ABSTRACT
BACKGROUND: Although protracted intravenous 5-fluorouracil is superior to bolus regimens in terms of tumour exposure to the drug during DNA synthesis as well as activity and safety, the oral fluoropyrimidine capecitabine is administered intermittently. In this phase I study, we investigated an alternative, dose-intense continuous regimen. MATERIALS AND METHODS: Oral capecitabine was administered twice daily continuously with weekend breaks, in patients with advanced solid tumours refractory to standard therapy. Dose escalation proceeded from 1,331 to 2,510 mg/m(2) daily. Dose limiting toxicity (DLT) consisted of any grade-3 or 4 adverse event except for alopecia and skin toxicity resolving within 7 days. RESULTS: Twenty-five heavily pretreated patients participated in the study. No DLT occurred in the first four cohorts. Two out of four patients developed grade III diarrhoea in the fourth week of capecitabine at 2,510 mg/m(2) (DLT). The most common toxic episodes during all cycles of treatment were grade 1-2 fatigue, skin erythema, abdominal cramps, nausea, constipation and neutropenia. Disease regression was seen in three and stabilisation with clinical benefit in ten patients (clinical benefit response 54%). Pharmacokinetic studies of capecitabine and metabolites in four patients at 2,250 mg/m(2 )daily showed rapid absorption, short plasma half-lives with the exception of FBAL and absence of accumulation or conversion saturation during the course of therapy. At this dose, administered dose intensity in eight patients was 99.3% of the planned one. CONCLUSIONS: Weekday on-weekend off capecitabine maximizes cytotoxic impact on tumour cells during S-phase by safely simulating protracted fluoropyrimidine therapy at a recommended dose (2,250 mg/m(2)) close to that of the intermittent schedule and clearly higher than the continuous one of 1,331 mg/m(2).
