Sequential treatment with irinotecan and doxifluridine: optimal dosing schedule in murine models and in a phase I study for metastatic colorectal cancer.
BACKGROUND
Irinotecan (CPT-11) and doxifluridine (5'-DFUR) are active agents against colorectal cancer. Each drug, however, has the possibility of causing diarrhea.


RESULTS
First, we determined the optimal dosing regimen in murine models. CPT-11 (i.v., q2d x 3) and 5'-DFUR (p.o., qd x 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.


CONCLUSIONS
For the phase II study, the recommended dose was set at CPT-11 150 mg/m2 and 5'-DFUR 800 mg.
Mishima
Hideyuki
H
Department of Surgery, Osaka National Hospital, Osaka, Japan. hmishima@onh.go.jp
Kato
Takeshi
T
Yanagisawa
Mieko
M
Tsujinaka
Toshimasa
T
Nishisho
Isamu
I
Tsujie
Masaki
M
Fujimoto-Ouchi
Kaori
K
Tanaka
Yutaka
Y
Kikkawa
Nobuteru
N
D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008207:Lymphatic Metastasis / Q000473:pathology*; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D014183:Transplantation, Heterologous
D005467:Floxuridine; D000077146:Irinotecan; C025034:doxifluridine; D002166:Camptothecin