategies focused on protecting the PNS from
the toxic effects of anticancer agents. This concept of neu-
roprotection should be distinguished from the concept of
treatment of the neuropathy, i.e., those strategies focused on
helping regenerate the PNS after the damaged has already
occurred. Sometimes neuroprotection and treatment over-
lap, since some agents have proved to be neuroprotective
and neuroregenerative alike. Treatment of established CIN
and treatment of neuropathic pain will be addressed below.
Prevention in CIN should start with the identification
of those patients at higher risk of suffering a neuropathy.
Those patents with previous damage in the PNS or with
conditions that damage the PNS or impair its regeneration,
such as diabetes mellitus, hypothyroidism, renal failure or
alcoholism, should be closely followed.
A good nutritional state should be assured to prevent a
CIN. Some vitamins are especially important in neurore-
generation and trophic maintenance of the PNS, such as
vitamin B1 or thiamine, vitamin B12 or cobalamin, vita-
min C, vitamin E, vitamin B6 or pyridoxine, and vitamin
B9 or folate. Some are being investigated as potential neu-
roprotectors, as seen below. Malnourished and alcoholic
patients and those with previous gastrointestinal surgery
are at special risk of developing neuropathy [62, 63], since
some of these essential vitamins have had their absorption
compromised.
Diabetics should have their glucose levels closely con-
trolled, especially if corticosteroids are used.
All patients should have a good basal neuroexamination
performed, with special attention to deep tendon reflexes
and vibration.
Strategies
Several strategies have been tried in the setting of neuro-
protection with neurotoxic drugs.
Changes in administration
Reducing the dose of the offending agent, slower infusion
rates or longer times between doses have been studied.
88
Sometimes the only way to prevent further damage to the
nerve is to stop treatment permanently.
Oxaliplatin and neuropathy: stop and go concept
Observations of reversibility of oxaliplatin-induced neuro-
toxicity led de Gramont et al. to develop a dosing scheme
termed the STOP and GO (OPTIMOX) strategy with the
goal of increasing the cumulative oxaliplatin dose that
can be given [64]. This strategy uses a 5-FU-LV infusion
(without bolus) over 46 h plus oxaliplatin 130 mg/m2 ev-
ery 2 weeks for 6 cycles; after this oxaliplatin is held and
treatment with 5-FU-LV is continued in the following.
The oxaliplatin is reintroduced after a 6-month hiatus. The
OPTIMOX arm showed significantly lower rates of Grade
3 neurotoxicity (13% vs. 19%; p=0.0017) without compro-
mising response rates (RRs) or progression-free survival
(PFS) (RR 63.1% vs. 59.8%; PFS 9.2 vs. 8.9 months). The
stop and go strategy appears to be a promising approach
to prolong the administration of platinum therapy without
compromising efficacy [65].
Nutritional supplements
Acetyl-L-carnitine
Acetyl-L-carnitine is an L-carnitine ester proposed to exert
neuroprotective effects by various mechanisms including
regulation of acetylCoA, acetylation of tubulin and increas-
ing NGF-induced histone acetylation. Acetyl-L-carnitine
has shown potential in neuroprotection in multiple animal
models of chemotherapy-induced neuropathy including
oxaliplatin, cisplatin, paclitaxel and vincristine. Recent
studies have reported that acetyl-L-carnitine has a neuro-
protective effect as well as being able to improve symp-
toms and electrophysiological parameters in patients with
paclitaxel- or cisplatin-induced neuropathy [66, 67].
Glutamine
Glutamine is a non-essential gluconeogenic amino acid that
is the main energy source for rapidly transporting nitrogen
between tissues. Glutamine also up-regulates nerve growth
factor mRNA, which may play a role in the protection of
patients undergoing chemotherapy with neurotoxic agents.
Some studies have demonstrated that there is a decrease in
nerve growth factor levels during therapy, which correlates
with severity of the neuropathy. There may be an additional
benefit of glutamine as a centrally acting mediator of pain
sensation by a complex mechanism involving glutamate
downregulation [68].
Alpha-lipoic acid
Alpha-lipoic acid is a cycle disulphide considered to be a
broad-spectrum antioxidant. It is also involved in recycling
other antioxidants such as glutathione, vitamin C and vi-
tamin E. It has proved its efficacy as a neuroprotector in
diabetic neuropathy. Two case series have reported that
alpha-lipoic acid may be beneficial in the treatment of neu-
Clin Transl Oncol (2010) 12:81-91
ropathy caused by a combination of docetaxel and cisplatin
or oxaliplatin alone [69, 70].
