Neurotoxicity in Oncology: is Neuroprotection Attainable?

Riv. It. Neurobiologia, 53 (3-4), 151-167, 2007

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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 neuropathy 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 relevance 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 objective 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, peripheral neuropathy, optic neuropathy

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Introduction

T

he 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 strategy 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 identification 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 efficacy but minimise the toxic action against the neural tissue; 2. to combine the drug with other(s) potentially 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 cellselective.

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 peripheral 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 common 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 accurate, because the attention of oncologists was captured by the fight against the tumour, and little care was paid to the characterisation of neurological 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 treatment 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 magnetic resonance imaging and other imaging techniques make easier the recognition of central 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 neuroprotective 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 tissues, 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 antitumor effect.

Major classes of chemioterapeutic drugs of proved neurological toxicity The taxanes (paclitaxel and docetaxel) are highly active cytotoxic antineoplastic agents.

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Common toxicities of the drugs include total alopecia, hypersensitivity reactions, bone marrow 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 neutropenia and a greater risk of peripheral neuropathy, compared to either 24-h infusion paclitaxel or docetaxel (1-h infusion). Neither paclitaxel nor docetaxel is associated with a high risk for significant emesis. High cumulative doses of docetaxel have been shown to produce fluid retention (e.g., oedema, ascitis, pleural effusions), while paclitaxel, when combined with doxorubicin, 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 profiles. In general, the side effects of taxanes are manageable, and few patients discontinue treatment 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 multiorgan toxicity, if continued. Early administration of anesthetics through the intrathecal route should be considered in case of ifosfamideinduced painful peripheral neuropathy(3) Epothilone. Tubulin polymerization into microtubules is a dynamic process, with the equilibrium between growth and shrinkage being essential for many cellular processes(4). The antineoplastic agent taxol hyperstabilizes polymerized microtubules, leading to mitotic arrest and cytotoxicity in proliferating cells. Using a sensitive filtration-calorimetric assay to detect microtubule 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 effects of taxol but also appear to bind to the same microtubule-binding site (5); epothilone has shown impressive antitumor activity in preclinical studies also in taxane-resistant models. Nonhematologic 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 toxicities and are present in up to 12% of treated patients; Ocular toxicity was documented in 8 patients, giving an incidence of 12%. Both bilateral pigmentary retinopathy and optic neuritis are also described; these complications are rare.

Prompt reporting of symptoms and yearly ophthalmic examinations are mandatory in patients on tamoxifen to detect toxic effects while these are still reversible. (7; 8-12)

Step I characterisation of systematic neurological side effects The neurological systemic side effects.

Both in adults and in children, the survival rates of patients with cancer have increased dramatically 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 common neurologic complications involve acute alterations in consciousness, leukoencephalopathy, seizures, cerebral infarctions, paralysis, neuropathy, and ototoxicity.

Monitoring of these aspects is greatly needed, as it may lead to a better understanding of

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how chemotherapy affects the nervous system and ultimately help develop more strategies to prevent drug-related neurotoxicity in cancer patients. (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 neuroprotective 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 alterations in consciousness, leukoencephalopathy, seizures, cerebral infarctions, paralysis, in addition to neuropathy, and ototoxicity. Most of the information on toxicity comes from prospective reports and the adult patient population.

Methotrexate, cyclosporin, and platinum compounds 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 continues 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 chemotherapeutic agents and a better understanding of

effective mechanisms will lead to novel treatment strategies that will protect neurons without decreasing therapeutic efficacy. (14) In this respect, the assessment of the efficacy and neurotoxicity of various chemotherapeutic agents is vital, for a determination of the maximum allowable dose. (14) The type and degree of neuropathy depend on the chemotherapy drug, dose-intensity, and cumulative dose. Disabling peripheral neuropathy has a significant negative impact on quality of life. Accordingly, a reliable assessment of chemotherapy-induced peripheral neurotoxicity is necessary, especially if potential neuroprotective 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 disturbing. 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 perhaps 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)

Step II characterisation of the so called “sporadic� side effects Retinopathy and optic neuritis are a relatively frequent complication of medical treatments, both in cancer and in other medical fields, like antiepileptic drugs.

