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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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In this context. without compromising antitumor efficacy. because the attention of oncologists was captured by the fight against the tumour. 3. the neurological syndromes become disturbing enough so as to hamper continuation of treatment or the use of other drugs. in the past. They aim to provide site-specific protection for normal tissues. 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. 152 . on the other side. either occasionally or in a more systematic way. A fundamental step in neuroprotection is represented by an accurate characterisation of the systematic side effects of anticancer drugs. The possible ways by which neuroprotection can be achieved are: 1. on the other hand. Major classes of chemioterapeutic drugs of proved neurological toxicity The taxanes (paclitaxel and docetaxel) are highly active cytotoxic antineoplastic agents. an overuse of treatment may be discouraged. Sometimes. to combine the drug with a vector able to optimize and make delivery tumor cellselective. the neurological side effects of therapy. SALMAGGI Introduction he improvement in health care systems and increasing needs in terms of quality of life. Several chemoprotectant compounds have been studied in recent clinical trials. neurotoxicity remains a major limitation of many drugs used in cancer patients and their list grows steadily. A. These trials must include sufficient dose-limiting events for study and assessment of both toxicity and antitumor effect. It is worth mentioning that. 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. as it will be reported later in the paper. one of the main and best known side effects of antitumoural therapy is represented by peripheral neuropathy (PN). The term neuroprotection defines the identification of strategies to prevent or minimise. Several drugs of proved antitumoral efficacy widely used in oncology have the inconvenience of causing some neurological complications.V. In this respect. Synthesis and thorough clinical testing of neuroprotective molecules remain therefore a major challenge (1). it could be more important to stop a treatment with devastating side effects. to characterize peripheral nervous system toxicity. scoring procedures and clinical neurophysiology make it easy. 2. On one side magnetic resonance imaging and other imaging techniques make easier the recognition of central nervous system toxicity. Therefore. the characterisation of side effects was not so accurate. the first part of the paper is addressed to the description of the most common and documented neurological complica- T tions associated with the most commonly used chemotherapeutic drugs. SCAIOLI. represent nowadays one of the main topics in the medical treatment and strategy in oncology. to combine the drug with other(s) potentially able to exert a protective action on the healthy nervous tissue. together with the ethical issues of dignity of death. directly or indirectly. with the term of Chemoprotectants we can define agents that have been developed to ameliorate the toxicity associated with cytotoxic drugs. at a certain point. in the light of increased attention about ethics and dignity of death. and acceptable by the patients. to modify the molecular conformation of the drug so as to maintain the antitumoral efficacy but minimise the toxic action against the neural tissue.

Symptoms of peripheral neuropathy after HDI may herald severe multiorgan toxicity. The most common neurologic complications involve acute alterations in consciousness. Neither paclitaxel nor docetaxel is associated with a high risk for significant emesis. Used at high doses (HDI) the drug may cause severe multiorgan toxicity. The antineoplastic agent taxol hyperstabilizes polymerized microtubules. therefore. myalgias. leading to mitotic arrest and cytotoxicity in proliferating cells. epothilone has shown impressive antitumor activity in preclinical studies also in taxane-resistant models. When administered as a 3-h infusion. keratopathy and subepithelial deposits are the main ocular toxicities and are present in up to 12% of treated patients. Chemotherapy can have. leukoencephalopathy. paclitaxel appears to be associated with a lower risk of neutropenia and a greater risk of peripheral neuropathy. as it may lead to a better understanding of 153 . when combined with doxorubicin. and peripheral neuropathy. and ototoxicity. Nonhematologic grade 3 to 4 toxicities observed were emesis and fatigue and they occurred only at 56 mg/m2. (2) Ifosfamide is successfully employed in the treatment of bone and soft tissue sarcomas in children and young adults. Ocular toxicity was documented in 8 patients. neuropathy. seizures.. while paclitaxel. High cumulative doses of docetaxel have been shown to produce fluid retention (e. 8-12) Step I characterisation of systematic neurological side effects The neurological systemic side effects. arthralgia. paralysis. it usually is an axonal. In general. increases the risk of anthracycline-induced heart failure. Early administration of anesthetics through the intrathecal route should be considered in case of ifosfamideinduced painful peripheral neuropathy(3) Epothilone. bone marrow suppression (principally neutropenia). with acceptable toxicity profiles. ascitis. Epothilones. and few patients discontinue treatment