A review on oxaliplatin-induced peripheral nerve damage

Cancer Treatment Reviews (2008) 34, 368– 377 available at www.sciencedirect.com journal homepage: www.elsevierhealth.com/journals/ctrv COMPLICATIONS OF TREATMENT A review on oxaliplatin-induced peripheral nerve damage Andreas A. Argyriou a, Panagiotis Polychronopoulos a, Gregoris Iconomou b, Elisabeth Chroni a, Haralabos P. Kalofonos b,* a Department of Neurology, EMG Laboratory, University of Patras Medical School, Rion-Patras, Greece Department of Medicine, Division of Oncology, University Hospital, University of Patras Medical School, 26504 Rion-Patras, Greece b Received 5 December 2007; received in revised form 7 January 2008; accepted 8 January 2008 KEYWORDS Summary Platinum compounds are a class of chemotherapy agents that posses a broad spectrum of activity against several solid malignancies. Oxaliplatin (OXL) is a third-generation organoplatinum compound with significant activity mainly against colorectal cancer (CRC). Peripheral neuropathy is a well recognized toxicity of OXL, usually resulting in dose modification. OXL induces two types of peripheral neuropathy; acute and chronic. The acute oxaliplatininduced peripheral neuropathy (OXLIPN) may be linked to the rapid chelation of calcium by OXL-induced oxalate and OXL is capable of altering the voltage-gated sodium channels through a pathway involving calcium ions. On the other hand, decreased cellular metabolism and axoplasmatic transport resulting from the accumulation of OXL in the dorsal root ganglia cells is the most widely accepted mechanism of chronic oxaliplatin-induced peripheral neuropathy (OXLIPN). As a result, OXL produces a symmetric, axonal, sensory distal primary neuronopathy without motor involvement. The incidence of OXLIPN is usually related to various risk factors, including treatment schedule, dosage, cumulative dose and time of infusion. The assessment of OXLIPN is primarily based on neurologic clinical examination and quantitative methods, such as nerve conduction study. To date, several neuroprotective agents including thiols, neurotrophic factors, anticonvulsants and antioxidants have been tested for their ability to prevent OXLIPN. However, the clinical data are still controversial. We herein review and discuss the pathogenesis, incidence, risk factors, diagnosis, characteristics and management of OXLIPN. We also highlight areas of future research. c 2008 Elsevier Ltd. All rights reserved. Oxaliplatin; Peripheral neuropathy; Incidence; Diagnosis; Neuroprotection  * Corresponding author. Tel.: +30 2610 999535; fax: +30 2610 994645. E-mail address: kalofon@med.upatras.gr (H.P. Kalofonos). 0305-7372/$ - see front matter c 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2008.01.003  A review on oxaliplatin-induced peripheral nerve damage Introduction Platinum Compounds (PC), a class of chemotherapy agents classified as DNA alkylating agents, are effective in treating various cancer types. These agents contain platinum complexes, which are believed to inhibit DNA synthesis by forming interstrand and intrastrand cross-linking of DNA molecules.1 Cisplatin is the first agent of PC, while carboplatin and oxaliplatin are also included in the same class. Oxaliplatin (OXL) is a third-generation organoplatinum compound with significant activity against advanced or metastatic colorectal cancer (CRC). In addition to CRC, OXL has shown promising activity against rectal, pancreatic and gastric malignancies.2 OXL acts by cross-binding of DNA as well as by blocking DNA synthesis3 and is typically administered with 5-fluorouracil (5-FU) and leucovorin (LV) in a combination regimen, known as FOLFOX4.4 Apart from other significant toxicities, peripheral neuropathy (PN) is a well recognized dose-limiting toxicity of OXL5 OXL induces two clinically distinct forms of PN.6 The acute syndrome, consisting of distal or perioral paresthesias and pharyngolaryngeal dysethesias, appears soon after the administration of OXL and is usually transient and completely reversible within hours or days. The chronic form is a pure sensory, axonal neuronopathy, closely resembling the cisplatin-induced peripheral neuropathy.7 High cumulative doses of OXL are strongly associated with occurrence of chronic peripheral nerve damage.8 We herein review and discuss the pathogenesis, incidence, risk factors, diagnosis, characteristics and management of oxaliplatin-induced peripheral neuropathy (OXLIPN), being based on our experience and recent evidence of the relevant literature. We also highlight areas of future research. Search strategy and selection criteria References for this review were identified by searches of PubMed from 1980 until October 2007 with the terms ‘‘platinum compounds and peripheral neuropathy’’, ‘‘oxaliplatin and neurotoxicity’’, ‘‘cisplatin-induced