Continuous intravenous 5 fluorouracil (5FU) chemotherapy may be associated with a bilateral 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 toxicity to 5FU. (17) A number of drugs cause ocular irritation (fluorouracil, methotrexate), canalicular fibrosis with epiphora (fluorouracil), retinopathy (mitotane, tamoxifen), corneal opacities (tamoxifen), 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 reactions of the most commonly used chemotherapeutic agents have been reviewed. (18; 19)

Step III how to characterise the neurological side effects: the scoring systems dilemma The best way to evaluate and score the severity of chemotherapy-induced peripheral neuropathy is still an unsettled matter; a number of scoring systems, involving both clinical and/or neurophysiological testing have been employed in the setting of clinical research. (20-22) (23; 24) Two main approaches are described: the former is based upon self-reported peripheral neuropathy and functional status (including physical 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 version thereof (25), ECOG score and NCI-CTC 2.0 scores).

In an early study, the severity of chemotherapy-induced peripheral neuropathy (CIPN) was evaluated in patients treated with cisplatin- and paclitaxel-based chemotherapy. A reduced version 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 neurotoxicity (CIPN), and to compare the results with those obtained with common toxicity scales. (24) A highly significant correlation was demonstrated 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 examination) allowed to grade accurately CIPN and correlated with the common toxicity scores. The correlation tended to be closer when the sensory items were considered, but also the TNSr motor items, which were not specifically investigated in any other previous study, significantly correlated with the results of the common toxicity 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 neuroprotection. (27) Overall, while clinical self-reporting scores and objective evaluations with neurophyisiological tests may be of help in assessing peripheral neurotoxicity in single patients, only a combination 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 experienced team in its application.

On the other hand, other scoring systems address neuroophtalmological systematic side-effects, since evidence grows for a selective toxicity 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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under active investigation. Recent reports of paclitaxel treated patients have emphasised the clinical relevance of ophtalmological and electrophysiological evaluation and characterisation of neuroophtalmological manifestation. (28; 29)

The strategies of neuroprotection a. Modification of the molecular structure of the drug The taxanes. Paclitaxel and its semi-synthetic 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 mutual tubulin binding site, mechanistic and pharmacological differences exist between these agents. For example, docetaxel has increased potency and an improved therapeutic index compared with paclitaxel, and its short 1-h infusion 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 cancer patients. In particular, neurotoxicity - a dominant side effect with both paclitaxel and cisplatin - occurs at a low incidence with docetaxel, making docetaxel a promising agent for combining cisplatin and other platinum compounds. 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 standard 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 determine if corticosteroid co-medication reduces the incidence and severity of docetaxel-induced neuropathy. (30; 31).

Neuropathy was evaluated by clinical sumscore for signs and symptoms and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to the National Cancer Institute’s ‘Common Toxicity Criteria’. The docetaxel-cisplatin 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 developed a neuropathy which was mild in 15, moderate in ten and severe in one patient.

Significant correlations were present between both the cumulative dose of docetaxel and cisplatin and the post-treatment sum-score of neuropathy (P < 0.01) as well as the post-treatment VPT (P < 0.01). The neurotoxic effects of this combination were more severe than either cisplatin or docetaxel as single agent at similar doses. (32) Oxaliplatin. Oxaliplatin is the only thirdgeneration platinum derivative to have found a place in routine cancer therapy and consequentely it has become an integral part of various chemotherapy protocols, in advanced colorectal cancer in particular (33; 34; 35). Compared with cisplatin, L-OHP has no renal toxicity, only mild hematological and gastrointestinal toxicity, while neurotoxicity is the limiting toxicity. In addition, Oxaliplatin-containing chemotherapy regimens are utilized commonly for metastatic colorectal cancer and increasingly in the adjuvant setting following surgical resection. Oxaliplatin-induced neurotoxicity consists of a rapid-onset, cold-induced, reversible acute sensory neuropathy and a late-onset cumulative 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 after treatment discontinuation. To date, oxaliplatin has proven to be a safe and effective therapy for colorectal cancer and side effects have been easy to manage with appropriate awareness 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 oxaliplatin are warranted. (37) Various strategies have been proposed to prevent or treat oxaliplatin-induced neurotoxicity. The â&#x20AC;&#x153;Stop-and-Goâ&#x20AC;? concept uses the reversibility of neurologic symptoms to aim at delivering higher cumulative oxaliplatin doses as long as the therapy is still effective. Several neuromodulatory agents such as calcium-magnesium infusions, antiepileptic drugs like carbamazepine or gabapentin, amifostine, alpha-lipoic acid, and glutathione have shown promising activity in prophylaxis and treatment of oxaliplatin-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-induced neurotoxicity. 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 patientâ&#x20AC;&#x2122;s clinical situation. (38) This side effect has been described as a transient 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, during 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 clinical and neurophysiological examinations

