title: A phase I study of 5-fluorouracil, leucovorin and levamisole.
abstract: OBJECTIVE
  The activity of 5-fluorouracil (5-FU) against colon cancer is enhanced by leucovorin and the combination of 5-FU and levamisole has activity in the adjuvant treatment of colonic malignancies. The combination of 5-FU with both leucovorin and levamisole may provide additional benefit in the treatment of colon cancer.
  
  
  METHODS
  A phase I study to assess qualitative and quantitative toxicities of this three-drug combination and to determine a dose for further phase II testing was undertaken. The role of levamisole as an immunomodulator was also assessed.
  
  
  RESULTS
  A group of 38 patients with incurable metastatic malignancies received 119 cycles of treatment at eight dose levels. 5-FU (375 mg/m2 per day) and leucovorin (200 mg/m2 per day) were administered intravenously (days 1-5). Levamisole was administered orally (days 1-3 and 15-17) at doses from 30 to 470 mg/m2 per day. Patients received both 5FU/leucovorin and 5-FU/leucovorin/levamisole in random order for their initial two cycles. All subsequent treatments were with the three-drug combination. Toxicities included nausea, vomiting, stomatitis, thrombocytopenia and granulocytopenia. Diarrhea was the dose-limiting toxicity at 470 mg/m2 per day levamisole. The addition of levamisole resulted in more toxicity than 5-FU and leucovorin alone. No clinical responses were seen with this regimen. The addition of levamisole resulted in more immunomodulation than 5-FU and leucovorin alone as evidenced by release of neopterin from monocytes.
  
  
  CONCLUSIONS
  With this schedule and dose of 5-FU and leucovorin, the maximum tolerated dose of levamisole was 354 mg/m2. However, given the lack of response and the absence of dose-dependent immunomodulation, this may not be the appropriate dose for further phase 11 studies.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, Madison 53792, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Cleary
authors.forename: R
authors.initials: R
authors.lastname: Arzoomanian
authors.forename: D
authors.initials: D
authors.lastname: Alberti
authors.forename: C
authors.initials: C
authors.lastname: Feierabend
authors.forename: B
authors.initials: B
authors.lastname: Storer
authors.forename: P
authors.initials: P
authors.lastname: Witt
authors.forename: P
authors.initials: P
authors.lastname: Carbone
authors.forename: G
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000931:Antidotes / Q000009:adverse effects / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use*; D007978:Levamisole / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D013280:Stomatitis / Q000139:chemically induced
chemical_list: D000276:Adjuvants, Immunologic; D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D007978:Levamisole; D002955:Leucovorin; D005472:Fluorouracil