03_neurotoxicity in oncology
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151
Riv. It. Neurobiologia, 53 (3-4), 151-167, 2007
Rassegna sintetica
NEUROTOXICITY IN ONCOLOGY:IS NEUROPROTECTION (NP) ATTAINABLE?
A CRITICAL REVIEW
VIDMER SCAIOLI (), ANDREA SALMAGGI (*)
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano;() Clinical Neurophysiology Unit; (*) Neuro-oncology Unit
SUMMARY
The remarkable advances in drug develompment and strategy in oncology
have greatly contributed to improve the survival rates of cancer; hovewer
they have also raised questions on ethics about quality of life of the patients.
One of the emerging practical issues in cancer therapy is that neurological
side effects represent more often one of the most common and threatening
side effects and dose limiting factors in cancer treatment. In this review we
have first tried to characterise the neurological side effects, either systemic
or sporadic. The systematic side effects are represented by peripheral neu-
ropathy and by the ocular manifestations optic neuritis and retinopathy. The
sporadic side effects enbody a wider range of neurological manifestations
spanning from encephalitis, to seizures, to atypical onset neuropathy and
peripheral nervous system complications. It is worth mentioning the rele-
vance of studying even the sporadic side effects because the search of the
mechanisms of the pathogenetic events can reveal congenital predisposing
factors that can be diagnosed before the beginning of the therapy and that
can improve the strategy of treatment. Secondly, we have offered an open
rewiev of the scoring systems, that is the either clinical, subjective or objec-
tive ways to score the side effects and quantitative methods; the latter are
particularly useful in order to characterise in a quantitative way the effect
of neuroprotection. Thirdly, we have reviewed the classic, still widely used,
drugs, responsible for the systematic or sporadic side effects. Fourthly, the
strategy of neuroprotection has been widely analysed, together with the
expected clinical outcome, and what is already defined and what is still in
progress, but nonetheless deserves verification or validation.
Key Words: Chemiotherapy, toxicity, neuroprotection, pe-
ripheral neuropathy, optic neuropathy
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I n t r o d u c t i o n
The improvement in health care systems
and increasing needs in terms of quality
of life, together with the ethical issues of
dignity of death, represent nowadays one of the
main topics in the medical treatment and strat-
egy in oncology.
Several drugs of proved antitumoral efficacy
widely used in oncology have the inconvenience
of causing some neurological complications,
either occasionally or in a more systematic way.
Sometimes, the neurological syndromes become
disturbing enough so as to hamper continuation
of treatment or the use of other drugs.
The term neuroprotection defines the identi-
fication of strategies to prevent or minimise,
directly or indirectly, the neurological side
effects of therapy.
The possible ways by which neuroprotection
can be achieved are:
1. to modify the molecular conformation of the
drug so as to maintain the antitumoral effi-
cacy but minimise the toxic action against
the neural tissue;
2. to combine the drug with other(s) poten-
tially able to exert a protective action on the
healthy nervous tissue;
3. to combine the drug with a vector able to
optimize and make delivery tumor cell-
selective.
A fundamental step in neuroprotection is
represented by an accurate characterisation of
the systematic side effects of anticancer drugs;
one of the main and best known side effects of
antitumoural therapy is represented by periph-
eral neuropathy (PN), as it will be reported later
in the paper.
With the term of systematic side effects we
can define the appearance of a variable degree
of clinical syndromes in most of the patients
undergoing a given treatment.
In this respect, the first part of the paper is
addressed to the description of the most com-
mon and documented neurological complica-
tions associated with the most commonly used
chemotherapeutic drugs.
It is worth mentioning that, in the past, the
characterisation of side effects was not so accu-
rate, because the attention of oncologists was
captured by the fight against the tumour, and lit-
tle care was paid to the characterisation of neu-
rological side effects. Only recently a certain
attention has been paid to the side effects and to
improved quality of life of the patients; on the
other hand, in the light of increased attention
about ethics and dignity of death, an overuse of
treatment may be discouraged; at a certain
point, it could be more important to stop a treat-
ment with devastating side effects.
Therefore, neurotoxicity remains a major
limitation of many drugs used in cancer patients
and their list grows steadily. On one side mag-
netic resonance imaging and other imaging
techniques make easier the recognition of cen-
tral nervous system toxicity; on the other side,
scoring procedures and clinical neurophysiology
make it easy, and acceptable by the patients, to
characterize peripheral nervous system toxicity.
Synthesis and thorough clinical testing of neuro-
protective molecules remain therefore a major
challenge (1).
In this context, with the term of
Chemoprotectants we can define agents that
have been developed to ameliorate the toxicity
associated with cytotoxic drugs. They aim to
provide site-specific protection for normal tis-
sues, without compromising antitumor efficacy.
Several chemoprotectant compounds have been
studied in recent clinical trials. These trials
must include sufficient dose-limiting events for
study and assessment of both toxicity and anti-
tumor effect.
Major c lasses of chemioterapeut ic drugs of
proved neurological toxic i ty
The taxanes (paclitaxel and docetaxel) are
highly active cytotoxic antineoplastic agents.
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how chemotherapy affects the nervous system
and ultimately help develop more strategies to
prevent drug-related neurotoxicity in cancer pa-
tients. (13).
The pathogenesis of central and peripheral
nervous system neurological manifestations
caused by anticancer agents is often poorly
understood, and is probably multifactorial.
