A randomized phase I and II study of short-term infusion of high-dose fluorouracil with or without N-(phosphonacetyl)-L-aspartic acid in patients with advanced pancreatic and colorectal cancers.
Fifty-two patients with advanced gastrointestinal (GI) malignancies who had not received previous chemotherapy or radiation therapy were randomized to be treated either with 24-hour infusion of weekly fluorouracil (5-FU) or the same plus N-(phosphonacetyl)-L-aspartic acid (PALA). Forty-seven patients were evaluable for the assessment of toxicity and antitumor activity. PALA was administered as an intravenous (IV) bolus over 15 minutes at a fixed dose, 250 mg/m2. The latter agent was administered 24 hours before the start of 5-FU infusion. 5-FU was initially administered at 750 mg/m2 and was incrementally increased to 3,400 mg/m2. In both arms of the randomized study, the courses were repeated every week. In both arms of the study, ataxia and myelosuppression were the dose-limiting toxic effects. At 5-FU dose of 3,400 mg/m2, one patient in each arm developed grade 3 hematologic toxicity. Other reversible side effects included grade 2 skin changes, nausea, and vomiting. During the administration of 2,600 mg/m2 of 5-FU over 24 hours, the steady state plasma 5-FU concentration was approximately 20 mumol/L. The maximum tolerated dose (MTD) for 5-FU for protracted treatment is 2,600 mg/m2 in either arm of the study. Therapeutic response was predominantly seen in the combination arm: there were two patients with complete response (CR) and 11 patients with partial response (PR) of 28 patients in the study. In the 5-FU alone arm there were four PR and 19 patients in the study.
Ardalan
B
B
Department of Medicine, University of Southern California School of Medicine, Los Angeles.
Singh
G
G
Silberman
H
H
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001224:Aspartic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009943:Organophosphorus Compounds / Q000009:adverse effects*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives; D011897:Random Allocation; D012004:Rectal Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D001224:Aspartic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D005472:Fluorouracil