title: A phase I study of 5-fluorouracil/leucovorin and arsenic trioxide for patients with refractory/relapsed colorectal carcinoma.
abstract: OBJECTIVE
  This Phase I study was designed to determine a safe combination dose of 5-fluorouracil (5-FU) and arsenic trioxide (ATO) to treat 5-FU-resistant relapsed/refractory colorectal cancer patients. We studied the effect of ATO in the downregulation of thymidylate synthase (TS) in peripheral blood mononuclear cells and in tumor biopsies.
  
  
  METHODS
  ATO was administered for 5 consecutive days during the first week and twice during weeks 2 to 3 and once on week 4. 5-FU/leucovorin (LV) was administered on days 8, 15, and 22. A modified accelerated titration design was used. 5-FU was dose escalated first followed by a planned dose increase for ATO.
  
  
  RESULTS
  No dose-limiting toxicities were seen in seven patients who received 0.15 mg/kg ATO; grade 3 toxicities were as follows: neutropenia 1, diarrhea 1, and bowel obstruction 1. In patients receiving 0.20 mg/kg ATO, grade 3 toxicities were QTc prolongation 1, fatigue 4, alkaline phosphatase elevation 2, diarrhea 2, and peripheral edema 1. TS gene expression in peripheral blood mononuclear cell decreased in all patients. Eight tumors were biopsied, four showed TS downregulation, three showed upregulations, and one did not change. Estimated median progression-free survival and overall survival were 3.1 and 13.9 months, respectively. In patients who showed TS increase or no change versus TS reduction, estimated median progression-free survival was 2.6 versus 7.9 months (P = 0.188) and overall survival was 8.6 versus 11.7 months (P = 0.44), respectively.
  
  
  CONCLUSIONS
  Thus, we determined 0.20 mg/kg ATO, 2,600 mg/m(2) 5-FU, and 500 mg/m(2) leucovorin (LV) to be the recommended phase II dose.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA. bardalan@med.miami.edu
authors.forename: Bach
authors.initials: B
authors.lastname: Ardalan
authors.forename: Pochi R
authors.initials: PR
authors.lastname: Subbarayan
authors.forename: Yipsel
authors.initials: Y
authors.lastname: Ramos
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Anthony
authors.initials: A
authors.lastname: Fernandez
authors.forename: Dmitry
authors.initials: D
authors.lastname: Mezentsev
authors.forename: Isildinha
authors.initials: I
authors.lastname: Reis
authors.forename: Robert
authors.initials: R
authors.lastname: Duncan
authors.forename: Lisa
authors.initials: L
authors.lastname: Podolsky
authors.forename: Kelvin
authors.initials: K
authors.lastname: Lee
authors.forename: Mayra
authors.initials: M
authors.lastname: Lima
authors.forename: Parvin
authors.initials: P
authors.lastname: Ganjei-Azar
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage* / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D010087:Oxides / Q000008:administration & dosage* / Q000009:adverse effects; D013940:Thymidylate Synthase / Q000378:metabolism
chemical_list: D001152:Arsenicals; D010087:Oxides; D013940:Thymidylate Synthase; D002955:Leucovorin; D000077237:Arsenic Trioxide; D005472:Fluorouracil