neurotoxicity’’, ‘‘oxaliplatin-induced peripheral neuropathy’’ and ‘‘chemotherapy-induced peripheral neuropathy’’. Pathogenesis of peripheral neuropathy The mechanisms underlying the acute and chronic OXLIPN have not as yet been clearly defined.9 The acute syndrome of jaw tightness, cramps and paresthesias occurs as a hallmark of both motor and sensory nerves hyperexcitability, while repetitive and neuromyotonic discharges are evident from the neurophysiologic point of view10 Neuromyotonia is spontaneous muscular activity resulting from repetitive motor unit action potentials of peripheral origin due to impairment of voltage-gated potassium channels. As a result of muscular hyperactivity, patients with neuromyotonia may present with muscle cramps, myotonia-like symptoms, excessive sweating, myokymia and fasciculations.11 Hence, in view of its clinical similarity with disorders of voltagegated ion channels, such as neuromyotonias, acute OXLIPN could be defined as a channelopathy. Even more, the 369 clinical similarity of the acute OXLIPN syndrome with conditions caused by impairment of neuronal or muscular ion channels, suggests that OXL interacts with ion channels located in the cellular membrane.12 In any case, there is no robust evidence to suggest that the impairment of voltage-gated potassium channels is the specific causal factor producing the acute hyperexcitability syndrome of OXL. In a recent ex vivo study, oxaliplatin-induced action potentials were not blocked by substances affecting both fast and slow voltage-gated potassium channels, thereby suggesting that oxaliplatin may mostly impair voltage-gated sodium channels.13 Recent data from a preclinical study suggest that the acute OXLIPN may be linked to the rapid chelation of calcium by OXL-induced oxalate and OXL is capable of altering the voltage-gated sodium channels through a pathway involving calcium ions.14 Even more, differences in nerve excitability measures, particularly refractoriness, further strengthened the critical involvement of voltage-gated sodium channels in the pathogenesis of acute OXLIPN.15 On the other hand, the chronic, sensory OXLIPN may be induced by the decreased cellular metabolism and axoplasmatic transport resulting from the accumulation of platinum compounds in dorsal root ganglia (DRG) cells.16 Histological examination of OXLIPN in animal models reveals axonal loss with selective secondary atrophy of the DRG cells,17 thus confining that OXIPN should be best described as a primary neuronopathy rather than an axonal neuropathy.18 One could suggest that in addition to morphologic and functional changes in the DRG cells, the prolonged activation of voltage-gated sodium channels could induce cellular stress, thereby affecting the sensory nerve cells. This view is supported by the results of a preclinical study, which reported alterations of sodium channel inactivation kinetics of the sural nerve after application of OXL and increase of sodium currents due to prolonged opening of sodium channels.19 OXL-induced mitochondrial damage has also been proposed as another potential mechanism of OXLIPN induction.16 The impairment of cellular mitochondrial oxygen consumption is a measure of drug cytotoxicity.20 In an in vitro study, cellular mitochondrial oxygen consumption has been compared for cisplatin, oxaliplatin and carboplatin and despite a tenfold difference in platinum DNA adducts between cisplatin and oxaliplatin it was shown that oxaliplatin exhibited similar or greater cytotoxicity, indicating that oxaliplatin lesions are more potent than cisplatin lesions.21 Diagnosis The assessment of OXLIPN is primarily based on clinical examination, being summarized by several comprehensive neurotoxicity grading scales. The most widely used grading systems for assessing OXLIPN are the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), Eastern Cooperative Oncology Group criteria, Ajani and the WHO criteria.22–25 An OXLIPN grading scale, which includes duration of symptoms has previously been introduced, while recently another scale has been arbitrarily created.26,27 Despite the different scales, accurate grading of OXLIPN still represents a matter of debate, mainly due to the fact 370 A.A. Argyriou et al. that there are variances in interpreting clinical aspects, thereby leading to poor reliability. Additionally, various impairment and functionality items are used in these scales, which clearly hamper their general interpretability, while limitations result also from intra- and interobserver variation of these scales.28 To date, no systematic clinimetric study has been performed in OXLIPN dealing with these aspects. Recently, Cavaletti et al.,29 compared the most widely used oncological grading scales for peripheral neurotoxicity to the Total Neuropathy Score (TNS) that was initially