We have previously shown that weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin (HDFL), a regimen initially designed for the treatment of advanced colorectal cancer, is also effective in the treatment of gastric cancer. This HDFL regimen is unique in that it is virtually non-myelosuppressive, and thus provides a comerstone on which ideal protocols may be developed. In this prospective phase II study, we examined the efficacy and toxicity of PE (cisplatin, etoposide)-HDFL, a HDFL-based combination chemotherapy, in the treatment of advanced-gastric cancer. This regimen consisted of cisplatin 60 mg/m2, i.v., D1; etoposide 65 mg/m2, i.v., D1-3; and 5-fluorouracil 2600 mg/m2 plus leucovorin 300 mg/m2, 24-hour i.v. infusion by an ambulatory infusion pump, D2,9,16; repeated every 4 weeks. The major eligibility criteria of the patients included: a) a histologically confirmed, objectively measurable, recurrent or primary inoperable gastric adenocarcinoma; b) age > or = 75 years; c) a Karnofsky performance status > or = 50%; d) an absolute granulocyte count (AGC) > or = 2000/mm3, and a platelet count > or = 100,000/mm3; e) a serum bilirubin concentration < or = 2.0 mg/dl; f) a serum creatinine concentration < or = 1.5 mg/dl; and g) a signed informed consent. Between March 1992 and June 1996, a total of 42 patients were enrolled onto the study. There were 31 men and 11 women with a median age of 54 (24-75) years; these included 16 primary metastatic, 3 locally advanced and inoperable, and 23 postgastrectomy recurrent gastric cancer patients. ECOG (Eastern Cooperative Oncology Group) grade III/IV leukopenia and thrombocytopenia developed in 34.0% and 11.0% of a total of 229 courses given, respectively. There was no treatment-related death. Four patients developed a reversible neurotoxicity; and two of them refused further chemotherapy. Among the 40 patients evaluable for responses, 9 [22.5%; 12-38%, 95% confidence interval (C.I.)] patients achieved complete remission, and 20 [50.0%; 33-67%, 95% C.I.] patients achieved partial remission. The overall response rate was 72.5% [56-86%, 95% C.I.]. The overall median survival and median time to progression of the responders were 10 and 7 months, respectively. The overall median survival of the whole group was 9 months. We concluded that PE-HDFL is a highly effective treatment for advanced gastric cancer. The treatment-related toxicity was mild and the patients' compliance was satisfactory.