neurotoxicity in oncology: is neuroprotection attainable?

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

V. SCAIOLI, A. SALMAGGI

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 ofchemioterapeut ic drugs of

proved neurologica l tox ic i ty

The taxanes (paclitaxel and docetaxel) are

highly active cytotoxic antineoplastic agents.

152

NEUROTOXICITY IN ONCOLOGY. A CRITICAL REVIEW

Common toxicities of the drugs include total

alopecia, hypersensitivity reactions, bone mar-

row suppression (principally neutropenia),

arthralgia, myalgias, and peripheral neuropathy.

When administered as a 3-h infusion, paclitaxel

appears to be associated with a lower risk of neu-

tropenia and a greater risk of peripheral neu-

ropathy, compared to either 24-h infusion pacli-

taxel or docetaxel (1-h infusion). Neither pacli-

taxel nor docetaxel is associated with a high risk

for significant emesis. High cumulative doses of

docetaxel have been shown to produce fluid re-

tention (e.g., oedema, ascitis, pleural effusions),

while paclitaxel, when combined with doxoru-

bicin, increases the risk of anthracycline-induced

heart failure. Both paclitaxel and docetaxel have

been administered at lower dose levels, on a

weekly schedule, with acceptable toxicity pro-

files. In general, the side effects of taxanes are

manageable, and few patients discontinue treat-

ment due to excessive toxicity. (2)

Ifosfamide is successfully employed in the

treatment of bone and soft tissue sarcomas in

children and young adults. Used at high doses

(HDI) the drug may cause severe multiorgan

toxicity. Acute peripheral neuropathy is a less

well-known side effect that may limit its use; it

usually is an axonal, mostly sensory neuropathy

with frequent pain. Symptoms of peripheral

neuropathy after HDI may herald severe multi-

organ toxicity, if continued. Early administration

of anesthetics through the intrathecal route

should be considered in case of ifosfamide-

induced painful peripheral neuropathy(3)

Epothilone. Tubulin polymerization into mi-

crotubules is a dynamic process, with the equi-

librium between growth and shrinkage being es-

sential for many cellular processes(4). The anti-

neoplastic agent taxol hyperstabilizes polymer-

ized microtubules, leading to mitotic arrest and

cytotoxicity in proliferating cells. Using a sensi-

tive filtration-calorimetric assay to detect micro-

tubule nucleating activity, epothilones A and B

have been identified as compounds that possess

all the biological effects of taxol both in vitro and

in cultured cells. Epothilones, therefore, repre-

sent a novel structural class of compounds, the

first to be described since the original discovery

of taxol, which not only mimic the biological ef-

fects of taxol but also appear to bind to the same

microtubule-binding site (5); epothilone has

shown impressive antitumor activity in preclini-

cal studies also in taxane-resistant models. Non-

hematologic grade 3 to 4 toxicities observed

were emesis and fatigue and they occurred only

at 56 mg/m2. Grade 1 to 2 peripheral neuropathy

was also observed. (6)

Tamoxifen. Neurological toxicity in the

course of tamoxifen therapy mainly involves the

eyes and the optic nerves; keratopathy and

subepithelial deposits are the main ocular toxic-

ities and are present in up to 12% of treated

patients; Ocular toxicity was documented in 8

patients, giving an incidence of 12%. Both bilat-

eral pigmentary retinopathy and optic neuritis

are also described; these complications are rare.

Prompt reporting of symptoms and yearly oph-

thalmic examinations are mandatory in patients

on tamoxifen to detect toxic effects while these

are still reversible. (7; 8-12)

S t e p I c h a r a c t e r i s a t i o n o fs y s t e m a t i c n e u r o l o g i c a l

s i d e e f f e c t s

The neurological systemic side effects.

Both in adults and in children, the survival

rates of patients with cancer have increased dra-

matically over the past few decades.

Development of new chemotherapeutic agents

and the expanded use of older agents have had

a major impact on this celebrated improvement.

Chemotherapy can have, however, significant

toxicity on the nervous system. The most com-

mon neurologic complications involve acute

alterations in consciousness, leukoencephalopa-

thy, seizures, cerebral infarctions, paralysis,

neuropathy, and ototoxicity.

Monitoring of these aspects is greatly need-

ed, as it may lead to a better understanding of

153


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).

154


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

155


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 drug

The 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 Institute’s

‘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

156


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 patient’s 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 agents

with 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

157


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. John’s 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

158


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)

159


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<0.05).

After 12 cycles, grade 2-4 sensory neuropathy

was observed in eight patients in arm B, one in

arm A (p<0.05). There were no significant elec-

trophysiological changes in arm A after 4, 8, or

12 cycles of chemotherapy. It is thus well-estab-

lished that oral N-acetylcysteine reduces the

160


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

161


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 the

tumor 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-

162


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 oxaliplatin’s

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 patient’s 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.

163


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Indirizzo:

Vidmer Scaioli

Fondazione IRCCS Istituto

Neurologico “C. Besta” Milano

Via Celoria 11 - 20133 Milano

Tel.:+390224942-2275

e-mail: [email protected]


166

Table 1.

Drug Type of Severity Prevalence Dose

neurotoxicity dependency

Sensory, axonal (ganglionopathy)

Cochlear toxicity

Inner layer cell damage

Anti-epileptic drugs

?

VitE supplementation

Fair

No data

No data

Cis-platin

Inhibition of microtubules

Vascular

Vascular

Anti-epileptic drugs

Drug discontinuation


Fair

Uncertain

Uncertain

Paclitaxel

Oligodendrocytic damage

Multiple



Uncertain,

recovery

possible

Uncertain

Tamoxifen

Inhibition of microtubules Stop-and-go schedule UncertainDocetaxel

Table 3.

Drug Mechanism(s) Neuroprotection Neuro

of neurotoxicity strategy protection

effectiveness

PN

Ototoxicity

Retinopathy

Moderate

Mild

Uncertain

Systematic

Occasional

Rare

Yes

Yes

Yes

Cis-platin

PN

Optic neuropathy

Retinopathy

Moderate to severe

Moderate to severe

Mild to moderate

Systematic

Occasional

Occasional

Yes

No

No

Paclitaxel

Optic neuropathy

Ophtalmologic

Mild to moderate

Mild to moderate

Frequent

Frequent

Yes

Yes

Tamoxifen

PN Moderate to severe Frequent NoDocetaxel

PN Severe Occasional NoOxaliplatin

PN Severe Occasional YesIfosfamide

PN Mild to moderate Frequent YesEpothilone

Optic neuropathy

Encephalopathy

Severe

Moderate to severe

Occasional

Occasional

No

No

5-fluorouracil

PN Mild Frequent YesNedaplatin

Table 2.

Scoring Symptom Objective Objective

scale scale scale scale

(neurological) (neuro

physiological)

NMS Yes Yes No

NSS Yes Yes No

TNS Yes Yes Yes

NCI-CTC 2.0 Yes Yes No

ECOG Yes Yes No


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

neurotoxicity in oncology: is neuroprotection attainable?

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