A phase I study of oral uracil-tegafur prior to weekly intravenous gemcitabine in patients with advanced pancreatic cancer.
BACKGROUND
Gemcitabine is widely accepted as the first-line agent for advanced pancreatic cancer. The antitumor cell activity of gemcitabine is higher when administered after 5-fluorouracil (5-FU) rather than before 5-FU in an in vitro study. The present study was conducted to define the maximum tolerated dose and dose-limiting toxicity associated with an oral fluoropyrimidine prodrug that combines uracil and tegafur (UFT), given prior to weekly intravenous gemcitabine in patients with advanced pancreatic cancer.


METHODS
Over a 21-day cycle, gemcitabine was given intravenously over 30 min on days 8 and 15, while UFT was given orally from days 1 to 14. The dose of UFT used was 400 mg per day, given as two doses. The dose of gemcitabine was escalated in a stepwise fashion from 800 (level 1, n = 3) to 900 mg/m2 (level 2, n = 6) and then to 1,000 mg/m2 (level 3, n = 3), such that totally 12 patients received the combination chemotherapy.


RESULTS
During the first cycle, grade 3 leukopenia was observed in 2 patients at dose level 1. Only 1 patient treated at dose level 2 experienced dose-limiting toxicity (grade 3 elevated transaminase), including additional patients treated at this dose level. No grade 3/4 toxicities occurred in patients treated at dose level 3. A significant response was observed in 1 out of 12 patients (8.3%). Seven patients (58.3%) had stable disease, while 4 patients (33.3%) showed disease progression.


CONCLUSIONS
The combination chemotherapy of oral UFT and gemcitabine was convenient, well tolerated and may benefit patients with advanced pancreatic cancer. Doses recommended for further study of this schedule are gemcitabine 1,000 mg/m2 and UFT 400 mg/day.
Tanno
Satoshi
S
Third Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Japan. tanno1se@asahikawa-med.ac.jp
Nakano
Yasuhiro
Y
Osanai
Manabu
M
Koizumi
Kazuya
K
Izawa
Tsutomu
T
Habiro
Atsuya
A
Mizukami
Yusuke
Y
Yanagawa
Nobuyuki
N
Fujii
Tsuneshi
T
Okumura
Toshikatsu
T
Kohgo
Yutaka
Y
D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000009:adverse effects / Q000627:therapeutic use*; D005641:Tegafur / Q000009:adverse effects / Q000627:therapeutic use; D014498:Uracil / Q000009:adverse effects / Q000627:therapeutic use; D000093542:Gemcitabine
D011355:Prodrugs; D003841:Deoxycytidine; D005641:Tegafur; D014498:Uracil; D000093542:Gemcitabine