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© 2002 American Society for Clinical Oncology
Acute Oxaliplatin-Induced Peripheral-Nerve HyperexcitabilityTechnical University, Munich, Germany To the Editor:The recent study by Wilson et al1 shows no benefit from carbamazepine to prevent acute, reversible oxaliplatin-induced neuropathy. This result is inconsistent with our own preliminary data in 10 patients receiving oxaliplatin (85 mg/m2, biweekly) and carbamazepine. In contrast with a historical control group, none of the carbamazepine-treated patients experienced neurotoxicity more than grade 1.2-4 Wilson et al1 administered 200 mg carbamazepine orally three times a day starting 5 days before the second infusion of oxaliplatin and continuing for only 2 days after infusion. Our patients get carbamazepine starting 5 days before the first infusion of oxaliplatin continuing until the disappearance of any oxaliplatin-induced dysesthesia. Blood levels of carbamazepine are determined weekly, and oral doses of carbamazepine are adapted to a blood level of 3 to 6 mg/L. Adelsberger et al5 found an increased Na+ influx in isolated rat sensory sural nerves due to prolonged opening of Na+ channels to be the mechanism that causes the neuropathic symptoms observed in patients under treatment with oxaliplatin. This effect could not be reversed by washout of oxaliplatin but kept increasing during the washout procedure. Therefore, carbamazepine, which is a potent Na+ channel blocker, should be given before the first application of oxaliplatin. A delayed application of carbamazepine will not prevent oxaliplatin-induced neuropathy. Wilson et al should perform their detailed neurologic examination, needle electromyography, and nerve conduction studies before and a few days after the first application of oxaliplatin. Wilson et al reported on acute, reversible neurotoxicities in all patients (100%) receiving oxaliplatin. Serious symptoms ie, jaw pain, eye pain, pain in the arm used for drug infusion, ptosis, leg cramps, and visual and voice changes were observed along with the well-known symptoms, ie, paresthesias, dysesthesias, and cold hypersensitivity. The incidence of grade 3 or 4 toxicity was 31%. It might be speculated that the combination of oxaliplatin and capecitabine might be responsible for the high percentage and the severity of side effects. However, giving this combination of oxaliplatin (130 mg/m2 on day 1) and capecitabine (1,250 mg/m2 bid on days 1 to 14 every 3 weeks), Borner et al6 found severe sensory neuropathy in only 16% and 8% of non–pre-treated and pre-treated colorectal cancer patients, respectively. In a further phase II study, Twelves et al7 found 8% grade 2 and no grade 3 to 4 neuropathy. A phase I study of Zeuli et al8 found a peripheral neuropathy in only 16% of the patients. Therefore, Wilson et al should discuss the high incidence of neurotoxicity in their patients. We think that prevention of oxaliplatin-induced neuropathy by carbamazepine should further be studied in patients before the first application of oxaliplatin. The promising results of our pilot study are re-evaluated in an ongoing randomized, prospective, open-label, multicenter phase II study. REFERENCES
1. Wilson RH, Lehky T, Thomas RR, et al: Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 20: 1767-1774, 2002 2. Lersch C, Eckel F, Assmann G, et al: Prevention of peripheral sensory neuropathy (PSN) by carbamazepine in patients with advanced colorectal cancers (ACRC) treated with oxaliplatin: A pilot study. Gastroenterology 118:S2:A522, 2000 (suppl, part 1) 3. 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) 4. Eckel F, Schmelz R, Adelsberger H, et al: Prevention of oxaliplatin-induced neuropathy by carbamazepine: A pilot study. Dtsch Med Wochenschr 127: 78-82, 2002[CrossRef][Medline] 5. Adelsberger H, Quasthoff S, Grosskreutz J, et al: The chemotherapeutic oxaliplatin alters voltage-gated Na+ channel kinetics on rat sensory neurons. Eur J Pharmacology 406: 25-32, 2000[CrossRef][Medline]
6. Borner MM, Dietrich D, Stupp R, et al: Phase II study of capecitabine and oxaliplatin in first- and second-line treatment of advanced or metastatic colorectal cancer. J Clin Oncol 20: 1759-1766, 2002 7. Twelves C, Butts C, Cassidy J, et al: Capecitabine in combination with oxaliplatin as first line therapy for patients (pts) with advanced colorectal cancer (ACRC): Preliminary results of an international multicenter phase II study. Eur J Cancer 37: A1005, 2001 (suppl)
8. Zeuli M, Di Costanzo F, Sdrobolini A, et al: Capecitabine and oxaliplatin in advanced colorectal cancer: A dose-finding study. Ann Oncol 12: 1737-1741, 2001
ResponseNational Cancer Institute, Bethesda, MD In 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. REFERENCES
1. Wilson RH, Lehky T, Thomas RR, et al: Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 20: 1767-1774, 2002 2. Eckel F, Schmelz R, Adelsberger H, et al: Prevention of oxaliplatin-induced neuropathy by carbamazepine: A pilot study. Dtsch Med Wochenschr 127: 78-82, 2002[CrossRef][Medline] 3. 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
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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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