validated by Cornblath et al.30 The TNS, a composite measure that includes symptoms, signs, ability aspects and electrophysiological measures, has demonstrated good validity with the second version of the NCI-CTC, the Eastern Cooperative Oncology Group (ECOG) and the Ajani score in chemotherapy-induced peripheral neuropathy (CIPN) and could be effectively used to assess the severity of CIPN.29 Even more, TNS showed a higher sensitivity than NCI-CTC to CIPN changes and therefore has also been proposed as a reliable method for assessing not only the severity but also the course of CIPN.31 Our group favours a grading scale, employing both clinical and electrophysiological evaluation, such as the TNS score. Table 1 describes the components making up the TNS score. We strongly support the view that clinical examination and nerve conduction study are capable of objectively assessing both the severity and course of peripheral nerve damage secondary to OXL administration.32 Considering the results from our previous studies, we strongly support the view that at least the estimation of vibration perception, deep tendon reflexes and amplitude of sural sensory action potential (a-SAP) is mandatory in assessing any CIPN, including OXLIPN.33 However, we acknowledge that the TNS is not validated in OXLIPN and thus should be established in future studies as a validated and reliable measure of neurotoxicity in Table 1 patients treated with OXL. In any case, different grading systems should be consolidated into an accurate widely accepted grading scale for assessing OXLIPN. Incidence and risk factors Summarized clinical data from studies involving over 1000 patients showed that the incidence of acute OXLIPN is very high. In these studies, OXL was administered in various regimens ranging from 85 to130 mg/m2, while the severity of OXLIPN was graded either using the NCI-CTC or WHO criteria. Acute OXLIPN occured in the vast majority of patients treated, with incidence rates, ranging from 65% to 98%.34–38 Likewise, the incidence of acute OXLIPN appeared to be strikingly high (up to 100%) in two well-designed studies that applied detailed clinical neurological and electrophysiological examination in 35 patients treated OXL plus capecitabine.39,40 Cold temperature represents the main risk factor of acute OXLIPN.12 The incidence of chronic OXLIPN is usually related to various risk factors, including treatment schedule, single dose per course, cumulative dose, time of infusion and pre-existing peripheral neuropathy.41 OXLIPN has been reported that may also be triggered by surgery.42 In the de Gramont et al., trial,35 grade 3 neurosensory toxicity occurred in 18.2% patients randomized to receive the FOLFOX4 regimen. Overall neurosensory toxicity was observed in 68% of these patients. The estimated incidence of grade 2 and 3 neuropathy, respectively, calculated for patients exposed to oxaliplatin, reached 10% after 3 and 9 cycles, 25% after 8 and 12 cycles and 50% after 10 and 14 cycles. This could be attributed to the OXL doses accumulation, since it is documented that at cumulative doses that reach 800 mg/m2, the occurrence of OXLIPN is highly likely, while severe (grade 3) OXLIPN occurs in 15% after Components making up the TNS score Total neuropathy score 0 1 2 3 4 Sensory symptoms None Motor symptoms Autonomic symptoms (n) Pin sensation None 0 Limited to fingers or toes Slight difficulty 1 Extend to ankle or wrist Moderate difficulty 2 Extend to knee or elbow Require help/assistance 3 Above knees/ elbows Disabled 4 or 5 Vibration sensibility Normal Strength Tendon Reflexes QST Vibration sensation Sural a-SAP Normal Normal Reduced in fingers or toes Reduced in fingers or toes Mild weakness Ankle reflex (AR) reduced 126–150 % ULN Reduced up to wrist/ankle Reduced up to wrist/ankle Moderate weakness Ankle reflex absent 151–200% ULN Reduced up to elbow/knee Reduced up to elbow/knee Severe weakness AR absent and others reduced 201–300% ULN Reduced above elbow/knee Reduced above elbow/knee Paralysis All reflexes absent >300% ULN 76–95% of LLN value 51–75% of LLN value 26–50% of LLN value 76–95% of LLN value 51–75% of LLN value 26–50% of LLN value 0–25% of LLN value 0–25% of LLN value Peroneal a-CMAP Normal Normal to 125% ULN Normal or reduced < 5% Normal or reduced < 5% a-SAP: amplitude of sensory action potentials, a-CMAP: compound muscle action potential, LLN: Lower limit of normal and ULN: Upper limit of normal. A review on oxaliplatin-induced peripheral nerve damage 371 cumulative doses of 750–850 mg/m2 and 50% after a total dose of 1170 mg/m2.41 In the Kemeny et al., study34 involving 214 patients with metastatic colorectal cancer, grade 3–4 neuropathy occurred only in 6% of patients assigned to be treated with the FOLFOX4 regimen. The rate of overall sensory symptoms was 82% (65% of any acute neuropathy and 57% of cumulative neuropathy). Persistent neuropathy (lasting > 14 days) grade 2 or 3 was seen in 18% and 3% in the FOLFOX4 group. After exposure to the FOLFOX6 regimen, grade 3–4 peripheral neuropathy has been observed in 16% of overall 60 cases. Because of this and other toxicities, only 36% of these patients received P90% of the scheduled oxaliplatin dose-intensity.43 The same group reported subsequently that 97% of patients experienced neurotoxicity after administration of the FOLFOX7regimen.44 In another study, FOLFOX6-induced neurotoxicity has been reported to involve 94% with 20% of cases with grades 3–4.45 In the adjuvant setting, results from the MOSAIC trial46 involving a total of 2246 patients with stage II or III colon cancer, showed that in patients allocated to the FOLFOX4 arm, the incidence of grade 3 sensory neuropathy was 12.4% during treatment, decreasing to 1.1% at 1 year follow-up; grade 2 neuropathy was 31.5% during treatment, decreasing to 5% at 1 year and grade 1 neuropathy was 48.1% during treatment, decreasing to 24% at 1 year. Our experience32 showed that the reported rate (64%) of patients that manifested OXLIPN after administration of the formal FOLFOX4 regimen is quite similar to that previously reported in several trials.34 As in most other previous publications,47 the majority of our patients experienced mild or moderate (grade 1–2) OXLIPN. In our study, grade 3 neurotoxicity was observed in 8% of patients, a rate quite similar to that observed in the MOSAIC trial,46 while it is lower than that observed in other studies.35 Differences in the nature of studies and the methodology applied could account for discrepancies between results. Most of all other studies35,46 evaluated the efficacy, general tolerability and safety profile of the FOLFOX-4 regimen. Our study has been focused on the detailed neurological monitoring of OXLIPN, based on validated clinical scales and longitudinal electrophysiological recordings.32 (CMAPs), while otherwise is normal. Needle EMG studies after OXL infusion reveal spontaneous high-frequency discharges of motor unit multiplets and bursts of muscle fibre action potentials.39,40 During voluntary contraction, a repetitive discharge of motor units is evident. These findings are characteristic of excessive nerve excitability, similar to the electrophysiological features of neuromyotonia.50 Chronic symptoms of OXLIPN are clinically characterized of distal sensory loss, suppression of deep tendon reflexes (DTR) and changes in proprioception, potentially resulting in dose reduction or treatment discontinuation.7 These sensory symptoms and proprioception changes do not subside between courses of therapy and may affect normal daily activities that require fine motor coordination.27 Few cases of central neuropathy, including Lhermitte sign, urinary retention and proprioception abnormalities have also been reported.51 From the electrophysiological point of view, nerve conduction study reveals low amplitude of sensory action potentials (a-SAPs), in keeping with a distal, sensory, axonal neuronopathy without motor involvement. The sural nerve is predominantly affected.15 Our experience on the topic corresponds with the existing knowledge. Clinical and electrophysiological examinations of 25 patients treated with 12 courses of the formal FOLFOX-4 regimen for metastatic colon cancer pointed towards a diagnosis of a symmetrical, axonal, distal, sensory neuronopathy.32 Positive sensory symptoms in a stockingand-glove distribution occurred in the distal lower extremities of our patients. Additionally, the decreased vibration and proprioception as well as the suppression of DTR indicated a dysfunction of sensory nerves.52 In respect to the electrophysiological findings, a decrease or abolition of aSAPs, with unchanged sensory conduction velocities was observed. No evidence of distal motor neuropathy was found, thoroughly confirming the predominance of sensory fibres involvement.32 Table 2 summarizes the overall clinical and electrophysiological characteristics of both acute and chronic OXLIPN. Clinical and electrophysiological characteristics The clinical symptoms of acute OXLIPN are usually reversible within few days without persistent impairment of sensory function and in the vast majority of cases does not require discontinuation of treatment or dose modification,7 while subclinical, electrophysiological abnormalities usually resolve by the third week after OXL infusion40 Dose reduction and subsequent treatment discontinuation should only be applied in patients with acute neurotoxicity lasting more than two weeks, even without motor symptoms or neurological signs.46 Symptoms of chronic OXLIPN are partly reversible in about 80% of patients and completely resolve after 6–8 months after discontinuation