title: Phase I and pharmacokinetic study of recombinant human granulocyte-macrophage colony-stimulating factor given in combination with fluorouracil plus calcium leucovorin in metastatic gastrointestinal adenocarcinoma.
abstract: OBJECTIVE
  To determine the toxicities and potential for dose escalation of intravenous (IV) bolus fluorouracil (5-FU) given with 500 mg/m2/d leucovorin (LCV) and granulocyte-macrophage colony-stimulating factor (GM-CSF).
  
  
  METHODS
  Thirty-seven patients received escalating doses of 5-FU/LCV on days 1 to 5 with subcutaneous GM-CSF either 5 or 10 micrograms/kg/d starting on day 6 or 3 micrograms/kg/d starting on day 1. 5-FU was escalated from 370 mg/m2/d by 15% increments between patient cohorts and within patients according to tolerance.
  
  
  RESULTS
  With GM-CSF starting on day 6, dose-limiting toxicity occurred during cycle no. 1 in all three patients entered at 5-FU 490 mg/m2/d. However, individual patients tolerated 5-FU doses up to 644 mg/m2/d. When all cycles were analyzed, grade 3 to 4 mucositis and grade 4 granulocytopenia complicated < or = 15% and < or = 6% of cycles with 5-FU doses < or = 560 mg/m2/d (115 cycles). With GM-CSF starting on day 1, dose-limiting granulocytopenia occurred during cycle no. 1 in five of 10 patients entered at 5-FU 490 mg/m2/d. Although the granulocyte nadirs were significantly lower at each 5-FU dose level with the concurrent GM-CSF schedule (eg, 490 mg/m2/d: median, 879/microL v3,286/microL; two-tailed P [P2] < .001), dose-limiting granulocytopenia complicated < or = 16% of cycles with 5-FU < or = 560 mg/m2/d (99 cycles); > or = grade 3 mucositis occurred in < or = 20% of cycles. Grade 3 to 4 diarrhea was unusual with either GM-CSF schedule. Most patients treated with GM-CSF > or = 5 micrograms/kg/d required dose reductions for constitutional toxicity; 3.0 to 3.8 micrograms/kg/d was better tolerated. Venous thrombosis occurred in 17% of patients (concurrent v sequential GM-CSF, 29% v 5%; P2 = .08). The median delivered 5-FU dose-intensity for GM-CSF starting either on day 6 or on day 1 was 615 and 647 mg/m2/wk (P2 = .41), respectively. Pharmacologic exposure to 5-FU increased with higher doses of 5-FU, and concurrent GM-CSF administration did not affect 5-FU clearance.
  
  
  CONCLUSIONS
  A starting dose of 425 mg/m2/d of 5-FU with LCV on days 1 to 5 could be safely combined with GM-CSF starting either on day 1 or day 6, with further 5-FU dose escalation according to individual tolerance.
authors.affiliation: Division of Cancer Treatment, National Cancer Institute, Bethesda, MD.
authors.forename: J L
authors.initials: JL
authors.lastname: Grem
authors.forename: N
authors.initials: N
authors.lastname: McAtee
authors.forename: R F
authors.initials: RF
authors.lastname: Murphy
authors.forename: J M
authors.initials: JM
authors.lastname: Hamilton
authors.forename: F
authors.initials: F
authors.lastname: Balis
authors.forename: S
authors.initials: S
authors.lastname: Steinberg
authors.forename: S G
authors.initials: SG
authors.lastname: Arbuck
authors.forename: A
authors.initials: A
authors.lastname: Setser
authors.forename: E
authors.initials: E
authors.lastname: Jordan
authors.forename: A
authors.initials: A
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D000328:Adult; D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced / Q000517:prevention & control; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002955:Leucovorin; D005472:Fluorouracil