Vitamin E
There are data to suggest that vitamin E, a fat-soluble vita-
min classified as an antioxidant, may potentially decrease
the incidence or severity of CIN. A pilot study published
by Argyrou et al. looked at the neuroprotective effect of vi-
tamin E for preventing CIPN in 47 patients receiving cispl-
atin chemotherapy who were randomised to receive either
vitamin E (300 mg/d) with cisplatin for three months after
cisplatin or cisplatin alone. They reported a significantly
decreased incidence of peripheral neuropathy (31%) com-
pared to the group without vitamin E (86%) [71]. Argyriou
et al. published similar results with an important benefit in
the vitamin E arm [72]. It is necessary to consider another
issue, that being the concern that vitamin E may interfere
with the oxidative breakdown of cellular DNA and cell
membranes necessary for cytotoxic agents to work. Some
authors have found a negative impact in survival in the
vitamin E arm in patients that had undergone radiation and
chemotherapy treatment. To be more certain of the safety
of using vitamin E with chemotherapy, it appears reason-
able to conduct an additional trial to attempt to better
clarify whether vitamin E will interfere with the anticancer
activity of chemotherapy in a more homogenous group [73,
74]. A randomised phase III trial has already started.
Group B vitamins
Vitamin B12 (cobalamin) and folate. Two biochemical
reactions depend on vitamin B12. One involves methylma-
lonic acid as precursor in the conversion of methylmalonyl
coenzyme-A (Co-A) to succinyl Co-A. The importance of
this to the nervous system is unclear. The other is a folate-
dependent reaction in which the methyl group of methyltet-
rahydrofolate is transferred to homocysteine to yield me-
thionine and tetrahydrofolate. The reaction depends on the
enzyme methionine synthase, which uses cobalamin as a
cofactor. Methionine is converted to S-adenosylmethionine
(SAM), which is used for methylation reactions in the ner-
vous system [75]. Its deficit causes a peripheral neuropathy
that can associate a myelopathy and encephalopathy if the
deficit is sustained. Vitamin B12 has been traditionally
used as a treatment for all types of neuropathies but there is
still a lack of evidence for its recommendation [76].
Pyridoxine. Although the term pyridoxine often is used
synonymously with vitamin B6, two other naturally occur-
ring compounds –pyridoxal and pyridoxamine– possess
biological activities similar to pyridoxine. All three com-
pounds are converted to pyridoxal phosphate, the active co-
enzyme important for amino acid metabolism. Pyridoxine
deficit causes a well recognised sensory neuropathy that
can progress to a motor neuropathy if the deficit persists.
Curiously, the use of high doses of pyridoxine (1000 mg/
day or more) for several months causes a sensory neu-
ropathy in a dose-dependent manner. Reported patients
ingesting such a high dose for a prolonged period had a
Clin Transl Oncol (2010) 12:81-91
syndrome of sensory ataxia, with impaired cutaneous and
deep sensation, areflexia and Romberg's sign [74]. There
is a phase III trial underway that is studying the potential
neuroprotective effect in CIN of group B vitamins [76].
Malnutrition
Several authors have demonstrated a potential role of
nutritional deficiencies in putting patients at higher risk
of developing neuropathy after chemotherapy treatment.
Ramchandrem et al. reported a higher incidence of neurop-
athy in children diagnosed with leukaemia and treated with
neurotoxic drugs compared to another series from more
developed countries without malnutrition [77].
Drugs
Several neuroprotective therapies have been sought. These
include amifostine, growth factors, glutathione, Org 2766,
acetyl-L-carnitine and vitamin E. This review identified 16
randomised controlled trials of five different potential neu-
roprotective therapies. Although the trials included a total
of 1420 participants, meta-analysis was possible for only a
small number of measures in very few trials. The data from
the trials were insufficient to conclude that any of the neu-
roprotective agents tested prevent or limit the neurotoxicity
of platinum drugs. More research is needed. Most of these
treatments have been used as neuroprotective agents in
other polyneuropathies, especially in diabetic neuropathy,
the most common neuropathy in the Western world.
Amifostine
Amifostine has been used as a radioprotective agent but
recently aminofostine has been postulated to be cytopro-
tective in chemotherapy. The proposed mechanisms of
cytoprotection are decreasing the cisplatin DNA adducts
as well as scavenging free radicals. Administration of
aminofostine with paclitaxel did not show neuroprotective
effects, as would be expected considering our understand-
ing that the mechanism of neurotoxicity with taxanes is by
disruption of microtubules [78].
Carbamazepine
Carbamazepine is a sodium channel inhibitor prescribed in
the treatment of epilepsy. Sodium channel dysfunction is
implicated in oxaliplatin-induced neuropathy. A small case
series reported a decrease in the severity of oxaliplatin-
induced peripheral neuropathy in patients on concurrent
carbamazepine, while another series of patients treated
with oxaliplatin noted no similar benefit.
Oxcarbazepine
Oxcarbazepine is a keto analogue of carbamazepine that
also has been identified as a candidate for preventing
oxaliplatin-induced peripheral neuropathies. Results from a
small randomised, open-label, controlled trial suggest that
oxacarbazepine may protect against oxaliplatin-induced
89
peripheral neuropathies [79]. A larger placebo controlled
trial is needed to confirm these results and is underway.