A recent observation indicates that genetic
polymorphism for methionine is a potent risk
factor for methtrexate-induced central nervous
system toxicity. Chronic peripheral neuropathy
still represents a major limiting factor in a series
of chemotherapeutic drugs, and the neuropro-
tective effect of several older and newer agents
is either deceptive or insufficiently proven. In
addition to chronic neuropathy, oxaliplatine
causes a unique acute syndrome which may
respond to calcium plus magnesium infusion.
Central nervous system. The most common
neurologic complications involve acute alter-
ations in consciousness, leukoencephalopathy,
seizures, cerebral infarctions, paralysis, in addi-
tion to neuropathy, and ototoxicity. Most of the
information on toxicity comes from prospective
reports and the adult patient population.
Methotrexate, cyclosporin, and platinum com-
pounds are the most frequently cited. No
prospective studies have been done to evaluate
chemotherapy-induced neurotoxicity in the
pediatric population, and the exact incidence of
such complications is unknown.
Mostly unpredictable encephalopathy contin-
ues to be sporadically reported even in patients
treated systemically with conventional
chemotherapy doses. Recently, capecitabine, a
5-fluorouracil prodrug, has been added to the
list. Magnetic resonance diffusion-weighted and
fluid-attenuated inversion-recovery imaging are
useful in demonstrating chemotherapy-induced
central nervous system lesions.
Peripheral Neuropathy is a dose-limiting
side effect for a number of effective chemother-
apeutic agents and a better understanding of
effective mechanisms will lead to novel treat-
ment strategies that will protect neurons with-
out decreasing therapeutic efficacy. (14) In this
respect, the assessment of the efficacy and neu-
rotoxicity of various chemotherapeutic agents is
vital, for a determination of the maximum allow-
able dose. (14)
The type and degree of neuropathy depend
on the chemotherapy drug, dose-intensity, and
cumulative dose. Disabling peripheral neuropa-
thy has a significant negative impact on quality
of life. Accordingly, a reliable assessment of
chemotherapy-induced peripheral neurotoxicity
is necessary, especially if potential neuroprotec-
tive agents are to be investigated.
PN can express itself either with negative or
positive symptoms. Among the positive, painful
paresthesia and disesthesia are the most dis-
turbing. However, pain arises from numerous
causes in cancer patients. On the whole, the
neuropathic pain occurs in 1% of the population
and is difficult to manage. Responses to single
drugs are limited in benefit. Thirty percent will
fail to respond altogether. (15)
Well known to cancer care providers, but per-
haps less well so to others, is that the main
causes of pain in cancer patients in fact arise
due to cancer treatments more frequently than
due to disease itself. In this paper clinical and
laboratory findings on the characteristics of
chemotherapy-induced neuropathic pain are
reviewed and a scheme for the underlying
mechanisms is outlined. (16)
S t e p I I c h a r a c t e r i s a t i o no f t h e s o c a l l e d s p o -
r a d i c s i d e e f f e c t s
Retinopathy and optic neuritis are a rela-
tively frequent complication of medical treat-
ments, both in cancer and in other medical
fields, like antiepileptic drugs.
Continuous intravenous 5 fluorouracil (5FU)
chemotherapy may be associated with a bilater-
al asymmetric anterior optic neuropathy (ON).
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Interestingly, a deficiency of dihydropyrimidine
dehydrogenase (DPD) was documented.
Patients with DPD deficiency are at increased
risk for developing unusual and/or severe toxic-
ity to 5FU. (17)
A number of drugs cause ocular irritation (flu-
orouracil, methotrexate), canalicular fibrosis
with epiphora (fluorouracil), retinopathy
(mitotane, tamoxifen), corneal opacities (tamox-
ifen), cataracts (busulfan, methotrexate), and
optic or ocular motor abnormalities (carmustine,
vinblastine, vincristine). Based on the data in the
National Registry of Drug-Induced Ocular Side
Effects and the literature, adverse ocular reac-
tions of the most commonly used chemothera-
peutic agents have been reviewed. (18; 19)
S t e p I I I h o w t o c h a r a c -t e r i s e t h e n e u r o l o g i c a ls i d e e f f e c t s : t h e s c o -r i n g s y s t e m s d i l e m m a
The best way to evaluate and score the sever-
ity of chemotherapy-induced peripheral neuropa-
thy is still an unsettled matter; a number of scor-
ing systems, involving both clinical and/or neuro-
physiological testing have been employed in the
setting of clinical research. (20-22) (23; 24)
Two main approaches are described: the for-
mer is based upon self-reported peripheral neu-
ropathy and functional status (including physi-
cal function and role function subscales), the
latter is based upon a combination of clinical
and neurophysiological scoring systems (total
neuropathy score,TNS and TNSr, a reduced ver-
sion thereof (25), ECOG score and NCI-CTC 2.0
scores).
