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© 2002 American Society for Clinical Oncology Acute Oxaliplatin-Induced Peripheral Nerve HyperexcitabilityByFrom the Center for Cancer Research, National Cancer Institute, and Electromyography Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. Address reprint requests to Jean L. Grem, MD, NCI-Navy Oncology, National Naval Medical Center, Building 8, Room 5101, 8901 Wisconsin Ave, Bethesda, MD, 20889-5105; email: gremj{at}mail.nih.gov
PURPOSE: Oxaliplatin is a novel platinum compound with clinical activity in several malignancies. Neurotoxicity is dose-limiting and occurs in two distinct forms, an acute neurologic symptom complex that occurs within hours or days of therapy and a chronic, cumulative sensory neuropathy. PATIENTS AND METHODS: Patients were treated in a phase I study designed to establish the maximum-tolerated dose of capecitabine given with oxaliplatin. Because of the unusual neurosensory toxicity of oxaliplatin, detailed neurologic examination, needle electromyography (EMG), and nerve conduction studies (NCS) were performed before and the day after oxaliplatin in a subset of 13 patients. Carbamazepine therapy was tried in 12 additional patients to determine whether the neurologic effects might be relieved. RESULTS: All patients experienced acute, reversible neurotoxicities with oxaliplatin. Symptoms included paresthesias, dysesthesias, cold hypersensitivity, jaw pain, eye pain, pain in the arm used for drug infusion, ptosis, leg cramps, and visual and voice changes. Serial EMG and NCS revealed striking signs of hyperexcitability in motor nerves after oxaliplatin. In patients who achieved therapeutic levels, carbamazepine did not alter the clinical or electromyographic abnormalities. CONCLUSION: The acute neurotoxicity seen with oxaliplatin is characterized by peripheral-nerve hyperexcitability, and the findings are similar to the clinical manifestations of neuromyotonia. Carbamezepine, which provides symptomatic relief in acquired neuromytonia, did not seem to be beneficial. Efforts to identify a successful neuroprotectant strategy would have a major impact on improving patient quality of life and the ability to deliver full doses of oxaliplatin.
OXALIPLATIN IS A novel cytotoxic platinum compound that differs both structurally and in its spectrum of activity from the related and widely used chemotherapeutic agents cisplatin and carboplatin. Platinum compounds exert their cytotoxic effects through the formation of DNA adducts that block both DNA replication and transcription, resulting in cell death in actively dividing cells as well as through the induction of apoptosis. Unlike these cis-diamine platinums, oxaliplatin contains a 1,2 diaminocyclohexane carrier ligand. This structural alteration results in formation of bulkier platinum-DNA adducts that may be more difficult to repair, leading to increased inhibition of DNA synthesis and induction of apoptosis.1 Many thousands of people have been treated worldwide with oxaliplatin since initial phase I studies, and it is currently licensed in many countries as treatment for patients with colorectal cancer. Oxaliplatin has established activity as a single agent and in combination with fluorouracil and leucovorin as both first-line and salvage therapy for metastatic colorectal cancer.2-5 Two randomized trials comparing oxaliplatin in combination with leucovorin-modulated fluorouracil versus fluorouracil/leucovorin alone in advanced colorectal cancer have shown higher response rates and longer times to disease progression in patients randomized to the oxaliplatin arm.3,4 Oxaliplatin has also shown activity in various other cancers, including ovarian, breast, and lung. Responses with oxaliplatin have been seen in tumors resistant to cisplatin.6-8 The combination of oxaliplatin with the new generation of oral fluorouracil prodrugs, such as capecitabine,9 is currently being evaluated. Neurotoxicity is the principal and dose-limiting toxicity of oxaliplatin, with two distinct syndromes. Long-term administration of oxaliplatin produces a sensory neuropathy, with loss of sensation and dysesthesias in the distal extremities. Development of sensory neuropathy is correlated with the cumulative dose of oxaliplatin, which is also true for cisplatin.10 Oxaliplatin also produces a unique syndrome of acute neurosensory toxicity. Shortly after infusion of oxaliplatin, patients develop striking paresthesias and dysesthesias of the hands, feet, and perioral region, jaw tightness, and unusual pharyngo-laryngo-dysesthesias. The latter is characterized by a loss of sensation of breathing without any objective evidence of respiratory distress but may rarely involve laryngospasm.4,11 Acute neurotoxicity may be triggered or exacerbated by exposure to cold. These symptoms occur within hours of exposure and are usually reversible over the following hours or days, and they may increase in both duration and severity with repeated administration. The differences in symptom onset and clinical spectrum suggest a different mechanism for the acute and chronic forms of oxaliplatin-associated neurotoxicity. On cessation of drug, the chronic neurotoxicities improve in the majority of patients within 4 to 6 months and will completely resolve in approximately 40% of patients by 6 to 8 months.12 The likelihood of symptomatic improvement on discontinuation of oxaliplatin correlates inversely with cumulative dose. We report on 13 representative patients who have had thorough neurologic assessment, both pretherapy and shortly after oxaliplatin, while participating in a phase I study of an oxaliplatin and capecitabine regimen. All patients, including this subset, have experienced acute neurosensory symptoms. In comparison with the pretherapy examinations, the patients demonstrated striking signs of reversible, peripheral-nerve hyperexcitability after administration of oxaliplatin. The clinical features are similar to those seen in neuromyotonia, a disorder associated with abnormal function of voltage-gated potassium channels in peripheral nerves. Carbamazepine may provide symptomatic relief in patients with congenital or acquired neuromyotonia. The similarity of the clinical features suggested to us that carbamazepine may be useful in ameliorating the acute neurotoxicity associated with oxaliplatin. In addition to a description of the clinical features, we report the results of a trial of intermittent carbamazepine therapy in a group of 12 of our patients on this protocol.