showed an acute and transient neurotoxicity and a cumulative dose-related sensory neuropathy in nearly all the patients. The reversibility of these effects was studied. Five patients continued to manifest symptoms and signs of neurotoxicity after a long follow-up, indicating persistence of this peculiar type of neuropathy(39) Nedaplatin. Nedaplatin (cis-diammineglycolatoplatinum) can be given without hydration; its dose-limiting toxicity is myelosuppression, in particular thrombocytopenia. Although activity has been shown, no data from randomized comparative 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 association 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 treatment 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 profiles. However, a widening body of research indicates alternative medicine may offer significant benefit to this patient population. Alpha-lipoic acid, acetyl-L-carnitine, benfotiamine, methylcobalamin, 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, glutathione, folate, pyridoxine, biotin, myo-inositol, omega-3 and -6 fatty acids, L-arginine, L-glutamine, taurine, N-acetylcysteine, zinc, magnesium, chromium, and St. Johnâ&#x20AC;&#x2122;s wort. In the realm of physical medicine, acupuncture, magnetic therapy, and yoga have been found to provide 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 chemotherapy and radiotherapy. It is thought to protect normal 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 protects them against cancer therapies has been debated. (42) Clinically relevant levels of amifostine toxicity were observed in several studies, but subcutaneous administration may reduce such toxicity. Amifostine showed protection against mucositis, esophagitis, neuropathy, and other side effects, although protection against cisplatin-induced ototoxicity was not observed. No evidence 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 deficiency, 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 vitamin 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 before treatment. These data suggest that an inadequate amount of the antioxidant vitamin E due to cisplatin treatment could be responsible of the peripheral nerve damage induced by freeradicals. Given the lack of toxicity of vitamin E, we need to systematically assess the possible neuroprotective role of vitamin E supplementation in patients treated with cisplatin chemotherapy. (43) The dose-limiting toxicity of the chemotherapeutic agent vincristine is peripheral neuropathy, for which there is no established therapy. (44) The amino acid glutamate has been proposed as a neuroprotectant for vincristine.

(44) Leukemia inhibitory factor (LIF) (45) The growth factor leukaemia inhibitory factor (LIF) has neuroprotectant activity in preclinical models 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 stimulates tumour growth. (45) These results suggest that LIF may be safely used in human trials as a neuroprotectant for patients receiving cisplatin, paclitaxel and carboplatin without concern for impairment of antitumour effect (45).

Glutathione (36) A randomized, doubleblind, placebo-controlled trial to assess the efficacy of glutathione (GSH) in the prevention of oxaliplatin-induced neurotoxicity was performed(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 indicated a significant response and survival advantage for those receiving high-dose (100 mg/m2) as compared with low-dose (50 mg/m2) cisplatin 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 antagonist that has provided protection from cisplatin-induced neurotoxicity in a rat model system.(46) These studies did not demonstrate a neuroprotective effect for nimodipine. The primary efficacy variable, i.e, the neurotoxicity score at the end of treatment, gave a significantly 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 protective and a curative role in chemotherapyinduced hyperalgesia was tested in vivo, in animal models of cisplatin-, paclitaxel- and vincristine-induced neuropathy. In addition, the possible interaction between ALC and vincristine 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 (“preventive” protocol) and when ALC administration was started later on during treatment (“curative” protocol). The ALC treatment significantly prevented the lowering of the mechanical nociceptive threshold when the administration started concomitantly and, respectively, with cisplatin, paclitaxel and vincristine as compared to each drug alone. Furthermore, when ALC administration was started later on during treatment, at the stage of well-established neuropathy, ALC was able to restore the mechanical nociceptive threshold within a few days. Finally, experiments indicated that ALC does not interfere with the antitumor effects of vincristine.

Considering the absence of any satisfactory treatment currently available for CIPN in a clinical 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 peripheral 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 significantly 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 symptoms 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 postexams was 32 days. For patients who received glutamine, there was a statistically significant reduction in the severity of peripheral neuropathy as measured by development of moderate to severe 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). Moderate 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-controlled 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 peripheral neuropathy is the dose-limiting toxicity. (50)

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Corticosteroid Two groups of patients treated 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 corticosteroid co-medication was recommended, while 49 female patients in group B with metastatic breast cancer were treated after comedication 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 neuropathy was documented. There was no statistically 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 sumscore, grade of paresthesias, and grade of neurosensory and neuromotor toxicity.

Corticosteroid co-medication does not reduce the development of docetaxel-related neuropathy. (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 clinical condition (lung cancer: 35; breast cancer: 31; gastrointestinal tract tumors: 14). Lung cancer patients were treated with cisplatin and etoposide, breast cancer patients with mitoxantrone, 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 frequent in patients concomitantly treated with MLT. Malaise and asthenia were also significantly less frequent in patients receiving MLT. Finally, stomatitis and neuropathy were less frequent in the MLT group, albeit without statistically 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 during chemotherapy may prevent some chemotherapy-induced side-effects, particularly myelosuppression and neuropathy.

Evaluation of the impact of MLT on chemotherapy 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 neuroprotective 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 leucovorin were randomized to oral N-acetylcysteine (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. Treatmentrelated 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 electrophysiological changes in arm A after 4, 8, or 12 cycles of chemotherapy. It is thus well-established that oral N-acetylcysteine reduces the

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incidence of oxaliplatin-induced neuropathy in colon cancer patients receiving oxaliplatinbased adjuvant chemotherapy. (53) Calcium and magnesium infusion. Infusions of oxalate chelators Ca/Mg seem to reduce incidence and intensity of acute oxaliplatin-induced symptoms and might delay cumulative neuropathy, especially in 85 mg/m(2) oxaliplatin dosage. (54; 54) (54).

Erythropoietin (55) In addition to its wellknown erythropoetic effect, erythropoietin (EPO) has also been shown to be neuroprotective 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 hippocampal 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 autoimmune encephalomyelitis and peripheral diabetic neuropathy. To date, EPO and CEPO have been exciting developments in the quest for the treatment of various types of neurotoxicity. The development of CEPO should continue. (55)

c. Medical treatment of peripheral nervous system neurotoxicity A few antiepileptic drugs are acquiring increasing popularity for non-epileptic syndromes, 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 Topiramate (Topamax; Jansen Cilag), a new antiepileptic 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 administration 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 lowdose topiramate could be active against the permanent neuropathy-related symptoms of oxaliplatin. Both agents allowed pain relief and a significant autonomy improvement so to further encourage venlafaxine hydrochloride and topiramate for the treatment of permanent anti-cancer 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 sideeffect 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 reported effective as therapy for several psychiatric disorders, most notably bipolar disorder. In addition, review of the published literature reveals the usefulness of gabapentin in movement disorders, migraine prophylaxis, and cocaine dependence. Future clinical studies will provide further insight into the range of conditions for which gabapentin is effective (58). In addition, they were later discovered to be effective in the treatment of neuropathic pain, creating a relatively novel class of analgesic drugs even useful for treating a wide range of neurologic and psychiatric conditions. Although its exact mechanism of action has yet to be determined, gabapentin is likely to have multiple

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V. SCAIOLI, A. SALMAGGI

effects. Laboratory evidence suggests that both gabapentin and pregabalin can inhibit hyperalgesia 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 comparative trials and pooled estimates from metaanalyses 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 neuropathic pain syndromes, and to further explore the role of these drugs in the rational polypharmacy 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 therapies 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 minimisation of damage to healthy tissues. (59)

Conclusion Survival rates for adults and children with cancer have increased dramatically 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. Recent advances in the development 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-induced peripheral neuropathy (CIPN).

Chemotherapy can have, however, significant toxicity on the central nervous system. Most of the information on toxicity comes from prospective reports and the adult patient population.

Methotrexate, cyclosporin, and platinum compounds are the most frequently cited. It is worth mentioning, however, that in spite of more exhaustive studies performed in adults, no prospective studies have been done to evaluate chemotherapy-induced neurotoxicity in the pediatric population, and the exact incidence of such complications is unknown. Such investigation 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 neurotoxicity 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 devastating ramifications of CIPN on quality of life, basic and clinical researchers have begun to investigate therapy to prevent neurotoxic injury.

In recent years, oxaliplatin-based chemotherapy protocols, particularly oxaliplatin in combination with infusional 5-fluorouracil/leucovorin, have emerged as the standard of care in first-

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NEUROTOXICITY IN ONCOLOGY. A CRITICAL REVIEW

and second-line therapy of advanced-stage colorectal 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 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 antitumor effect.

