Intermittent FLDP: 24-h infusion of 5-FU on days 1, 3 and 5 combined with low-dose cisplatin on days 1-5 for gastric cancer, and its pharmacologic and kinetic rationale.
OBJECTIVE
To improve the therapeutic efficacy and minimize the toxicity of 5-fluorouracil (5-FU), intermittent therapy consisting of alternate 24-h intravenous infusion and based on differences in generation time (T(G)) between normal cells and tumor cells was investigated.


METHODS
Two human gastric cancer cell lines MKN-7 and MKN-74 with T(G) of 35 h and 17 h, respectively, were used in an in vitro cytotoxic assay. The drug exposure schedule consisted of a continuous 144-h exposure and alternate 24-h exposures. In a clinical trial, a total of 23 patients with advanced or recurrent gastric cancer were treated with intermittent therapy consisting of 24-h intravenous infusion with 5-FU 700 mg/m(2) per day on days 1, 3 and 5 in combination with low-dose cisplatin (CDDP) at 3.3 mg/m(2) per day on days 1 to 5. One cycle of the combined chemotherapy lasted for four consecutive weeks, followed by withdrawal over 1-2 weeks. Plasma 5-FU concentrations were measured by high-performance liquid chromatography in 15 patients and dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells (PBMC) was measured in 13 patients.


RESULTS
The in vitro study revealed no statistically significant difference in cytotoxicity of 5-FU between the two drug exposure schedules in MKN-7 cells. In MKN-74 cells, however, a statistically significant decrease in cytotoxicity was found with the alternate 24-h exposure. In a clinical trial, plasma 5-FU concentrations showed a trapezoidal pattern. There was a significant correlation between DPD activity in PBMC and total body clearance of 5-FU. There were eight partial responders (8/22, 36%). Toxicities were very mild in severity, with no grade 3 or 4 toxicity. In particular, diarrhea and stomatitis were infrequent (one patient), and none of the patients developed thrombocytopenia.


CONCLUSIONS
Toxicities which may be observed in rapidly growing cells such as bone marrow cells and gastrointestinal epithelial cells following continuous intravenous infusion of 5-FU seemed to be reduced by intermittent therapy of 5-FU consisting of alternate 24-h intravenous infusions.
Terashima
Masanori
M
Department of Surgery 1, Fukushima Medical University, 1 Hikarigaoka, 960-1295, Fukushima, Japan. mterashi@fmu.ac.jp
Irinoda
Takashi
T
Kawamura
Hidenobu
H
Takagane
Akinori
A
Abe
Kaoru
K
Oyama
Kenichi
K
Fujiwara
Hisataka
H
Saito
Kazuyoshi
K
Gotoh
Mitsukazu
M
Shirasaka
Tetsuhiko
T
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002453:Cell Cycle; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013280:Stomatitis / Q000139:chemically induced; D014407:Tumor Cells, Cultured