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NEUROPATHIC PAIN (E EISENBERG, SECTION EDITOR)
Emerging Trends in Understanding Chemotherapy-Induced
Peripheral Neuropathy
Jérémy Ferrier & Vanessa Pereira & Jérome Busserolles &
Nicolas Authier & David Balayssac
#
Springer Science+Business Media New York 2013
Abstract Chemotherapy-induced peripheral neuropathy
(CIPN) is a major concern in oncology practice given the
increasing number of cancer survivors and the lack of effec-
tive treatment. The incidence of peripheral neuropathy de-
pends upon the anticancer drug used, but is commonly
under-reported in clinical trials. Several animal models have
been developed in an attempt to better characterize the path-
ophysiological mechanisms underlying these CIPN and to
find more specific treatments. Over the past two decades, three
main trends have emerged from preclinical research on CIPN.
There is a compelling body of evidence that neurotoxic anti-
cancer drugs affect the peripheral sensory nerve by directly
targeting the mitochondria and producing oxidative stress, by
functionally impairing the ion channels and/or by triggering
immunological mechanisms through the activation of satellite
glial cells. These various neurotoxic events may account for
the lack of effective treatment, as neuroprotection may prob-
ably only be achieved using a polytherapy that targets all of
these mechanisms. The aim of this review is to describe the
clinical features of CIPN and to summarize the recent trends in
understanding its pathophysiology.
Keywords Anticancer drugs
.
Neurotoxicity
.
Ion channels
.
Mitochondria
.
Oxidative stress
.
Glial cells
.
Neuropathic pain
Introduction
The number of cancer survivors is constantly increasing
in the western world, attesting to the therapeutic prog-
ress of improved cancer management and increased
survival rates. Consequently, taking into account the
long-term consequences of cancer treatments is of major
importance in oncology practice. Chemotherapy-induced
peripheral neuropathy (CIPN) is a major dose-limiting
adverse effect of many anticancer drugs such as plati-
num salts (cisplatin, carboplatin and oxaliplatin), spindle
poisons (taxanes and vinca alkaloids), bortezomib and
thalidomide [1]. Patients experience a combination of
sensory and motor symptoms that can be both painful
and painless, the m ost reported being numbness, loss of
balance, muscle weakness, tingling and burning pain [2].
The incidence, severity and persistence of these neuropa-
thies strongly depend on the anticancer drug involved. Clini-
cal assessment is challenging due to the lack of reliable,
standardized and validated tests that could help the physician
to identify the presence and severity of CIPN [3]. Subjective
methods, such as the Patient Neurotoxicity Questionnaire
(PNQ), have been developed that could help to identify pa-
tients at risk of developing a CIPN or to measure the patient’s
response to a treatment. A recent study has reported a very
significant difference between the physician’s diagnosis of
CIPN, using a standardized neurological examination with
National Cancer Institute—Common Terminology Criteria
(NCI-CTC) grading, and the patients self-reported intensity
and severity using the PNQ [4]. Hence, CIPN is very likely to
be under-reported by physicians and the severity and func-
tional impact on daily activities are often underestimated
regarding patients subjective experience.
This article is part of the Topical Collection on Neuropathic Pain
J. Ferrier
:
V. Pereira
:
J. Busserolles
:
N. Authier
:
D. Balayssac
Clermont Université, Université d’Auvergne,
Pharmacologie fondamentale et clinique de la douleur,
63000 Clermont-Ferrand, France
J. Ferrier
:
V. Pereira
:
J. Busserolles
:
N. Authier
:
D. Balayssac
INSERM, U1107 NEURO-DOL, 63001 Clermont-Ferrand, France
N. Authier
:
D. Balayssac
CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France
D. Balayssac (*)
Laboratory of Toxicology, Faculty of Pharmacy, 28, place Henri
Dunant, BP 38, 63000 Clermont-Ferrand cedex 01, France
e-mail: dbalayssac@chu-clermontferrand.fr
Curr Pain Headache Rep (2013) 17:364
DOI 10.1007/s11916-013-0364-5
Several therapeutic strategies have been tried in order to
prevent or overcome the neurotoxic effects of these com-
pounds, but so far without success. CIPN is currently treated
symptomatically, but no effective neuroprotective agent has
been reported. CIPN is considered to be resistant to most of
first-line treatments for neuropathic pain [5]. Dose reduction or
treatment discontinuation is the only recourse of the oncolo-
gists to limit the apparition of neuropathic symptoms. Howev-
er, these dosage adjustments may strongly affect the prognosis
of cancer remission. In addition, neurotoxicity of anticancer
drugs has an important negative impact on patients quality of
life and especially on daily living activities [6], eventually
leading to emotional distress [2]. Patients with CIPN are also
associated with a great economic burden, with considerably
higher healthcare costs than cancer patients without peripheral
neuropathy [7]. Hence, there is a strong need for improvement
in CIPN management and prevention, which requires a greater
understanding of its particular pathophysiology.