Preliminary studies have shown promise for some agents including glutamine, glutathione, vitamin E, acetyl-L-carnitine, calcium, and magnesium infusions, but final recommendations await prospective confirmatory studies. (60) The stop-and-go concept uses the predictability and reversibility of neurologic symptoms to allow patients to stay on an oxaliplatincontaining first-line therapy for a prolonged period. Several neuromodulatory agents such as calcium-magnesium infusions; antiepileptic drugs like carbamazepine, gabapentin, and venlafaxine; amifostine; a-lipoic acid; and glutathione have demonstrated some activity in the prophylaxis and treatment of oxaliplatininduced acute neuropathy.

However, randomized trials demonstrating a prophylactic or therapeutic effect on oxaliplatinâ&#x20AC;&#x2122;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 patientâ&#x20AC;&#x2122;s clinical 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 neurotoxicity and not tumor progression could become the dominating treatment-limiting issue in the first-line therapy of advanced colorectal cancer. (61) A more specific clinical problem is represented by the treatment of the neuropathic pain and new drugs and treatment algorithms in the management of neuropathic pain have been proposed. 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, selective noradrenaline and serotonin reuptake inhibitors (SNRIs and SSRIs) have evidence for benefit and reduced toxicity without an economic disadvantage compared to tricyclic antidepressants (TCAs). Pregabalin and gabapentin are effective in diabetic neuropathy and postherpetic 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 central 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 becoming increasingly important issues in the care of patients with cancer (63); physicians should be aware of the potential harmful effects of prescribed therapies as well as of the therapeutic tools in the overall management of their patients.

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Reference List 25.

1. Hildebrand J. Neurological complications of cancer chemotherapy. Curr Opin Oncol 2006; 18(4):321-324.

2. Markman M. Management of toxicities associated with the administration of taxanes. Expert Opin Drug Saf 2003; 2(2):141-146.

3. Frisk P, Stalberg E, Stromberg B, Jakobson A. Painful peripheral neuropathy after treatment with high-dose ifosfamide.

Med Pediatr Oncol 2001; 37(4):379-382.

4. Bollag DM. Epothilones: novel microtubule-stabilising agents.

Expert Opin Investig Drugs 1997; 6(7):867-873.

5. Bollag DM, McQueney PA, Zhu J, Hensens O, Koupal L, Liesch J et al. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 1995; 55(11):2325-2333.

6. Gadgeel SM, Wozniak A, Boinpally RR, Wiegand R, Heilbrun LK, Jain V et al. Phase I clinical trial of BMS-247550, a derivative of epothilone B, using accelerated titration 2B design.

Clin Cancer Res 2005; 11(17):6233-6239.

7. Noureddin BN, Seoud M, Bashshur Z, Salem Z, Shamseddin A, Khalil A. Ocular toxicity in low-dose tamoxifen: a prospective study. Eye 1999; 13 ( Pt 6):729-733.

8. Ah-Song R, Sasco AJ. Tamoxifen and ocular toxicity. Cancer Detect Prev 1997; 21(6):522-531.

9. Gerner EW. Ocular toxicity of tamoxifen. Ann Ophthalmol 1989; 21(11):420-423.

10. Mihm LM, Barton TL. Tamoxifen-induced ocular toxicity. Ann Pharmacother 1994; 28(6):740-742.

11. Pavlidis NA, Petris C, Briassoulis E, Klouvas G, Psilas C, Rempapis J et al. Clear evidence that long-term, low-dose tamoxifen treatment can induce ocular toxicity. A prospective study of 63 patients. Cancer 1992; 69(12):2961-2964.

12. Ashford AR, Donev I, Tiwari RP, Garrett TJ. Reversible ocular toxicity related to tamoxifen therapy. Cancer 1988; 61(1):3335.

13. Reddy AT, Witek K. Neurologic complications of chemotherapy for children with cancer. Curr Neurol Neurosci Rep 2003; 3(2):137-142.

14. Beinert T, Masuhr F, Mwela E, Schweigert M, Flath B, Harder H et al. Neuropathy under chemotherapy. Eur J Med Res 2000; 5(10):415-423.

15. Davis MP. What is new in neuropathic pain? Support Care Cancer 2006.

16. Cata JP, Weng HR, Lee BN, Reuben JM, Dougherty PM. Clinical and experimental findings in humans and animals with chemotherapy-induced peripheral neuropathy. Minerva Anestesiol 2006; 72(3):151-169.