of OXL treatment in about 40% of patients.35,46,53 In a recent study, detailed clinical assessment and neurophysiological examination was performed in 6 patients with advanced CRC after completion of OXL therapy. The results of this study showed that chronic OXLIPN did not reverse after 6–9 months.15 Our Oxaliplatin causes a unique spectrum of acute neurological toxicities that have not been observed in patients receiving either cisplatin or carboplatin. Signs and symptoms may begin during the infusion or within 1–2 days of OXL administration.48 Clinically, sensory alterations are most prominent, particularly cold-induced and perioral paresthesias. Shortness of breath or difficulty in swallowing, but without any objective evidence of respiratory distress may occur. Rare cases of laryngospasm have only been reported.35 Other symptoms, including cramps, jaw stiffness, visible fasciculations, voice changes, ptosis, and visual field changes suggest that motor nerves or muscles may also be involved as a clinical hallmark of hyperexcitability syndrome.49 From the electrophysiological point of view, nerve conduction study reveals repetitive compound action potentials Natural course of OXLIPN after discontinuation of treatment 372 Table 2 A.A. Argyriou et al. Clinical and electrophysiological features of acute and chronic OXLIPN Acute OXLIPN Chronic OXLIPN Clinical symptoms Electrophysiological findings Cold-induced and perioral paresthesias. Shortness of breath or difficulty in swallowing, usually without any objective evidence of respiratory distress. Cramps, jaw stiffness, visible fasciculations, voice changes, ptosis, and visual field changes, in keeping with hyperexcitability NCS: Repetitive CMAPs, otherwise normal Distal sensory loss, suppression of deep tendon reflexes and proprioception abnormalities EMG: Spontaneous bursts of irregular high-frequency discharges and multiplets during voluntary contraction NCS: Reduction or abolition of a-SAPs. Normal motor and F wave study EMG: Essentially normal motor unit configuration NCS: Nerve conduction study, CMAPs: Compound muscle action potentials, EMG: Electromyography, a-SAPs: amplitude of sensory action potentials. experience (unpublished data) from clinical and electrophysiological follow-up study in 12 patients with advanced CRC showed that there was no evidence of OXLIPN reversibility six months after the discontinuation of OXL chemotherapy, corresponding well with the findings of the latter study.15 Even more, further progression of OXLIPN, as particularly demonstrated by the electrophysiological study, was evident 6 months after the discontinuation of chemotherapy. The fact that OXLIPN may persist for at least 6 months after the discontinuation of OXL-based chemotherapy should be attributed to OXL administration, since this phenomenon, called coasting, is characteristic of platinum compounds-based therapy and it results from their capacity to accumulate in DRG for a long time.54 Until recently, there was no evidence that delayed appearance of OXLIPN can occur in asymptomatic patients after completion of therapy. Choi et al.,55 provided for the first time a case report of delayed grade 3, chronic OXLIPN arising in a patient six months following completion of adjuvant OXL-based chemotherapy for stage III colon cancer with no preceding neurologic symptomatology. However, whether this delayed event should be definitely linked to OXL needs further study. Options for neuroprotection To date, several neuroprotective agents, including various anticonvulsants and Calcium–magnesium (Ca/Mg) infusions have been tested for their ability to prevent acute OXLIPN. The main candidate was Carbamazepine (CBZ), which is known to block sodium channels, thereby reducing the hyperexcitability of damaged peripheral nerves.56 CBZ therapy was tried in 12 patients treated with an OXL (130 mg/ m2)-based regimen to determine whether the acute neurologic effects might be relieved. As authors mention, the results were disappointing since there was no apparent benefit from CBZ in terms of neuroprotection from acute OXLIPN. Additionally, the majority of patients manifested CBZ-related adverse events.39 Gabapentin is a new antiepileptic drug with promising efficacy against several neuropathic pain syndromes, at a dose ranging from 300 to 400 mg tid. In the Wong et al., study57 that assessed 115 patients with neurotoxicity secondary to various treatment regimens, gabapentin has not significantly decreased pain intensity and acute symptoms of OXLIPN. Pregabalin is a very modern anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures. It was designed as a more potent successor to gabapentin.58 Recently, it was described a case report of hyperexcitability syndrome that was developed during the treatment of pancreatic cancer with oxaliplatin and