In an early study, the severity of chemother-
apy-induced peripheral neuropathy (CIPN) was
evaluated in patients treated with cisplatin- and
paclitaxel-based chemotherapy. A reduced ver-
sion of TNS (TNSr) was also compared. It was
concluded that the TNS and TNSr can be used
to assess the severity of CIPN effectively, and
the results of this evaluation can be reliably cor-
related with the oncologic grading of sensory
peripheral neurotoxicity. (23)
Later on, a multi-center study was developed
to comparatively assess the reduced versions of
the Total Neuropathy Score (TNS), the severity
of chemotherapy-induced peripheral neurotoxic-
ity (CIPN), and to compare the results with those
obtained with common toxicity scales. (24)
A highly significant correlation was demon-
strated between the TNSr and the NCI-CTC 2.0
and ECOG scores; but the TNSr evaluation was
more accurate in view of the more extended
score range. Also, the simpler and faster TNSc
(based only on the clinical neurological exami-
nation) allowed to grade accurately CIPN and
correlated with the common toxicity scores. The
correlation tended to be closer when the senso-
ry items were considered, but also the TNSr
motor items, which were not specifically investi-
gated in any other previous study, significantly
correlated with the results of the common toxi-
city scales. (24; 26)
In a recent paper, the peripheral neuropathy
temporal course has been evaluated by means of
the total neuropathy scoring system (TNS). The
temporal relationships between the PN and
paclitaxel were robustly characterised, and thus
provide reference data and a model for testing
the efficacy of drugs designed to provide neuro-
protection. (27)
Overall, while clinical self-reporting scores
and objective evaluations with neurophyisiologi-
cal tests may be of help in assessing peripheral
neurotoxicity in single patients, only a combina-
tion of these is a reliable tool in the evaluation of
groups of patients undergoing potentially toxic
and/or neuroprotective treatments.
The TNS is presently the most reliable tool in
this context, despite the need for an experi-
enced team in its application.
On the other hand, other scoring systems ad-
dress neuroophtalmological systematic side-ef-
fects, since evidence grows for a selective toxic-
ity on these structures by new agents used in
therapy. Also in this respect, a combination of
both clinical and neurophysiological tests are
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V. SCAIOLI, A. SALMAGGI
under active investigation. Recent reports of pa-
clitaxel treated patients have emphasised the
clinical relevance of ophtalmological and elec-
trophysiological evaluation and characterisation
of neuroophtalmological manifestation. (28; 29)
T h e s t r a t e g i e s o f n e u -r o p r o t e c t i o n
a. Modification of the molecular structu-re of the drugThe taxanes. Paclitaxel and its semi-syn-
thetic derivative docetaxel are potent
chemotherapeutic agents that block tubulin
depolymerisation, leading to the inhibition of
microtubule dynamics and cell cycle arrest.
Although docetaxel and paclitaxel share a mutu-
al tubulin binding site, mechanistic and pharma-
cological differences exist between these
agents. For example, docetaxel has increased
potency and an improved therapeutic index
compared with paclitaxel, and its short 1-h infu-
sion offers a substantial clinical advantage over
the prolonged infusion durations required with
paclitaxel. In clinical studies, docetaxel
monotherapy demonstrated good response
rates and an acceptable toxicity profile in both
paclitaxel- and platinum-refractory ovarian can-
cer patients. In particular, neurotoxicity - a
dominant side effect with both paclitaxel and
cisplatin - occurs at a low incidence with doc-
etaxel, making docetaxel a promising agent for
combining cisplatin and other platinum com-
pounds. In Phase II studies, the combination of
docetaxel with either cisplatin or carboplatin
has yielded impressive response rates of 69-74
and 81-87%, respectively. Furthermore, Phase
III data suggest that docetaxel-carboplatin and
paclitaxel-carboplatin are similarly efficacious
with respect to progression-free survival and
clinical response, although neurotoxicity occurs
more frequently with the paclitaxel regimen.
While paclitaxel-carboplatin remains the stan-
dard treatment for the management of advanced
ovarian cancer, docetaxel-carboplatin appears
to be a promising alternative, particularly in
terms of minimising the incidence and severity
of peripheral neuropathy. (30)
A prospective study was performed to deter-
mine if corticosteroid co-medication reduces
the incidence and severity of docetaxel-induced
neuropathy. (30; 31).
Neuropathy was evaluated by clinical sum-
score for signs and symptoms and by measure-
ment of the vibration perception threshold
(VPT). The severity of neuropathy was graded
according to the National Cancer Institutes
Common Toxicity Criteria. The docetaxel-cis-
platin combination chemotherapy induced a
predominantly sensory neuropathy in 29 (53%)
out of 55 evaluable patients. At cumulative
doses of both cisplatin and docetaxel above 200
mg m(-2), 26 (74%) out of 35 patients devel-
oped a neuropathy which was mild in 15, mod-
erate in ten and severe in one patient.