The molecular and cellular mechanisms leading to CIPN
have been extensively studied over the past two decades.
Animal models that mimic the clinical neuropathic symptoms
have been developed in an attempt to understand the integrat-
ed mechanisms of neurotoxicity and the molecular events
leading to CIPN [8]. However, the pathophysiology of these
neuropathies is still a matter of debate. Three main mecha-
nisms have emerged from preclinical studies: (1) mitotoxicity
and oxidative stress, (2) ion channel involvement, and (3)
inflammatory processes through the activation of glial
cells. This article will review and discuss the latest
findings on CIPN research and highlight the recent
advances in its therapeutic treatment.
Clinical Features
Platinum Salts
Cisplatin is used as a first or second line of treatment against a
wide range of solid tumors (lung, ovary, bladder , testicular,
head and neck, esophagus, stomach, colon, pancreas, melano-
ma, breast, prostate, mesothelioma, leiomyosarcoma and glio-
ma) [9]. Cisplatin-induced neuropathy is dependent on the
cumulative dose and generally appears after 400–700 mg/m
2
[10]. About 28 % of patien ts develop symptomatic neuropa-
thies, of which 6 % suffer from incapacitating polyneuropathies
[11]. This CIPN is primarily sensory-based, with paresthesias,
sensory ataxia, loss of vibratory sensitivity and a decrease or
loss of tendon reflexes [10]. Proprioceptive alterations, muscu-
lar cramps and Lhermitte’s sign are described in severe cases of
neuropathy [12]. These symptoms are usually reversible after
discontinuation of treatment, but recovery is often very slow.
Oxaliplatin is widely used for the treatment of advanced
colorectal cancer. Neurotoxicity is the dose-limiting adverse
effect, with two components: an acute nerve hyperexcitability
and a chronic cumulative peripheral neuropathy. In more than
90 % of treated patients, oxaliplatin is responsible for sensory
symptoms including cold-induced dysesthesias in the hands
and the circumoral area, numbness and tingling in the extrem-
ities, muscle weakness and neuropathic pain [13, 14]. Muscle
spasms or cramps are often reported, sometimes described as
stiffness in the hands and feet or an inability to release the grip.
These symptoms are more likely to develop shortly after
chemotherapy (within hours or a couple of days of comple-
tion) and are usually self-limited, resolving in a few days.
However, they usually reoccur following subsequent admin-
istration and increase in both duration and severity. In addi-
tion, pharyngolaryngospasm syndrome, distinct from cold-
induced pharyngolaryngeal dysesthesias, can appear in less
than 1 % of patients within hours of oxaliplatin infusion and
without any sign of respiratory distress [15, 16].
W ith the repetition of chemotherapy cycles, 50 to 70 % of
patients develop a persistent peripheral neuropathy, manifesting
as a symmetric, distal, primarily sensory polyneuropathy char -
acterized by the persistence of paresthesias between the che-
motherapy cycles, numbness in the hands and feet and neuro-
pathic pain. In the most severe cases, patients may suffer from
sensory ataxia as well as a deep and superficial sensory loss,
eventually leading to functional impairment [17]. The severity
of this CIPN depends on both the cumulated dose received and
its intensity. The median time to onset of grade 3 neurotoxicity
is at the 10th cycle, namely a cumulative dose of 874 mg/m
2
[18]. Improvement of the neurological symptoms is observed
after discontinuation of treatment, with a median time to recov-
eryof13weeks[18]. However, a recent study has shown the
persistence of neuropathic symptoms 29 months after the last
chemotherapy cycle for almost 80 % of treated patients, seri-
ously challenging the reversibility of this neuropathy [19].
