Prophylactic effect of scopolamine butylbromide, a competitive antagonist of muscarinic acetylcholine receptor, on irinotecan-related cholinergic syndrome

Background/aim Cholinergic syndrome frequently occurs within the first 24 h after irinotecan injection. We evaluated the prophylactic effect of scopolamine butylbromide on irinotecan-related cholinergic syndrome. Patients and methods Fifty-nine patients who received irinotecan-based regimens at our outpatient chemotherapy clinic between April 2013 and May 2014 were enrolled. Patients who developed irinotecan-related cholinergic syndrome were prophylactically administered scopolamine butylbromide at the next scheduled treatment. Risk factors for irinotecan-related cholinergic syndrome were determined using logistic regression analysis. Results Irinotecan-related cholinergic syndrome occurred in 50.8% of patients. Scopolamine butylbromide administration significantly reduced the incidence to 3.4% (P < 0.01). The irinotecan dose (≥ 150 mg/m2) was the only risk factor associated with irinotecan-related cholinergic syndrome. The incidence of cholinergic syndrome in patients with this risk factor was 75%. Conclusion Scopolamine butylbromide was effective in preventing irinotecan-related cholinergic syndrome. It is recommended for patients receiving ≥ 150 mg/m2 irinotecan who may develop cholinergic syndrome at high frequency.

Clinical studies have shown that patients who receive irinotecan often experience acute adverse events, such as bradycardia, hypotension, hypersalivation, abdominal cramps, acute diarrhea, diaphoresis and other symptoms that are characteristic of cholinergic syndrome [9][10][11]. These symptoms are characterized by their occurrence during or shortly after administration of irinotecan and their amelioration within a few hours of completing the irinotecan injection [11]. The pathophysiological mechanisms underlying irinotecan-induced cholinergic syndrome remain to be clarified. Dodds and Rivory [12] demonstrated that irinotecan is a potent inhibitor of acetylcholinesterase at clinically relevant concentrations and revealed its mechanism of inhibition as being instantly reversible and apparently non-competitive. On the other hand, Blandizzi et al. [13] reported in an in vivo study that cholinergic syndrome does not arise due to the inhibition of acetylcholinesterase by irinotecan and SN-38. Instead, they demonstrated that irinotecan activated various nerve fibers and induced vagal reflexes at peripheral sites to trigger a cholinergic response. It is therefore to note that the management of acute diarrhea induced by irinotecan differs from delayed diarrhea occurring more than 24 h after irinotecan administration which is induced by exposure of intestinal epithelia to the released SN-38 [14].
Several reports have shown that the symptoms associated with irinotecan injection can be prevented or ameliorated by premedication with anticholinergic drugs such as atropine, scopolamine and scopolamine butylbromide [15][16][17]. Scopolamine butylbromide, unlike atropine and scopolamine which are tertiary amines, is a quaternary ammonium derivative and has little effect on the central nervous system because of passing through the blood-brain barrier [18][19][20]. However, the prophylactic effect of anticholinergic drugs on irinotecan-related cholinergic syndrome is unclear in Japanese patients receiving irinotecan. In addition, the prophylactic effect of anticholinergic drugs on irinotecan-related cholinergic syndrome in patients who develop irinotecanrelated cholinergic syndrome while receiving irinotecanbased regimens has not been studied.
We examined the prophylactic effect of scopolamine butylbromide on irinotecan-related cholinergic syndrome at the next scheduled treatment with irinotecan in Japanese patients who developed this cholinergic syndrome. Moreover, we identified the risk factors associated with the development of irinotecan-related cholinergic syndrome.