gemcitabine (GEMOX) and was successfully treated with pregabalin.59 Finally, Ca/Mg infusions have been retrospectively tested in a cohort of 161 patients receiving FOLFOX for advanced CRC for their ability to prevent acute OXLIPN. Acute symptoms, such as distal and lingual paresthesia were much less frequent and severe, while pseudolaryngospasm was never reported in the Ca/Mg group, supporting the view that Ca/ Mg infusions seem to reduce both the incidence and intensity of acute OXLIPN.60 Non-pharmacological approaches to prevent acute OXLIPN include avoidance of cold liquids and instruction of patients to use scarves and face masks and cotton socks in cold weather.41 In any case, as no medications exist for convincingly relieving acute symptoms of OXLIPN further prospective studies on the topic are clearly warranted. The ideal candidate for neuroprotection against chronic, cumulative OXLIPN should clearly demonstrate efficacy and safety, but mostly it should not interfere with the cytotoxic activity of chemotherapy. The clinical data on potential neuroprotective agents are still controversial, since the majority of the relevant trials were no RCTs and have drawn conclusions from recruitment of small sample sizes or even case reports. Hence, a neuroprotective agent that would document efficacy and safety against cumulative OXLIPN is still lacking.41 Table 3 summarizes the agents that have been evaluated in clinical trials for their potential efficacy against chronic OXLIPN. Amifostine (WR-2721) is an organic thiophosphate prodrug, used as a cytoprotective adjuvant in cancer chemotherapy. The selective protection of non-malignant tissues is believed to be due to higher alkaline phosphatase activity, higher pH, vascular permeation of normal tissues and scavenging free radicals.61 Protective effect of amifostine A review on oxaliplatin-induced peripheral nerve damage Table 3 373 Agents that have been tested in clinical trials for their efficacy to protect peripheral nerves from chronic OXLIPN Treatment Subcutaneous Amifostine Glutathione A-lipoic acid Ca/Mg infusions Xaliproden Carbamazepine Topiramate Gabapentin Oxcarbazepine Reference Design Nb of pts Penz et al., 2001 Cascinu et al., 2002 Wang et al.., 2007 Gedlicka et al., 2002 Gamelin et al., 2004 Pilot study DB-RCT RCT Pilot study Retrospective 9 52 86 15 161 Gibson et al., 2006 Eckel et al., 2002 Von Delius et al., 2007 Durand et al., 2005 Mariani et al., 2000 Mitchell et al., 2006 Argyriou et al., 2006 DB-RCT Pilot study DB-RCT Cases report Pilot study RCT Pilot RCT 649 10 36 2 15 81 32 OXL dose Outcome 2 130 mg/m 100 mg/m2 85 mg/m2 130 mg/m2 3 regimens from 85 to 130 mg/m2 85 mg/m2 85 mg/m2 85 mg/m2 85 mg/m2 85 mg/m2 100 mg/m2 85 mg/m2 Effective Effective Effective Effective Effective for 85 mg/m2 Effective Effective Ineffective Effective Effective Ineffective Effective DB-RCT: Double-blinded randomized controlled trial. given subcutaneously has been found in a small pilot study of patients treated with an oxaliplatin (130 mg/m2)-based regimen. Their data suggested that amifostine 500 mg given as s.c. injection 20 min before OXL administration was able to counteract OXLIPN in 10 of 15 patients enrolled.62 These preliminary results need to be confirmed in larger doubleblinded RCTs. Glutathione (GSH) is a tripeptide, gluconeogenic nonessential amino acid, stored primarily in skeletal muscle and liver, acting as antioxidant, thus protecting cells from toxins such as free radicals.63 Data from in vitro studies have showed that GSH might be able to prevent the accumulation of platinum adducts in the DRG.64 The results from clinical trials on the efficacy of GSH for prophylaxis against OXLIPN are very promising. A randomized, double-blind, placebocontrolled trial provided evidence that GSH is effective in preventing OXLIPN, and that it does not reduce the clinical activity of oxaliplatin. Fifty-two patients treated with a bimonthly OXL-based regimen were randomized to receive GSH (1.500 mg/m2 over a 15-min infusion period before oxaliplatin) or normal saline solution. After 12 cycles, grade 2–4 neurotoxicity according to NCI-CTC criteria was observed in three patients in the GSH arm and in eight patients in the placebo arm (P = 0.004). The neurophysiologic investigations showed a statistically significant reduction of the values only in the placebo arm. The response rate was equal between arms, showing no reduction in activity of OXL.65 Even more, a pilot RCT assessing 86 patients with metastatic CRC was conducted to assess the efficacy of oral glutamine for preventing OXLIPN. Patients were randomized to receive chemotherapy plus glutamine (n = 42) or chemotherapy alone (controls, n = 44). A lower percentage of grade 1–2 peripheral neuropathy was observed in the glutamine group (16.7% versus 38.6%) after two cycles