Moreover, peripheral neuropathy may develop and worsen
several months after cessation of chemotherapy [20]. This
phenomenon, known as coasting, is shared by all platinum
drugs and highlights the import ance of finding early clinical
markers of chronic neuropathy. Interestingly, the intensity of
acute thermal hypersensitivity (especially cold allodynia) is a
relevant clinical marker of early oxaliplatin neurotoxicity and
may predict an increased risk of developing chronic and
severe CIPN [21].
Spindle Poisons
Vinca Alkaloids
Vincristine is a major anticancer drug in hematology and
pediatrics (sarcoma) but represents the most neurotoxic among
the Vinca alkaloids [22]. Around 50 % of patients experience
sensory-motor peripheral neuropathies [23]. Vincristine neuro-
toxicity is cumulative and dose-dependent [24]. Symptoms
364, Page 2 of 9 Curr Pain Headache Rep (2013) 17:364
appear after a cumulative dose of 12 mg while chemotherapy
should be stopped after a cumulative dose of 30–50 mg [25,
26]. Neuropathy includes numbness and tingling of the hands
and feet with paresthesias and dysesthesias, and a loss of deep
tendon reflexes. The most severe cases can be associated with
distal muscle weakness. Autonomic disorders can also be
found in more than a third of patients [24]. More rarely,
patients develop eye movement disturbances and paralysis of
the vocal cords [24]. After treatment discontinuation, the re-
versal of neurological symptoms is usually slow, taking several
months [25].
Taxanes
Paclitaxel is approved for the treatment of various tumors
(ovary, breast, head and neck, and lung) [27]. It is responsible
for sensory neuropathy which may begin as early as 24–
72 hours after the administration of a single high dose and
affects 59–78 % of patients [23, 28]. The neuropathy is
dependent on the cumulative dose (>1,400 mg/m
2
), the dose
magnitude during each cycle (>200 mg/m
2
)andtheperfusion
duration (short duration) [10, 29]. This CIPN is associated
with paresthesia, numbness, tingling and burning, and me-
chanical and cold allodynia. Patients describe the symptoms
as a “stocking-and-glove” distribution that affects the feet and
the toes [28]. Perioral numbness has also been reported [30].
Loss of tendon reflexes, vibration sensation and propriocep-
tion can also be observed [28]. More rarely, motor symptoms
such as mild distal weakness with myalgia are found, affecting
toeextensormuscles[31, 32].
As with paclitaxel, docetaxel is mainly used for the treat-
ment of solid tumors (breast, lung, stomach and androgen-
independent prostate cancer) [33]. Docetaxel-induced neurop-
athy is mainly sensory and correlated to cumulative
dose. Severe neuropathies may appear after a cumula-
tive dose of 600 mg/m
2
[34] and can be associated with motor
impairment [35]. However, compared to paclitaxel, docetaxel-
induced neuropathy is less frequent (1–9 %; grade 3/4) [36],
with only mild sensory symptoms that reverse spontaneously
after treatment discontinuation [34].
Thalidomide
Thalidomide is used in the treatment of multiple mye-
loma [37]. About 40 % of patients experience neuropa-
thy and this proportion increases to 100 % after
7 months of thalidomide therapy [38, 39]. This CIPN
is characterized by sensory neuropathy associated with
paresthesia, tingling, dysesthesia and a slight loss of
tactile sensation at the extremities of the limbs [39].
The sev erity of the neuropathy is pr obably dose-
dependen t but definitive correlation with doses or treatment
durations has yet to be clarified [40, 41].
Bortezomib
Bortezomib is also approved for the treatment of multiple
myeloma [42]. Neurotoxicity, generally occurring within the
first chemotherapy courses, is one of the most non-
hematologic al and dose-limiting toxicities of bortezomib [22].
Pain is the most prominent symptom in neuropathic patients
[43] and is reported in approximately 50 % of previously
untreated patients and 81 % of previously treated patients
[44]. In the majority of cases, the neuropathy is reversible [45].
Pathophysiology: Cellular and Subcellular Targets
In the past two decades, the development of in vitro and
in vivo models has provided valuable tools for the study of
the pathogenesis of CIPN [8]. Nowadays, it is well known that
one anticancer drug may act on various subcellular targets of
peripheral sensory nerves, and that one mechanism of neuro-
toxicity may be shared by several chemotherapeutic agents,
independent of their antitumor properties. Hence, there is still
no consensus on the molecular mechanisms leading to the
development of CIPN. The main neurotoxic mechanisms of
anticancer drugs identified so far are summarized in Fig. 1.