17. Delval L, Klastersky J. Optic neuropathy in cancer patients.

Report of a case possibly related to 5 fluorouracil toxicity and review of the literature. J Neurooncol 2002; 60(2):165-169.

18. Fraunfelder FT, Meyer SM. Ocular toxicity of antineoplastic agents. Ophthalmology 1983; 90(1):1-3.

19. Burke E, Teeling M, Carney D, Eustace P. The retinotoxic effects of oncological agents. Bull Soc Belge Ophtalmol 1987; 224:77-79.

20. Chaudhry V, Corse AM, Freimer ML, Glass JD, Mellits ED, Kuncl RW et al. Inter- and intraexaminer reliability of nerve conduction measurements in patients with diabetic neuropathy. Neurology 1994; 44(8):1459-1462.

21. Chaudhry V, Rowinsky EK, Sartorius SE, Donehower RC, Cornblath DR. Peripheral neuropathy from taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies. Ann Neurol 1994; 35(3):304-311.

22. Cornblath DR, Chaudhry V, Carter K, Lee D, Seysedadr M, Miernicki M et al. Total neuropathy score: validation and reliability study. Neurology 1999; 53(8):1660-1664.

23. Cavaletti G, Bogliun G, Marzorati L, Zincone A, Piatti M, Colombo N et al. Grading of chemotherapy-induced peripheral neurotoxicity using the Total Neuropathy Scale. Neurology 2003; 61(9):1297-1300.

24. Cavaletti G, Jann S, Pace A, Plasmati R, Siciliano G, Briani C

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

164

et al. Multi-center assessment of the Total Neuropathy Score for chemotherapy-induced peripheral neurotoxicity. J Peripher Nerv Syst 2006; 11(2):135-141.

Almadrones L, McGuire DB, Walczak JR, Florio CM, Tian C. Psychometric evaluation of two scales assessing functional status and peripheral neuropathy associated with chemotherapy for ovarian cancer: a gynecologic oncology group study.

Oncol Nurs Forum 2004; 31(3):615-623.

Postma TJ, Heimans JJ, Muller MJ, Ossenkoppele GJ, Vermorken JB, Aaronson NK. Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy. Ann Oncol 1998; 9(7):739-744.

Augusto C, Pietro M, Cinzia M, Sergio C, Sara C, Luca G et al.

Peripheral neuropathy due to paclitaxel: study of the temporal relationships between the therapeutic schedule and the clinical quantitative score (QST) and comparison with neurophysiological findings. J Neurooncol 2007.

Scaioli V, Caraceni A, Martini C, Palazzini E, Tarenzi E, Fulfaro F et al. Visual evoked potentials findings in course of paclitaxel doxorubicin combination chemotherapy. Report of a case. J Neurooncol 1995; 25(3):221-225.

Scaioli V, Caraceni A, Martini C, Curzi S, Capri G, Luca G. Electrophysiological evaluation of visual pathways in paclitaxel-treated patients. J Neurooncol 2006; 77(1):79-87.

Katsumata N. Docetaxel: an alternative taxane in ovarian cancer. Br J Cancer 2003; 89 Suppl 3:S9-S15.

Pronk LC, Hilkens PH, van den Bent MJ, van Putten WL, Stoter G, Verweij J. Corticosteroid co-medication does not reduce the incidence and severity of neurotoxicity induced by docetaxel. Anticancer Drugs 1998; 9(9):759-764.

Hilkens PH, Pronk LC, Verweij J, Vecht CJ, van Putten WL, van den Bent MJ. Peripheral neuropathy induced by combination chemotherapy of docetaxel and cisplatin. Br J Cancer 1997; 75(3):417-422.

Vermorken JB. The integration of paclitaxel and new platinum compounds in the treatment of advanced ovarian cancer. Int J Gynecol Cancer 2001; 11 Suppl 1:21-30.

Shord SS, Bernard SA, Lindley C, Blodgett A, Mehta V, Churchel MA et al. Oxaliplatin biotransformation and pharmacokinetics: a pilot study to determine the possible relationship to neurotoxicity. Anticancer Res 2002; 22(4):2301-2309.

Cassidy J, Misset JL. Oxaliplatin-related side effects: characteristics and management. Semin Oncol 2002; 29(5 Suppl 15):11-20.

Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P, Baldelli AM et al. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2002; 20(16):3478-3483.

