Irinotecan-Related Cholinergic Syndrome Induced by Coadministration of Oxaliplatin

Camptothecins are anticancer agents whose inhibition of topoisomerase I renders them non-cross-resistant with other common cytotoxic compounds (1–3). Promising results have been obtained with the two substances available at the moment, topotecan and irinotecan (CPT-11), in heavily pretreated patients with cancers usually resistant to secondline chemotherapy, such as small-cell lung cancer (4) or colorectal cancer (5). While both drugs share the mechanism involved in antitumor activity, CPT-11 requires metabolization to the active structure SN-38 (6) and displays a toxicity profile different from that of topotecan. Apart from its myelosuppressive properties, CPT-11 is characterized by a higher frequency of diarrhea as well as episodes of an acute cholinergic syndrome, including hypersalivation, abdominal cramps, and a drop in systemic blood pressure (7). We report on a case in which a 53year-old woman underwent chemotherapy in a phase 11 study with oxaliplatin combined with CPT-11 for colorectal cancer refractory to fluorouracil-leucovorin treatment. Therapy consisted of 85 mg/m2 oxaliplatin given over a 2hour period on days 1 and 15 followed by CPT-11 given over a 1-hour period at a dose of 80 mg/m2 on days 1, 8, and 15. After uneventful administration of oxaliplatin, the patient complained of hypersalivation and abdominal pain along with a decreased blood pressure immediately after the first infusion of CPT11. Symptoms promptly resolved after treatment with subcutaneous atropine. The patient experienced no side effects with the second dose of CPT-11 given as the only cytotoxic drug on day 8 according to the regimen. On day 15, however, symptoms promptly recurred during the infusion of the camptothecin analogue following oxaliplatin administration. After this second episode, the regimen was modified, and oxaliplatin was infused on days 1 and 14, while CPT-11 was given on days 2, 8, and 15. The second cycle of treatment with this split schedule was tolerated without any side effects. However, when we rechallenged our patient with the original schedule of both drugs given on the same day, symptoms compatible with a cholinergic syndrome were again experienced by our patient and were promptly abrogated by the administration of atropine. We believe that the cholinergic syndrome attributable to CPT-11 was at least triggered by the coadministration of oxaliplatin in this case, since it was not seen with the application of CPT-11 alone. While the cholinergic syndrome has been described repeatedly with CPT-11, it has not been reported to be attributable to infusion of platinum compounds. Furthermore, a causative role of oxaliplatin alone in the development of these symptoms seems highly unlikely, since no side effects were seen with the application of oxaliplatin on days 1 and 14 during the second cycle, suggesting a potential interaction of both drugs in our patient. To our knowledge, this phenomenon has not been described before, and this patient was the only one out of 15 patients treated with this combination so far to develop this special form of cholinergic syndrome. Nevertheless, clinicians using similar treatment regimens should be aware of this potential drug interaction.