Weekly 24-Hour Infusion of High-Dose 5-Fluorouracil and Leucovorin in the Treatment of Advanced Gastric Cancers

Abstract

Systemic chemotherapy for advanced gastric cancer is frequently associated with significant treatment-related toxicity, which is particularly severe in patients presenting with a poor general condition. A search for effective and low-toxic regimens for this group of patients is mandatory. A weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (HDFL) has previously been demonstrated to be an effective treatment for advanced colorectal cancer with minimal toxicity. In the past 3 years, this regimen has been tested at our institutes in patients with advanced gastric cancer, the general condition of whom had made the use of intensive combination chemotherapy impossible. The regimen consisted of a weekly 24-hour infusion of 2,600 mg/ m² of 5-FU and 300 mg/m² of leucovorin. From August 1992 to December 1995, 34 patients had been treated with this regimen for a total of 488 courses (average: 14.4 per patient). Hematological toxicity of this regimen was minimal, with grade 3 or 4 leukopenia developing in only 1 (2.9%) patient. Other nonhematological toxicities were also negligible except a reversible neurotoxicity which developed in 2 patients. Twenty-five patients were eligible for response analysis. One complete response, 11 partial responses, 5 stable diseases, and 8 progressive diseases were observed. The response rate was 48% (32-72%, 95% CI). The median overall survival (OS) of the whole group was 7 months (range: 1-18+). The median OS and time to progression of the responders were 8.5 months (range: 2-18) and 5 months (range: 2-10+), respectively. The palliative effect was satisfactory with the Karnofsky performance status of the responders improving from a median of 50% (range: 20-90%) to 70% (range: 50-100%). Our retrospective data suggested that HDFL is an effective and low-toxic palliative treatment even in patients with a very poor general condition. We advocated that this regimen should be further tested in ordinary patients with advanced gastric cancer.

Phase II study of weekly oxaliplatin and 24-h infusion of high-dose 5-fluorouracil and folinic acid in the treatment of advanced gastric cancer

“…We have previously demonstrated that weekly 24-h infusion of high-dose 5-FU and folinic acid (FA), the HDFL regimen originally described by Ardalan et al (1991), appears to be particularly useful in gastric cancer (Yeh and Cheng, 1994;Hsu et al, 1997;Yeh and Cheng, 1998). We have also provided evidence that prolonged exposure of gastric cancer cells to low concentration 5-FU for 24 h enhances the inhibition of thymidylate synthase, and thereby increases the cytotoxicity of 5-FU (Yeh et al, 2000b).…”

A phase II study of S-1 monotherapy administered for 2 weeks of a 3-week cycle in advanced gastric cancer patients with poor performance status

“…In advanced gastric cancer, patients are likely to suffer from poor general condition due to anorexia and weight loss, often as a consequence of peritoneal carcinomatosis. These patients have been excluded from clinical trials, and chemotherapeutic options for them are quite limited (Cunningham et al, 1987;Hsu et al, 1997).…”

Complete Remission After Combination Chemotherapy for Stage Iv Gastric Cancer With Peritoneal Dissemination and Liver Metastases

“…The antitumor effect of 5-FU depends on inhibition of DNA synthesis by the formation of a ternary complex between FdUMP (a metabolite of 5-FU), methylenetetrahydrofolate (CH2FH4), and thymidylate synthase (TS), leading to the inactivation of TS (Hsu, Yeh et al, 1997;Kim, Murakami et al, 1999;Chen, Liu et al, 1999). On the other hand, CDDP blocks the uptake of methionine by cells in addition to inhibition of DNA synthesis.…”

“…Most patients with such tumors undergo palliative surgery to relieve gastrointestinal obstruction and receive systemic chemotherapy in an attempt to prolong survival (Kondo, Murase et al, 1996;Ogawa, Maki et al, 1999;Mori, Masaki et al, 1999;Shinkai, Kida et al, 1999). As chemotherapy for advanced gastric cancer, regimens based on 5-fluorouracil (5-FU) are often used, such as 5-FU + cisplatin (CDDP), 5-FU + methotrexate, and 5-FU + leucovorin (LV) (Konishi, Hirishi et al, 1994;Hsu, Yeh et al, 1997;Iwamoto, Kimoto et al, 1998;Perez, Lacava et al, 1998;Kim, Murakami et al, 1999;Chen, Liu et al, 1999;Enjoji and the Nagasaki Digestive Organ Cancer Chemotherapy Study Group;. In Japan, postoperative adjuvant therapy with 5-FU and low-dose CDDP as the modulator is often performed as first-line chemotherapy (Kondo, Murase et al, 1996;Ogawa, Maki et al, 1999;Mori, Masaki et al, 1999, Shinkai, Kida et al, 1999.…”