Toxicokinetics of Anticancer Drugs
Recent work has suggested a specific relationship between the
toxicokinetics of anticancer drugs and their neurotoxicity,
suggesting that several membrane transporters could contrib-
ute to the uptake of the anticancer drugs by dorsal root ganglia
(DRG) and nerves [46, 47, 48•]. Platinum salts are substrates
for ATP-Binding Cassette (ABC) proteins (ABCC1, 2 and 4),
solute carrier (SLC) proteins (SLC22A, 31A and 47A) and
ATPase membrane proteins (ATP7A and 7B), which means
that these drug carriers can influence the influx or efflux of
platinum salts across cell membranes, and consequently their
cellular uptake [48•]. For example, copper transporters may be
associated with the neurotoxicity of platinum drugs in rats [49,
50]. Ctr1 and ATP7A transporters were overexpressed in rat
DRG with a neu ron specific pa ttern; large-sized neurons
expressed rCtr1 and medium- or small-sized neurons expressed
ATP 7A [ 49, 50]. What
’s more, in treated rats, equitoxic doses
of oxaliplatin, cisplatin or carboplatin caused a selective toxic-
ity in rCtr1-expressing DRG neurons, but not in ATP7A ex-
pressing neurons [49]. The organic cation/carnitine transporters
rOctn1 (SLC22A4) and rOctn2 (SLC22A5) can mediate
oxaliplatin neurotoxicity and are strongly expressed in rat
DRG [51]. Inversely, low-level ABCC2 (Multidrug Resistance
Protein 2 [MRP2]) gene expressionwasfoundinDRGcom-
pared to the brain and spinal cord of the rat, which could
facilitate peripheral neurotoxicity with cisplatin by decreasing
the platinum salt efflux out of cells [47]. The same observation
Curr Pain Headache Rep (2013) 17:364 Page 3 of 9, 364
hasbeenmadeforVinca alkaloids and taxanes, which are
substrates of ABCB1 (P-glycoprotein [P-gp]). In the rats,
ABCB1 genes were less expressed in the DRG compared to
the brain and spinal cord, and the activity of the efflux proteins
(measured by the incorporation of a radioactive substrate,
99m
Tc-sestamibi) was lower in the peripheral n ervous system
(PNS) (DRG and sciatic nerve) compared to the central nervous
system (CNS) (brain and spinal cord). These results suggest
that the PNS would be less protected by the blood nerve barrier
than the CNS would be with the blood brain barrier, explaining
the susceptibility of the PNS to neurotoxic anticanc er drugs [46,
47]. In agreement with this suggestion, DRG concentrations of
platinum salts or paclitaxel are close to those achievable in
tumor tissue, while much lower concentrations can be
detected in the CNS [52–54]. However, more experiments
(histology, pharmacology and toxicology) will be required to
advance our understanding of these cellular transportation
mechanisms.
Platinum Salts
Oxaliplatin-induced acute neurotoxicity has been described as
a channelopathy, involving voltage-gated sodium and potassi-
um channels. Oxaliplatin would shift the voltage dependence
of both Na
+
and K
+
channels toward more negative voltages
(the channels become activated by lower positive charges),
thus leading to a transient nerve hyperexcitability [55–59]. As
first hypothesized by Grolleau et al. (2001), oxaliplatin-
associated acute neurologic disorders have long been attributed
to oxalate, an oxaliplatin metabolite, which could induce a
transient and non-functional disruption of voltage-gated ion
channels by chelating intracellular calcium ions in neurons
[57]. However, recent evidence questions this hypothesis. First-
ly, intracellular calcium concentrations have been shown to be
unaffected following acute exposure to oxaliplatin [60]. Sec-
ondly, the concentrations of oxaliplatin used in these studies
were sometimes very high (up to 500 μM), while it has been
shown that the max imum plasmatic concentration of
oxaliplatin after a dose of 85 mg/m
2
infused over 2 hours
(FOLFOX regimen) is about 5 μM[61]. Oxalate is known to
be responsible for renal and neurological damage caused by the
formation of calcium oxalate crystals, as in ethylene glycol
poisoning [62]. It is very likely that an oxalate concentration
sufficiently high to influence the voltage dependency of sodi-
um channels would also cause a strong renal toxicity associated
with hypocalcaemia, which is rarely observed in patients re-
ceiving oxaliplatin [15]. Similarly, although ethylene glycol
toxicity is associated with neuromuscular symptoms that re-
semble those induced by oxaliplatin, cold-induced dysesthesia
has never been documented in any case of ethylene glycol
intoxication [62]. Recent evidence suggests that oxaliplatin
has a specific effect on voltage-gated channels [63], although
the exact mechanism of action remains unknown. Dimitrov
and Dimitrova (2011) recently provided a new potential mech-
anism for oxaliplatin-induced acute nerve hyperexcitability that
involves the impairment of fast potassium channel functioning
in myelinated axon internodes, forming internodal sources of
after-discharges in response to a saltatory action potential [64•].