due to excessive toxicity. repre- sent a novel structural class of compounds. (6) Tamoxifen. mostly sensory neuropathy with frequent pain. on a weekly schedule. which not only mimic the biological effects of taxol but also appear to bind to the same microtubule-binding site (5). the side effects of taxanes are manageable. Acute peripheral neuropathy is a less well-known side effect that may limit its use. Both bilateral pigmentary retinopathy and optic neuritis are also described. pleural effusions). Both paclitaxel and docetaxel have been administered at lower dose levels.NEUROTOXICITY IN ONCOLOGY. Monitoring of these aspects is greatly needed. however. Prompt reporting of symptoms and yearly ophthalmic examinations are mandatory in patients on tamoxifen to detect toxic effects while these are still reversible. Grade 1 to 2 peripheral neuropathy was also observed. Using a sensitive filtration-calorimetric assay to detect microtubule nucleating activity. compared to either 24-h infusion paclitaxel or docetaxel (1-h infusion). significant toxicity on the nervous system. Both in adults and in children. Development of new chemotherapeutic agents and the expanded use of older agents have had a major impact on this celebrated improvement. giving an incidence of 12%. if continued. cerebral infarctions. epothilones A and B have been identified as compounds that possess all the biological effects of taxol both in vitro and in cultured cells. Neurological toxicity in the course of tamoxifen therapy mainly involves the eyes and the optic nerves. with the equilibrium between growth and shrinkage being essential for many cellular processes(4).g. (7. the survival rates of patients with cancer have increased dramatically over the past few decades. these complications are rare. hypersensitivity reactions. the first to be described since the original discovery of taxol. oedema. Tubulin polymerization into microtubules is a dynamic process. A CRITICAL REVIEW Common toxicities of the drugs include total alopecia.

(13). Mostly unpredictable encephalopathy continues to be sporadically reported even in patients treated systemically with conventional chemotherapy doses. On the whole. (14) In this respect. in addition to neuropathy. Recently. capecitabine. Most of the information on toxicity comes from prospective reports and the adult patient population. A. paralysis. the neuropathic pain occurs in 1% of the population and is difficult to manage. Responses to single drugs are limited in benefit. but perhaps less well so to others. like antiepileptic drugs. pain arises from numerous causes in cancer patients. and the neuroprotective effect of several older and newer agents is either deceptive or insufficiently proven. and the exact incidence of such complications is unknown. painful paresthesia and disesthesia are the most disturbing. has been added to the list. (15) Well known to cancer care providers. SCAIOLI. However. cerebral infarctions. leukoencephalopathy. 154 . and cumulative dose. Methotrexate. Among the positive. Thirty percent will fail to respond altogether. 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. especially if potential neuroprotective agents are to be investigated. SALMAGGI how chemotherapy affects the nervous system and ultimately help develop more strategies to prevent drug-related neurotoxicity in cancer patients. In addition to chronic neuropathy. for a determination of the maximum allowable dose. A recent observation indicates that genetic polymorphism for methionine is a potent risk factor for methtrexate-induced central nervous system toxicity. PN can express itself either with negative or positive symptoms. oxaliplatine causes a unique acute syndrome which may respond to calcium plus magnesium infusion.V. Central nervous system. a reliable assessment of chemotherapy-induced peripheral neurotoxicity is necessary. Accordingly. dose-intensity. (14) The type and degree of neuropathy depend on the chemotherapy drug. Magnetic resonance diffusion-weighted and fluid-attenuated inversion-recovery imaging are useful in demonstrating chemotherapy-induced central nervous system lesions. and platinum compounds are the most frequently cited. The most common neurologic complications involve acute alterations in consciousness. Chronic peripheral neuropathy still represents a major limiting factor in a series of chemotherapeutic drugs. Disabling peripheral neuropathy has a significant negative impact on quality of life. a 5-fluorouracil prodrug. and ototoxicity. seizures. (16) Step II characterisation of the so called “sporadic” side effects Retinopathy and optic neuritis are a relatively frequent complication of medical treatments. 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. The pathogenesis of central and peripheral nervous system neurological manifestations caused by anticancer agents is often poorly understood. and is probably multifactorial. No prospective studies have been done to evaluate chemotherapy-induced neurotoxicity in the pediatric population. is that the main causes of pain in cancer patients in fact arise due to cancer treatments more frequently than due to disease itself. Continuous intravenous 5 fluorouracil (5FU) chemotherapy may be associated with a bilateral asymmetric anterior optic neuropathy (ON). the assessment of the efficacy and neurotoxicity of various chemotherapeutic agents is vital. both in cancer and in other medical fields. cyclosporin.