Ca/Mg infusion
Divalent cations have the ability to modify voltage-gated
sodium channels. It is hypothesised that the acute neuro-
toxicity of oxaliplatin is related to the ability of oxalate to
chelate calcium. Increases in extracellular calcium have
been shown to increase the probability of sodium channel
closure, decreasing the hyperexcitability of peripheral neu-
rons seen in oxaliplatin-induced neuropathy. Magnesium
supplementation has been previously studied in preventing
cisplatin-induced hypomagnesaemia. This promising treat-
ment is based on a retrospective study by Gamelin. The
percentage of patients treated with oxaliplatin regimens
with grade 3 distal paraesthesias was significantly lower
in the Ca/Mg group (7% vs. 26%, p=0.001). The Ca/Mg
infusions had no bearing on treatment efficacy [80]. This is
a simple strategy to help ameliorate the symptoms of acute
oxaliplatin-induced neuropathy, but further investigation
is warranted to determine if this treatment is effective in
preventing chronic, cumulative neurotoxicity. It must be
borne in mind that this strategy is based on a single retro-
spective analysis of a non-randomised study. Prospective,
randomised studies (such as the CONCEPT study) are
underway to validate the benefit of these minerals in ame-
liorating the neurotoxicity of oxaliplatin [81].
Glutathione
Glutathione is a naturally occurring tripeptide with a high af-
finity for heavy metals. Platinum deposits (and neuropathy)
in humans undergoing chemotherapy with cisplatin have
been shown to decrease after coadministration of glutathi-
one. The mechanism of neurotoxicity induced by platinum-
based antineoplastic agents has been shown in preclinical stu-
dies to involve heavy metal accumulation in the PNS [82].
Xaliproden
Xaliproden is an orally administered non-peptide neu-
rotrophic agent. Results of a large, randomised, double-
blind, placebo-controlled, phase III study demonstrated a
lower incidence of CIN in patients treated with oxaliplatin
compared to those patients that did not receive xaliprodem.
In addition, this drug did not appear to reduce cancer RRs.
A phase III trial is ongoing to try and confirm these results
and to investigate the benefit of continuing this agent after
discontinuation of oxaliplatin [83].
Gabapentine and pregabaline
These drugs have been used in established CIN treatment
with success. For this reason they have been studied to pre-
vent chemotherapy acute neuropathy. In this way, several
trials have been developed with disappointing results [84].
Nimodipine
Nimodipine is a calcium antagonist most commonly used
for its potent and selective cerebral vasodilatory effects.
Animal studies suggest that nimodipine-induced limitation
90 Clin Transl Oncol (2010) 12:81-91

of intracellular calcium may provide neuroprotection to at-
risk (ischaemic) neural tissues. Unfortunately, human trials
were discontinued because of medication intolerance [85].
Recombinant human leukaemia inhibitory factor (HLIF)
Recombinant human leukaemia inhibitory factor (HLIF)
is a cytokine involved in a variety of functions including
stem cell differentiation and regeneration of neurons. HLIF
expression has been shown to be up-regulated in response
to neural damage. Although animal studies have demon-
strated some benefit, a randomised, double-blind, placebo-
controlled study showed no evidence of neuroprotection in
humans [86].
Goshajinkigan (GJG)
Goshajinkigan (GJG) is an extracted traditional Japanese
herbal medicine (Kampo) that is mainly used for the im-
provement of symptoms like numbness, cold sensation and
limb pain associated with diabetic neuropathy. Moreover,
Mamiya et al. and Shindo et al. recently reported that pe-
ripheral neurotoxicity due to oxaliplatin was relieved by
administration of GJG in patients with advanced colorectal
cancer that were receiving FOLFOX therapy [87, 88].
ORG 2766
Despite early preclinical data and clinical experience sug-
gesting benefit from ORG2766 (an adrenocorticotropic
hormone analogue) for prevention of cisplatin-induced
neuropathies, larger randomised placebo-controlled trials
failed to demonstrate any reduction in peripheral neuropa-
thy, with one trial actually suggesting that it may increase
neuropathy [89].
Conclusion
CIN is a common and important problem in cancer treat-
ment. The oncologist must effectively treat cancer while
trying to reduce the toxicity of the cancer treatment on
other organs. Some new and old drugs show promise in the
bid to diminish toxicity to the PNS. New diagnostic tech-
niques are being developed that can detect early damage
to nerves. In the near future it will be possible to identify
those patients more susceptible CIN, so we will be able to
protect them better and treat their cancers more vigorously.
It is necessary to continue investigating prognostic factors,
early neuropathy biomarkers, more sensitive diagnostic
techniques, and new drugs and neuroprotective strategies
that can protect our patients against neuropathy induced
chemotherapy.
Conflict of interest The authors declare that they have no conflict of
interest relating to the publication of this manuscript.

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