Fig. 1 Schematic representation
of the main cellular and
subcellular actors involved in the
pathogenesis of CIPN at the
dorsal root ganglia level.
Although neurotoxic anticancer
drugs display different
pharmacological mechanisms,
several neurotoxic mechanisms
(i.e., neuronal targets) are shared
by various chemotherapeutic
agents from different classes
364, Page 4 of 9 Curr Pain Headache Rep (2013) 17:364
Oxaliplatin-induced chronic neuropathy resembles that of
the other platinum compounds, cisplatin and carboplatin. In
the same way, animal studies have demonstrated similar mor-
phological changes in nervous tissues [65•]. Cisplatin was
responsible of nucleolar alterations (rather than nuclear ones)
and a disorganization of ribosomes, with a shrinkage of the
Nissl substance and an increase in neurofilaments. The somat-
ic, nuclear and nucleolar size of DRG neurons showed a
significant and dose dependent cellular atrophy without obvi-
ous neuronal loss [66]. In contrast, satellite cells were less
altered than neurons [66]. Pathological changes in the periph-
eral nerves were very mild in comparison to neuron body cells
[67]. Platinum salts have a strong affinity for the DNA of
DRG cells and the neurotoxicity is believed to result from the
effect of their alkylating properties on the DNA [53, 68, 69].
When plat inum adducts exceed the DNA-repair c apacity,
neurons undergo cell death through apoptotic mechanisms.
More precisely, cisplatin is able to induce cell cycle re-entry in
postmitotic neurons, thus triggering apoptosis through cell
cycle checkpoint signaling [70]. Recently, the formation of
platinum adducts on mitochondrial DNA following cisplatin
exposure has been demonstrated in vitro and in vivo. Mito-
chondrial toxicity could also represent an important patho-
physiological basis for platinum salt neurotoxicity [71], as
well as satellite glial cell activation in DRG [72].
Several studies in animal models of CIPN have pointed out
the involvement of ion channels in the pathogenesis of neu-
ropathic pain. In particular, transient receptor potential (TRP)
channels have been extensively studied for their role in tem-
perature perception and mechanosensation, two commonly
altered features in patients with CIPN. Oxaliplatin-induced
acute and chronic sensory disorders have been associated with
sensitization of TRP V1 and TRPA1 in cultured rat DRG
neurons, potentially accounting for hot and cold hypersensi-
tivity, respectively [73]. TRPM8 was found to be up-regulated
in mice DRG at day 3 after a single oxaliplatin administration,
while capsazepine (a non-selective TRPM8 channel blocker)
significantly decreased cold allodynia [74]. More recently,
Descoeur et al.(2011)demonstratedanimpairedexpression
profile of several ion channels in mice DRG following a single
oxaliplatin injection: a decreased e xpression of TREK-1,
TRAAK and Kv1.1 and an up-regulation of Nav1.8, TRPA1
and HNC1 (hyperpolarization-activated cyclic nucleotide-
gated 1) mRNA. Ivabradine, a non-selective HCN inhibitor,
succes sfully reduced oxaliplatin-evoked co ld a llodynia in
mice [75]. Oxaliplatin-induced acute and chronic sensory
disorders have been associated with sensitization of TRPV1
and TRPA1 in cultured rat DRG neurons, potentially account-
ing for hot and cold hypersensitivity, respectively [73]. In
mice lacking TRPA1, Nassini et al. (2011) demonstrated that
oxaliplatin- and cisplatin-induced mechanical allodynia
were absent and reduced, respectively [76]. Additionally,
cisplatin-induced mechanical hypersensitivity has been
associated with an increased expression of TRPV2, P2X3
and ASIC3 channels in DRG neurons [77].