Study Protocol The major objective of this phase I study is to determine the safety profile and efficacy of oral capecitabine in combination with a fixed dose of intravenous oxaliplatin (130 mg/m2 given over 2 hours intravenously on day 1 every 3 weeks). A single dose of capecitabine is given the week before starting oxaliplatin for phamacokinetic sampling, and then is given twice daily on days 2 to 5 and 8 to 12; in subsequent cycles, capecitabine is given days 1 to 5 and 8 to 12 (the total daily dose ranges from 1,200 to 3,000 mg/m2). Dose adjustments for oxaliplatin and capecitabine are made based on individual patient tolerance. For the first occurrence of toxicities common to both oxaliplatin and capecitabine (diarrhea, mucositis, and myelosuppression), the dose of capecitabine is decreased initially; if the toxicity recurs despite capecitabine dose reduction, then the dose of oxaliplatin is decreased in the subsequent cycle. The dose of oxaliplatin is reduced in 25% increments for paresthesias or dysesthesias that either persist between cycles and/or interfere with activities of daily living. The drug is discontinued if severe neurotoxicity persists between cycles and for disabling or life-threatening neurotoxicity. Patients on this study are counseled to avoid cold drinks and exposure to cold water or air. Patients with stable or responsive disease continue on therapy until evidence of disease progression or unacceptable toxicity. Adults with advanced, histologically confirmed, incurable adenocarcinoma of the large or small bowel who meet standard inclusion criteria are eligible, provided they have measurable disease, an Eastern Cooperative Oncology Group performance status of 2 or better, and normal renal, hepatic, and bone marrow function. Exclusion criteria include symptomatic sensory neuropathy or clinical evidence of sensory neuropathy on physical examination and known brain metastases or leptomeningeal carcinomatosis. Written informed consent for protocol therapy that includes electrophysiologic studies is obtained from all patients. The protocol has been approved by the Cancer Therapy Evaluation Program, National Cancer Institute, and the Institutional Review Boards of the National Cancer Institute and the National Naval Medical Center.
Neurologic Assessment
In addition to the usual baseline chemistries to evaluate the patient’s metabolic status, the following additional tests are performed to screen for common causes of peripheral neuropathy: antinuclear antigen, rheumatoid factor, erythrocyte sedimentation rate, thyroid function tests, vitamin B12 level, serum and red cell folate, and magnetic resonance imaging of the brain or spine if clinically indicated. In patients with abnormal studies while receiving therapy, serial evaluation permits assessment of the course of the polyneuropathy and the degree of potential stabilization or improvement with oxaliplatin dose reduction. The same two neurologic examiners performed all the assessments. Although they knew which exams were performed before therapy and after oxaliplatin, they were blinded to the serum carbamazepine levels for the subsequent cohort of patients.
