SIGNIFICANCE OF METHOTREXATE SERUM LEVEL ACHIEVED IN PATIENTS WITH GASTROINTESTINAL MALIGNANCIES TREATED WITH SEQUENTIAL METHOTREXATE, L-FOLINIC ACID AND 5-FLUOROURACIL

Twenty-one patients affected by advanced carcinoma of the digestive tr act, all but 2 previously treated, received on day 1 every 2 weeks a 2 -hour intravenous (i.v.) infusion of methotrexate (MTX), 250 mg/m(2), followed 24 h later by a 2-hour i.v. infusion of L-folinic acid (LFA), 250 mg/m(2), and 5-fluorouracil (FU), 600 mg/m(2) as an i.v. bolus. O nly 1 previously untreated patient obtained a partial response. The MT X serum level assessed 24 h after its infusion (24-hour sMTX) ranged f rom 0.3 to 5.7 (median: 0.9) mu M, and in only 8/21 patients reached a concentration > 1 mu M. A further 46 patients (of whom 22 had been pr eviously treated) received the same treatment as above but with a doub le dosage (500 mg/m(2)) of MTX. Twelve of these 46 patients (26%, 95% confidence interval = 14-41%) achieved a partial response with this re gimen. Responses were obtained in chemotherapy-naive patients (8/24) a nd in previously treated patients (4/22). The 24-hour sMTX ranged from 1.2 to 9.5 mu M) (median: 2.3) and was greater than or equal to 2 mu M in 30/46 patients. Among patients showing a 24-hour sMTX value great er than or equal to 2 mu M, the response rate was 39% (45% in previous ly untreated patients), while no patient with a 24-hour sMTX value bel ow 2 mu M at 24 h obtained a major response (p = 0.0017). Our findings demonstrate that 500 mg/m(2) of MTX given as a 2-hour i.v. infusion i s required to reach a serum concentration of at least 1 mu M for 24 h. Furthermore, the double biochemical modulation of FU may obtain an ob jective response in patients previously treated with fluoropyrimidines .