Choi J, Kong K, Mozaffar T, Holcombe RF. Delayed oxaliplatinassociated neurotoxicity following adjuvant chemotherapy for stage III colon cancer. Anticancer Drugs 2006; 17(1):103-105.

Grothey A. Oxaliplatin-safety profile: neurotoxicity. Semin Oncol 2003; 30(4 Suppl 15):5-13.

Pietrangeli A, Leandri M, Terzoli E, Jandolo B, Garufi C. Persistence of high-dose oxaliplatin-induced neuropathy at long-term follow-up. Eur Neurol 2006; 56(1):13-16.

Wasserheit C, Frazein A, Oratz R, Sorich J, Downey A, Hochster H et al. Phase II trial of paclitaxel and cisplatin in women with advanced breast cancer: an active regimen with limiting neurotoxicity. J Clin Oncol 1996; 14(7):1993-1999.

Head KA. Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern Med Rev 2006; 11(4):294329.

Block KI, Gyllenhaal C. Commentary: the pharmacological antioxidant amifostine â&#x20AC;&#x201D; implications of recent research for integrative cancer care. Integr Cancer Ther 2005; 4(4):329351.

Bove L, Picardo M, Maresca V, Jandolo B, Pace A. A pilot study on the relation between cisplatin neuropathy and vitamin E. J Exp Clin Cancer Res 2001; 20(2):277-280.

Boyle FM, Wheeler HR, Shenfield GM. Glutamate ameliorates experimental vincristine neuropathy. J Pharmacol Exp Ther 1996; 279(1):410-415.

NEUROTOXICITY IN ONCOLOGY. A CRITICAL REVIEW

45. Boyle FM, Beatson C, Monk R, Grant SL, Kurek JB. The experimental neuroprotectant leukaemia inhibitory factor (LIF) does not compromise antitumour activity of paclitaxel, cisplatin and carboplatin. Cancer Chemother Pharmacol 2001; 48(6):429-434.

46. Cassidy J, Paul J, Soukop M, Habeshaw T, Reed NS, Parkin D et al. Clinical trials of nimodipine as a potential neuroprotector in ovarian cancer patients treated with cisplatin. Cancer Chemother Pharmacol 1998; 41(2):161-166.

47. Ghirardi O, Vertechy M, Vesci L, Canta A, Nicolini G, Galbiati S et al. Chemotherapy-induced allodinia: neuroprotective effect of acetyl-L-carnitine. In Vivo 2005; 19(3):631-637.

48. Bianchi G, Vitali G, Caraceni A, Ravaglia S, Capri G, Cundari S et al. Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine. Eur J Cancer 2005; 41(12):1746-1750.

49. Maestri A, De Pasquale CA, Cundari S, Zanna C, Cortesi E, Crino L. A pilot study on the effect of acetyl-L-carnitine in paclitaxel- and cisplatin-induced peripheral neuropathy.

Tumori 2005; 91(2):135-138.

50. Vahdat L, Papadopoulos K, Lange D, Leuin S, Kaufman E, Donovan D et al. Reduction of paclitaxel-induced peripheral neuropathy with glutamine. Clin Cancer Res 2001; 7(5):11921197.

51. Stubblefield MD, Vahdat LT, Balmaceda CM, Troxel AB, Hesdorffer CS, Gooch CL. Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and electrophysiologic study. Clin Oncol (R Coll Radiol ) 2005; 17(4):271-276.

52. Lissoni P, Tancini G, Barni S, Paolorossi F, Ardizzoia A, Conti A et al. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Support Care Cancer 1997; 5(2):126-129.

53. Lin PC, Lee MY, Wang WS, Yen CC, Chao TC, Hsiao LT et al.

N-acetylcysteine has neuroprotective effects against oxaliplatin-based adjuvant chemotherapy in colon cancer patients:

preliminary data. Support Care Cancer 2006; 14(5):484-487.

54. Gamelin L, Boisdron-Celle M, Delva R, Guerin-Meyer V, Ifrah N, Morel A et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5Fluorouracil and leucovorin for advanced colorectal cancer.

Clin Cancer Res 2004; 10(12 Pt 1):4055-4061.

55. Doggrell SA. A neuroprotective derivative of erythropoietin that is not erythropoietic. Expert Opin Investig Drugs 2004; 13(11):1517-1519.