Spindle Poisons
The mechanism of action of taxanes and Vinca alkaloids
involves, respectively, excessive stabilization and inhibition
of mitotic spindle microtubule formation. Although DRG
cells are non-proliferative, differentiated neurons, microtu-
bules are essential for the transport of proteins from the cell
body into and down the length of the axon. By impairing
microtubule formation, the spindle poisons disrupt the axo-
plasmic transport which eventually leads to neuronal death.
Longer axons are more vulnerable to axonal transport disrup-
tion which explains the stocking-and glove pattern of the
resulting neuropathy, affecting primarily the lower limbs.
Nerve sections from paclitaxel or docetaxel treated animals
showed an axonopathy with axonal degeneration and col-
lapsed or fragmented myelin sheaths, when examined by light
microscopy [78]. Electron microscopic examination of pe-
ripheral nerves showed primary axonal degeneration, but also
the presence of Schwann cells with condensed chromatin and
“nucleolus-like” formations or enlarged cytoplasmic organ-
elles [78
]. In skin biopsies of rat foot pads, intra-epidermal
nerve fiber density was decreased and correlated with the
neurophysiological assessment [79]. Paclitaxel induces mito-
chondrial abnormalities in peripheral nerves by impairing
Complex I– and Complex II–mediated respiration and ATP
production [80], manifesting as an increase incidence of swol-
len and vacuolated mitochondria in sensory axons [81]but
without affecting the motor nerves [82]. This mitochondrial
impairment results in the production of reactive oxygen spe-
cies (ROS) reinforced by a reduction of the antioxidant de-
fenses in peripheral neurons, suggesting a strong involvement
of oxidative stress in paclitaxel-induced neuropathy [83]. The
pharmacological inhibition of ROS by a non-specific scaven-
ger prevented mechanical hypersensitivity and attenuated
established paclitaxel-induced pain [84]. The involvement of
glial cells in the pathogenesis of paclitaxel-induced neuropa-
thy has also been demonstrated. In rodents, paclitaxel treat-
ment induces an activation of satellite glial cells in the DRG
[72] and spinal cord [80], and a loss of intraepidermal nerve
fibers associated with the activation of Langerhans cells [85].
An accumulation of macrophages within the DRG has also
been described following paclitaxel treatment in rats [86]. A
marked reduction of DRG nerve blood supply by a direct
toxicity on the endothelial cells of the vasa nervorum has also
been demonstrated in animals [87]. Finally, a role for TRP
receptors in the pathogenesis of paclitaxel-associated pain
symptoms has been shown in animals. Paclitaxel-induced pain
hypersensitivity was strongly reduced by selective antagonists
of TRPV1, TRPV4 and TRPA1 (depending on stimulus mo-
dality) [88]aswellasinmicelackingTRPV4[89].
Curr Pain Headache Rep (2013) 17:364 Page 5 of 9, 364
The pathophysiology of Vinca alkaloids induced peripheral
neuropathy remains poorly understood. In animals, vincristine
induces an axonopathy with Wallerian-like degeneration of
myelinated and unmyelinated fibers correlated with neuropath-
ic pain symptoms [65•]. In a rat model, this CIPN has been
associated with an increase of calcium levels and oxidative
stress in peripheral nerves, probably mediated by a mitochon-
drialimpairment[90]. An important role of inflammatory me-
diators has also been linked to vincristine-indu ced neuropath y.
An increased number of Langerhans cells and a loss of intra-
epidermal nerve fibers have also been observed in the skin of
vincristine-treated animals [85], as well as an increased number
of macrophages in the DRG [91]. TRPV4 has also been found
to be involved in the develop ment of sensory disorders follow-
ing vincristine treatment [89]. Finally, abnormal serotonin neu-
rotransmission may be involved in the development of neuro-
pathic pain following vincristine administration, as evidenced
by an increased expression of 5HT2A receptors in the superfi-
cial layers of the dorsal horn spinal cord and in the small- and
medium-sized DRG cells [92]. Mice lacking the serotonin
transporter 5HTT are also less sensitive to vincristine-induced
neuropathic pain but not to neuroto xicity [91].
