title: Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer.
abstract: OBJECTIVE
  Capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes that results in the preferential release of 5-FU at the tumor site.
  
  
  METHODS
  In this phase I study, capecitabine was administered twice daily as outpatient therapy, each cycle administered for 2 weeks followed by 1 week of rest. Thirty-four patients with solid tumors, all of whom except three patients were pretreated, were treated at dose levels from 502 to 3,514 mg/m2 daily.
  
  
  RESULTS
  The median treatment duration was four cycles (85 days; range, 14 to 833+ days). Two patients continue on treatment at 686 and 833+ days. Capecitabine 3,000 mg/m2 daily was not tolerable, with dose-limiting toxicities of diarrhea with hypotension, abdominal pain, and leukopenia. Palmar-plantar erythrodysesthesia (PPE) became evident at higher dose levels after prolonged treatment. Evidence of objective tumor response was reported in four patients at 2,510 mg/m2 daily and greater (one complete response [CR] and three partial responses [PRs]) with subjective minor tumor responses in a further seven patients. Pharmacokinetic studies showed rapid gastrointestinal absorption of capecitabine, followed by extensive conversion into 5'-deoxy-5-fluorouridine (5'-DFUR), with only low systemic 5-FU levels.
  
  
  CONCLUSIONS
  Capecitabine is a tolerable oral outpatient therapy that shows promising clinical activity in a variety of cancers. The recommended phase II dose is 2,510 mg/m2 daily administered by this intermittent schedule.
authors.affiliation: Department of Medical Oncology, Beatson Oncology Centre, Glasgow, UK. mmackcan@udcf.gla.ac.uk
authors.forename: M
authors.initials: M
authors.lastname: Mackean
authors.forename: A
authors.initials: A
authors.lastname: Planting
authors.forename: C
authors.initials: C
authors.lastname: Twelves
authors.forename: J
authors.initials: J
authors.lastname: Schellens
authors.forename: D
authors.initials: D
authors.lastname: Allman
authors.forename: B
authors.initials: B
authors.lastname: Osterwalder
authors.forename: B
authors.initials: B
authors.lastname: Reigner
authors.forename: T
authors.initials: T
authors.lastname: Griffin
authors.forename: S
authors.initials: S
authors.lastname: Kaye
authors.forename: J
authors.initials: J
authors.lastname: Verweij
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil