title: A controlled evaluation of recent approaches to biochemical modulation or enhancement of 5-fluorouracil therapy in colorectal carcinoma.
abstract: Three hundred thirty-five previously untreated patients with advanced colorectal carcinoma were randomly assigned to treatment with 5-fluorouracil (5-FU) alone, 5-FU plus N-(phosphonacetyl)-L-aspartic acid (PALA), 5-FU plus high-dose thymidine, 5-FU plus levamisole, or 5-FU plus methyl CCNU, vincristine, and streptozotocin (MOF-Strept). Dosages were designed to produce definite toxicity in the majority of patients, although the nature of dose-limiting reactions varied considerably among regimens. 5-FU alone and 5-FU plus levamisole produced mucocutaneous reactions, diarrhea, and leukopenia; 5-FU plus PALA produced primarily mucocutaneous reactions and diarrhea; 5-FU plus thymidine produced leukopenia with occasional neurotoxicity and hypotension; and MOF-Strept produced substantial nausea and vomiting with both thrombocytopenia and leukopenia. Objective response rates among patients with measurable disease varied from 12% (5-FU plus PALA) to 34% (MOF-Strept), but none of the regimens were significantly superior to 5-FU alone. Both interval to progression and survival were comparable among the five regimens with no reasonable chance that any combination regimen could produce as much as a 50% improvement when compared with 5-FU alone. Whereas we observed definite modulation of 5-FU dose--toxicity relationships, particularly with the thymidine and PALA combinations, this did not result in a detectable improvement in therapeutic effect. None of the combination regimens, administered in the dosages and schedules we used, can be recommended as standard therapy of advanced colorectal carcinoma.
authors.forename: T R
authors.initials: TR
authors.lastname: Buroker
authors.forename: C G
authors.initials: CG
authors.lastname: Moertel
authors.forename: T R
authors.initials: TR
authors.lastname: Fleming
authors.forename: L K
authors.initials: LK
authors.lastname: Everson
authors.forename: S A
authors.initials: SA
authors.lastname: Cullinan
authors.forename: J E
authors.initials: JE
authors.lastname: Krook
authors.forename: J A
authors.initials: JA
authors.lastname: Mailliard
authors.forename: R F
authors.initials: RF
authors.lastname: Marschke
authors.forename: D J
authors.initials: DJ
authors.lastname: Klaassen
authors.forename: J A
authors.initials: JA
authors.lastname: Laurie
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004341:Drug Evaluation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007978:Levamisole / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D011897:Random Allocation; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012673:Semustine / Q000008:administration & dosage; D013311:Streptozocin / Q000009:adverse effects / Q000627:therapeutic use; D013936:Thymidine / Q000008:administration & dosage; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D012673:Semustine; D007978:Levamisole; D001224:Aspartic Acid; D014750:Vincristine; D013311:Streptozocin; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D005472:Fluorouracil; D013936:Thymidine