title: A Japanese phase I study of continuous oral capecitabine in patients with malignant solid tumors.
abstract: BACKGROUND
  This study aimed to evaluate the tolerability and pharmacokinetics of capecitabine, given twice daily for 6 weeks without interruption, and to identify the maximum tolerated dose (MTD) and the suggested phase II schedule.
  
  
  METHODS
  The initial dose of capecitabine was 251 mg/m2 twice daily, without interruption, and a dose escalation schedule was planned according to a modified Fibonacci scheme. Patients received oral capecitabine twice daily for at least 6 weeks unless grade 3 or 4 toxicity was observed. Blood and urine samples were collected for pharmocokinetic analysis on days 1 and 15.
  
  
  RESULTS
  Sixteen patients with malignant solid tumors (seven breast, seven colorectal, and two gastric) were enrolled, all of whom were evaluable. Among 4 patients treated with capecitabine 1255 mg/m2 twice daily, one experienced grade 4 hemorrhagic gastric ulcer and one experienced grade 3 skin toxicity. Consequently, this dose was defined as the MTD, and gastrointestinal and cutaneous effects were identified as dose-limiting toxicities. There was no grade 3/4 diarrhea at any dose level. There was also no grade 4 hematologic toxicity at doses below the MTD, and there were no treatment-related deaths. Two patients with breast cancer had partial responses, at capecitabine doses of 502 mg/m2 and 1255 mg/m2, twice daily. Pharmacokinetic data show that high concentrations of doxifluridine (5'-DFUR) occur in tumor cells within 2 h after administration of capecitabine.
  
  
  CONCLUSIONS
  The MTD of continuous oral capecitabine over 6 weeks was 1255 mg/m2 twice daily. Because of the higher occurrence of skin disorders reported in this study with a continuous treatment regimen, an intermittent treatment regimen of 828 mg/m2, administered twice daily for 3 weeks, followed by a 1-week rest period, was recommended for phase II studies. This regimen is being evaluated in phase II studies in Japanese patients with gastric, colorectal, and breast cancers.
authors.affiliation: Department of Clinical Research and Surgery, National Hospital Organization Shikoku Cancer Center, Ehime, Japan. tsaeki@saitama-med.ac.jp
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Saeki
authors.forename: Shigemitsu
authors.initials: S
authors.lastname: Takashima
authors.forename: Masanori
authors.initials: M
authors.lastname: Terashima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Satoh
authors.forename: Masakazu
authors.initials: M
authors.lastname: Toi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Osaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Toge
authors.forename: Shinji
authors.initials: S
authors.lastname: Ohno
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nomura
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fukuyama
authors.forename: Wasaburo
authors.initials: W
authors.lastname: Koizumi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Taguchi
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil