5-Fluorouracil (5-FU) is a fluoropyrimidine analog that is inactive in its parent form, and requires metabolic activation to generate the active metabolites responsible for cytotoxicity.The cytotoxic metabolites of 5-FU are incorporated into ribonucleic acid (RNA) and DNA, respectively, and they interfere with the processes of RNA and DNA biosynthesis. In addition, the 5-FU metabolite, FdUMP, is a potent inhibitor of de novo thymidylate synthesis, and inhibition of this process causes an eventual loss of thymidine triphosphate, which is a necessary constituent for DNA synthesis.
For nearly 40 years, 5-FU was the only active chemotherapy available to treat advanced CRC in the first-line setting.4 However, response rates to 5-FU in patients with advanced disease were generally in the 10% to 15% range.To improve the clinical efficacy of 5- FU, the addition of certain biomodulation agents such as the reduced folate leucovorin (LV) and/or a change in the schedule of administration of 5-FU from bolus to continuous infusion were investigated.5,6 While response rates have significantly increased with these maneuvers, overall survival has not been substantively altered.
Capecitabine is a third-generation oral prodrug of 5-FU that was rationally designed to closely simulate infusional administration of 5-FU.7 It is rapidly and nearly completely absorbed from the intestine and is then activated by a series of three enzymatic steps to generate 5-FU and its cytotoxic metabolites. The unique localization of activating enzymes results in the selective generation of 5-FU in tumor cells after the oral administration of capecitabine, and this fact has been confirmed in preclinical human cancer xenograft models and in patients with CRC.8,9A randomized Phase II study of patients with advanced CRC helped to establish the efficacy and safety of capecitabine and identified the most appropriate monotherapy regimen for evaluation in Phase III trials.10 The optimal regimen was shown to be an oral dose of 1,250mg/m2 twice-daily (bid) for 14 days, followed by a seven-day rest period. This dosing regimen was subsequently used in two randomized Phase III trials comparing capecitabine with bolus 5-FU/LV (Mayo Clinic regimen).11,12 Both Phase III studies showed that capecitabine significantly increased overall response rates in comparison with bolus 5-FU/LV, with equivalent median overall survival and time to tumor progression.Of note, the incidence of diarrhea, stomatitis, nausea, alopecia, and grade 3/4 neutropenia was significantly lower in patients treated with capecitabine, whereas the incidence of hand–foot syndrome was higher.Treatment with capecitabine also resulted in a reduced incidence of hospitalizations for adverse events in comparison with treatment with bolus 5-FU/LV. An integrated analysis revealed that the response rate was significantly greater with capecitabine than with 5-FU/LV (25.7% versus 1 16.7%; P<0.0002), while secondary measures of time-to- tumor progression (TTP) and survival were equivalent.13