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 double biochemical modulation of 5-fluorouracil (5-FU) by means of methotrexate (MTX) and levo-folinic acid (LFA) in patients with advanced carcinoma of the digestive tract, and to assess the prognostic significance of MTX serum concentrations achieved in these patients. 94 patients affected by advanced carcinoma of the colon-rectum, stomach or biliary tract (47 of them previously untreated) received a regimen consisting of MTX 500 mg/m(2) as a 2-h i.v. infusion on day 1, followed by LFA 250 mg/m(2) as a 2-h i.v. infusion and 5-FU 600 mg/m(2) as an i.v. bolus on day 2. Cycles were repeated every 2 weeks. Treatment was administered until tumour progression or for a maximum of 24 courses. MTX serum level was assessed soon after and 24 h (24-h MTXs) after its infusion in 61 patients. One complete and 22 partial responses were obtained, giving an overall activity of 24% (95% confidence interval, 16-34%). Response rate was 30% in chemotherapy-naive patients (colorectal, 26%; gastric, 37%; and biliary-tract, 22%) and 19% in those previously treated (all with fluoropyrimidines). A poor performance status adversely affected the response and survival of patients. The toxicity of treatment was very mild, and occurrence of severe diarrhoea (11% of patients) and mucositis (3%) was lower than that reported with other modulations of 5-FU. A cut-off value of 24-h MTXs was identified as a strong prognostic indicator. Patients with 24-h MTXs greater than or equal to 2 mu M had a significantly better probability of response (37% versus 5%; P = 0.032), longer progression-free survival (5.3 versus 2.3 months; P = 0.023) and overall survival (10.8 versus 8.3 months; P = 0.045) on multivariate analysis. In chemotherapy-naive colorectal cancer patients, those with 24-h MTXs greater than or equal to 2 mu M had a response 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 serum levels yielded a 31% (4/13) response rate even in colorectal patients who had previously received a 5-FU-FA treatment. Copyright (C) 1996 Elsevier Science Ltd