A PHASE-I STUDY OF CONTINUOUS-INFUSION 5-FLUOROURACIL PLUS CALCIUM LEUCOVORIN IN COMBINATION WITH N-(PHOSPHONACETYL)-L-ASPARTATE IN METASTATIC GASTROINTESTINAL ADENOCARCINOMA

Citation
Jl. Grem et al., A PHASE-I STUDY OF CONTINUOUS-INFUSION 5-FLUOROURACIL PLUS CALCIUM LEUCOVORIN IN COMBINATION WITH N-(PHOSPHONACETYL)-L-ASPARTATE IN METASTATIC GASTROINTESTINAL ADENOCARCINOMA, Cancer research, 53(20), 1993, pp. 4828-4836
Citations number
52
Categorie Soggetti
Oncology
Journal title
ISSN journal
00085472
Volume
53
Issue
20
Year of publication
1993
Pages
4828 - 4836
Database
ISI
SICI code
0008-5472(1993)53:20<4828:APSOC5>2.0.ZU;2-I
Abstract
Preclinical studies suggest that the biochemical effects of N-(phospho nacetyl)-L-aspartate (PALA), an inhibitor of aspartate carbamoyl-trans ferase (ACTase), may increase the metabolic activation of 5-fluorourac il (5-FU) and enhance its cytotoxicity through both RNA- and DNA-direc ted mechanisms. In this Phase I trial, 22 evaluable patients with aden ocarcinoma of the gastrointestinal tract were entered at escalating do ses of 5-FU starting at 1150 mg/m2/day given as a concurrent 72-h i.v. infusion with a fixed dose of leucovorin (LCV), 500 mg/m2/day. The do se of 5-FU was escalated within patients according to individual toler ance, and then PALA at 250 mg/m2 was added 24 h prior to the initiatio n of the 5-FU/LCV infusion of the subsequent cycle. Dose-limiting muco sitis and myelosuppression occurred during the initial cycle in 3 of 5 patients treated with 2300 mg/m2/day 5-FU; therefore, the recommended dose of 5-FU with concurrent LCV is 2000 mg/m2/day. Twenty-seven addi tional patients were then treated with escalating doses of PALA rangin g from 375 to 2848 mg/m2, i.v., followed 24 h later by 2000 mg/m2/day 5-FU with high-dose LCV. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 2 of 3 patients entered at 2848 m g/m2 PALA. Dose-limiting mucositis and skin rash ultimately required b oth PALA and 5-FU dose reductions in 4 of 6 patients treated with 1899 mg/m2 PALA. Toxicity was similar, however, in patients receiving PALA at doses ranging from 375 to 1266 mg/m2. The mean steady-state plasma concentration of 5-FU at 2000 mg/m2/day was 6.5 +/- 0.9 muM; patients with 5-FU levels >9 muM had a significantly higher incidence of serio us gastrointestinal and hematological toxicity. Compared to each patie nt's own baseline, a significant trend for decreasing ACTase activity with increasing PALA dose was evident using cytosol isolated from peri pheral blood mononuclear cells 24 h after PALA treatment (P2 = 0.01). PALA less-than-or-equal-to 844 mg/m2 failed to appreciably inhibit ACT ase activity at 24 h in most patients; furthermore, a decrease in ACTa se activity by >50% from baseline was seen in only 29% of cycles. More consistent inhibition of ACTase activity was seen with PALA greater-t han-or-equal-to 1266 mg/m2. Even with the highest PALA doses, however, ACTase activity returned to baseline by 96 h in most patients. In con trast, a modest decrease in plasma uridine levels was noted at all PAL A doses, but the decrease was greater-than-or-equal-to 50% in only 21% of cycles at 24 h. PALA less-than-or-equal-to 1266 mg/m2 could be saf ely combined with a 72-h i.v. infusion of 5-FU 2000 mg/m2/day with LCV 500 mg/m2/day starting 24 h after PALA. Because the delivered 5-FU do se intensity for patients entered at or above 1750 mg/m2/day in this t rial was similar at PALA doses less-than-or-equal-to 1266 mg/m2, we ha ve selected 1266 mg/m2 for future studies.