| Japanese Journal of Clinical Oncology | Pages |
Bradycardia Induced by Irinotecan: A Case Report
Introduction
Case Report
Discussion
References
Bradycardia Induced by Irinotecan: A Case Report
Irinotecan chloride (CPT-11) is a new semi-synthetic camptothecin analogue which has encouraging antitumor activity against various malignancies. The major and unique toxicity of CPT-11 is diarrhea. Cardiovascular toxicity is rare and has not been found in clinical trials performed in Japan except for a very few cases of insignificant tachycardiac arrhythmia. We report a case of a 69-year-old man with recurrent colon cancer who suffered from bradycardia induced by infusion of CPT-11. Other toxicities including hematological toxicity and diarrhea were mild. Pharmacokinetic analysis using a limited sampling model revealed that the occurrence of bradycardia did not correlate with the excess of drug exposure. Although all of the cholinergic actions reported in the literature were mild, cardiotoxicity may come to be a clinically significant problem. If the events were examined more thoroughly, the cholinergic effect may be discovered more frequently. To administer CPT-11 safely needs meticulous monitoring not only for hematological toxicity and diarrhea but also for other cholinergic actions including bradycardia.
INTRODUCTION
Irinotecan chloride (CPT-11) is a semi-synthetic derivative of camptothecin, a plant alkaloid derived from the Chinese tree Camptotheca acuminata (1). The unique antitumor activity is obtained by inhibition of the nuclear enzyme topoisomerase I (2). In vivo, CPT-11 is metabolized by carboxyl esterase to an active compound, SN-38, which plays an essential role in the cytotoxicity of CPT-11 (3). Several clinical trials have demonstrated that it has an encouraging therapeutic index against lung (4), cervical (5), colorectal (6) and other (7) cancers. The dose-limiting toxicities are known to be leukopenia and diarrhea (4). It is also believed that cardiovascular toxicity occurs very rarely. We report a case of a man with recurrent colon carcinoma who suffered bradycardia induced by CPT-11.
CASE REPORT
a
 |
b
 |
Figure 1. Findings of abdominal CT scan (a) on admissionand (b) after the first course of chemotherapy with CPT-11. Para-aortic lymph nodes enlarged by recurrent colon carcinoma were markedly shrunk by the treatment.
A 69-year-old man received right hemicolectomy with a diagnosis of Dukes C type adenocarcinoma of the ascending colon in April 1996. In January 1997, he was admitted to Kyorin University Hospital because of a recurrent lesion of the cancer detected as enlarged para-aortic lymph nodes on an abdominal CT scan (Fig. 1a). No other metastatic lesion was found on abdominal and chest CT films. The patient had normal hepatic, renal and cardiac functions with a heart rate of 65/min and blood pressure of 124/76 mmHg at the time of admission and there was no apparent abnormal value in hematological and blood chemistry tests (Table 1). Ischemic heart disease or other cardiovascular disorders were not evident in the past history. He had a good performance status and no complaint associated with the recurrent carcinoma.
Table 1.
| Parameter | On admission | At nadir |
| WBC (/µl) | 6600 | 3200 |
| Plt (×104/µl) | 22.3 | 16.1 |
| Hb (g/dl) | 11.8 | 9.9 |
| TP (g/dl) | 6.7 | 6.1 |
| Alb (g/dl) | 3.4 | 3.0 |
| GOT (IU/l) | 17 | 14 |
| GPT (IU/l) | 7 | 25 |
| Cre (mg/dl) | 0.8 | 0.8 |
| Ccr (ml/min) | 68.7 | - |
| CEA (ng/ml) | 55.7 | - |
| Nausea | 0 | 1 |
| Diarrhea | 0 | 1 |
| PS | 0 | 0 |
In the initial course of the treatment, CPT-11 at a dose of 100 mg/m2 with 500 ml of 5% glucose was administered over 90 min on days 1, 8 and 15. Antiemetic regimens comprising 8 mg of dexamethasone and 3 mg of granisetrone were also administered just before the CPT-11 infusion. Immediately after the first infusion started on day 1, the heart rate decreased to 30-40/min and sinus bradycardia without ischemic change was demonstrated on an electrocardiogram (Fig. 2). Bradycardia continued about 48 h and afterward returned to normocardia (Fig. 3). On days 8 and 15, similar episodes of bradycardia occurred repeatedly accompanying the infusion of CPT-11, which required support with infusions of atropine sulfate and dopamine. There was mild hypotension associated with the treatment but the patient had no symptoms or complaints accompanying the cardiac toxicity during the therapeutic course. Other non-hematological toxicities such as diarrhea, nausea or neuralgia were not apparent and the hematological toxicities were also not clinically significant (Table 1). The treatment resulted in marked shrinkage of the tumor by more than 90% in diameter on an abdominal CT scan (Fig. 1b). Despite the adverse effect, the patient subsequently received second and third cycles of treatment because of the excellent response. On days 1 and 8 of the second cycle, CPT-11 was administered without dexamethasone and granisetrone, respectively. Reproducible bradycardia also appeared during or immediately after infusion, ensuring that bradycardia was not induced by dexamethasone or granisetrone but by CPT-11. Atropine support was required and was successful in maintaining a heart rate in the normal range.
