MODULATION OF 5-FLUOROURACIL WITH METHOTREXATE AND LOW-DOSE N-(PHOSPHONACETYL)-1-ASPARTATE IN PATIENTS WITH ADVANCED COLORECTAL-CANCER - RESULTS OF A PHASE-II STUDY

Methotrexate (MTX) and N-phosphonacetyl-L-aspartate acid (PALA) have b een shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU). A phase II study was initiated to evaluate the feasibility, toxicity a nd efficacy of PALA/MTX and 5-FU in patients with metastatic colorecta l cancer. 26 patients received PALA 250 mg/m(2) as an intravenous 15-m in infusion plus MTX 200 mg/m(2) as a 30-min intravenous (i.v.) infusi on on day 1 and 5-FU 600 mg/m(2) as i.v. push on day 2. Cycles were re peated every 14 days and the 5-FU dose was escalated in the individual patient in steps of 100 mg/m(2) for the third, fifth and seventh cycl e in the absence of toxicity. 7 patients had received prior 5-FU-based chemotherapy while 19 patients were chemotherapy naive. Objective res ponses occurred in 23% of patients (1 CR, 5 PR of which 2 were pretrea ted), no change in 13 patients (50%) and tumour progression (6 patient s) or toxic death (one patient) in 27%. Responses lasted for a median of 7 months (range 6-9), the median time to progression was 4 months a nd median survival 13 months. Toxicity was mainly gastrointestinal wit h diarrhoea and mucositis, and severe or life threatening in only 3 pa tients. In 3 patients an increase in serum glucose levels occurred whi le being treated with PALA/MTX and 5-FU. 2 patients with insulin-depen dent diabetes had a 33% increase in insulin requirement and 1 patient with dietary-controlled diabetes died due to a ketoacidotic coma. PALA /MTX/5-FU in this dose and schedule is active in patients with colorec tal cancer. Hyperglycaemia may be a potential side-effect of PALA-cont aining regimens especially in patients with diabetes. Careful monitori ng of serum glucose levels in these patients is indicated. (C) 1997 El sevier Science Ltd.