significantly correlated with the results of the common toxicity scales. 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). (24. In an early study. A reduced version of TNS (TNSr) was also compared. (18. tamoxifen). 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. and thus provide reference data and a model for testing the efficacy of drugs designed to provide neuroprotection. the severity of chemotherapy-induced peripheral neuropathy (CIPN) was evaluated in patients treated with cisplatin. the latter is based upon a combination of clinical and neurophysiological scoring systems (total neuropathy score. the peripheral neuropathy temporal course has been evaluated by means of the total neuropathy scoring system (TNS).0 and ECOG scores. only a combination of these is a reliable tool in the evaluation of groups of patients undergoing potentially toxic and/or neuroprotective treatments. It was concluded that the TNS and TNSr can be used to assess the severity of CIPN effectively. The temporal relationships between the PN and paclitaxel were robustly characterised. involving both clinical and/or neurophysiological testing have been employed in the setting of clinical research. while clinical self-reporting scores and objective evaluations with neurophyisiological tests may be of help in assessing peripheral neurotoxicity in single patients. Also in this respect.0 scores). 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. since evidence grows for a selective toxicity on these structures by new agents used in therapy. corneal opacities (tamoxifen). and the results of this evaluation can be reliably cor- related with the oncologic grading of sensory peripheral neurotoxicity. ECOG score and NCI-CTC 2. a combination of both clinical and neurophysiological tests are 155 . a multi-center study was developed to comparatively assess the reduced versions of the Total Neuropathy Score (TNS). and to compare the results with those obtained with common toxicity scales. Also. a number of scoring systems. canalicular fibrosis with epiphora (fluorouracil). (24) A highly significant correlation was demonstrated between the TNSr and the NCI-CTC 2. Based on the data in the National Registry of Drug-Induced Ocular Side Effects and the literature. which were not specifically investigated in any other previous study. The TNS is presently the most reliable tool in this context. other scoring systems address neuroophtalmological systematic side-effects. (20-22) (23. A CRITICAL REVIEW Interestingly.NEUROTOXICITY IN ONCOLOGY. despite the need for an experienced team in its application. methotrexate). vinblastine. but the TNSr evaluation was more accurate in view of the more extended score range. The correlation tended to be closer when the sensory items were considered. adverse ocular reactions of the most commonly used chemotherapeutic agents have been reviewed. On the other hand. retinopathy (mitotane. the simpler and faster TNSc (based only on the clinical neurological examination) allowed to grade accurately CIPN and correlated with the common toxicity scores. 26) In a recent paper. vincristine). but also the TNSr motor items. and optic or ocular motor abnormalities (carmustine.TNS and TNSr. methotrexate). (17) A number of drugs cause ocular irritation (fluorouracil. the severity of chemotherapy-induced peripheral neurotoxicity (CIPN). (27) Overall.and paclitaxel-based chemotherapy. a reduced version thereof (25). cataracts (busulfan. (23) Later on.

26 (74%) out of 35 patients developed a neuropathy which was mild in 15. Oxaliplatin-induced neurotoxicity consists of a rapid-onset. In particular. Phase III data suggest that docetaxel-carboplatin and paclitaxel-carboplatin are similarly efficacious with respect to progression-free survival and clinical response. Although docetaxel and paclitaxel share a mutual tubulin binding site. The neurotoxic effects of this combination were more severe than either cisplatin or docetaxel as single agent at similar doses. respectively. While paclitaxel-carboplatin remains the standard treatment for the management of advanced ovarian cancer. SALMAGGI under active investigation. Oxaliplatin-containing chemotherapy regimens are utilized commonly for metastatic colorectal cancer and increasingly in the adjuvant setting following surgical resection.a dominant side effect with both paclitaxel and cisplatin . leading to the inhibition of microtubule dynamics and cell cycle arrest. while neurotoxicity is the limiting toxicity. docetaxel has increased potency and an improved therapeutic index compared with paclitaxel. the combination of docetaxel with either cisplatin or carboplatin has yielded impressive response rates of 69-74 and 81-87%. 35).V. 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.and platinum-refractory ovarian cancer patients. Neuropathy was evaluated by clinical sumscore for signs and symptoms and by measurement of the vibration perception threshold (VPT). 34. (30.occurs at a low incidence with docetaxel. Recent reports of paclitaxel treated patients have emphasised the clinical relevance of ophtalmological and electrophysiological evaluation and characterisation of neuroophtalmological manifestation. (30) A prospective study was performed to determine if corticosteroid co-medication reduces the incidence and severity of docetaxel-induced neuropathy. The severity of neuropathy was graded according to the National Cancer Institute’s ‘Common Toxicity Criteria’. reversible acute sensory neuropathy and a late-onset cumulative sensory neuropathy that occurs after 156 . in advanced colorectal cancer in particular (33. (32) Oxaliplatin. docetaxel monotherapy demonstrated good response rates and an acceptable toxicity profile in both paclitaxel. 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. Modification of the molecular structure of the drug The taxanes. particularly in terms of minimising the incidence and severity of peripheral neuropathy. neurotoxicity . making docetaxel a promising agent for combining cisplatin and other platinum compounds. In Phase II studies. only mild hematological and gastrointestinal toxicity.01). In addition. L-OHP has no renal toxicity. Furthermore. SCAIOLI. although neurotoxicity occurs more frequently with the paclitaxel regimen. A. Paclitaxel and its semi-synthetic derivative docetaxel are potent chemotherapeutic agents that block tubulin depolymerisation. In clinical studies.01) as well as the post-treatment VPT (P < 0. (28. docetaxel-carboplatin appears to be a promising alternative. Compared with cisplatin. 31). cold-induced. and its short 1-h infusion offers a substantial clinical advantage over the prolonged infusion durations required with paclitaxel. 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). For example. mechanistic and pharmacological differences exist between these agents. 29) The strategies of neuroprotection a.

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. associated with diabetes. its dose-limiting toxicity is myelosuppression. Nedaplatin (cis-diammineglycolatoplatinum) can be given without hydration. Several neuromodulatory agents such as calcium-magnesium infusions. during treatment. human immunodeficiency virus (HIV)/antiretroviral drugs. However. antiepileptic drugs like carbamazepine or gabapentin. no evidence-based recommendation can be given for the prophylaxis of oxaliplatin-induced neurotoxicity. alpha-lipoic acid.033. methylcobalamin. heavy metal toxicity. indicating persistence of this peculiar type of neuropathy(39) Nedaplatin. (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. To date. no data from randomized comparative trials are available to allow a judgement on its potential advantages. results in significant morbidity. in particular thrombocytopenia. Two groups of patients (18 and 13) with advanced colorectal cancer. (38) This side effect has been described as a transient distal dysesthesia. enhanced by exposure to cold. Peripheral neuropathy (PN). Although activity has been shown. 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. The reversibility of these effects was studied. Five patients continued to manifest symptoms and signs of neurotoxicity after a long follow-up. The “Stop-and-Go” concept uses the reversibility of neurologic symptoms to aim at delivering higher cumulative oxaliplatin doses as long as the therapy is still effective. (37) Various strategies have been proposed to prevent or treat oxaliplatin-induced neurotoxicity. Conventional pain medications primarily mask symptoms and have significant side effects and addiction profiles. neurotoxic chemotherapy. acetyl-L-carnitine. The clinical and neurophysiological examinations showed an acute and transient neurotoxicity and a cumulative dose-related sensory neuropathy in nearly all the patients. and other etiologies. However. amifostine. In about three fourths of patients. a widening body of research indicates alternative medicine may offer significant benefit to this patient population. and as a dose-related cumulative mild sensitive neuropathy. 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 clinical situation.NEUROTOXICITY IN ONCOLOGY. treated with median cumulative doses of L-OHP 862 mg/m2 and 1. alcoholism. and topical capsaicin are among the best-researched alternative options for the treatment of PN.5 mg/m2. Alpha-lipoic acid. nutritional deficiencies. neurotoxicity is reversible with a median time to recovery of 13 weeks after treatment discontinuation. (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. benfotiamine. A CRITICAL REVIEW several cycles of therapy(36). Other potential nutrient or 157 . The goal of this approach is to keep the score of neurotoxicity at a level compatible with treatment continuation. All the patients had been evaluated previously. were studied. 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. to date. and glutathione have shown promising activity in prophylaxis and treatment of oxaliplatin-induced neurotoxicity. larger confirmatory trials are still lacking so that.