of treatment, and a significantly lower incidence of grade 3–4 neuropathy was noted in the glutamine group after four (4.8% versus 18.2%) and six (11.9% versus 31.8%) cycles. No between-group difference was found in the response to chemotherapy.66 A-lipoic acid is another antioxidant that has been found in a small trial to be effective in treating OXLIPN. Fifteen patients with advanced CRC treated with an OXL (130 mg/ m2)-based regimen and experienced Pgrade 2 OXLIPN were studied. Their results showed that in eight (53%) out of 15 patients who received alpha-lipoic acid, the severity of this dose-limiting oxaliplatin-related side effect has been effectively reduced, thus concluding that alpha-lipoic acid 600 mg given intravenously once a week for 3–5 weeks followed by 600 mg three times a day orally is able to counteract cumulative OXLIPN.67 Oxalate chelators, such as Calcium–magnesium (Ca/Mg) infusions have been evaluated to assess their potential efficacy in reducing OXLIPN. Gamelin et al.,60 retrospectively assessed 161 patients with CRC treated with three different OXL-based regimens. Ninety-six patients received infusions of Ca gluconate and Mg sulfate (1 g) before and after oxaliplatin (Ca/Mg group) and 65 did not. Only 4% of patients withdrew for neurotoxicity in the Ca/Mg group versus 31% in the control group (P = 0.000). The percentage of patients with grade 3 distal paresthesia was lower in Ca/Mg group (7% versus 26%, P = 0.001). At the end of the treatment, 20% of patients in Ca/Mg group had neuropathy versus 45% (P = 0.003). Thus, the authors concluded that Ca/Mg infusions might be able to delay cumulative neuropathy, especially in 85 mg/m2 oxaliplatin dosage. However, of great clinical importance are the efficacy results of the Combined Oxaliplatin Neuropathy Prevention Trial (CONCEPT) for first-line therapy of metastatic colorectal cancer, which showed that Ca/Mg IV supplementation strategy is not advisable in combination with the FOLFOX regimen. This phase III trial was early terminated, because patients receiving FOLFOX plus Ca/Mg had significantly decreased response rates, compared to patients treated with FOLFOX alone. Bearing in mind the preliminary and unconfirmed nature of these data, the final results of this trial are urgently awaited to clarify this issue.68 Xaliproden, an experimental non-peptide compound, found in research to have neurotrophic and neuroprotective effects,69 has been reported as being capable of significantly reducing the occurrence of OXLIPN.70 Robust evidence about its efficacy was evident after completion of the Xenox study, aiming to evaluate the potential of xaliproden in reducing the risk of recurrence of severe (Grade 3–4) OXLIPN. Six hundred forty nine patients with metastatic colorectal cancer not previously treated with oxaliplatin 374 and without any sign of PN were randomly treated with FOLFOX4 plus xaliproden 1 mg po qd or FOLFOX4 plus placebo. The results showed a 39% reduction in the risk of occurrence of grade 3 neurotoxicity in the xaliproden arm without any impact on the activity of FOLFOX4 regimen as shown by the response rate. However, it should be pointed-out that Xaliproden reduced the rate of grade 3 toxicity but not the risk of grade 2/3 toxicity. Furthermore, the arm receiving xaliproden plus FOLFOX was not able to receive a higher median number of cycles of oxaliplatin compared to the FOLFOX arm alone.71 Due to their mode of action, certain AEDs may target central and peripheral sensitization mechanisms involved in neuropathic pain.56 CBZ is a conventional AED and mood stabilizing drug. It is also used to treat certain types of neuropathic pain.72 Taking under consideration that OXL is capable of altering the voltage-gated sodium channels14 and the mechanism of CBZ action is mainly based in blocking sodium channels in a voltage-dependent manner, its use as a potential neuroprotective candidate agent against OXLIPN has a solid rationale. In a pilot study enrolling 10 patients with CRC, it was reported that OXLIPN more than grade 1 (WHO criteria) may be prevented by CBZ.73 However, the final results of this study on an expanded sample size were negative. Thirty-six patients treated with the FUFOX regimen were randomly assigned to either receive chemotherapy with CBZ (n = 19) or controls (n = 17). CBZ was given in a dosage for targeted plasma levels of 4–6 mg/L and neurotoxicity was assessed using a Peripheral Neuropathy (PNP) Score. Between groups, there were no major differences when considering worst neurotoxicity during the study period (p = 0.46). Grade 3/4 neurotoxicity occurred in 4/19 patients receiving CBZ versus 6/17 controls, while no major differences emerged between groups in each category of the PNP score. Thus, this randomised, controlled, multicenter phase II study failed to support