56. Gilron I, Flatters SJ. Gabapentin and pregabalin for the treatment of neuropathic pain: A review of laboratory and clinical evidence. Pain Res Manag 2006; 11 Suppl A:16A-29A. 57. Durand JP, Alexandre J, Guillevin L, Goldwasser F. Clinical activity of venlafaxine and topiramate against oxaliplatininduced disabling permanent neuropathy. Anticancer Drugs 2005; 16(5):587-591.

58. Magnus L. Nonepileptic uses of gabapentin. Epilepsia 1999; 40 Suppl 6:S66-S72.

59. Hamada K, Desaki J, Nakagawa K, Zhang T, Shirakawa T, Gotoh A et al. Carrier cell-mediated delivery of a replicationcompetent adenovirus for cancer gene therapy. Mol Ther 2007; 15(6):1121-1128.

60. Stillman M, Cata JP. Management of chemotherapy-induced peripheral neuropathy. Curr Pain Headache Rep 2006; 10(4):279-287.

61. Grothey A. Clinical management of oxaliplatin-associated neurotoxicity. Clin Colorectal Cancer 2005; 5 Suppl 1:S38S46.

62. Ocean AJ, Vahdat LT. Chemotherapy-induced peripheral neuropathy: pathogenesis and emerging therapies. Support Care Cancer 2004; 12(9):619-625.

63. Armstrong T, Almadrones L, Gilbert MR. Chemotherapyinduced peripheral neuropathy. Oncol Nurs Forum 2005; 32(2):305-311.

Indirizzo: Vidmer Scaioli Fondazione IRCCS Istituto Neurologico â&#x20AC;&#x153;C. Bestaâ&#x20AC;? Milano Via Celoria 11 - 20133 Milano Tel.:+390224942-2275 e-mail: vidmer@scaioli.net

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Table 1.

Drug

Type of neurotoxicity

Severity

Prevalence

Dose dependency

Docetaxel

PN Ototoxicity Retinopathy PN Optic neuropathy Retinopathy Optic neuropathy Ophtalmologic PN

Moderate Mild Uncertain Moderate to severe Moderate to severe Mild to moderate Mild to moderate Mild to moderate Moderate to severe

Systematic Occasional Rare Systematic Occasional Occasional Frequent Frequent Frequent

Yes Yes Yes Yes No No Yes Yes No

Oxaliplatin

PN

Severe

Occasional

No

Ifosfamide

PN

Severe

Occasional

Yes

Epothilone

PN

Mild to moderate

Frequent

Yes

5-fluorouracil

Optic neuropathy Severe Encephalopathy Moderate to severe

Occasional Occasional

No No

Nedaplatin

PN

Frequent

Yes

Cis-platin

Paclitaxel

Tamoxifen

Mild

Table 2.

Scoring scale

Table 3.

Drug

Cis-platin

Paclitaxel

Tamoxifen

Docetaxel

Symptom scale

Objective scale (neurological)

Objective scale (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

Mechanism(s) of neurotoxicity

Neuroprotection Neuro strategy protection effectiveness

Sensory, axonal (ganglionopathy) Anti-epileptic drugs Cochlear toxicity Inner layer cell damage ?

VitE supplementation Inhibition of microtubules Anti-epileptic drugs Vascular Drug discontinuation Vascular Drug discontinuation

Fair

Oligodendrocytic damage

Drug discontinuation

Multiple

Drug discontinuation

Inhibition of microtubules

Stop-and-go schedule

Uncertain, recovery possible Uncertain Uncertain

166

No data No data Fair Uncertain Uncertain

NEUROTOXICITY IN ONCOLOGY. A CRITICAL REVIEW

Table 4.

Neuroprotective ChemoStrategy agent therapeutic drug Vit E

Expected result * Strength of evidence

Cisplatin, Oxaliplatin, Concomitant administration N-acetyl-cisteine Oxaliplatin Concomitant administration

Reduced incidence of retinopathy Reduced incidence of sensory positive symptoms Pretreatment Reduced severity of PN Concomitant Delayed cumulative toxicity Concomitant Delayed cumulative toxicity

Erythropoietin Chelants Ca/Mg Melatonin

Various Oxaliplatin Various

Antiepileptic drugs

Various

Subsequent; Concomitant

Gabapentin; pregabalin

Various

Concomitant / Subsequent treatment

167

Reduced severity; Post-chemotherapy treatment Increased tolerability

Fair Good

Weak Fair Fair Good

Good