SCHEDULE-SELECTIVE BIOCHEMICAL MODULATION OF 5-FLUOROURACIL IN ADVANCED COLORECTAL-CANCER - A MULTICENTRIC PHASE-II STUDY

We have recently reported high clinical activity against advanced colo rectal cancer of a regimen-alternating bolus FUra, modulated by methot rexate (MTX), and continuous infusion FUra, modulated by 6-s-leucovori n (6-s-LV). Considering the low toxicity of the bolus part of this reg imen and our recent in vitro finding of a strong synergism between bol us FUra and natural-beta-IFN (n-beta-IFN), this cytokine was incorpora ted in the bolus part of our treatment programme. Fifty-six patients w ith untreated, advanced, measurable colorectal cancer were treated wit h two biweekly cycles of FUra bolus (600 mg m(-2)), modulated by MTX ( 24 h earlier, 200 mg m(-2)), and n-beta-IFN (3 x 10(6) IU i.m. every 1 2 h, starting at the time of FUra administration for four doses), alte rnating with a 3-week continuous infusion of FUra (200 mg m(-2) daily) , modulated by 6-s-LV (20 mg m(-2) weekly bolus). After a 1-week rest, the whole cycle (8 weeks) was repeated if indicated. A total of 5 com plete and 17 partial responses were obtained (response rate, 41%; 95% confidence limits, 28-55%) in 54 assessable patients. After a median f ollow-up time of 36 months, five patients are still alive. Overall, th e median time to treatment failure was 6.4 months. The median duration of survival was 15.0 months. There was one treatment-related death af ter a course of MTX --> bolus FUra/n-beta-IFN and grade III-IV toxicit y occurred in 18% of the patients. As the addition of n-beta-IFN resul ts in high toxicity, whereas the efficacy seems to be similar to that of the same regimen without the cytokine, our groups are currently ran domizing the original regimen, without IFN, against standard modulated bolus FUra.