DOUBLE BIOCHEMICAL MODULATION OF 5-FLUOROURACIL BY METHOTREXATE AND LEVO-FOLINIC ACID IN THE TREATMENT OF ADVANCED DIGESTIVE-TRACT MALIGNANCIES

The aim of this study was to evaluate the activity and toxicity of a d ouble biochemical modulation of 5-fluorouracil (5-FU) by means of meth otrexate (MTX) and levo-folinic acid (LFA) in patients with advanced c arcinoma of the digestive tract, and to assess the prognostic signific ance of MTX serum concentrations achieved in these patients. 94 patien ts affected by advanced carcinoma of the colon-rectum, stomach or bili ary tract (47 of them previously untreated) received a regimen consist ing of MTX 500 mg/m(2) as a 2-h i.v. infusion on day 1, followed by LF A 250 mg/m(2) as a 2-h i.v. infusion and 5-FU 600 mg/m(2) as an i.v. b olus on day 2. Cycles were repeated every 2 weeks. Treatment was admin istered until tumour progression or for a maximum of 24 courses. MTX s erum level was assessed soon after and 24 h (24-h MTXs) after its infu sion in 61 patients. One complete and 22 partial responses were obtain ed, giving an overall activity of 24% (95% confidence interval, 16-34% ). Response rate was 30% in chemotherapy-naive patients (colorectal, 2 6%; gastric, 37%; and biliary-tract, 22%) and 19% in those previously treated (all with fluoropyrimidines). A poor performance status advers ely affected the response and survival of patients. The toxicity of tr eatment was very mild, and occurrence of severe diarrhoea (11% of pati ents) and mucositis (3%) was lower than that reported with other modul ations of 5-FU. A cut-off value of 24-h MTXs was identified as a stron g prognostic indicator. Patients with 24-h MTXs greater than or equal to 2 mu M had a significantly better probability of response (37% vers us 5%; P = 0.032), longer progression-free survival (5.3 versus 2.3 mo nths; P = 0.023) and overall survival (10.8 versus 8.3 months; P = 0.0 45) on multivariate analysis. In chemotherapy-naive colorectal cancer patients, those with 24-h MTXs greater than or equal to 2 mu M had a r esponse rate of 38% (3/8), with a 19.6-month median survival time, as compared to no responses (0/4) and a 9.9-month median survival in the group with a lower serum concentration. The achievement of such MTX se rum levels yielded a 31% (4/13) response rate even in colorectal patie nts who had previously received a 5-FU-FA treatment. Copyright (C) 199 6 Elsevier Science Ltd