the routine use of CBZ as the ideal neuroprotective agent against OXLIPN.74 Among modern AEDs, gabapentin, appeared to be effective in a pilot study,75 but results on its efficacy have been disappointing in future randomized clinical trials assessing relative larger sample sizes.57,76 Topiramate is another modern antiepileptic drug (AED) that shares some evidence of clinical activity against neuropathic pain.77 Combination treatment of low dose topiramate (50 mg bi.d) and venlafaxine (37.5 mg bi.d), a serotoninergic-like antidepressant, has been found capable of being active in two patients with CRC against chronic OXLIPN, providing pain relief and significant autonomy improvement related to OXL treatment.78 Oxcarbazepine (OXC) is also a modern AED that has been developed through structural variation of CBZ with the intention to avoid metabolites causing adverse effects.79 Our experience showed that the use of OXC is promising in protecting peripheral nerves from chronic OXLIPN. OXC modulates both voltage-sensitive sodium channels and high-voltage activated N-type calcium channels and by this mechanism of action may be another suitable preventive measure against OXLIPN. Our study was a RCT in which 32 patients with advanced colon cancer received 12 courses of the FOLFOX-4 regimen and were randomly assigned to receive OXC (600 mg bi.d) or chemotherapy without OXC. A modified TNS was performed during chemotherapy. The A.A. Argyriou et al. incidence of OXLIPN was strikingly decreased in patients receiving OXC (31.2% versus 75%), while OXC was safe and well tolerated.80 Non-pharmacological treatment strategies against OXLIPN are primarily based on the ‘‘Stop-and-Go’’ concept, which uses the predictability and reversibility of neurological symptoms, to aim at delivering higher cumulative OXL doses as long as the therapy is still effective.41 Successful use of the ‘‘Stop-and-Go’’ concept has been previously reported. Petrioli et al.,81 studied 32 patients treated with FOLFOX-4. Patients achieving objective response or stable disease received oral capecitabine 2500 mg/m2 days 1–14 every 3 weeks; OXL was reintroduced as soon as progression occurred. Twenty-eight patients (87.5%) manifested peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 1 patient (3.1%), thus supporting the view that the FOLFOX-4 stop and go and capecitabine maintenance chemotherapy is associated with a very low incidence of grade 3 neurotoxicity. In the OPTIMOX study,82 a continuous FOLFOX-4 regimen was compared to an intermittent FOLFOX-7 regimen (6 cycles) with maintenance 5-FU/LV (12 cycles) and reintroduction of FOLFOX7 (6 cycles). Importantly, the number of grade 3/4 neurotoxicities was significantly reduced (Grade 3 sensory neuropathy was observed in 17.9% in FOLFOX-7 arm versus 13.3% of patients in FOLFOX-4 arm), supporting the use of the ‘‘Stop-and-Go’’ concept in preventing OXLIPN. However, reservations concerning the interpretation of results and the conclusions drawn were expressed soon after the results of the OPTIMOX study has been published.83 The OPTIMOX type 2 regimen with celecoxib has been associated with grade 3–4 neuropathy rate of 9.5%.84 Conclusions and future research perspectives Peripheral neuropathy is the major non-haematological dose-limiting adverse effect of OXL-based chemotherapy, obviously deteriorating the QOL of patients with cancer. OXLIPN is presented with two distinct syndromes, producing a unique syndrome of acute neurosensory toxicity and the chronic form that closely resembles in character the cisplatin-induced peripheral neuropathy. A widely accepted grading scale of OXL is lacking and therefore it should be developed and employed in clinical trials, so that data concerning the efficacy of neuroprotective agents can be objectively compared between each other. At present, the results of clinical trials on the efficacy of various candidates for neuroprotection against both acute and chronic OXLIPN are still a matter of debate. Improved understanding of the pathophysiological mechanism of OXLIPN in animal models would facilitate the identification of effective and safe neuroprotective agents, not interfering at the same time with the cytotoxic activity of OXL. Conflicts of interest statement We have no conflicts of interest. No funding source had a role in the preparation of this paper or in the decision to submit it for publication. A review on oxaliplatin-induced peripheral nerve damage Acknowledgements Each author contributed equally in the preparation of this review. All authors have seen and approved the final version. References 1. Brabec V, Kasparkova J. Modifications of DNA by platinum complexes. Relation to resistance of tumors to platinum antitumor drugs. Drug Resist Updat 2005;8(3):131–46. 2. 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