Significant correlations were present between
both the cumulative dose of docetaxel and cis-
platin and the post-treatment sum-score of neu-
ropathy (P < 0.01) as well as the post-treatment
VPT (P < 0.01). The neurotoxic effects of this
combination were more severe than either cis-
platin or docetaxel as single agent at similar
doses. (32)
Oxaliplatin. Oxaliplatin is the only third-
generation platinum derivative to have found a
place in routine cancer therapy and conse-
quentely it has become an integral part of vari-
ous chemotherapy protocols, in advanced col-
orectal cancer in particular (33; 34; 35). Com-
pared with cisplatin, L-OHP has no renal toxici-
ty, only mild hematological and gastrointestinal
toxicity, while neurotoxicity is the limiting toxi-
city. In addition, Oxaliplatin-containing
chemotherapy regimens are utilized commonly
for metastatic colorectal cancer and increasing-
ly in the adjuvant setting following surgical re-
section. Oxaliplatin-induced neurotoxicity con-
sists of a rapid-onset, cold-induced, reversible
acute sensory neuropathy and a late-onset cu-
mulative sensory neuropathy that occurs after
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several cycles of therapy(36). In about three
fourths of patients, neurotoxicity is reversible
with a median time to recovery of 13 weeks af-
ter treatment discontinuation. To date, oxali-
platin has proven to be a safe and effective ther-
apy for colorectal cancer and side effects have
been easy to manage with appropriate aware-
ness from patients and care providers. (35)
Delayed neurotoxicity is a complication
which must be considered for patients receiving
adjuvant therapy and attempts to utilize the
minimum effective cumulative dose of oxali-
platin are warranted. (37)
Various strategies have been proposed to
prevent or treat oxaliplatin-induced neurotoxic-
ity. The Stop-and-Go concept uses the re-
versibility of neurologic symptoms to aim at de-
livering higher cumulative oxaliplatin doses as
long as the therapy is still effective. Several neu-
romodulatory agents such as calcium-magne-
sium infusions, antiepileptic drugs like carba-
mazepine or gabapentin, amifostine, alpha-lipoic
acid, and glutathione have shown promising ac-
tivity in prophylaxis and treatment of oxali-
platin-induced neurotoxicity. However, larger
confirmatory trials are still lacking so that, to
date, no evidence-based recommendation can
be given for the prophylaxis of oxaliplatin-in-
duced neurotoxicity. The predictability of neuro-
toxicity associated with oxaliplatin-based thera-
py should allow patients and doctors to develop
strategies to manage this side effect in view of
the individual patients clinical situation. (38)
This side effect has been described as a tran-
sient distal dysesthesia, enhanced by exposure
to cold, and as a dose-related cumulative mild
sensitive neuropathy. Two groups of patients
(18 and 13) with advanced colorectal cancer,
treated with median cumulative doses of L-OHP
862 mg/m2 and 1,033.5 mg/m2, were studied. All
the patients had been evaluated previously, dur-
ing treatment, after discontinuation and after a
long follow-up of 5 years to verify the incidence
and the characteristics of the neuropathy
induced by this antineoplastic agent. The clini-
cal and neurophysiological examinations
showed an acute and transient neurotoxicity
and a cumulative dose-related sensory neuropa-
thy in nearly all the patients. The reversibility of
these effects was studied. Five patients contin-
ued to manifest symptoms and signs of neuro-
toxicity after a long follow-up, indicating per-
sistence of this peculiar type of neuropathy(39)
Nedaplatin. Nedaplatin (cis-diammineglyco-
latoplatinum) can be given without hydration;
its dose-limiting toxicity is myelosuppression, in
particular thrombocytopenia. Although activity
has been shown, no data from randomized com-
parative trials are available to allow a judgement
on its potential advantages. (33) It is worth
mentioning that this association is of potentially
clinical relevance given that the traditional asso-
ciation of paclitaxel and cisplatin results in a
cumulative neurotoxicity severe enough to
result dose-limiting in the majority of the
patients treated with this association (40)
b. Combination of neuroprotective agentswith neurotoxic drugs:
The contemporary or sequential treatment
with a number of agents has been shown to be of
some effectiveness in minimizing neurotoxicity.
The goal of this approach is to keep the score of
neurotoxicity at a level compatible with treat-
ment continuation.
Peripheral neuropathy (PN), associated with
diabetes, neurotoxic chemotherapy, human
immunodeficiency virus (HIV)/antiretroviral
drugs, alcoholism, nutritional deficiencies,
heavy metal toxicity, and other etiologies,
results in significant morbidity. Conventional
pain medications primarily mask symptoms and
have significant side effects and addiction pro-
files. However, a widening body of research indi-
cates alternative medicine may offer significant
benefit to this patient population. Alpha-lipoic
acid, acetyl-L-carnitine, benfotiamine, methyl-
cobalamin, and topical capsaicin are among the
best-researched alternative options for the
treatment of PN. Other potential nutrient or
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botanical therapies include vitamin E, glu-
tathione, folate, pyridoxine, biotin, myo-inositol,
omega-3 and -6 fatty acids, L-arginine, L-gluta-
mine, taurine, N-acetylcysteine, zinc, magne-
sium, chromium, and St. Johns wort. In the
realm of physical medicine, acupuncture, mag-
netic therapy, and yoga have been found to pro-
vide benefit. New cutting-edge conventional
therapies, including dual-action peptides, may
also hold promise. (41)
Amifostine is a pharmacological antioxidant
used as a cytoprotectant in cancer chemothera-
py and radiotherapy. It is thought to protect nor-
mal tissues relative to tumor tissue against
oxidative damage inflicted by cancer therapies
by becoming concentrated at higher levels in
normal tissues. The degree to which amifostine
nevertheless accumulates in tumors and pro-
tects them against cancer therapies has been
debated. (42)
Clinically relevant levels of amifostine toxici-
ty were observed in several studies, but subcu-
taneous administration may reduce such toxici-
ty. Amifostine showed protection against mu-
cositis, esophagitis, neuropathy, and other side
effects, although protection against cisplatin-in-
duced ototoxicity was not observed. No evi-
dence of tumor protection was observed. (42)
Vitamin E. Peripheral sensory neuropathy is
the main non-haematological side-effect related
to cisplatin chemotherapy. The strong similarity
between clinical and neuropathological aspects
in peripheral neuropathy induced by cisplatin
and neurologic syndromes due to vitamin E de-
ficiency, prompted Bove and Colleagues (43) to
investigate the relationship between cisplatin
neuropathy and plasmatic levels of vitamin E
(alpha-tocopherol). In a study vitamin E levels
were measured in the plasma of 5 patients
(Group 1) who developed severe neurotoxicity
after cisplatin treatment and in another group of
5 patients (Group 2); the plasmatic levels of vi-
tamin E were analysed before and after 2 or 4
cycles of cisplatin treatment. The results
showed that patients of group 1 presented low
plasmatic levels of vitamin E and that patients of
group 2 presented significantly lower levels of
vitamin E after 2 or 4 cycles of cisplatin than be-
fore treatment. These data suggest that an inad-
equate amount of the antioxidant vitamin E due
to cisplatin treatment could be responsible of
the peripheral nerve damage induced by free-
radicals. Given the lack of toxicity of vitamin E,
we need to systematically assess the possible
neuroprotective role of vitamin E supplementa-
tion in patients treated with cisplatin
chemotherapy. (43)
The dose-limiting toxicity of the chemothera-
peutic agent vincristine is peripheral neuropathy,
for which there is no established therapy. (44)
The amino acid glutamate has been pro-
posed as a neuroprotectant for vincristine.
