title: Phase I clinical and pharmacokinetic study of S-1 plus oral leucovorin in patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  S-1 has shown a response rate of 35% in chemonaïve patients with metastatic colorectal cancer (mCRC). Leucovorin enhances the antitumor activity of 5-fluorouracil, and concurrent oral administration of S-1 and leucovorin may represent a more active treatment option for mCRC.
  
  
  METHODS
  S-1 (35 mg/m2) and leucovorin (25 mg/body) were orally administered twice daily to chemonaïve patients with mCRC. Predefined dose (schedule)-limiting toxicities (DLTs) during the first course and treatment continuity during the first two courses were evaluated during three periods of treatment with S-1 plus leucovorin (level 0, 2 weeks; level 1, 3 weeks; and level 2, 4 weeks), each followed by a 2-week rest. The pharmacokinetics (PK) of S-1 and leucovorin were studied on days 1 and 14 of the first course.
  
  
  RESULTS
  Fifteen patients were enrolled. All three patients had DLTs at level 2, and this level was considered the maximum tolerated schedule. Level 0 was designated as the recommended schedule based on the incidences of DLTs and treatment continuity. The main toxic effects were gastrointestinal, such as diarrhea and stomatitis. There was no grade 4 adverse event or treatment-related death. The overall response rate was 67% (95% confidence interval, 38-88%). The PK profiles of S-1 plus leucovorin were similar to those in previous studies.
  
  
  CONCLUSIONS
  The recommended schedule was 2 weeks of S-1 plus leucovorin followed by a 2-week rest. The increased response and gastrointestinal toxicities of S-1 plus leucovorin as compared with S-1 monotherapy suggest that co-administration of leucovorin enhanced the activity of S-1.
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. tyoshino@east.ncc.go.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Division of Gastroenterology, University of Tsukuba, Tsukuba, Japan.
authors.forename: Ichinosuke
authors.initials: I
authors.lastname: Hyodo
authors.affiliation: Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishina
authors.affiliation: Division of Clinical Research Center, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Narahara
authors.affiliation: Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Sugimoto
authors.affiliation: Pharmacokinetics Research Laboratories, Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd, Tsukuba, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yoshisue
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Institute Hospital, Tokyo, Japan.
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005641:Tegafur / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D002955:Leucovorin
keywords: Colorectal cancer; Leucovorin; Pharmacokinetics; Phase I study; Recommended schedule; S-1