Irinotecan adverse effects

The concomitant use of irinotecan as a 1-hour infusion immediately following a 2-hour infusion of oxaliplatin resulted in more severe hypersalivation and abdominal pain than irinotecan monotherapy (275). Acute intervention with atropine alleviated these adverse effects. When the drugs were separated by 1 day, the cholinergic symptoms were not exacerbated. The authors postulated that oxaliplatin might have some acetylcholinesterase inhibitory activity. 

Exatecan is a novel synthetic camptothecin derivative with a unique hexacyclic structure. It does not require metabolic activation, whereas irinotecan does. In vitro experiments in various cell lines have suggested that exatecan may be 6 and 28 times more active than SN-38 (7-ethyl-lO-hydroxycamptothecin, the active metabolite of irinotecan) and topotecan respectively. Furthermore, it has a 2-10 times higher therapeutic index than irinotecan and topotecan. In addition, exatecan may even be active in P-glycoprotein-mediated multidrug-resistant tumor cells. Its dose-limiting adverse effects are neutropenia and liver dysfunction. The recommended dosages of exatecan for phase II trials are 0.5 mg/m /day or 0.3 mg/ m /day as a 30-minute infusion on 5 consecutive days for minimally pretreated and heavily pretreated patients respectively (14,15). 

Leukopenia is a dose-Umiting adverse effect of irinotecan. Weekly intravenous doses (for example 100-125 mg/m ) appear to produce a slightly greater incidence of grade 3 neutropenia compared with 3-weekly schedules (350 mg/m ) (16-28 versus 14-22%). The median leukocyte nadir occurs on day 21 (15-27) and recovers 8 days later. Severe anemia (hemoglobin concentrations below 8 g/dl) and severe thrombocytopenia (platelet count below 50 x 10 /1) occur in 15 and 2% of patients respectively. There is eosinophilia in up to one-third of patients (2,3). 

Besides leukopenia, diarrhea is the major dose-limiting adverse effect of irinotecan (105,106). There are two different forms. The acute form occurs very early and is due to inhibition of acetylcholinesterase. The delayed-onset form occurs simultaneously with the leukocyte nadir and depends on the concentration of the active compound SN-38 in the plasma and bowel. 

The acute form of diarrhea is short-lived and can be effectively prevented or rapidly suppressed by concomitant atropine. The cholinergic symptoms are accompanied by abdominal cramps (36%), sweating (57%), salivation (11%), visual disturbances (15%), lacrimation (12%), and piloerection (3%). The recommended dose of atropine is 0.25 mg intravenously for prevention or 0.25-1.0 mg for acute treatment of patients with early cholinergic symptoms. As cholinergic symptoms have not been observed with other camptothecin derivatives, it can be speculated that these adverse effects are restricted to irinotecan, whose piperidino group bears some structural similarity to the potent nicotine receptor stimulant dimethylphenylpiperazinium (106). 

Irinotecan treatment schedules differ from 125 to 150 mg/m2 once a week for 4 wk followed by a 2-wk drug free interval (United States), to 350 mg/m2 once every 3 wk (Europe), or 100 mg/m2/wk or 150 mg/m2 every 2 wk (Japan). Differing intermittent treatment schedules using cytokine support for neutropenia, or intensive loperamide to counteract diarrhea, have also been reported (14). These tolerable CPT-11 regimens have produced median durations of response that range from 5.6 to 10.6 mo in colorectal patients disease stabilization occurs in 30 to 71 % (40). Response rates of 26% and 32% have been reported for previously untreated colorectal cancer patients higher response rates have been reported for non-5-FU-refractory patients (only 7-21%). Symptoms of diarrhea, nausea, and vomiting are common toxicities other side effects are asthenia, abdominal pain, leukopenia, and neutropenia. In the US trials at least one of these adverse... 

Irinotecan is a prodrug that is converted mainly in the liver by the carboxylesterase enzyme to the SN-38 metabolite, which is 1000-fold more potent as an inhibitor of topoisomerase I than the parent compound. In contrast to topotecan, irinotecan and SN-38 are mainly eliminated in bile and feces, and dose reduction is required in the setting of liver dysfunction. Irinotecan was originally approved as second-line monotherapy in patients with metastatic colorectal cancer who had failed fluorouracil-based therapy. It is now approved as first-line therapy when used in combination with 5-FU and leucovorin. Myelosuppression and diarrhea are the two most common adverse events. There are two forms of diarrhea an early form that occurs within 24 hours after administration and is thought to be a cholinergic event effectively treated with atropine, and a late form that usually occurs 2-10 days after treatment. The late diarrhea can be severe, leading to significant electrolyte imbalance and dehydration in some cases. 

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