(44)
Leukemia inhibitory factor (LIF) (45) The
growth factor leukaemia inhibitory factor (LIF)
has neuroprotectant activity in preclinical mod-
els of nerve injury and degeneration and is now
in a phase II trial in chemotherapy-induced
peripheral neuropathy (CIPN). It is therefore
important to ensure that LIF neither inhibits the
antitumour activity of these drugs, nor stimu-
lates tumour growth. (45)
These results suggest that LIF may be safely
used in human trials as a neuroprotectant for
patients receiving cisplatin, paclitaxel and car-
boplatin without concern for impairment of anti-
tumour effect (45).
Glutathione (36) A randomized, double-
blind, placebo-controlled trial to assess the effi-
cacy of glutathione (GSH) in the prevention of
oxaliplatin-induced neurotoxicity was per-
formed(36) The study provided evidence that
GSH is a promising drug for the prevention of
oxaliplatin-induced neuropathy, and that it does
not reduce the clinical activity of oxaliplatin(36)
Nimodipine (46) Previous randomised trial
in patients with advanced ovarian cancer indi-
cated a significant response and survival advan-
tage for those receiving high-dose (100 mg/m2)
as compared with low-dose (50 mg/m2) cis-
platin in combination with cyclophosphamide
(750 mg/m2). However, this was accompanied
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by more toxicity; peripheral neuropathy was
troublesome, with 32% of patients experiencing
> or = WHO grade 2 at the cisplatin dose of 100
mg/m2. Nimodipine is a calcium-channel antag-
onist that has provided protection from cis-
platin-induced neurotoxicity in a rat model sys-
tem.(46) These studies did not demonstrate a
neuroprotective effect for nimodipine. The pri-
mary efficacy variable, i.e, the neurotoxicity
score at the end of treatment, gave a signifi-
cantly lower mean for placebo patients than for
nimodipine patients. (46)
Acetyl-L-carnitine (47; 48) The hypothesis
that acetyl-L-carnitine (ALC) may have a pro-
tective and a curative role in chemotherapy-
induced hyperalgesia was tested in vivo, in ani-
mal models of cisplatin-, paclitaxel- and vin-
cristine-induced neuropathy. In addition, the
possible interaction between ALC and vin-
cristine antineoplastic action was assessed.
Chemotherapy-induced peripheral neuropathy
(CIPN) was induced in different groups of rats.
The effect of ALC was evaluated both when its
administration was started together with the
administration of anticancer drugs (preven-
tive protocol) and when ALC administration
was started later on during treatment (cura-
tive protocol). The ALC treatment significantly
prevented the lowering of the mechanical noci-
ceptive threshold when the administration start-
ed concomitantly and, respectively, with cis-
platin, paclitaxel and vincristine as compared to
each drug alone. Furthermore, when ALC
administration was started later on during treat-
ment, at the stage of well-established neuropa-
thy, ALC was able to restore the mechanical
nociceptive threshold within a few days. Finally,
experiments indicated that ALC does not inter-
fere with the antitumor effects of vincristine.
Considering the absence of any satisfactory
treatment currently available for CIPN in a clin-
ical setting, these are important observations,
opening up the possibility of using ALC to treat
a wide range of patients who have undergone
chemotherapy and developed sensory peripher-
al neuropathy. (47; 49)
Glutamine (44; 50; 51) In a non-randomised
study neurologic signs and symptoms, and
changes in nerve-conduction, were studied in 46
consecutive patients given high-dose paclitaxel
either with (n=17) or without (n=29) glutamine.