Study design and patients
Irinotecan-induced hyperhidrosis, abdominal pain, rhinitis and acute diarrhea that developed within 24 h after irinotecan administration were defined as cholinergic syndrome. Patients who received irinotecan-based regimens in our outpatient chemotherapy clinic between April 2013 and May 2014 were enrolled. Among these patients, those who developed cholinergic syndrome were prophylactically administered scopolamine butylbromide at the next scheduled treatment with irinotecan.
Incidence of cholinergic syndrome during or after administration of irinotecan was monitored by nurses, pharmacists and physicians. All patients were provided with a daily checklist to record adverse events, at their first visit to the outpatient chemotherapy clinic. The medical staffs asked the occurrence of cholinergic syndrome in an interview for all patients who visited the next cycle, and recorded it on an electronic medical chart. The symptoms monitored included hyperhidrosis, abdominal pain, diarrhea and rhinitis. The severity of cholinergic syndrome was graded according to the Common Terminology Criteria for Adverse Events (CTCAE, National Cancer Institute, MD, USA) version 4.0. Rhinitis was evaluated based on allergic rhinitis in CTCAE version 4.0.

Prophylactic administration of scopolamine butylbromide
A 20-mg scopolamine butylbromide injection was mixed with normal saline or dextrose 5% in water used to dissolve irinotecan, and the solution was infused intravenously over 90 min.

Risk analysis for irinotecan-related cholinergic syndrome
Demographics of patients who received the irinotecan-based regimens were compared between those who did and did not develop cholinergic syndrome. A P value was calculated for each demographic item. Items for which the P value was ≤ 0.05 were subsequently tested using logistic regression analysis. Receiver operating characteristic (ROC) curves were used to determine the cutoff of the irinotecan dose for logistic regression analysis.

Data analysis
Parametric analysis was conducted using a t test, while nonparametric analysis was performed using a Mann-Whitney U test, McNemar's test or Chi squared test. Data were analyzed using SPSS version 22 (SPSS Inc., Chicago, IL, USA). P values less than 0.05 were considered statistically significant.

Ethics statement
The present study was conducted according to the guidelines for human studies of the ethics committee of Gifu University Graduate School of Medicine and the Government of Japan, and was approved by the university's institutional review board (Approval no. 26-153). In view of the retrospective nature of the study, informed consent from the subjects was not mandated.

Risk factors associated with the incidence of irinotecan-related cholinergic syndrome
To determine the risk factors associated with irinotecanrelated cholinergic syndrome, the demographics of patients were compared between patients who did and did not develop irinotecan-related cholinergic syndrome. As shown in Table 3, the dose of irinotecan (135.2 ± 25.8 mg/m 2 vs. 99.3 ± 37.7 mg/m 2 , P < 0.001) and incidence of colon cancer (83.3% vs. 48.3%, P = 0.010) were significantly different between the two groups.

Discussion
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   [21]. Further, Kanbayashi et al. [22] conducted a retrospective study in 150 cancer outpatients treated with 34.7-180.0 mg/m 2 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 [18]. 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, Fig. 1 Overall incidence of irinotecan-related cholinergic syndrome (a) and incidence according to individual symptoms (b) before and after intervention with prophylactic administration of scopolamine butylbromide in patients who developed cholinergic syndrome. McNemar's test was used to analyze the data. **P < 0.01 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) [15]. Yumuk et al. conducted a retrospective analysis in 66 metastatic colorectal cancer patients who received 85 mg/m 2 irinotecan once a week or 350 mg/m 2 irinotecan every 3 weeks. All patients were administrated atropine sulfate subcutaneously before irinotecan infusion, and no cholinergic symptoms, specifically early diarrhea, were observed [16]. 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. [17] 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/m 2 or greater was the only risk factor for the development of irinotecan-related cholinergic syndrome, as determined using ROC curves. Recently, Kanbayashi et al. [22] 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/m 2 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/ m 2 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/m 2 who develop irinotecan-related cholinergic syndrome.
Funding None declared.  . 2 Comparison of the incidence of irinotecan-related cholinergic syndrome between patients who did and did not receive irinotecan at 150 mg/m 2 or greater. Chi squared test was used to analyze the data. **P < 0.01