Neurologic assessments were planned before oxaliplatin therapy and periodically thereafter, with the intention to assess the cumulative neurosensory toxicity. Because of logistical issues, the index patient (patient no. 19) had his initial neurologic assessment the day after the first dose of oxaliplatin. Striking abnormalities were noted (described in detail below), including visible fasciculations and episodic spontaneous muscle cramps (Table 1). Repeat evaluation 3 weeks later immediately before the next dose of oxaliplatin indicated mild residual symptoms of cold hypersensitivity. A marked decline in spontaneous and electrically induced repetitive potentials was noted compared with the first electrophysiology studies, whereas repetitive motor unit firing with voluntary contraction persisted. Subsequent testing the day after oxaliplatin dosing again revealed the abnormal NCS/EMG patterns observed after the first dose of oxaliplatin. This serendipitous finding prompted us to study additional patients who agreed to be evaluated shortly after oxaliplatin infusion to more fully document these acute abnormalities. No patient reported symptomatic sensory neuropathy when they entered the study, although patient nos. 26 and 29 reported focal intermittent paresthesias and patient no. 19 reported periodic leg cramps. Several patients had disorders that may predispose to neuropathy, such as diabetes mellitus, but had normal clinical neurologic examinations before initiation of chemotherapy. Baseline electrophysiologic studies were, in general, unremarkable, although a few patients had evidence of mild sensory neuropathy, median or ulnar neuropathy, and one patient had findings indicative of lumbar radiculopathy. These findings were readily distinguishable from the postoxaliplatin abnormalities in the motor nerves. The erythrocyte sedimentation rate, thyroid function, vitamin B12 level, and serum and red cell folate levels were within normal limits in all patients. No patients had symptoms of rheumatoid arthritis or connective tissue disorders, and none had elevated antinuclear antigen or rheumatoid factor. After oxaliplatin infusion, all patients reported cold-induced paresthesias, particularly of the hands and throat, which diminished in severity after the first day. Perioral numbness was commonly noted during infusion, as was slurred speech and jaw pain during chewing. A smaller number of patients reported paresthesias in the extremities or calf cramps with walking that tended to persist for days to weeks. Neurologic examination within the first day after oxaliplatin infusion typically showed no change in strength, sensation, or deep tendon reflexes. After oxaliplatin infusion, seven of 10 patients evaluated exhibited delayed relaxation of the finger extensor muscles for several seconds after percussion over the posterior interosseus nerve (Fig 1). The first three patients evaluated shortly after oxaliplatin infusion had documentation of delayed relaxation on digital videotape. Frame counts showed that after nerve percussion, the fingers remained extended for periods ranging from 4 to 7 seconds, instead of the few hundred milliseconds seen in normal individuals. In the other patients, the delay in relaxation was 2 seconds or longer. Direct percussion of the muscle did not produce a similar effect.
In all patients, no abnormalities were observed on sensory nerve conduction studies. After oxaliplatin, although no changes in the amplitude, distal latency, or conduction velocity of motor nerve potentials was evident compared with baseline, single electrical stimuli to the motor nerves produced a series of small repetitive potentials after the main compound muscle action potential in 12 of 13 patients. Panel A in Fig 2 shows that at baseline, stimulation of the tibial nerve of patient no. 32 with a single electrical stimulus at the onset of the trace produces only the normal CMAP. The day after infusion, an electrical stimulus of the same intensity produced a CMAP followed by a series of repetitive discharges (Fig 2, panel B). Panels A and B each show 16 trials superimposed. In both panels, the portion to the left of the dotted line is at a low amplification, and the portion to the right of the dotted line is at a higher amplification. Panel C shows a raster display of 10 consecutive firings of a representative motor unit sampled from the tibialis anterior muscle during voluntary contraction in patient no. 34. Before infusion, only a single discharge (arrow) occurred with each voluntary activation, whereas on the day after oxaliplatin infusion, most motor units in this patient fired repetitive discharges (multiplets). The arrow indicates the discharge of the first motor unit.
In all patients, needle EMG studies after oxaliplatin showed spontaneous high-frequency discharges of motor unit multiplets and bursts of muscle fiber action potentials in at least one nerve tested (Fig 3). During voluntary activation, motor units also discharged repetitively with two to 10 potentials similar to that depicted in Fig 2.
This constellation of findings is characteristic of neuromyotonia, which is produced by excessive nerve excitability. Like the repetitive discharges that occurred after electrical stimulation of nerves, the EMG abnormalities were found in some, but not all, muscles in every patient. There was a propensity for more marked changes in distal muscles. There was no obvious correlation between the severity of electrophysiologic findings and the time interval after completion of the oxaliplatin infusion.
