Schedule specific biochemical modulation of 5-fluorouracil in advanced colorectal cancer: A randomized study

Background: We have recently suggested that bolus 5-fluorouracil (5-FU) may work via a RNA directed mechanism while continuous infusion 5-FU may kill cells via a thymidylate synthase related pathway. It may thus be possible t o selectively modulate each schedule biochemically. We have compared an alt ernating regimen of bolus and continuous infusion 5-FU, selectively modulat ed for the schedule of administration, with modulated bolus 5-FU in advance d colorectal cancer patients. Patients and methods: Two hundred fourteen patients from nineteen Italian c enters were randomized to the control arm consisting of biweekly cycles of MTX, 200 mg/m(2) on day 1, followed by bolus 5-FU 600 mg/m(2) on day 2 and 6-S-leucovorin rescue, or to the experimental arm consisting of two biweekl y cycles of the same regimen as in the control arm alternated to three week s of continuous infusion 5-FU (200 mg/m(2) day) + weekly bolus 6-S-leucovor in, 20 mg/m(2). Results: Nine CR and twenty-seven PR were obtained on one hundred eleven ev aluable patients treated in experimental arm (RR = 32%, 95% confidence inte rval (95% CI): 24%-42%), while two CR and eleven PR were observed among one hunderd three evaluable patients in control arm (RR = 13%, 95% CI: 7%-21%) . WHO grade 3-4 toxicity occurred in 13% of cycles of experimental arm and in 8% of cycles in control arm. The PFS was significantly longer in experim ental arm (6.2 vs. 4.3 months, odds ratio 0.66, P = 0.003), while the overa ll survival was similar in both arms (14.8 months in experimental arm vs. 1 4.1 months in control arm); quality of life was similar as well. Eighty per cent of patients receiving second-line chemotherapy in control arm were tre ated with continuous infusion 5-FU. Conclusions: Alternating, schedule-specific biochemical modulation of FU is more active than MTX --> 5-FU as first-line treatment of advanced colorect al cancer. However, the overall survival was similar suggesting that altern ating bolus and infusional 5-FU upfront may be as effective as giving them in sequence as first- and second-line treatment.