In the realm of physical medicine. for which there is no established therapy. we need to systematically assess the possible neuroprotective role of vitamin E supplementation in patients treated with cisplatin chemotherapy. SCAIOLI.V. No evidence of tumor protection was observed. The degree to which amifostine nevertheless accumulates in tumors and protects them against cancer therapies has been debated. biotin. and St. The strong similarity between clinical and neuropathological aspects in peripheral neuropathy induced by cisplatin and neurologic syndromes due to vitamin E deficiency. (44) The amino acid glutamate has been proposed as a neuroprotectant for vincristine. the plasmatic levels of vitamin E were analysed before and after 2 or 4 cycles of cisplatin treatment. and yoga have been found to provide benefit. (41) Amifostine is a pharmacological antioxidant used as a cytoprotectant in cancer chemotherapy and radiotherapy. (45) These results suggest that LIF may be safely used in human trials as a neuroprotectant for patients receiving cisplatin. folate. 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. Glutathione (36) A randomized. this was accompanied 158 . although protection against cisplatin-induced ototoxicity was not observed. and other side effects. zinc. It is therefore important to ensure that LIF neither inhibits the antitumour activity of these drugs. esophagitis. 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. New cutting-edge conventional therapies. magnesium. magnetic therapy. nor stimulates tumour growth. SALMAGGI botanical therapies include vitamin E. omega-3 and -6 fatty acids. 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). Amifostine showed protection against mucositis. 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. (42) Vitamin E. (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). myo-inositol. pyridoxine. glutathione. Given the lack of toxicity of vitamin E. N-acetylcysteine. doubleblind. acupuncture. A. paclitaxel and carboplatin without concern for impairment of antitumour effect (45). may also hold promise. but subcutaneous administration may reduce such toxicity. Peripheral sensory neuropathy is the main non-haematological side-effect related to cisplatin chemotherapy. chromium. 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). neuropathy. L-arginine. (43) The dose-limiting toxicity of the chemotherapeutic agent vincristine is peripheral neuropathy. However. L-glutamine. 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. including dual-action peptides. taurine. prompted Bove and Colleagues (43) to investigate the relationship between cisplatin neuropathy and plasmatic levels of vitamin E (alpha-tocopherol). John’s wort. (42) Clinically relevant levels of amifostine toxicity were observed in several studies.

with 32% of patients experiencing > or = WHO grade 2 at the cisplatin dose of 100 mg/m2. The primary efficacy variable.and vincristine-induced neuropathy.e. although this value was not statistically significant. results from randomized. i. Considering the absence of any satisfactory treatment currently available for CIPN in a clinical setting. 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. when ALC administration was started later on during treatment. (50) 159 .001). ALC was able to restore the mechanical nociceptive threshold within a few days. paclitaxel. but this finding was not statistically significant in these small groups. 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). In addition. in animal models of cisplatin-. at the stage of well-established neuropathy. Furthermore.04) as well as deterioration in gait (85 versus 45%. peripheral neuropathy was troublesome. (51) In another study. Nimodipine is a calcium-channel antagonist that has provided protection from cisplatin-induced neurotoxicity in a rat model system. It was concluded that glutamine may reduce the severity of peripheral neuropathy associated with high-dose paclitaxel.NEUROTOXICITY IN ONCOLOGY. All of these toxicities were reversible over time. P = 0. and changes in nerve-conduction.02). The median interval between pre.(46) These studies did not demonstrate a neuroprotective effect for nimodipine.and post-paclitaxel evaluations on 33 patients who did not receive glutamine and 12 patients who did. respectively. (46) Acetyl-L-carnitine (47. 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. Moderate to severe paresthesias in the fingers and toes were also reduced (55 versus 42% and 64 versus 50%.05). The ALC treatment significantly prevented the lowering of the mechanical nociceptive threshold when the administration started concomitantly and.016) and interference with activities of daily living (85 versus 27%. if any. less loss of vibratory sensation (P = 0. 51) In a non-randomised study neurologic signs and symptoms. with cisplatin. Chemotherapy-induced peripheral neuropathy (CIPN) was induced in different groups of rats. experiments indicated that ALC does not interfere with the antitumor effects of vincristine. respectively). these are important observations. A CRITICAL REVIEW by more toxicity. P = 0. the neurotoxicity score at the end of treatment.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. 50. For patients who received glutamine. 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. P = 0.04) and less toe numbness (P = 0. the possible interaction between ALC and vincristine antineoplastic action was assessed. opening up the possibility of using ALC to treat a wide range of patients who have undergone chemotherapy and developed sensory peripheral neuropathy. paclitaxel and vincristine as compared to each drug alone. 48) The hypothesis that acetyl-L-carnitine (ALC) may have a protective and a curative role in chemotherapyinduced hyperalgesia was tested in vivo. there were paired pre.and postexams was 32 days. however. were studied in 46 consecutive patients given high-dose paclitaxel either with (n=17) or without (n=29) glutamine. 49) Glutamine (44. placebo-controlled clinical trials will be needed to fully assess its impact. Finally. Patients who received glutamine developed significantly less weakness (P = 0. (47. The degree and incidence of motor weakness was reduced (56 versus 25%. gave a significantly lower mean for placebo patients than for nimodipine patients.or motor-nerve-conduction studies.

