Capecitabine (Xeloda): from the laboratory to the patient's home

Attempts at improving the efficacy of 5-fluorouracil (5-FU) by protracted continuous infusion and/or biochemical modulation have been hindered by the need for indwelling central venous catheters and their associated toxicity. Capecitabine, an oral fluoropyrimidine carbamate, has been rationally synthesized as an inactive precursor that is absorbed intact through the intestinal mucosa and is sequentially converted by an enzymatic cascade involving 3 distinct enzymes to 5'-deoxy-5-fluorocytidine, to 5'-deoxy-5-fluorouridine (5'-DFUR), and finally to 5-FU. Preclinical studies provided evidence of preferential intratumoral conversion of inactive 5'-DFUR to active 5-FU due to the relative overexpression of the final anabolizing enzyme, thymidine phosphorylase, in tumor tissues, with a resultant decrease of 5-FU exposure in normal tissues. The safety of capecitabine and optimal dosing schedules have been explored in phase I/II studies, resulting in the evaluation of the intermittent schedule (1250 mg/m2 twice daily for 14 days, every 3 weeks) in most subsequent clinical trials. Two large randomized phase III studies in patients with metastatic colon cancer established at least equivalent efficacy and improved tolerability with capecitabine compared to the Mayo Clinic bolus 5-FU/leucovorin regimen. The most common treatment-related adverse events are palmar-plantar erythrodysesthesia, diarrhea, and stomatitis, with grade 3/4 events occurring in 17%, 15%, and 2%-8% of patients, respectively. Myelosuppression was minimal. Overall toxicity was easily managed, with a significant reduction in the frequency of hospitalizations and medical resource use. The spectrum of clinical efficacy of capecitabine is expected to encompass other tumor types and administration in the adjuvant setting. As a home-based outpatient regimen, capecitabine represents a safe and effective advance in modern drug development.