A phase II trial of 5-fluorouracil and high-dose intravenous leucovorin in gastric carcinoma.

Abstract

Twenty-eight patients with advanced measurable gastric carcinoma were treated with leucovorin (dl-CF; folinic acid; dl-5-formyltetrahydrofolic acid) 500 mg/m2 administered as a two-hour infusion and 5-fluorouracil (5-FU) 600 mg/m2 intravenous (IV) push midinfusion. Treatment was administered weekly for 6 weeks followed by a 2-week rest. Twenty-five patients were evaluable for response. Twelve of them had received previous combination chemotherapy that included 5-FU. Median age was 59 years, and median Eastern Cooperative Oncology Group (ECOG) performance status was 2. Three patients had partial responses and two of them had been treated previously with 5-FU. Twelve patients had stable disease. Five of these patients had subjective improvement with improved performance status and/or decreased dysphagia. The 95% confidence interval for response is 3% to 32%. Median survival time for all 28 patients enrolled in the study was 22 weeks. Toxicity was moderate and consisted primarily of diarrhea. Myelosuppression, skin rash, and increased lacrimation also occurred. Plasma concentrations of the active reduced folates, I-CF and 5-methyltetrahydrofolic acid (5-CH3FH4), were greater than the 10 mumol/L levels that potentiate 5-FU activity in in vitro models, for more than four hours in all five patients in whom pharmacokinetics were studied. 5-FU and high-dose dl-CF has activity in patients with gastric carcinoma including patients who had previously progressed on 5-FU-containing combinations. Further study in a larger patient population is necessary to determine the usefulness of this regimen in gastric carcinoma.

A less toxic regimen of 5-fluorouracil and high-dose folinic acid for advanced gastrointestinal adenocarcinomas

“…The response rate seen was in accord with those obtained in other colorectal cancer studies (De Gramont et al, 1988;Petrelli et al, 1988;Petrelli et al, 1989;Poon et al, 1989;Machover et al, 1986;Erlichman et al, 1988;Arbuck, 1989), suggesting similar efficacy, although clearly a phase III trial would be required to confirm this. The response rate in gastric cancers is comparable to that described for more toxic combination regimens (Macdonald et al, 1979;Gastrointestinal Tumor Study Group 1982;Douglass et al, 1984) and considerably better than that reported previously for 5-fluourouracil and folinic acid (Arbuck et al, 1987;Berenberg et al, 1989). Although the numbers treated are small it certainly appears worthy of further evaluation.…”

“…One phase II trial showed a response rate of 48% (Machover et al, 1986) but another only 12% (Arbuck et al, 1987) and a third 24% (Berenberg et al, 1989). These reports also describe toxicity different from that produced by 5-fluorouracil alone: Regimens using weekly bolus injections are reported as frequently causing diarrhoea (in 22-80% of patients) with occasional toxic deaths from this (Petrelli et al, 1988;Petrelli et al, 1989), whilst those employing daily injections for one week in four report both diarrhoea and oral mucositis -the latter in 40-80% of patients (Machover et al, 1986;Erlichman et al, 1988;Poon et al, 1989).…”

Randomized, Multicenter, Phase III Trial of Heptaplatin 1-hour Infusion and 5-Fluorouracil Combination Chemotherapy Comparing with Cisplatin and 5-Fluorouracil Combination Chemotherapy in Patients with Advanced Gastric Cancer

“…5-FU monotherapy, a standard treatment in Japan, is associated with a response rate of approximately 20% and an overall survival time of between 5 and 7 months in phase III randomized studies (8,9). The modulation of 5-FU with leucovorin has generally enhanced the antitumor efficacy (10,11), and has been shown to have activity in patients who had previously progressed on 5-FU-containing combinations (12).…”

Infusional 5-fluorouracil, cisplatin and mitomycin C in advanced gastric cancer: A low cost effective regimen

“…The choice of these drugs and schedule was made based on the following: 5-FU, epiADR and CDDP remain the most active single agents in gastric cancer (Schipper and Wagener, 1996); 5-FU and CDDP are potentially synergistic (Leichman and Berry, 1991); LV can enhance 5-FU activity (Arbuck et al, 1987); weekly administration allows more drug to be administered per unit time, which minimizes side effects (Young, 1990); filgrastim may contribute to perform weekly administrations of drugs reducing the incidence of neutropenia. This weekly intensive regimen confirmed its activity also in locally advanced gastric cancer enabling resection on half of previously inoperable tumour with a moderate toxicity (Cascinu et al, 1998), and now a randomized trial in the adjuvant setting is being carried out in Italy.…”