No abstract

Irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.

Purpose: To determine the recommended starting doses and pharmacokinetics of irinotecan in cancer patients with impaired liver function treated on a weekly schedule. Experimental Design: Patients with solid tumors who had impaired liver function were enrolled into four groups based on baseline serum total bilirubin and aspartate aminotransferase (AST)/ alanine aminotransferase (ALT): Group 1 (n = 19): total bilirubin 1.5 to 3.0 Â institutional upper limit of normal (IULN) and ALT/AST V5.0 Â IULN; Group 2 (n = 7): total bilirubin 3.1to 5.0 Â IULN and ALT/AST V5.0 Â IULN; Group 3 (n = 6): total bilirubin V1.5 Â IULN and ALT/AST 5.1 to 20.0 Â IULN; Group 4 (n = 10): total bilirubin 1.5 to 3.0 Â IULN and ALT/AST 5.1to 20.0 Â IULN. Irinotecan was given as a 90-minute i.v. infusion weekly for the first 4 weeks in each 6-week cycle at starting doses which escalated from 40 to as much as 75 mg/m 2 . After the first treatment, doses were adjusted based on individual patient toxicities. Starting doses for patients with hepatic dysfunction were derived from the maximum tolerated doses noted in the four hepatic dysfunction groups. Results: Forty-two patients were treated. Among the most frequent adverse events were neutropenia (41%, grades 3/4), diarrhea (15%, grades 3/4), nausea (10%, grade 3), and vomiting (5%, grades 3/4). Two patients died from drug-induced neutropenic sepsis. Two patients had objective tumor responses (complete response, liver metastases from unknown primary; partial response, colon cancer). Hepatic dysfunction reduced irinotecan clearance while increasing relative exposure to the active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). SN-38 exposures in patients receiving doses of 40 to 75 mg/m 2 were comparable to exposures in patients with normal liver function treated with a starting dose of 125 mg/m 2 . Conclusions: Irinotecan starting doses that seem to be safe for hepatically impaired patients treated with the weekly schedule are 60, 50, 60, and 40 mg/m 2 for groups 1 to 4, respectively. At these starting doses, exposure to SN-38 and the adverse event profile are similar to that observed in patients with normal liver function and antitumor activity can be observed.The broad-spectrum, cytotoxic drug irinotecan (CPT-11; Camptosar irinotecan hydrochloride injection) is a semisynthetic, water-soluble derivative of the plant product, camptothecin. Irinotecan is a prodrug that is metabolized by carboxylesterases to the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxycamptothecin), which seems to be primarily responsible for the antitumor effects of irinotecan (1). The clinical pharmacology and anticancer applications of irinotecan have been the subject of several recent reviews (2 -6).Based on the results of several phase 3 survival trials (7 -11), irinotecan administered i.v. has been approved for first-and

No abstract

Irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.