Because carbamazepine has been used to alleviate symptoms of patients with neuromyotonia, the protocol was amended to study whether carbamazepine 200 mg orally three times daily might potentially ameliorate the acute oxaliplatin neurotoxicity. The drug was started 5 days before oxaliplatin to allow the average plasma levels over the dosing interval to reach steady state, and was continued through day 3, with oxaliplatin given day 1. Twelve patients were studied at baseline and after cycle 1 of oxaliplatin, and 11 were studied after the second dose of oxaliplatin (Table 2). In the baseline electrophysiologic studies, no repetitive discharges followed the stimulus for the CMAP, and the motor units on EMG examination were normal without multiplets or myotonia. Of 10 patients who indicated they took a full course of carbamazepine, nine had serum levels
Oxaliplatin causes a unique spectrum of acute neurologic toxicities that have not been observed in patients receiving either cisplatin or carboplatin. Clinically, sensory alterations are most prominent, particularly cold-induced and perioral paresthesias. Other symptoms, such as cramps, jaw stiffness, voice changes, ptosis, and visual field changes suggest that motor nerves or muscles may also be involved. The electrophysiologic studies reported here provide evidence that oxaliplatin produces hyperexcitability of the motor nerves. The amplitude of the sensory nerve action potential is much smaller than that of the CMAP, and any potential repetitive discharges associated with oxaliplatin may not be detectable because of background noise. Our findings in motor nerves are best viewed as an overt manifestation of a more generalized peripheral-nerve hyperexcitability. It was not possible to blind the neurologists as to the timing of oxaliplatin therapy, because the baseline study was a planned part of the protocol, assessment of patient symptoms is an integral part of the neurologic assessment, and all patients had acute oxaliplatin-related symptoms after receiving drug. Although this may introduce a potential bias, the abnormalities in the EMG/NCS examinations after oxaliplatin were quite striking rather than subtle. After oxaliplatin, abnormal findings of repetitive CMAPs after a single electrical stimulus were seen in at least some motor nerves in almost all patients, and the neuromytonic abnormalities were seen in at least one or more nerves in all patients. The interpreters were not aware of whether the carbamazepine levels were in the therapeutic range. These acute electrophysiologic findings after oxaliplatin are the same as are seen in neuromyotonia. Clinically, neuromyotonia is a rare condition characterized by muscle stiffness, slowed muscle relaxation, and increased sweating, and less commonly paresthesias.15 Slowed muscle relaxation is accentuated by repetitive activation and cold.16 Neuromyotonia has several causes. It may be idiopathic,17 autoimmune mediated,16 associated with neuropathy,18 or a rare side effect of drugs, radiotherapy, or toxins.19,20 The underlying abnormality in neuromyotonia is hyperexcitability of the peripheral axon. Either persistent sodium channel activity or decreased potassium conductances can be a mechanism for producing axonal hyperexcitability and repetitive discharges. Noninactivating sodium channels in sensory axons are thought to produce the repetitive discharges that underlie paresthesias.21 Autoimmune blockade of voltage-gated potassium channels22-24 and exposure of sodium channels in para-nodal regions25 have been implicated in neuromyotonia. In our patients, symptoms of acute neurotoxicity coincided with the time course of elevated plasma oxaliplatin levels, which are known to peak about 1 hour after infusion followed by a prolonged terminal half-life of around 10 days.26 The time course suggests that oxaliplatin could act as a direct toxin against axonal ion channels, affecting either voltage-gated potassium channels or sodium channels. A direct action of oxaliplatin on sodium channels in rat sensory neurons has recently been reported,27 supporting the proposal that oxaliplatin causes a transient channelopathy. Whether oxaliplatin acts on persistent sodium channels or the sodium channels underlying the action potential remains to be explored. Neuromyotonia has been successfully treated with anticonvulsant drugs such as phenytoin and carbamazepine in some patients.16,17 Carbamazepine blocks repetitive firing of neurons in vitro.28 The action of carbamazepine is complex; it does not alter the membrane potential directly but acts on active voltage-gated sodium channels to enhance their inactivation, as well as on calcium channels and some subclasses of potassium channels.29,30 The similarities between acute oxaliplatin neurotoxicity and neuromyotonia led us to initiate an empiric trial of carbamazepine to ameliorate the neurotoxic symptoms. Carbamazepine did not seem to be efficacious in blocking either the electrophysiologic abnormalities or the symptoms of acute oxaliplatin neurotoxicity. These findings suggest that the mechanism of acute oxaliplatin toxicity differs from other causes of neuromyotonia. Possibilities include a limited action on persistent sodium channels, persistent effects on the inactivation properties of voltage-gated sodium channels, or effects on electrogenic pumps. Empirical intervention for oxaliplatin neurotoxicity has previously been reported.31,32 