title: Four decades of continuing innovation with fluorouracil: current and future approaches to fluorouracil chemoradiation therapy.
abstract: OBJECTIVE
  Chemoradiotherapy, the combination of external radiation therapy and concurrent chemotherapy, has been the basis for the oncologic management of many patients since its development in the 1960s. Fluorouracil (FU) chemoradiotherapy has demonstrated success in several organ sites with multiple dosing schedules that now guide the selection of oral analogs of FU to provide new chemoradiotherapy options.
  
  
  METHODS
  This article reviews the metabolism and pharmacology of FU and the advantages of administration of FU by continuous infusion or bolus. The potential role and impact of the oral fluorouracil prodrugs UFT, S-1, BOF-A2, and capecitabine as replacements for intravenous administration are discussed. The results of recent chemoradiotherapy studies with FU from 2000 to 2003 are summarized in rectal, head and neck, esophageal, gastric, pancreatic, biliary, anal, and cervical cancers.
  
  
  RESULTS
  Chemoradiotherapy with FU has the potential to widen the therapeutic window by minimizing normal tissue toxicity while maintaining effective tumor toxicity. Overall, FU chemoradiotherapy maximizes local control and, for some tumor sites (such as head and neck, pancreatic, biliary, cervical, esophageal, and gastric cancers), improves survival rates. Moreover, FU chemoradiotherapy results in improved organ preservation with excellent functional outcome in several anatomic sites including head and neck cancer, anal, and rectal cancer, with improved sphincter preservation.
  
  
  CONCLUSIONS
  FU chemoradiotherapy continues to play an important role in the management of many cancer sites. During the last four decades, optimal dosing schedules have produced a therapeutic gain. The introduction of oral prodrug analogs will likely further improve the results of FU therapy in several organ systems, such as the rectum, head and neck, and esophagus.
authors.affiliation: FACR, Department of Radiation Oncology, University of Virginia Health System, PO Box 800383, Charlottesville, VA 22908-0383, USA. tar4d@virginia.edu
authors.forename: Tyvin A
authors.initials: TA
authors.lastname: Rich
authors.forename: Robert C
authors.initials: RC
authors.lastname: Shepard
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Mosley
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000069287:Capecitabine; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011743:Pyrimidines / Q000008:administration & dosage; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil