title: Phase I trial of oral S-1 combined with gemcitabine and cisplatin for advanced biliary tract cancer (KHBO1002).
abstract: OBJECTIVE
  We aimed to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the addition of S-1, an oral fluorouracil derivative, to gemcitabine and cisplatin combination therapy, which is the current standard treatment for advanced biliary tract cancer.
  
  
  METHODS
  Patients with histologically or cytologically confirmed unresectable or recurrent biliary tract cancer were eligible for inclusion. The planned dosages of gemcitabine (mg/m(2))/cisplatin (mg/m(2))/S-1 (mg/m(2)/day) were as follows: level 0, 800/25/60; level 1, 1,000/25/60; and levels 2 and 3, 1,000/25/80. In each cycle, gemcitabine and cisplatin were intravenously administered on day 1 (or days 1 and 8 at level 3), and S-1 was orally administered twice daily on days 1-7 (or days 1-14 at level 3); this was repeated every 14 days (or 21 days at level 3).
  
  
  RESULTS
  Seventeen patients were enrolled, and level 1 was chosen as the starting dose. Two of six patients developed DLTs (grade 4 neutropenia and grade 3 febrile neutropenia) at level 1, and the dose was escalated to level 2. DLTs (grade 3 rashes and grade 3 vasovagal reactions) occurred in two of six assessable patients at level 2; we then proceeded to level 3. The first three assessable patients enrolled at level 3 developed DLTs (two cases of grade 4 neutropenia, one of grade 4 leucopenia, two of grade 3 fatigue, one of grade 3 anorexia, and one of grade 3 febrile neutropenia) during their first cycle, and this dose was determined to be the MTD. Therefore, we selected level 2 as the recommended dose (RD) for a subsequent phase II study.
  
  
  CONCLUSIONS
  We determined the RD of gemcitabine/cisplatin/S-1 combination therapy for advanced biliary tract cancer; we are proceeding to a phase II study to investigate the efficacy of this combination therapy for advanced biliary tract cancer.
authors.affiliation: Outpatient Oncology Unit, Kyoto University Hospital, Kyoto, Japan. kanai@kuhp.kyoto-u.ac.jp
authors.forename: Masashi
authors.initials: M
authors.lastname: Kanai
authors.forename: Etsuro
authors.initials: E
authors.lastname: Hatano
authors.forename: Syogo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sakai
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Kodama
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ajiki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ioka
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010094:Oxonic Acid / Q000008:administration & dosage; D005641:Tegafur / Q000008:administration & dosage; D000093542:Gemcitabine
chemical_list: D004338:Drug Combinations; D003841:Deoxycytidine; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D002945:Cisplatin; D000093542:Gemcitabine