ALTERNATING BOLUS AND CONTINUOUS-INFUSION 5-FLUOROURACIL - A STRATEGYTO OVERCOME RESISTANCE TO THIS FLUOROPYRIMIDINE IN ADVANCED COLORECTAL-CANCER PATIENTS

Focusing our effort on the importance of FUra scheduling we have teste d the hypothesis that pulse and continuous infusion (CI) of the fluoro pyrimidine have different mechanisms of cytotoxicity. Our initial appr oach was to compare the mechanism of resistance of a cell line resista nt to a short term exposure to FUra (HCT-8/FU4hR) to that of a cell li ne resistant to a prolonged exposure to the fluoropyrimidine (HCT-8/FU 7dR). Cytotoxicity studies showed that HCT-8/FU4hR cells were still se nsitive to FUra given as a 7-d exposure, suggesting different mechanis ms of resistance. Indeed, rapid recovery of TS activity after drug rem oval was evident in the HTC-8/FU7dR cell line while HCT-8/FU4hR cells were similar to the parental cell line with regard to both the degree of in situ TS inhibition by FUra and duration of inhibition after FUra removal. In contrast, labelling studies with [H-3-6] FUra (4 h exposu re, 100 mu M) showed that the incorporation of the fluoropyrimidine in to RNA is significantly decreased in HCT-8/FU4hR cells as compared to parental HCT-8 cells. Given the lack of cross resistance between the t wo schedules in vitro, a pilot trial was done on patients with colorec tal cancer refractory to bolus FUra. On 15 patients failing after FUra +LV or FUra alone 1 PR, 3 MR, 3 SD and 8 P were observed, confirming a certain degree of activity of CI FUra in patients clinically resistan t to bolus FUra. Based on this rationale, a phase II trial of schedule -oriented biochemical modulation of FUra in advanced colorectal cancer patients was conducted, employing a hybrid regimen of 2 biweekly cycl es of FUra bolus (600 m/sqm), preceeded by (24 h interval) methotrexat e, 200 mg/sqm (in order to maximize the RNA effect of the drug) altern ating with FUra continuous infusion, 200 mg/sqm daily for 3 weeks, mod ulated by leucovorin, 20 mg/sqm weekly bolus (in order to maximize the DNA effect). Thirty-three consecutive patients (median ECOG PS 1) wit h advanced measurable colorectal cancer and no prior therapy for metas tatic disease entered the study, from February 1992 to August 1993. Th ree complete and 13 partial responses were obtained among these 33 pat ients (RR = 48%, 95% confidence limis, 31-66%). After a median follow- up time of 23 months, 16 patients are still alive. The median progress ion free survival and overall survival were 9.6 and 20.8 months, respe ctively. No toxic deaths or grade 4 toxicity occurred. The incidence o f grade 3 toxicity per patient in any cycle was: mucositis 6%, diarrhe a 3% and vomiting 3% for the bolus part and 21%, 3% and 6% respectivel y, for the continuous infusion part of the regimen. Hand-foot syndrome occurred in 27% of the patients treated with the continuous infusion regimen. In conclusion, this experimental and clinical project has gen erated a novel regimen of schedule oriented biochemical modulation tha t is twice as active and half as toxic compared to bolus FU + LV given with either the daily x 5 or the weekly schedule. This high clinical activity is very encouraging, especially considering that 1) consecuti ve patients were entered, 2) the responses were independently reviewed , 3) the progression free survival and survival were much longer than those actually reported for this disease, 4) the toxicity of the progr am, in particular the bolus regimen, was relatively low allowing furth er intensification.