In the first study, gabapentin was administered at the onset of neurosensory symptoms to a cohort of 18 patients receiving oxaliplatin, fluorouracil, and leucovorin.31 Doses of 200 to 600 mg daily resulted in partial (61%) or complete (39%) resolution of neurotoxicity in all patients and prevented dose modification for neurotoxicity. However, four patients in our study (not included in this report) who received gabapentin at these doses for cumulative neurotoxicity derived no major benefit. In the second study, carbamazepine was administered at a dose adapted to provide a serum level of 3 to 6 µg/mL in an effort to limit neurotoxicity.32 This group treated 40 patients with oxaliplatin, fluorouracil, and leucovorin. Thirty patients received chemotherapy alone, and 10 subsequent patients received chemotherapy plus carbamazepine. Data obtained from direct patient questioning by the responsible physician indicated a reduction in the incidence of grade 2 to 4 peripheral sensory neuropathy despite similar oxaliplatin cumulative dosages in the two groups. Presumably, the authors focused on the cumulative sensory neuropathy rather than the acute neurotoxicities because the oxaliplatin dose is generally not reduced for transient neurotoxicity. Oxaliplatin neurotoxicity is detrimental to patients in terms both of unpleasant and disturbing symptoms and the need to dose reduce or discontinue the chemotherapy. The importance of fully defining the mechanism of acute and chronic oxaliplatin neurotoxicity is clear. A channelopathy seems to be involved in the acute neurotoxicity. Once mechanistic studies have been performed, a targeted intervention may then be possible. Chronic, cumulative neurotoxicity of platinum drugs including oxaliplatin is associated with the accumulation of platinum within sensory nerves and ganglia.33 For the chronic neurotoxicity of all platinum drugs, further study of investigational neuroprotectant agents is warranted. These acute neurologic abnormalities led us to amend our protocol to include a trial of intermittent carbamazepine therapy. Although carbamazepine, a standard treatment for neuromyotonia, is capable of blocking sodium channels, it failed to ameliorate the acute neurosensory toxicity in our patients either clinically or on electromyography. Further efforts to diminish the neurosensory toxicity of oxaliplatin are warranted to improve the quality of life and permit delivery of full doses to patients who demonstrate benefit.
Supported by the National Institutes of Health intramural program. Oxaliplatin is supplied by Sanofi-Synthelabo Inc., Malvern, PA, to the National Cancer Institute under a Cooperative Research and Development Agreement. We thank the following members of the NCI-Navy Gastrointestinal Oncology Team who have participated in the care of patients on this protocol: S. Fioravanti, L. Grochow, J.M. Hamilton, N. Harold, J. Hopkins, B.P. Monahan, G. Morrison, M.W. Saif, B. Schuler, E. Szabo, and C.H. Takimoto.
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McLean MJ, Macdonald RL: Carbamazepine and 10,11-epoxycarbamazepine produce use- and voltage-dependent limitation of rapidly firing action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 238: 727-738, 1986 29. Macdonald RL, Kelly KM: Antiepileptic drug mechanisms of action. Epilepsia 36: S2-S12, 1995 30. Matsumoto Y, Enomoto K, Moritake K, et al: Effects of carbamazepine on nerve activity and transmitter release in neuroblastoma-glioma hybrid cells and the frog neuromuscular junction. Cell Biol Toxicol 14: 191-198, 1998[CrossRef][Medline] 31. Mariani G, Garrone O, Granetto C, et al: Oxaliplatin-induced neuropathy: Could gabapentin be the answer. Proc Am Soc Clin Oncol 19: 609, 2000 (abstr 2397) 32. Eckel F, Schmelz R, Erdmann J, et al: Prevention of oxaliplatin induced peripheral sensory neuropathy by carbamazepine in patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 20: 146, 2001 (abstr 579) 33. Screnci D, McKeage MJ, Galettis P, et al: Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs. Br J Cancer 82: 966-972, 2000[CrossRef][Medline] Submitted March 9, 2001; accepted December 23, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
6.7 µg/mL (therapeutic range for anticonvulsant effects, 8 to 12 µg/mL in our clinical laboratory). Two patients did not receive the full course of carbamazepine because of drug intolerance. In the nine patients with near-therapeutic levels of carbamazepine, only one reported some lessening of cold-induced paresthesias. There was no apparent benefit from carbamazepine in terms of abnormal EMG/NCS results when analyzed either by the number of abnormal nerves or by a marginal homogeneity test assessing whether individual patients had improvements in the number of abnormal nerves before and after carbamazepine. There was a trend for the number of nerves with abnormal CMAPs to be higher in the patients with therapeutic or near-therapeutic levels of carbamazepine (P = .063, signed rank test), however, this might simply be due to the fact that the examinations with carbamazepine were performed after the second dose of oxaliplatin. Even though this represents only a small number of patients, the disappointing results and the fact that seven of the 12 patients had adverse effects from the carbamazepine has quelled our interest in further evaluating this strategy for acute oxaliplatin peripheral-nerve hyperexcitability. 
