ABSTRACT
The first clinical application of biochemical modulation (BCM) of 5-fluorouracil (5-FU) was the sequential MTX/5-FU regimen proposed in 1977 by Bertino for the treatment of colorectal cancer. In Japan, sequential MTX/5-FU therapy was mainly used as a new method of treating gastric cancer, and attracted a great deal of attention because it proved effective in many cases of advanced gastric cancer that had been unresponsive to the previous chemotherapy, particularly scirrhous gastric cancer with poor prognosis. Its therapeutic efficacy varied according to histologic type, it was effective in cases of peritoneal dissemination and disseminated intravascular coagulopathy (DIC), it was associated with fewer adverse effects, and it was a multidrug chemotherapy based on a clear rationale. With sequential MTX/5-FU therapy as a starting point, fundamental studies of BCM and its clinical applications have expanded rapidly in Japan. This paper provides an outline of sequential MTX/5-FU therapy from the aspects of its mechanism of action, indications, therapeutic efficacy, relevance to adjuvant therapy, counter-measures to adverse effects, and emergence of resistance to the drugs involved. The high therapeutic efficacy of this therapy in certain histologic types is also discussed, and its combined use with other forms of BCM, as in triple BCM (LV/5-FU + CDDP/5-FU + MTX/5-FU), is introduced.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Fluorouracil/pharmacology , Methotrexate/pharmacology , Stomach Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , DNA/biosynthesis , Drug Administration Schedule , Drug Synergism , Fluorouracil/administration & dosage , Humans , Methotrexate/administration & dosage , Stomach Neoplasms/chemistryABSTRACT
At present curative resection is the only radical treatment for gastric cancer, although recently developed combination chemotherapy shows increased activity in treating locally advanced and metastatic disease. Among several combination regimens, those based on biochemical modulation, such as sequential methotrexate/5-fluorouracil or low-dose CDDP/5-fluorouracil, are thought to provide increased efficacy with decreasing adverse reactions in unresectable gastric cancer. Therefore, a prospective randomized clinical trial comparing the prognosis of patients receiving adjuvant multi-agent chemotherapy with those treated only surgically should be pursued for estimation of the clinical benefit of these agents.