grade 3-4 sensory neuropathy also increases. Malaise and asthenia were also significantly less frequent in patients receiving MLT. After eight cycles.200 mg) (arm A) or placebo (arm B). SCAIOLI. To determine whether oral N-acetylcysteine is neuroprotective against oxaliplatin-induced neuropathy. 8. 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. Finally. stomatitis and neuropathy were less frequent in the MLT group. none in arm A (p<0. MLT has been shown to inhibit the production of free radicals. Treatmentrelated toxicity was evaluated based on National Cancer Institute (NCI) Criteria. albeit without statistically significant differences. (31) Melatonin (52) Experimental data have suggested that the pineal hormone melatonin (MLT) may counteract chemotherapy-induced myelosuppression and immunosuppression. five experienced sensory neuropathy (grade 2-4 toxicity) in arm B. After 12 cycles. breast cancer: 31. Thrombocytopenia was significantly less frequent in patients concomitantly treated with MLT. There was no statistically significant difference in neurotoxicity between group A and B. 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. and grade of neurosensory and neuromotor toxicity. A. Corticosteroid co-medication does not reduce the development of docetaxel-related neuropathy. In 42% of patients of group A and in 65% of patients of group B a mainly mild neuropathy was documented.o.05). grade of paresthesias. and 12 treatment cycles. in the evening). breast cancer patients with mitoxantrone. which play a part in mediating the toxicity of chemotherapy. It is thus well-established that oral N-acetylcysteine reduces the 160 . Neuropathy was evaluated by a clinical sum-score for symptoms and signs. particularly myelosuppression and neuropathy. The cumulative dose of docetaxel showed a significant correlation with post-treatment scores of VPT. while 49 female patients in group B with metastatic breast cancer were treated after comedication with corticosteroids was introduced as a routine. After four cycles of chemotherapy.05). SALMAGGI Corticosteroid Two groups of patients treated with docetaxel in subsequent cohorts were prospectively analyzed for neurotoxicity. A study was therefore performed in an attempt to evaluate the influence of MLT on chemotherapy toxicity. and by measurement of the vibration perception threshold (VPT). one in arm A (p<0. Lung cancer patients were treated with cisplatin and etoposide. sensory sumscore. seven of nine patients in arm B and two of five in arm A experienced grade 1 sensory neuropathy. gastrointestinal tract tumors: 14). grade 2-4 sensory neuropathy was observed in eight patients in arm B. Group A consisted of 38 patients with a variety of solid tumors. Patients were randomised to receive chemotherapy alone or chemotherapy plus MLT (20 mg/day p. a pilot study was undertaken. and gastrointestinal tract tumor patients with 5-fluorouracil plus folates. who were treated in studies before corticosteroid co-medication was recommended. The severity of neuropathy was graded according to NCI Common Toxicity Criteria. Alopecia and vomiting were not influenced by MLT. In addition.V. There were no significant electrophysiological changes in arm A after 4. 8. or 12 cycles of chemotherapy. Clinical neurological and electrophysiological evaluations were performed at baseline and after 4. This pilot study seems to suggest that the concomitant administration of the pineal hormone MLT during chemotherapy may prevent some chemotherapy-induced side-effects. The study involved 80 patients with metastatic solid tumors who were in poor clinical condition (lung cancer: 35.

most notably bipolar disorder. a new antiepileptic drug. Although its exact mechanism of action has yet to be determined. they were later discovered to be effective in the treatment of neuropathic pain. Pfizer Canada Inc) were initially developed as antiepileptic drugs and unlike conventional AEDs used to treat nonepileptic disorders (e. topiramate. 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.. A CRITICAL REVIEW incidence of oxaliplatin-induced neuropathy in colon cancer patients receiving oxaliplatinbased adjuvant chemotherapy.g. To date. and cocaine dependence. and movement disorders. valproate) gabapentin offers the advantages of low toxicity and a favorable sideeffect profile. However. EPO and CEPO have been exciting developments in the quest for the treatment of various types of neurotoxicity. (53) Calcium and magnesium infusion. creating a relatively novel class of analgesic drugs even useful for treating a wide range of neurologic and psychiatric conditions. phenytoin. Infusions of oxalate chelators Ca/Mg seem to reduce incidence and intensity of acute oxaliplatin-induced symptoms and might delay cumulative neuropathy. venlafaxine and pregabalin (56) (57). carbamazepine. review of the published literature reveals the usefulness of gabapentin in movement disorders. Medical treatment of peripheral nervous system neurotoxicity A few antiepileptic drugs are acquiring increasing popularity for non-epileptic syndromes. (54. 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. CEPO does inhibit the apoptosis associated with glutamate toxicity in hippocampal cells. (57) Gabapentin (Neurontin. Wyeth Lederle). Venlafaxine (Efexor. for decades. 