title: Phase II trial of PN401, 5-FU, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach: a Southwest Oncology Group study.
abstract: From February, 2001 to September, 2002, the Southwest Oncology Group (SWOG) accrued 65 patients with advanced gastric adenocarcinoma to a phase II trial of weekly 5-FU, leucovorin, and the orally-administered uridine analog PN401. Of these 65 patients, 57 were assessable for survival and toxicity, which were the endpoints for the study. Treatment consisted of the administration of 1200 mg/m(2) of 5-FU, 500 mg/m(2) of leucovorin, and 6 grams of PN401 every 8 h, beginning 8 h after the completion of the 5-FU infusion, and continuing for a total of 8 doses (48 grams) during each weekly chemotherapy session. Therapy was delivered for six weeks out of every 8-week treatment cycle. The gastrointestinal toxicity of this regimen was mild with 2 patients experiencing grade 3 stomatitis, and 6 patients having grade 3 diarrhea; and the hematologic toxicity was acceptable with 6 of 57 patients found to have had grade 3 or 4 leukopenia, and 14 of 57 patients experiencing grade 3 or 4 neutropenia. There were two deaths judged possibly related to treatment; one in a patient who experienced a variety of Grade 2 gastrointestinal toxicities and died at home with an unknown cause of death; and a second patient who also died at home, and for whom treatment-related sepsis could not be ruled out. The overall median survival was 7.2 months. The ability to safely deliver twice the usual dose of 5-FU with leucovorin on a weekly schedule suggests that oral uridine analog supplementation with PN401 may enhance the therapeutic index of the fluoropyrimidines.
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, City of Hope National Medical Center, Duarte, CA, USA. doroshoj@mail.nih.gov
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: Sheryl
authors.initials: S
authors.lastname: McCoy
authors.forename: John S
authors.initials: JS
authors.lastname: Macdonald
authors.forename: Brian F
authors.initials: BF
authors.lastname: Issell
authors.forename: Taral
authors.initials: T
authors.lastname: Patel
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Cobb
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Yost
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
mesh_terms: D000085:Acetates; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D014529:Uridine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000085:Acetates; C000609666:uridine triacetate; D002955:Leucovorin; D005472:Fluorouracil; D014529:Uridine