Sequential Treatment with Irinotecan and Doxifluridine: Optimal Dosing Schedule in Murine Models and in a Phase I Study for Metastatic Colorectal Cancer

Vol. 51, No. 1, 2005

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Clinical Trial

Sequential Treatment with Irinotecan and Doxifluridine: Optimal Dosing Schedule in Murine Models and in a Phase I Study for Metastatic Colorectal Cancer
Hideyuki Mishima^a, Takeshi Kato^b, Mieko Yanagisawa^c, Toshimasa Tsujinaka^a, Isamu Nishisho^a, Masaki Tsujie^b, Kaori Fujimoto-Ouchi^c, Yutaka Tanaka^c, Nobuteru Kikkawa^b

Departments of Surgery,
^aOsaka National Hospital, and
^bMinoh City Hospital, Osaka, and
^cProduct Research, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan

Address of Corresponding Author

Chemotherapy 2005;51:32-39 (DOI: 10.1159/000084416)

Key Words

Camptothecin
Colorectal cancer
Combination chemotherapy
Doxifluridine

Abstract

Background: Irinotecan (CPT-11) and doxifluridine (5'-DFUR) are active agents against colorectal cancer. Each drug, however, has the possibility of causing diarrhea. Methods and Results: First, we determined the optimal dosing regimen in murine models. CPT-11 (i.v., q2d ×3) and 5'-DFUR (p.o., qd ×14) were administered to mice bearing a human colorectal cancer xenograft model. Diarrhea was stronger in the simultaneously administered schedule but not much stronger in the sequentially administered schedule compared with monotherapies. Both schedules yielded similar antitumor efficacies. Next, we conducted a phase I study combining CPT-11 on days 1 and 15, and 5'-DFUR on days 3-14 and 17-28 every 5 weeks in 19 patients with metastatic colorectal cancer. The doses of CPT-11 ranged from 80 to 150 mg/m² and those of 5'-DFUR from 800 to 1,200 mg. Diarrhea of grade 3/4 developed in only 1 patient at 100 mg/m²/800-mg doses. Dose-limiting toxicities were hyperbilirubinemia and skipping doses due to fatigue at 150 mg/m²/1,200-mg doses. Conclusion: For the phase II study, the recommended dose was set at CPT-11 150 mg/m² and 5'-DFUR 800 mg.

Author Contacts

Hideyuki Mishima, MD
Department of Surgery, Osaka National Hospital
2-1-14 Hoenzaka, Chuo-ku
Osaka 540-0006 (Japan)
Tel. +81 6 6942 1331, Fax +81 6 6943 6467, E-Mail hmishima@onh.go.jp

Article Information

Received: March 29, 2004
Accepted after revision: September 24, 2004
Published online: March 14, 2005
Number of Print Pages : 8
Number of Figures : 2, Number of Tables : 4, Number of References : 19

Medline Abstract (ID 15767743)

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