54) (54). The largest area of nonepileptic use of gabapentin is neuropathic pain. especially in 85 mg/m(2) oxaliplatin dosage. in common with EPO. in which it has demonstrated efficacy in treatment of postherpetic neuralgia. The development of CEPO should continue. Future clinical studies will provide further insight into the range of conditions for which gabapentin is effective (58). Like EPO. and trigeminal neuralgia.NEUROTOXICITY IN ONCOLOGY. antiepileptic drugs (AEDs) have been used to treat a variety of nonepileptic conditions such as chronic pain. migraine prophylaxis. sciatic nerve compression. (55) c. and particularly for the treatment of painful neuropathy (56) (57). Erythropoietin (55) In addition to its wellknown erythropoetic effect. Pfizer Canada Inc) and pregabalin (Lyrica. carbamylated EPO (CEPO) does not bind to the EPO receptor on UT7 cells or have any haematopoietic/proliferative activity on these cells. erythropoietin (EPO) has also been shown to be neuroprotective in various animal models. and Topiramate (Topamax. gabapentin is likely to have multiple 161 . a serotoninergic-like anti-depressant. shares some evidence of clinical activity in the treatment of neuropathic pain. No medication is presently known to be active against oxaliplatin permanent neurosensory toxicity. It has also been reported effective as therapy for several psychiatric disorders. As a matter of fact. In addition. It has been observed that venlafaxine hydrochloride or lowdose topiramate could be active against the permanent neuropathy-related symptoms of oxaliplatin. In contrast to EPO. In vivo studies in mice and rats showed that even high doses of CEPO for long periods are not erythropoietic. In addition. CEPO is neuroprotective in a wide range of animal models of neurotoxicity: middle cerebral artery occlusion model of ischaemic stroke. diabetic neuropathy. experimental autoimmune encephalomyelitis and peripheral diabetic neuropathy. spinal cord depression. psychiatric disorders. Jansen Cilag). namely gabapentin (58).

Chemotherapy can have. cyclosporin. basic and clinical researchers have begun to investigate therapy to prevent neurotoxic injury. (59) Conclusion Survival rates for adults and children with cancer have increased dramatically over the past few decades. A. (60) Chemotherapeutic agents used to treat haematologic and solid tumors target a variety of structures and functions in the peripheral nervous system. Future research efforts are warranted to fully understand the mechanism of action of these drugs. diabetes and chemotherapy. the myelin sheath. In the peripheral nervous system. and recent study in this field has yielded clearer ideas on how to mitigate injury. and platinum compounds are the most frequently cited. 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. no prospective studies have been done to evaluate chemotherapy-induced neurotoxicity in the pediatric population. Methotrexate. and the exact incidence of such complications is unknown.V. the most attractive aspects of these two drugs include their tolerability. In recent years. significant toxicity on the central nervous system. however. and to further explore the role of these drugs in the rational polypharmacy of neuropathic pain. the axonal transport system. that in spite of more exhaustive studies performed in adults. Combined with the call for a greater recognition of the potentially devastating ramifications of CIPN on quality of life. Development of new chemotherapeutic agents and the expanded use of older agents have had a major impact on this celebrated improvement. the major brunt of the toxicity is directed against the peripheral nerve. including the neuronal cell body. however. SCAIOLI. chemotherapy-induced neurotoxicity is frequently delayed in onset and may progress over time. including peripheral trauma. Unlike more immediate toxicities that affect the gastrointestinal tract and bone marrow. particularly oxaliplatin in combination with infusional 5-fluorouracil/leucovorin. Such investigation is greatly needed. lack of serious toxicity and ease of use. However. Most of the information on toxicity comes from prospective reports and the adult patient population. 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. It is worth mentioning. SALMAGGI effects. to clearly characterize the safety and efficacy of gabapentin and pregabalin in all clinical neuropathic pain syndromes. Current opinion suggests these antinociceptive effects occur because of drug interaction with the alpha2-delta subunit of voltage-gated calcium channels. Recent advances in the development and administration of chemotherapy for malignant diseases have been rewarded with prolonged survival rates. Each agent exhibits a spectrum of toxic effects unique to its mechanism of toxic injury. resulting in chemotherapy-induced peripheral neuropathy (CIPN). oxaliplatin-based chemotherapy protocols. 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. Laboratory evidence suggests that both gabapentin and pregabalin can inhibit hyperalgesia and allodynia evoked by a variety of neural insults. The cost of progress has come at a price and the nervous system is frequently the target of chemotherapy-induced neurotoxicity. (56) d. and glial support structures. have emerged as the standard of care in first- 162 .