Patients who received glutamine developed sig-
nificantly less weakness (P = 0.02), less loss of
vibratory sensation (P = 0.04) and less toe
numbness (P = 0.004) than controls. The per
cent change in the compound motor action
potential (CMAP) and sensory nerve action
potential (SNAP) amplitudes after paclitaxel
treatment was lower in the glutamine group, but
this finding was not statistically significant in
these small groups. The study indicated that
serial neurologic assessment of patient symp-
toms and signs seemed to be a better indicator
of a possible glutamine effect than sensory- or
motor-nerve-conduction studies. (51)
In another study, there were paired pre- and
post-paclitaxel evaluations on 33 patients who
did not receive glutamine and 12 patients who
did. The median interval between pre- and post-
exams was 32 days. For patients who received
glutamine, there was a statistically significant re-
duction in the severity of peripheral neuropathy
as measured by development of moderate to se-
vere dysesthesias and numbness in the fingers
and toes (P < 0.05). The degree and incidence of
motor weakness was reduced (56 versus 25%; P
= 0.04) as well as deterioration in gait (85 versus
45%; P = 0.016) and interference with activities
of daily living (85 versus 27%; P = 0.001). Moder-
ate to severe paresthesias in the fingers and toes
were also reduced (55 versus 42% and 64 versus
50%, respectively), although this value was not
statistically significant. All of these toxicities
were reversible over time. It was concluded that
glutamine may reduce the severity of peripheral
neuropathy associated with high-dose paclitaxel;
however, results from randomized, placebo-con-
trolled clinical trials will be needed to fully assess
its impact, if any. Trials are currently ongoing to
assess its efficacy for standard-dose paclitaxel in
breast cancer and other tumors for which periph-
eral neuropathy is the dose-limiting toxicity. (50)
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V. SCAIOLI, A. SALMAGGI
Corticosteroid Two groups of patients treat-
ed with docetaxel in subsequent cohorts were
prospectively analyzed for neurotoxicity. Group
A consisted of 38 patients with a variety of solid
tumors, who were treated in studies before cor-
ticosteroid co-medication was recommended,
while 49 female patients in group B with
metastatic breast cancer were treated after co-
medication with corticosteroids was introduced
as a routine. Neuropathy was evaluated by a
clinical sum-score for symptoms and signs, and
by measurement of the vibration perception
threshold (VPT). The severity of neuropathy
was graded according to NCI Common Toxicity
Criteria. In 42% of patients of group A and in
65% of patients of group B a mainly mild neu-
ropathy was documented. There was no statisti-
cally significant difference in neurotoxicity
between group A and B. The cumulative dose of
docetaxel showed a significant correlation with
post-treatment scores of VPT, sensory sum-
score, grade of paresthesias, and grade of neu-
rosensory and neuromotor toxicity.
Corticosteroid co-medication does not reduce
the development of docetaxel-related neuropa-
thy. (31)
Melatonin (52) Experimental data have
suggested that the pineal hormone melatonin
(MLT) may counteract chemotherapy-induced
myelosuppression and immunosuppression. In
addition, MLT has been shown to inhibit the
production of free radicals, which play a part in
mediating the toxicity of chemotherapy. A
study was therefore performed in an attempt to
evaluate the influence of MLT on chemotherapy
toxicity. The study involved 80 patients with
metastatic solid tumors who were in poor clini-
cal condition (lung cancer: 35; breast cancer:
31; gastrointestinal tract tumors: 14). Lung can-
cer patients were treated with cisplatin and
etoposide, breast cancer patients with mitox-
antrone, and gastrointestinal tract tumor
patients with 5-fluorouracil plus folates.
Patients were randomised to receive
chemotherapy alone or chemotherapy plus MLT
(20 mg/day p.o. in the evening).
Thrombocytopenia was significantly less fre-
quent in patients concomitantly treated with
MLT. Malaise and asthenia were also significant-
ly less frequent in patients receiving MLT.
Finally, stomatitis and neuropathy were less
frequent in the MLT group, albeit without sta-
tistically significant differences. Alopecia and
vomiting were not influenced by MLT. This pilot
study seems to suggest that the concomitant
administration of the pineal hormone MLT dur-
ing chemotherapy may prevent some
chemotherapy-induced side-effects, particular-
ly myelosuppression and neuropathy.
Evaluation of the impact of MLT on chemother-
apy efficacy will be the aim of future clinical
investigations(52)
N-acetyl-cisteine (53) Although adding
oxaliplatin to fluorouracil and leucovorin in
adjuvant chemotherapy for colon cancer may
improve disease-free survival, grade 3-4 sensory
neuropathy also increases. To determine
whether oral N-acetylcysteine is neuroprotec-
tive against oxaliplatin-induced neuropathy, a
pilot study was undertaken. Fourteen stage III
colon cancer patients with 4 or more regional
lymph nodes metastasis (N2 disease) receiving
adjuvant biweekly oxaliplatin (85 mg/m(2)) plus
weekly fluorouracil boluses and low-dose leu-
covorin were randomized to oral N-acetylcys-
teine (1,200 mg) (arm A) or placebo (arm B).
Clinical neurological and electrophysiological
evaluations were performed at baseline and
after 4, 8, and 12 treatment cycles. Treatment-
related toxicity was evaluated based on National
Cancer Institute (NCI) Criteria. After four
cycles of chemotherapy, seven of nine patients
in arm B and two of five in arm A experienced
grade 1 sensory neuropathy. After eight cycles,
five experienced sensory neuropathy (grade 2-4
toxicity) in arm B; none in arm A (p
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NEUROTOXICITY IN ONCOLOGY. A CRITICAL REVIEW
incidence of oxaliplatin-induced neuropathy in
colon cancer patients receiving oxaliplatin-
based adjuvant chemotherapy. (53)
Calcium and magnesium infusion. Infu-
sions of oxalate chelators Ca/Mg seem to reduce
incidence and intensity of acute oxaliplatin-in-
duced symptoms and might delay cumulative
neuropathy, especially in 85 mg/m(2) oxaliplatin
dosage. (54; 54) (54).
Erythropoietin (55) In addition to its well-
known erythropoetic effect, erythropoietin
(EPO) has also been shown to be neuroprotec-
tive in various animal models. In contrast to
EPO, carbamylated EPO (CEPO) does not bind
to the EPO receptor on UT7 cells or have any
haematopoietic/proliferative activity on these
cells. In vivo studies in mice and rats showed
that even high doses of CEPO for long periods
are not erythropoietic. However, in common
with EPO, CEPO does inhibit the apoptosis
associated with glutamate toxicity in hippocam-
pal cells. Like EPO, CEPO is neuroprotective in
a wide range of animal models of neurotoxicity:
middle cerebral artery occlusion model of
ischaemic stroke, sciatic nerve compression,
spinal cord depression, experimental autoim-
mune encephalomyelitis and peripheral diabetic
neuropathy. To date, EPO and CEPO have been
exciting developments in the quest for the treat-
ment of various types of neurotoxicity. The
development of CEPO should continue. (55)
c. Medical treatment of peripheral ner-vous system neurotoxicity
A few antiepileptic drugs are acquiring
increasing popularity for non-epileptic syn-
dromes, and particularly for the treatment of
painful neuropathy (56) (57); namely
gabapentin (58), topiramate, venlafaxine and
pregabalin (56) (57). As a matter of fact, for
decades, antiepileptic drugs (AEDs) have been
used to treat a variety of nonepileptic conditions
such as chronic pain, psychiatric disorders, and
movement disorders.
