title: Phase I study of irinotecan and S-1 combination therapy in patients with metastatic gastric cancer.
abstract: BACKGROUND
  Irinotecan plus intravenous 5-fluorouracil with leucovorin is effective against gastrointestinal cancer. S-1 is an oral fluoropyrimidine derivative combining tegafur with the modulators 5-chloro-2,4-dihydroxypyrimidine (a potent dihydropyrimidine dehydrogenase inhibitor), and potassium oxonate (an orotate phosphoribosyl transferase inhibitor), in a molar ratio of 1 : 0.4 : 1. S-1 has a high response rate, of about 40%, in advanced gastric cancer. A phase I study was conducted to assess the maximum tolerated dose and the recommended dose of the combination of irinotecan and S-1.
  
  
  METHODS
  Irinotecan was given intravenously over the course of 90 min on day 1 and S-1 was given orally from days 1 to 14 of a 21-day cycle. The dose of S-1 was 80 mg/m2 per day, given in two divided doses. The dose of irinotecan was escalated in a stepwise fashion from 100 mg/m2 (level 1; n = 3), to 125 mg/m2 (level 2; n = 3), and 150 mg/m2 (level 3; n = 6).
  
  
  RESULTS
  Dose-limiting toxicity did not occur during cycle 1, and the recommended dose for phase II studies was determined to be level 3, which was associated with grade 3 diarrhea in one patient, and with refusal to continue treatment because of prolonged fatigue in two patients. Grade 3 neutropenia developed in one of three patients at level 1 and level 2, and in two of six during cycle 1 of level 3. The recommended dose was determined to be 150 mg/m2 of irinotecan on day 1 and 80 mg/m2 per day of S-1 on days 1 to 14 of a 21-day cycle. Five of seven patients with measurable lesions had a partial response.
  
  
  CONCLUSIONS
  A combination of irinotecan and S-1 can be recommended for further phase II studies in patients with gastric cancer.
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. yayamada@ncc.go.jp
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Hisateru
authors.initials: H
authors.lastname: Yasui
authors.forename: Ayumu
authors.initials: A
authors.lastname: Goto
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Arai
authors.forename: Takashi
authors.initials: T
authors.lastname: Ura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: Kei
authors.initials: K
authors.lastname: Muro
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004338:Drug Combinations; D005221:Fatigue / Q000209:etiology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D010094:Oxonic Acid / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D013274:Stomach Neoplasms / Q000188:drug therapy*; D005641:Tegafur / Q000008:administration & dosage
chemical_list: D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D000077146:Irinotecan; D002166:Camptothecin