Chemoprotectants are agents that have been developed to ameliorate the toxicity associated with cytotoxic drugs and to provide site-specific protection for normal tissues. randomized trials demonstrating a prophylactic or therapeutic effect on oxaliplatin’s cumulative neurotoxicity are still lacking. Several chemoprotectant compounds have been studied in recent clinical trials. (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. amifostine. but final recommendations await prospective confirmatory studies. Treatment paradigms are shifting from sequential single drug trials to multiple drug therapies. 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. cumulative sensory neuropathy resembling that caused by cis-platin and completely reversible. For this reason. calcium. 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. Various strategies have been proposed to prevent or treat oxaliplatin-induced neurotoxicity. neurotoxicity treatment and prevention are becoming increasingly important issues in the care of patients with cancer (63). a-lipoic acid. A CRITICAL REVIEW and second-line therapy of advanced-stage colorectal cancer. However. and magnesium infusions. glutathione. gabapentin. and glutathione have demonstrated some activity in the prophylaxis and treatment of oxaliplatininduced acute neuropathy. vitamin E. Identification of these higher-risk patients may enable us to devise prevention strategies prior to the onset of this potentially debilitating complication. This is of increasing importance. Newer antidepressants. (62) With their significant impact on quality of life. 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. Drug choices are now based not only on efficacy but also on toxicity and drug interactions. an acute sensory neuropathy and a chronic. 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 clinical situation. and venlafaxine. (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. 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). These trials must include sufficient dose-limiting events for study and assessment of both toxicity and antitumor effect. 163 . acetyl-L-carnitine. 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. its clinically dominating toxicity affects the peripheral sensory nervous system in the form of 2 distinct types of neurotoxicity. without compromising antitumor efficacy. Although oxaliplatin by itself has only mild hematologic and gastrointestinal side effects. SNRIs and gabapentin/pregabalin have become popular though efficacy is not better than for TCAs (15). antiepileptic drugs like carbamazepine. Preliminary studies have shown promise for some agents including glutamine. Several neuromodulatory agents such as calcium-magnesium infusions. Pregabalin and gabapentin are effective in diabetic neuropathy and postherpetic neuralgia.NEUROTOXICITY IN ONCOLOGY. Evidence is needed to justify this change in treatment approach.

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V.0 ECOG Yes Yes Yes Yes Yes Table 3. Drug Type of neurotoxicity PN Ototoxicity Retinopathy PN Optic neuropathy Retinopathy Optic neuropathy Ophtalmologic PN PN PN PN Severity Prevalence Dose dependency Yes Yes Yes Yes No No Yes Yes No No Yes Yes No No Yes Cis-platin Paclitaxel Tamoxifen Docetaxel Oxaliplatin Ifosfamide Epothilone 5-fluorouracil Nedaplatin Moderate Mild Uncertain Moderate to severe Moderate to severe Mild to moderate Mild to moderate Mild to moderate Moderate to severe Severe Severe Mild to moderate Systematic Occasional Rare Systematic Occasional Occasional Frequent Frequent Frequent Occasional Occasional Frequent Occasional Occasional Frequent Optic neuropathy Severe Encephalopathy Moderate to severe PN Mild Table 2. SALMAGGI Table 1. recovery possible Uncertain Uncertain Cis-platin Paclitaxel Sensory. A. Scoring scale Symptom scale Objective scale (neurological) Yes Yes Yes Yes Yes Objective scale (neuro physiological) No No Yes No No NMS NSS TNS NCI-CTC 2. Drug Mechanism(s) of neurotoxicity Neuroprotection Neuro strategy protection effectiveness Fair No data No data Fair Uncertain Uncertain Uncertain. SCAIOLI. 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 Oligodendrocytic damage Multiple Drug discontinuation Drug discontinuation Stop-and-go schedule Tamoxifen Docetaxel Inhibition of microtubules 166 .

Oxaliplatin. A CRITICAL REVIEW Table 4. Concomitant administration N-acetyl-cisteine Oxaliplatin Concomitant administration Erythropoietin Chelants Ca/Mg Melatonin Antiepileptic drugs Gabapentin. Concomitant Reduced severity. Neuroprotective ChemoStrategy agent therapeutic drug Cisplatin.NEUROTOXICITY IN ONCOLOGY. Post-chemotherapy treatment Increased tolerability Weak Fair Fair Good Various Concomitant / Subsequent treatment Good 167 . pregabalin Various Oxaliplatin Various Various Vit E Expected result * Strength of evidence Fair Good Reduced incidence of retinopathy Reduced incidence of sensory positive symptoms Pretreatment Reduced severity of PN Concomitant Delayed cumulative toxicity Concomitant Delayed cumulative toxicity Subsequent.