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Figure 2. Metabolic pathways of irinotecan (CPT-11) indicating carboxylesterase (CE) mediated conversion to SN-38, cytochrome P450 3A4 (CYP3A4) mediated oxidation to APC and NPC, glu-curonidation of SN-38 by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) to SN-38 glucuronide (SN-38G), and its deconjugation by bacterial ^-glucuronidase.

In single agent regimens, diarrhea is the most important side effect of irinotecan. The early onset diarrhea with abdominal cramping, flushes and transpiration, suggestive of a release of vaso-active compounds, responds well to treatment with atropine. The late onset secretory diarrhea seems to be correlated with the extent of biliary secretion of SN-38 into the intestinal lumen. In addition, a high fecal SN-38 to SN-38G ratio has been found to be related to structural and functional injuries to the intestinal tract by SN-38, leading to diarrhea. In a small clinical study co-administration of the poorly-absorbed aminoglycoside antibiotic neomycin with the second course of irinotecan reduced fecal ยก-glucuronidase levels to undetectable levels, resulting in a decrease of fecal concentrations of SN-38 without affecting systemic SN-38 levels [85]. The observation that 6 out of 7 patients having diarrhea in the first cycle had less symptoms in the second cycle with neomycin co-administration is currently the subject of a larger confirmatory study.

Recently, several publications have shown a relationship between the occurrence of a TATA-box polymorphism in the promoter of the UGT1A1 gene (i.e., UGTA1*28) and the severity of diarrhea and neutropenia following irinotecan treatment, which is due to a decreased ability to glucuronidate of SN-38 [86]. In addition, genetic polymorphism in the ABCB1 gene, which encodes the efflux transporter P-glycoprotein, was found to be associated with altered exposure to irinotecan [87].

The oral bioavailability of irinotecan was reported to be low, although due to extensive presystemic conversion by enzymes in the small intestine, favorable SN-38 to irinotecan AUC ratios have been observed in both animals and humans.

Clinical development Colon cancer

The optimal administration schedule for irinotecan in the treatment of col-orectal cancer remains unclear. The approved administration schedule in second-line treatment of advanced or metastatic colon cancer in the United States is 125 mg/m2 weekly for 4 of 6 weeks. In Europe, the most widely used schedule is 350 mg/m2 every 3 weeks, whereas in Japan 100 mg/m2 every week or 150 mg/m2 every other week is being used. A Phase III study comparing the United States versus the European schedule in patients with colon cancer showed comparable responses and toxicity profiles [88]. The Food and Drug Administration (FDA) approval for the use of irinotecan in second-line colon cancer in 1998, after accelerated approval in 1996, was based on a response rate of 32% in first-line setting [89] and survival benefit in 5-fluorouracil refractory patients in two Phase III studies [90, 91]. Consequently, two parallel Phase III trials combining irinotecan and 5-fluorouracil in first-line disease were conducted in the US and Europe [92, 93]. Both studies showed significant improvement of response rates (39-49 versus 21-31%), progression-free survival (7.0-6.7 versus 4.3-4.4 months) and overall survival (14.8-17.4 versus 12.6-14.1 months) with the combination as compared to single agent 5-fluouracil.

The development of diarrhea and dehydration in combination with neutropenia needs early recognition and treatment, especially in the bolus regimen [94]. Recent developments with irinotecan in colorectal cancer include combinations with oral 5-fluorouracil analogs [95] and oxaliplatin [96], yielding response rates of 46% and 56% and a median survival of 21 months.

Other malignancies

Apart from the antitumor activity in colorectal carcinoma, encouraging response rates with single agent irinotecan were observed in patients with various tumor types such as mesothelioma, glioblastoma multiforme, (non) small-cell-lung cancer, head- and neck cancer, esophageal cancer, gastric cancer, breast cancer, cervical cancer and ovarian cancer [97]. Combination therapy with, for example, topoisomerase II inhibitors, platinum-derivatives, taxanes and 5-fluorouracil or its analogs seems to be promising in several tumor types as well [92-103]. In Japan, a combination regimen of irinotecan and cisplatin has shown improvement in overall survival over the global standard regimen of etoposide and cisplatin in extensive-stage small-cell-lung cancer [98]. Three randomized trials are in progress to confirm the data [99]. In non-small-cell lung cancer the combination of irinotecan and cisplatin produced superior response rates compared to cisplatin/vindesine [100]. Different doublet and triplet irinotecan combinations are currently being tested against the more commonly used cisplatin combination regimens [101].

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