Bortezomib
Bortezomib-induced neurotoxicity has been correlated with
morphological changes in DRG, affecting predominantly the
Schwann and satellite cells [93]. Mitochondrial toxicity and
endoplasmic reticulum stress represent the two main re-
sponses in Schwann cells following bortezomib treatment,
leading to pathological adaptive responses such as demyelin-
ation and macrophage recruitment [94]. Inhibition of tran-
scription, transport and cytoplasmic translation of mRNAs in
DRG neurons, caused by the accumulation of ubiquitin-
conjugated proteins, has also been reported [95]. Recent find-
ings suggest that bortezomib neurotoxicity may also be inde-
pendent from its proteasome inhibition properties [96]. This
CIPN may be caused by an indirect increase in microtubules
stabilization due to an increased expression of microtubule-
associated proteins [97]
Thalidomide
The toxicodynamic effects of thalidomide on per ipheral
nerves remains poorly elucidated. Neurotoxicity may result
from the inhibition of NF-κB leading to a dysregulation of
neurotrophin sensitivity and to impaired nerve growth factor-
mediated neuron survival [98]. However, this hypothesis is yet
to be demonstrated. Interestingly, thalidomide has been shown
to induce microvascular damage at the vasa nervorum level
due to its antiangiogenic properties. Subsequent decreased
nerve blood flow in DRG could represent a core pathological
mechanism of neurotoxicity [87]. Further studies are needed
to understand the pathogenesis of thalidomide-associated neu-
ropathy, especially in animals.
Therapeutic Strategies
Two therapeutic strategies have been proposed to manage
CIPN, with symptomatic and preventive treatments [99]. The
current pharmacotherapies used to treat CIPN involve tricyclic
antidepressants (amitriptyline, nortriptyline) and anticonvul-
sants (gabapentin, valproic acid, lamotrigine). However these
drugs have limited to no efficacy in the treatment of CIPN and
are associated with important adverse drug ef fects that limit
their chronic use [99]. A recent and robust clinical trial has
demonstrated the efficacy of duloxetine (5 weeks of treatment)
in reducing pain symptoms in patients suffering from
paclitaxel- or oxaliplatin-induced neuropathies compared to
placebo [100••]. This is the first phase III study demonstrating
a beneficial effect in the treatment of CIPN. However , although
duloxetine has been proven to be superior to placebo with
regards to pain relief, its efficacy remains relative (59 % of
patients reported a pain reduction versus 38 % in the placebo
group). New therapeutic opportunities have emerged for the
treatment of CIPN with the use of cannabinoids, which must be
assessed in large scale trials [101].
The use of neuroprotectants, according to the profile of
anticancer drug cytotoxicity (e.g., amifostine/platinum salts
and neurotrophic factors/taxanes), has also revealed a very
weak efficacy in limiting or preventing CIPN [102]. In this
context, the nutraceuticals (e.g., vitamin E, vitamin B6, mag-
nesium, calcium, acetyl-L-carnitine, glutamine, glutathione,
n-acetyl cysteine, omega-3 fatty acids, alpha lipoic acid), as
alternative strategies to pharmacotherapy, have given promis-
ing early results in the treatment or the prevention of CIPN
(for review see [103•]).
Overall, the clinical assessment of therapeutic strategies
suffers from the lack of harmonization among outcome mea-
sures (qualitative or quantitative) and the standardization of
CIPN assessment procedures (objective v ersus subjective
evaluation) [103•]. Consequently, for a validated evidenced
based medicinal treatment, therapeutic strategies for the man-
agement of CIPN must be assessed in large scale randomized
controlled trials.
Conclusion
As highlighted in this review, CIPN still represents a real
problem for the therapeutic management of cancer patients
as it compromises both the oncological prognosis and the
patient’s quality of life. The number of affected patients each
year is probably very high. In clinical trials, CIPN is often
under-rated and under-reported by clinicians due to the lack of
364, Page 6 of 9 Curr Pain Headache Rep (2013) 17:364
consensus about its evaluation. A lot of effort has been made
to characterize the cellular and subcellular mechanisms un-
derlying the neurotoxicity of anticancer drugs. Actual knowl-
edge suggests that neurotoxicity result from several molecular
events in peripheral nerves that may account for the failure of
investigated drugs to prevent CIPN. Indeed, it is highly likely
that only a combination of several treatments that target the
highlighted mechanisms will be successful in providing
neuroprotection.
Compliance with Ethics Guidelines
Conflict of Interest Dr. Jérémy Ferrier reported no potential conflicts
of interest relevant to this article.
Dr. Vanessa Pereira reported no potential conflicts of interest relevant
to this article.
Dr. Jérome Busserolles reported no potential conflicts of interest
relevant to this article.
Dr. Nicolas Authier reported no potential conflicts of interest relevant
to this article.
Dr . David Balayssac reported receiving a grant from Ligue contre le
cancer.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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