[Prevention of oxaliplatin-induced neuropathy by carbamazepine. A pilot study].
BACKGROUND
Oxaliplatin has been proven antitumoral activity in numerous clinical trials. Peripheral sensory neuropathy with predominantly hyperpathic symptoms induced by cold is the most severe and dose-limiting toxicity resulting from oxaliplatin therapy. We demonstrated that oxaliplatin alters sodium channel kinetics on sensory neurons. This effect could be antagonized in vitro by the sodium channel blocker carbamazepine. Therefore a pilot study was initiated to investigate if carbamazepine prevents oxaliplatin-induced neuropathy in patients with colorectal cancer.


METHODS
Ten patients (six males, four females, mean age 56 +/- 12 years) refractory to 5-fluorouracil were treated with oxaliplatin, 5-fluorouracil, and folinic acid. The patients additionally received carbamazepine. Doses were adapted to a serum level of 3 - 6 mg/l. Patients were questioned about side-effects weekly and treatment-related toxicities were documented using the modified WHO scale. Results were compared with 30 historic controls treated with the same chemotherapy without carbamazepine.


RESULTS
The cumulative oxaliplatin dose was higher in the carbamazepine group (median 722 mg/m(2) and 510 mg/m(2), respectively, p = 0.020). Carbamazepine levels were 4.5 +/- 1.5 mg/l. In contrast to the control group no neuropathy higher than grade 1 occurred in the carbamazepine group. Rate of carbamazepine-induced side effects was low.


CONCLUSIONS
These observations demonstrate that oxaliplatin-induced sensory neuropathy more than grade 1 may be prevented by carbamazepine. Prevention of oxaliplatin-induced neurotoxicity by carbamazepine would possibly enable chemotherapy with considerable higher doses of oxapliplatin and thus enhance activity. A multicenter trial will elucidate if more serious distal neurotoxicities, which occur after application of higher cumulative doses of oxaliplatin, can also be prevented by carbamazepine.
Eckel
F
F
Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Germany. florian.eckel@lrz.tum.de
Schmelz
R
R
Adelsberger
H
H
Erdmann
J
J
Quasthoff
S
S
Lersch
C
C
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002220:Carbamazepine / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control*; D010865:Pilot Projects; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002220:Carbamazepine; D002955:Leucovorin; D005472:Fluorouracil