Acute Oxaliplatin-Induced Peripheral-Nerve Hyperexcitability
Authors: Renate Schmelz, Christian Lersch, Jean L. Grem, Tanya Lehky, Rebecca Thomas, May Quinn, Mary Kay Floeter
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.99.020 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12177120 Acute Oxaliplatin-Induced Peripheral-Nerve Hyperexcitability Renate SchmelzxRenate SchmelzSearch for articles by this author , Christian LerschxChristian LerschSearch for articles by this author Jean L. GremxJean L. GremSearch for articles by this author , , Tanya LehkyxTanya LehkySearch for articles by this author , Rebecca ThomasxRebecca ThomasSearch for articles by this author , May QuinnxMay QuinnSearch for articles by this author , Mary Kay FloeterxMary Kay FloeterSearch for articles by this author Show More Technical University, Munich, GermanyNational Cancer Institute, Bethesda, MD https://doi.org/10.1200/JCO.2002.99.020 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15082002In Reply:Schmelz and Lersch raise a number of issues in their letter concerning our article "Acute Oxaliplatin-Associated Peripheral Nerve Hyperexcitability".1 They treated 10 patients with 85 mg/m2 oxaliplatin every 2 weeks in combination with leucovorin-modulated fluorouracil and carbamazepine starting 5 days before the first oxaliplatin infusion, continuing until the disappearance of any oxaliplatin-induced dysesthesia.2 The dose was adjusted to achieve carbamazepine levels of 3 to 6 mg/L. Neurotoxicity was assessed by weekly questioning of the patient by the treating physician and was scored according to the modified World Health Organization toxicity criteria. No patient experienced greater than grade 1 neurotoxicity, and these preliminary results have prompted an open-label randomized phase II trial. In vitro studies using isolated rat sensory neurons exposed to 250 μmol/L oxaliplatin for 45 minutes showed a two-fold increase in the amplitude and duration of compound action potentials, which persisted for up to 1 hour after washout.3 Concurrent exposure to 1 mmol/L carbamazepine antagonized the oxaliplatin-induced effects. Based on these results, they suggest that delayed application of carbamazepine is unlikely to affect oxaliplatin-induced neurotoxicity.The World Health Organization criteria pertains to the chronic neurosensory toxicity typically associated with certain chemotherapy drugs. For example, grade 1 and 2 is defined as mild or moderate paresthesias, and the implication is that these are persistent. The acute neurotoxicity with oxaliplatin is unique. Fleeting symptoms that have resolved by the next week may not be reported by the patient, and specific questioning is needed. There is always a potential for bias when the treating oncologist is scoring the neurotoxicity. We used the Sanofi-Synthelabo toxicity scale for sensory neuropathies associated with oxaliplatin. By this scale, paresthesias/dysesthesias of short duration (that may be exacerbated by cold) that resolve and do not interfere with function are scored as grade 1. Most of the toxicities that we described for our patients were transient, lasting from a few seconds to a few hours, whereas cold-induced paresthesias may occur for several days. No patient required a dose reduction for these acute, transient toxicities. There are some limitations of extrapolating findings from an in vitro model to the clinical situation. Although the results of the experiments using rat sensory neurons are interesting, the concentration of oxaliplatin used was higher than the maximal plasma concentration achieved in patients (approximately 13 μmol/L).2 Further, the concentration of carbamazepine used to antagonize the oxaliplatin effect (1 mmol/L or 264 mg/L) is not achievable in patients.Our hypothesis was that oxaliplatin is associated with two distinct forms of neurotoxicity. The acute, transient neurotoxicity was characterized by rigorous neurologic examination and objective tests of nerve conduction studies and electromyography performed by independent neurologists. In addition, patients were carefully questioned on the day of and the days after oxaliplatin therapy to capture short-lived symptoms. No abnormalities were observed on sensory nerve conduction studies. Although no changes in the amplitude, distal latency, or conduction velocity of motor nerve potentials was evident compared with baseline, striking signs of hyperexcitability were identified in the motor nerves the day after oxaliplatin therapy. Both the symptoms and clinical signs of hyperexcitability had resolved when the patients returned 3 weeks later for the next cycle. We started carbamazepine 5 days before the second dose of oxaliplatin to allow steady state to be reached and continued for 2 days after oxaliplatin (by which time the transient symptoms had largely resolved). In 10 patients who completed the full course of carbamazepine, the median trough level was 9.8 mg/L and was above 6 mg/L in nine patients. Repeat neurologic evaluation including Nerve Conduction Studies and electromyogram clearly documented no amelioration of the hyperexcitability in the carbamazepine-treated patients. The abnormalities we observed are clearly different than that reported in the isolated rat sensory nerve model and that noted in patients who develop oxaliplatin-associated cumulative, persistent peripheral sensory neuropathy. Our study was not designed to assess the potential effect of carbamazepine on the cumulative sensory neuropathy. We believe that further mechanistic studies are needed to define the etiology of the acute neurotoxicity and to investigate the impact of novel therapeutic strategies to abrogate these effects in experimental models. Because isolated neurons remain viable for only a few hours, animal models will be required to evaluate the chronic, cumulative sensory neuropathy.1. Wilson RH, Lehky T, Thomas RR, et al: Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 20:: 1767,2002-1774, Link, Google Scholar2. Eckel F, Schmelz R, Adelsberger H, et al: Prevention of oxaliplatin-induced neuropathy by carbamazepine: A pilot study. Dtsch Med Wochenschr 127:: 78,2002-82, Crossref, Medline, Google Scholar3. Adelsberger H, Quathoff S, Grosskreutz J, et al: The chemotherapeutic oxaliplatin alters voltage-gated Na channel kinetics on rat sensory neurons. Eur J Pharmacol 406:: 25032,,2000 + Google Scholar