We found that 50.8% (30/59) of patients who received irinotecan-based regimens in our outpatient chemotherapy clinic developed irinotecan-related cholinergic syndrome, with varying rates of hyperhidrosis (76.7%), abdominal pain (33.3%), rhinitis (26.7%) and diarrhea (6.7%). A wide variation in the incidence of overall irinotecan-related cholinergic syndrome, ranging from 31.3 to 83.0%, has been reported in patients receiving chemotherapies including irinotecan [11, 21, 22]. Such a difference in the incidence of this cholinergic syndrome may be attributable to differences in the dose of irinotecan. In our study, patients were treated with irinotecan (55–152 mg/m2) administered by intravenous infusion for 90 min. In contrast, Pitot et al. conducted a Phase I study in 34 patients with advanced refractory solid malignancies who were treated with irinotecan (240–340 mg/m2) administered by intravenous infusion for 90 min. They reported that the incidence of cholinergic symptoms ranged from 33% for patients who received 240 mg/m2 doses to 83% for patients treated with a starting dose of 340 mg/m2 . Further, Kanbayashi et al.  conducted a retrospective study in 150 cancer outpatients treated with 34.7–180.0 mg/m2 irinotecan, and reported that cholinergic syndrome, graded according to their original criteria, occurred in 31.3% of patients.
In this study, patients who experienced irinotecan-related cholinergic syndrome were prophylactically administered scopolamine butylbromide at the next scheduled treatment with irinotecan. Prophylactic administration of scopolamine butylbromide significantly reduced the overall incidence of irinotecan-related cholinergic syndrome (50.8% vs. 3.4%, P < 0.01). Moreover, all symptoms of cholinergic syndrome including hyperhidrosis, abdominal pain, rhinitis, and diarrhea were also significantly reduced by this intervention. Scopolamine butylbromide, a competitive antagonist of muscarinic acetylcholine receptors, is a quaternary ammonium derivative, and does not pass through the blood–brain barrier. As a consequence, scopolamine butylbromide has little central effects, such as sedation, confusion or paradoxical excitation . In fact, no central nervous system adverse events associated with scopolamine butylbromide were observed in the present study (data not shown).
Two reports showed the prophylactic effect of atropine and scopolamine on irinotecan-related cholinergic syndrome [15, 16]. Cheng et al. reported a retrospective, nonrandomized, cohort study in 80 cancer patients who were pre-treated with atropine diphenoxylate or hyoscyamine before receiving irinotecan. The overall incidence of cholinergic syndrome was not significantly different between the atropine–diphenoxylate (8.2%) and hyoscyamine (9.0%) groups (P = 0.760) . Yumuk et al. conducted a retrospective analysis in 66 metastatic colorectal cancer patients who received 85 mg/m2 irinotecan once a week or 350 mg/m2 irinotecan every 3 weeks. All patients were administrated atropine sulfate subcutaneously before irinotecan infusion, and no cholinergic symptoms, specifically early diarrhea, were observed . In both reports, anticholinergic drugs were prophylactically administered to all patients who received irinotecan, unlike in the present study. Additionally, atropine and hyoscyamine, which are tertiary amines, pass through the blood–brain barrier and can cause central effects, such as sedation, confusion, or paradoxical excitation, especially in the elderly [19, 20]. In contrast, in the third report, Zampa et al.  investigated the prophylactic effect of scopolamine butylbromide on irinotecan-related cholinergic syndrome in 13 patients who were administered scopolamine butylbromide 30 min before irinotecan. Scopolamine butylbromide was administered to 2 patients who showed evidence of cholinergic syndrome symptoms and subsequently to all other patients to prevent these symptoms. No further patients showed cholinergic syndrome symptoms. However, it is important to note that the sample size of this study was very small.
Several studies have reported that the development of irinotecan-related cholinergic syndrome is dose dependent [9, 21, 22]. Our multivariate logistic regression analysis showed that an irinotecan dose of 150 mg/m2 or greater was the only risk factor for the development of irinotecan-related cholinergic syndrome, as determined using ROC curves. Recently, Kanbayashi et al.  reported that irinotecan dose (≥ 175 mg), in addition to female sex, was a significant risk factor for developing irinotecan-related cholinergic syndrome, which is mostly consistent with our present finding. We found that 75% of patients who received irinotecan doses of 150 mg/m2 or greater developed irinotecan-related cholinergic syndrome. Therefore, prophylactic administration of scopolamine butylbromide is recommended for the treatment of irinotecan-related cholinergic syndrome in patients with this risk factor.
There were several limitations in the present study. First, this was a retrospective study; therefore, potentially relevant confounding factors may have been excluded. Second, the sample size was small and data were obtained from a single institution. Therefore, a larger scale, randomized control study is needed to confirm the prophylactic effect of scopolamine butylbromide against irinotecan-related cholinergic syndrome in patients receiving irinotecan-based regimens.
In conclusion, scopolamine butylbromide was effective in reducing the incidence of irinotecan-related cholinergic syndrome among patients receiving irinotecan-based regimens who developed cholinergic syndrome. Scopolamine butylbromide, unlike atropine and scopolamine, has no central effects. In addition, an irinotecan dose of 150 mg/m2 or greater was a risk factor for irinotecan-related cholinergic syndrome. Therefore, prophylactic administration of scopolamine butylbromide is recommended for patients receiving irinotecan doses ≥ 150 mg/m2 who develop irinotecan-related cholinergic syndrome.