Venlafaxine (Efexor; Wyeth Lederle), a
serotoninergic-like anti-depressant, and Topira-
mate (Topamax; Jansen Cilag), a new anti-
epileptic drug, shares some evidence of clinical
activity in the treatment of neuropathic pain.
Several anti-cancer agents have neurosensory
toxicity as limiting toxicity of their repeated ad-
ministration and one of the most recent and
most widely used is oxaliplatin. No medication is
presently known to be active against oxaliplatin
permanent neurosensory toxicity. It has been
observed that venlafaxine hydrochloride or low-
dose topiramate could be active against the per-
manent neuropathy-related symptoms of oxali-
platin. Both agents allowed pain relief and a sig-
nificant autonomy improvement so to further
encourage venlafaxine hydrochloride and topi-
ramate for the treatment of permanent anti-can-
cer chemotherapy-induced neuropathies. (57)
Gabapentin (Neurontin, Pfizer Canada Inc)
and pregabalin (Lyrica, Pfizer Canada Inc)
were initially developed as antiepileptic drugs
and unlike conventional AEDs used to treat
nonepileptic disorders (e.g., carbamazepine,
phenytoin, valproate) gabapentin offers the
advantages of low toxicity and a favorable side-
effect profile. The largest area of nonepileptic
use of gabapentin is neuropathic pain, in which
it has demonstrated efficacy in treatment of
postherpetic neuralgia, diabetic neuropathy,
and trigeminal neuralgia. It has also been report-
ed effective as therapy for several psychiatric
disorders, most notably bipolar disorder. In
addition, review of the published literature
reveals the usefulness of gabapentin in move-
ment disorders, migraine prophylaxis, and
cocaine dependence. Future clinical studies will
provide further insight into the range of condi-
tions for which gabapentin is effective (58). In
addition, they were later discovered to be effec-
tive in the treatment of neuropathic pain, creat-
ing a relatively novel class of analgesic drugs
even useful for treating a wide range of neuro-
logic and psychiatric conditions. Although its
exact mechanism of action has yet to be deter-
mined, gabapentin is likely to have multiple
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effects. Laboratory evidence suggests that both
gabapentin and pregabalin can inhibit hyperal-
gesia and allodynia evoked by a variety of neural
insults, including peripheral trauma, diabetes
and chemotherapy. Current opinion suggests
these antinociceptive effects occur because of
drug interaction with the alpha2-delta subunit
of voltage-gated calcium channels. Early com-
parative trials and pooled estimates from meta-
analyses suggest that analgesic efficacy of
gabapentin and pregabalin is perhaps slightly
lower than that of tricyclic antidepressants or
opioids. However, the most attractive aspects of
these two drugs include their tolerability, lack of
serious toxicity and ease of use. Future research
efforts are warranted to fully understand the
mechanism of action of these drugs, to clearly
characterize the safety and efficacy of
gabapentin and pregabalin in all clinical neuro-
pathic pain syndromes, and to further explore
the role of these drugs in the rational polyphar-
macy of neuropathic pain. (56)
d. modification of the sensitivity of thetumor to the action of the drug
Recent developments in the treatment of
cancer have involved the use of cellular thera-
pies by the use of carrier cells infected with
viruses able to interfere with survival/replication
of cancer cells. The refinements of this
approach could lead in prospective to minimisa-
tion of damage to healthy tissues. (59)
C o n c l u s i o n
Survival rates for adults and children with
cancer have increased dramatically over the past
few decades. Development of new chemothera-
peutic agents and the expanded use of older
agents have had a major impact on this celebrat-
ed improvement. Recent advances in the devel-
opment and administration of chemotherapy for
malignant diseases have been rewarded with
prolonged survival rates. The cost of progress
has come at a price and the nervous system is
frequently the target of chemotherapy-induced
neurotoxicity. Unlike more immediate toxicities
that affect the gastrointestinal tract and bone
marrow, chemotherapy-induced neurotoxicity is
frequently delayed in onset and may progress
over time. In the peripheral nervous system, the
major brunt of the toxicity is directed against the
peripheral nerve, resulting in chemotherapy-in-
duced peripheral neuropathy (CIPN).
Chemotherapy can have, however, significant
toxicity on the central nervous system. Most of
the information on toxicity comes from prospec-
tive reports and the adult patient population.
Methotrexate, cyclosporin, and platinum com-
pounds are the most frequently cited. It is worth
mentioning, however, that in spite of more ex-
haustive studies performed in adults, no
prospective studies have been done to evaluate
chemotherapy-induced neurotoxicity in the pe-
diatric population, and the exact incidence of
such complications is unknown. Such investiga-
tion is greatly needed, as it may lead to a better
understanding of how chemotherapy affects the
nervous system and ultimately help develop
more strategies to prevent drug-related neuro-
toxicity in pediatric cancer patients. (60)
Chemotherapeutic agents used to treat
haematologic and solid tumors target a variety
of structures and functions in the peripheral
nervous system, including the neuronal cell
body, the axonal transport system, the myelin
sheath, and glial support structures. Each agent
exhibits a spectrum of toxic effects unique to its
mechanism of toxic injury, and recent study in
this field has yielded clearer ideas on how to
mitigate injury. Combined with the call for a
greater recognition of the potentially devastat-
ing ramifications of CIPN on quality of life, basic
and clinical researchers have begun to investi-
gate therapy to prevent neurotoxic injury.
