Where do we stand with 5-fluorouracil?
For nearly four decades, 5-fluorouracil (5-FU) has been the mainstay of treatment for colorectal cancer. Due to the lack of other agents with significant activity, tremendous efforts have been undertaken to increase the efficacy of 5-FU by investigating alternative schedules of delivery and biomodulation. However, bolus 5-FU in combination with folinic acid (FA), either as the Mayo Clinic or Roswell Park protocol, still represents the standard treatment for adjuvant and first-line palliative chemotherapy of colorectal cancer. In a recent meta-analysis, infusional protocols of 5-FU demonstrated increased response rates (14% to 22%) and a marginal, but significant survival benefit of 3 weeks (11.3 to 12.1 months). In view of the much higher costs and complicated management of infusional 5-FU regimens, this marginal survival benefit does not yet allow protracted 5-FU application to be defined as standard therapy. However, protracted 5-FU infusion in combination with radiation can be considered standard therapy as adjuvant treatment of rectal cancer, since it has demonstrated a significant increase in survival. In the future, oral 5-FU prodrugs may be substituted for infusional 5-FU. Furthermore, current data indicate that 5-FU will also be an essential component of combination chemotherapy protocols with the new active agents oxaliplatin, irinotecan, and raltitrexed. Preclinical studies show synergistic antitumor activity of 5-FU with these agents, which corresponds well with clinical response rates of 50% in untreated and 15% to 25% in 5-FU-refractory patients. Moreover, 5-FU-based pro-drug-active drug systems serve as excellent models for tumor-targeted gene therapy.
Schmoll
H J
HJ
Department of Hematology/Oncology, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Büchele
T
T
Grothey
A
A
Dempke
W
W
D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D019454:Chronotherapy; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004176:Dipyridamole / Q000008:administration & dosage; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007372:Interferons / Q000008:administration & dosage; D002955:Leucovorin / Q000008:administration & dosage; D007978:Levamisole / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D016597:Trimetrexate / Q000008:administration & dosage; D015215:Zidovudine / Q000008:administration & dosage
D000964:Antimetabolites, Antineoplastic; D011838:Radiation-Sensitizing Agents; D007978:Levamisole; D001224:Aspartic Acid; D015215:Zidovudine; D004176:Dipyridamole; C013195:sparfosic acid; D007372:Interferons; D010746:Phosphonoacetic Acid; D002955:Leucovorin; D005472:Fluorouracil; D016597:Trimetrexate; D008727:Methotrexate