title: Trial of sequential trimetrexate, fluorouracil, and high-dose leucovorin in previously treated patients with gastrointestinal carcinoma.
abstract: OBJECTIVE
  Trimetrexate (TMTX) is a dihydrofolate reductase inhibitor, which, like methotrexate (MTX), has been shown to potentiate fluorouracil (FU) cytotoxicity by increasing phosphoribosylpyrophosphate (PRPP) levels. We investigated the safety and efficacy of a sequential TMTX/FU/leucovorin (LV) combination.
  
  
  METHODS
  Forty-one patients with advanced gastrointestinal carcinoma (mostly colorectal) received variable doses of TMTX followed 24 hours later by FU/LV (500 mg/m2 of each drug). Almost all patients had received previous chemotherapy. The initial 19 patients were treated on a 3-week-on/1-week-off schedule without any significant toxicity; the remaining patients were treated for 6 consecutive weeks followed by a 2-week rest period. TMTX was escalated in 30-mg/m2 increments from 20 to 110 mg/m2 in separate patient cohorts. When the 110-mg/m2 dose of TMTX was reached, the FU dose was escalated from 500 mg/m2 to 600 mg/m2.
  
  
  RESULTS
  The partial response (PR) rate in assessable patients with colorectal cancer (all previously treated) was 20% (seven of 35; 95% confidence interval, 7% to 33%), and with other gastrointestinal cancers was one of four patients. Median survival has not been reached with a median follow-up of 13.5 months. The maximum-tolerated dose (MTD) was 110 mg/m2 for TMTX, 500 mg/m2 for FU, and 500 mg/m2 for LV on a 6-weeks-on/2-weeks-off cycle. The principal toxicities were grade 3 or 4 diarrhea, which occurred in 17% of patients, and hypersensitivity reactions, which occurred in 26% of patients.
  
  
  CONCLUSIONS
  TMTX can be administered at maximal doses in combination with FU and LV without increasing toxicity. The PR rate of 20% in advanced colorectal carcinoma patients previously treated with chemotherapy is encouraging and merits further study.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, NY 10021.
authors.forename: J A
authors.initials: JA
authors.lastname: Conti
authors.forename: N
authors.initials: N
authors.lastname: Kemeny
authors.forename: K
authors.initials: K
authors.lastname: Seiter
authors.forename: E
authors.initials: E
authors.lastname: Goker
authors.forename: W
authors.initials: W
authors.lastname: Tong
authors.forename: M
authors.initials: M
authors.lastname: André
authors.forename: K
authors.initials: K
authors.lastname: Ragusa
authors.forename: J R
authors.initials: JR
authors.lastname: Bertino
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004067:Digestive System Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome; D016597:Trimetrexate / Q000008:administration & dosage
chemical_list: D010754:Phosphoribosyl Pyrophosphate; D002955:Leucovorin; D005472:Fluorouracil; D016597:Trimetrexate