BIOCHEMICAL MODULATION OF 5-FLUOROURACIL WITH METHOTREXATE IN ADVANCED COLORECTAL-CANCER PATIENTS PRETREATED WITH ADJUVANT 5-FLUOROURACIL AND LEUCOVORIN

Purpose. 5-fluoracil (5-FU) remains the standard treatment in advanced colorectal cancer patients. An increasing number of recurring patient s, however, have already received this drug as adjuvant after surgery. An attempt to increase 5-FU cytotoxicity through biochemical modulati on is justified in this setting. In our study, a combination regimen o f methotrexate followed by 5-FU, with leucovorin rescue, was employed. Methods. Patients were required to have symptomatic, measurable, inop erable lesions from colorectal cancer, recurring after adequate radica l surgery of the primary tumor and adjuvant 5-FU + leucovorin conclude d at least 3 months before recurrence. Patients received methotrexate. 250 mg/m(2) as a 2-hour i.v. infusion, followed by two doses of 5-FU, 500 mg/m(2) as i.v bolus 1 hour and 21 hours after the end of methotr exate infusion. Leucovorin rescue, 15 mg orally every six hours for 7 times, was started 1 hour after the second 5-FU dose. The cycle was re peated every 2 weeks. Results. Twenty-two patients entered the trial, and 21 were evaluable. An objective response was observed in one patie nt (4.8%), 7 patients (33.3%) obtained tumor regression <50% or diseas e stabilization. Thirteen patients (61.9%) progressed. Median survival in the whole group was 11 months. Subjective responses were observed in 7 patients (33.3%). Toxicity was mild. Conclusions. Biochemical mod ulation with methotrexate does not seem a satisfactory means of increa sing 5-FU activity, when the patient has been previously exposed to 5- FU plus leucovorin. On the other hand, any possible advantages in trim s of quality and prolongation of life with this schedule were obtained at the cost of very acceptable toxicity.