Figure 2. Electrocardiogram findings (a) on admission and (b) at the time of CPT-11 infusion. Figure 3. Clinical course during the first course of the treatment. The pharmacokinetic parameters were estimated by using the limited sampling model developed by Sasaki et al. (9). Briefly, the blood samples were collected at 2.5 and 13.5 h after the initiation of infusion and the area under the time versus concentration curve (AUC) was estimated using the following equations:AUCCPT-11 = (3.7891 × C2.5) + (14.0479 × C13.5) + 1.5463AUCSN-38 = (0.5319 × C2.5) + (19.1468 × C13.5) + 72.7349 where C2.5 and C13.5 are the plasma concentrations of CPT-11 (µg/ml) and SN-38 (ng/ml) at 2.5 and 13.5 h after the initiation of CPT-11 infusion, respectively. The estimated AUC of CPT-11 was calculated as 5164 ng/ml.h and that of SN-38 174.7 ng/ml.h (Table 2). Table 2. 
CPT-11 (µg/ml)
SN-38 (ng/ml)
AUCCPT-11 (ng/ml.h)
AUCSN-38 (ng/ml.h)
C2.5
C13.5
C2.5
C13.5
Present case
0.51
0.120
15.4
4.9
5154
174.7
Sasaki et al. (10)
0.53
0.100
19.0
6.0
5434
200.1
DISCUSSION
Bradycardia as a toxicity of CPT-11 has not been reported in phase I and II trials performed in Japan (4-7,10). The unique and major adverse effect of CPT-11 is diarrhea. SN-38 is metabolized from CPT-11 and subsequently conjugated to SN-38-glucuronidase in the liver to be eliminated in the bile juice (11). Although the exact mechanism of diarrhea has not been established, it is hypothesized that glucuronized SN-38 excreted from the biliary tract into the intestine is reversed to the active form of SN-38 deglucuronised by the intestinal flora inducing injury to the bowel mucosa (11). Ikuno et al. (12) reported a mucosal change in the ileum and cecum in CPT-11-treated mice, which explains the etiology of delayed phase diarrhea. However, acute phase diarrhea or abdominal cramps which occur during or immediately after CPT-11 infusion were often observed (13) and the mechanisms of the acute phase reaction cannot be explained merely by a mucosal change in the digestive tract. In a phase I trial performed in France, the dose of CPT-11 could be raised to as high as 750 mg/m2 with intensive high-dose loperamide support for controlling diarrhea (14). This finding implies that the cause of diarrhea is at least partially related to the cholinergic action. In addition, cholinergic-like symptoms appearing in the acute phase such as diaphoresis and abdominal cramp and less frequent symptoms including visual disturbance, lacrimation, malaise, salivation, myosis and piloerection have been reported (15). These adverse symptoms demonstrate that CPT-11 has a cholinergic effect that may induce bradycardia.
In pharmacokinetic analysis of the current case, the estimated AUCs of CPT-11 and SN-38 were not significantly different from those reported in previous papers by Sasaki et al. (9,10). In addition, the patient did not suffer from any of the other significant adverse effects including hematological toxicity corresponding to the excessive drug exposure. We therefore concluded that the occurrence of bradycardia was not correlated with the variation of pharmacokinetics of CPT-11 and SN-38.
Although all of the cholinergic actions reported in the literature were mild, cardiotoxicity may come to be a clinically significant problem. If the events were examined more thoroughly, the presence of a cholinergic effect may be discovered in more instances. To administer CPT-11 safely needs meticulous monitoring not only for hematological toxicity and diarrhea but also for other cholinergic actions including bradycardia.
References
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Last modification: 24 Nov 1998
Copyright©Japanese Journal of Clinical Oncology, 1998.
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