N-(phosphonacetyl)-L-aspartate and calcium leucovorin modulation of fluorouracil administered by constant rate and circadian pattern of infusion over 72 hours in metastatic gastrointestinal adenocarcinoma

J. L. Grem, L. K. Yee, B. Schuler, J. M. Hamilton, A. P. Chen, C. Chabuk, F. Grollman, M. Grabenc, C. J. Allegra, C. H. Takimoto

Research output: Contribution to journalArticlepeer-review

Abstract

Background: We have reported that N-(phosphonacetyl)-L-aspartic acid (PALA) 1266 mg/m2 can safety be given 24 hours prior to the start of a 72-hour infusion of fluorouracil (FUra) and leucovorin (LV) at doses of 2000 and 500 mg/m2/day. Since inhibition of aspartate carbamoyltransferase (ACTase) activity was evident 4 hours post PALA, we wished to evaluate PALA given 1 hour prior to FUra. Further, we studied the toxicity and pharmacokinetics with FUra given by either fixed-or variable-rate infusion. Patients and methods: Twenty-seven patients with gastrointestinal tract adenocarcinomas were treated with PALA 1266 mg/m2/15 min followed by a 72-hour infusion of FUra and LV (1750 & 500 mg/m2/day) given by fixed- or variable-rate (peak at 4:00 A.M.). Results: Clinical toxicity was similar in two consecutive cycles in 17 patients receiving fixed- and variable-rate infusion at the same FUra dose. Overall, grade 3 stomatitis and hand-foot syndrome occurred in 12% and 4% patients receiving fixed- and in 16% and 10.5% of patients receiving variable-rate infusions. Six of 24 evaluable patients (25%) had a partial response. The profile of FUra plasma levels (Cp) over a 24-hour period during fixed- and variable-rate infusions were strikingly different, but the average Cp and area under the concentration-time curves were comparable. ACTase activity was significantly decreased at 4 and 24 hours after PALA (12% and 18% of baseline; P < 0.001), but enzyme activity had recovered to 40% by 72 hours. Conclusions: This regimen was active and well tolerated with similar toxicities with FUra given by either fixed- or variable rate infusion. PALA 1266 mg/m2 significantly inhibited ACTase activity for at least 24 hours.

Original languageEnglish (US)
Pages (from-to)1581-1587
Number of pages7
JournalAnnals of Oncology
Volume12
Issue number11
DOIs
StatePublished - 2001

Keywords

  • Biochemical modulation
  • Chronomodulation
  • Fluorouracil
  • Gastrointestinal cancer
  • PALA

ASJC Scopus subject areas

  • Hematology
  • Oncology

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