In recent years, oxaliplatin-based chemother-
apy protocols, particularly oxaliplatin in combi-
nation with infusional 5-fluorouracil/leucovorin,
have emerged as the standard of care in first-
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and second-line therapy of advanced-stage col-
orectal cancer. Although oxaliplatin by itself has
only mild hematologic and gastrointestinal side
effects, its clinically dominating toxicity affects
the peripheral sensory nervous system in the
form of 2 distinct types of neurotoxicity, an acute
sensory neuropathy and a chronic, cumulative
sensory neuropathy resembling that caused by
cis-platin and completely reversible. Various
strategies have been proposed to prevent or
treat oxaliplatin-induced neurotoxicity.
Chemoprotectants are agents that have been
developed to ameliorate the toxicity associated
with cytotoxic drugs and to provide site-specific
protection for normal tissues, without compro-
mising antitumor efficacy. Several chemoprotec-
tant compounds have been studied in recent
clinical trials. These trials must include suffi-
cient dose-limiting events for study and assess-
ment of both toxicity and antitumor effect.
Preliminary studies have shown promise for
some agents including glutamine, glutathione,
vitamin E, acetyl-L-carnitine, calcium, and mag-
nesium infusions, but final recommendations
await prospective confirmatory studies. (60)
The stop-and-go concept uses the pre-
dictability and reversibility of neurologic symp-
toms to allow patients to stay on an oxaliplatin-
containing first-line therapy for a prolonged
period. Several neuromodulatory agents such as
calcium-magnesium infusions; antiepileptic
drugs like carbamazepine, gabapentin, and ven-
lafaxine; amifostine; a-lipoic acid; and glu-
tathione have demonstrated some activity in the
prophylaxis and treatment of oxaliplatin-
induced acute neuropathy.
However, randomized trials demonstrating a
prophylactic or therapeutic effect on oxaliplatins
cumulative neurotoxicity are still lacking. The
predictability of neurotoxicity associated with
oxaliplatin-based therapy should allow patients
and doctors to develop strategies to manage this
side effect in view of the individual patients clin-
ical situation. This is of increasing importance,
because the addition of bevacizumab to FOLFOX
will conceivably further prolong the progression-
free survival achieved with FOLFOX so that neu-
rotoxicity and not tumor progression could be-
come the dominating treatment-limiting issue in
the first-line therapy of advanced colorectal can-
cer. (61)
A more specific clinical problem is represent-
ed by the treatment of the neuropathic pain and
new drugs and treatment algorithms in the man-
agement of neuropathic pain have been pro-
posed. New information on opioids (tramadol
and buprenorphine) suggests benefits in the
management of neuropathic pain and has
increased interest in their use earlier in the
course of illness. Newer antidepressants, selec-
tive noradrenaline and serotonin reuptake
inhibitors (SNRIs and SSRIs) have evidence for
benefit and reduced toxicity without an eco-
nomic disadvantage compared to tricyclic anti-
depressants (TCAs). Pregabalin and gabapentin
are effective in diabetic neuropathy and pos-
therpetic neuralgia. Treatment paradigms are
shifting from sequential single drug trials to
multiple drug therapies. Evidence is needed to
justify this change in treatment approach. Drug
choices are now based not only on efficacy but
also on toxicity and drug interactions. For this
reason, SNRIs and gabapentin/pregabalin have
become popular though efficacy is not better
than for TCAs (15).
A future avenue of investigation includes the
identification of patients at higher risk for the
development of peripheral neuropathy and cen-
tral nervous system toxicity (17) based on their
genotype. Identification of these higher-risk
patients may enable us to devise prevention
strategies prior to the onset of this potentially
debilitating complication. (62)
With their significant impact on quality of life,
neurotoxicity treatment and prevention are be-
coming increasingly important issues in the care
of patients with cancer (63); physicians should
be aware of the potential harmful effects of pre-
scribed therapies as well as of the therapeutic
tools in the overall management of their pa-
tients.
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165
Indirizzo:
Vidmer Scaioli
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Neurologico C. Besta Milano
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NEUROTOXICITY IN ONCOLOGY. A CRITICAL REVIEW
167
Cisplatin, Oxaliplatin, Concomitant
administration
Reduced incidence
of retinopathy
Fair
Table 4.
Neuroprotective Chemo- Strategy Expected result * Strength
agent therapeutic drug of evidence
Vit E
Oxaliplatin Concomitant
administration
Reduced incidence
of sensory positive
symptoms
GoodN-acetyl-cisteine
Various
Oxaliplatin
Various
Pretreatment
Concomitant
Concomitant
Reduced severity of PN
Delayed cumulative toxicity
Delayed cumulative toxicity
Weak
Fair
Fair
Erythropoietin
Chelants Ca/Mg
Melatonin
Various Subsequent;
Concomitant
Reduced severity;
Post-chemotherapy
treatment
GoodAntiepileptic
drugs
Various Concomitant /
Subsequent
treatment
Increased tolerability GoodGabapentin;
pregabalin