Irinotecan chemotherapy associated with transient dysarthria and aphasia

Introduction

Irinotecan (CPT-11) is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata. It is a member of the topoisomerase I inhibitor class and exerts its activity by inhibiting DNA double-strand replication. The combination of irinotecan and 5-fluorouracil has become one of the most frequently used regimens in advanced colorectal cancer [1Go], and has shown to be active in several other solid tumors.

The principal toxicities of CPT-11 are a cholinergic syndrome (with acute diarrhea), delayed diarrhea, nausea and vomiting, and neutropenia. Other minor toxic effects include additional hematological toxicities (such as anemia, thrombocytopenia), alopecia, skin reactions, stomatitis and abdominal pain [2Go]. Dysarthria has rarely been described [3Go–5Go].

Case history

A 64-year-old man with a history of Crohn's disease presented to our department with metastatic adenocarcinoma of the right colon. In January 2004 he received his first course of FOLFIRI chemotherapy (CPT-11 180 mg/m2 i.v. on day 1 in a 60 min infusion, followed by 5-fluorouracil 1000 mg/m2/day for two consecutive days) [1Go]. Premedication included dexamethasone, ondansetron and atropine. The patient had been receiving tramadol for pain as his only other medication. Within 30 min of initiation of the CPT-11 infusion the patient developed progressive dysarthria, which in a few minutes developed into frank aphasia. The treatment was temporarily stopped, and the dysarthria and aphasia were resolved within 15 min without the use of any medications. Complete neurological examination and a brain computed tomography scan were normal (Figure 1Go). The CPT-11 infusion was re-initiated and completed without any other acute toxic effects.



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Figure 1 Normal brain computed tomography scan.

 
Discussion

An Internet-based literature search (Pubmed, Medline) revealed only three other reported cases in which irinotecan seemed to be correlated with temporary dysarthria [3Go–5Go].

The pharmacokinetics of irinotecan and its principal active metabolite, SN-38, are characterized by high plasma distribution due to its strong binding to plasma proteins and tissues [6Go]. In human subjects, no clear evidence of cerebrospinal fluid distribution has been demonstrated. In animal models, such as primates, the presence of this drug and its metabolites, such as other topoisomerase inhibitors (topotecan), have been found in the central nervous system (CNS) [7Go]. Nonetheless, the pathogenesis of irinotecan neurotoxicity has not been investigated thoroughly. Naranjo has developed criteria that estimate the probability that an adverse reaction can be due to a specific drug [8Go]. In this patient, as in the other three cases reported in the literature, the adverse event was most likely correlated to the irinotecan infusion.

The pharmacokinetics of irinotecan and its plasma levels should be more intensely studied because the tri-phase model of irinotecan elimination may explain a reaction in the first few minutes of infusion. In this case, however, the side-effects were observed after 30 min. The short duration and self-resolution of symptoms may be due to rapid clearance of the drug from the CNS.

Conclusions

This case history elucidates a rare, seemingly not dose-limiting and self-resolving toxic effect of irinotecan, which should be recognized by the medical oncology community given the increasing utilization worldwide of irinotecan.

S. De Marco*, E. Squilloni, L. Vigna, M. F. Bertagnolio and C. N. Sternberg

Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy

*; Email: sdemarco{at}scamilloforlanini.rm.it

References

1. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for colorectal cancer: a multicenter randomized trial. Lancet 2000; 355: 1041–1047.[CrossRef][ISI][Medline]

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: 606–623.[ISI][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.[Free Full Text]

4. Baz DV, Bofill JS, Nogueira JA. Irinotecan-induced dysarthria. J Natl Cancer Inst 2001; 93: 1419–1420.[Free Full Text]

5. Ceccaldi B, Kara F, Mommeja-Marin H et al. Dysarthria during irinotecan administration. Rev Med Intern 2002; 23: 950–951.[ISI]

6. Klein CE, Gupta E, Reid JM et al. Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide. Clin Pharmacol Ther 2002; 72: 638–647.[CrossRef][ISI][Medline]

7. Blaney SM, Takimoto C, Murry DJ 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: 464–468.[CrossRef][ISI][Medline]

8. Naranjo CA, Busto U, Pharm D et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239–245.[ISI][Medline]





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