Affiliation of authors: Medical Oncology Service, Hospital Universitario "Virgen del Rocío," Sevilla, Spain.
Correspondence to: David Vicente Baz, M.D., Medical Oncology Service, CDT Hospital Universitario Virgen del Rocío, Avda. Manuel Siurot s/n, Apartado 41013, Sevilla, Spain (e-mail: vibaz{at}arrakis.es).
Irinotecan (CPT-11) is a semisynthetic analogue of camptothecin with antitumor activity in solid neoplasias. Camptothecin inhibits topoisomerase I and impedes the uncoiling of the DNA double helix, thus delaying its replication and cell division. Currently, CPT-11 combined with 5-fluorouracil (5-FU) is used as a first-line treatment of advanced colorectal cancer (1), and its effectiveness in other neoplasias is being recognized. The principal toxic effects of CPT-11 are acute cholinergic syndrome, delayed diarrhea, nausea and vomiting, and neutropenia. Diarrhea and neutropenia are the dose-limiting toxic effects. Other toxic effects include alopecia, anemia, thrombopenia, constipation, fever, cutaneous reactions, abdominal pain, and stomatitis (2).
A detailed literature search revealed only one case in which CPT-11 could have been the cause of transient dysarthria (3).
A 38-year-old woman with adenocarcinoma of the sigmoid loop, stage IV with bilateral pulmonary nodules and bone metastases, had been treated with CPT-11 (150 mg/m2 given intravenously continuously for 30 minutes) plus 5-FU (1000 mg/m2 per day given intravenously continuously for 4 days). The treatment was repeated every 15 days for a total of four cycles. Premedications administered were ondansetron, dexamethasone, and atropine. In each cycle, within a few minutes of commencing the CPT-11 infusion and before starting the 5-FU, the patient developed dysarthria that progressed, on two occasions, to motor aphasia that lasted about 45 minutes. On recovery, the patient remained asymptomatic. Complete neurologic explorations including nuclear magnetic resonance with gadolinium were normal (Fig. 1). Her treatment was suspended because of disease progression, and treatment with oxaliplatin (85 mg/m2 given intravenously continuously for 2 hours) and 5-FU (1000 mg/m2 per day given intravenously continuously for 4 days) was initiated for a further cycle. The patient died 2 months later as a result of pulmonary progression of her disease. With second-line treatment, the patient had no toxicity reaction. During both lines of treatment, fentanyl patches, as well as oral diazepam and amitriptyline, had been prescribed.
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Applying the criteria validated by Naranjo et al. (5) that determine the probability that an adverse reaction could be due to a specific pharmacologic agent, it is almost incontestable that the observed effect was due to the administration of CPT-11. Based on its pharmacokinetics, the relatively short duration of the dysarthria (always coinciding with the first minutes of administration) would correspond to the primary phase of the triphase model of CPT-11 elimination.
Our data thus confirm that CPT-11 can induce toxicity in the central nervous system, which needs to be taken into account in future studies. The toxicity seems reversible, is of short duration, and is not dose limiting.
REFERENCES
1 Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial [published erratum appears in Lancet 2000;355:1372]. Lancet 2000;355:10417.
2 Wiseman LR, Markham A. Irinotecan. A review of its pharmacological properties and clinical efficacy in the management of advanced colorectal cancer. Drugs 1996;52:60623.[Medline]
3
Sevilla Garcia I, Rueda A, Alba E. Irinotecan-induced central nervous system toxicity: a case report [letter]. J Natl Cancer Inst 1999;91:647.
4 Blaney SM, Takimoto C, Murry DJ, Kuttesch N, McCully C, Cole DE, et al. Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates. Cancer Chemother Pharmacol 1998;41:4648.[Medline]
5 Naranjo CA, Busto U, Pharm D, Sellers EM, Sandor P, Ruiz I, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:23945.[Medline]
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