The rational development of capecitabine from the laboratory to the clinic.

Although the anti-neoplastic activity of 5-Fluorouracil (5-FU) is improved by continuous infusion or biochemical modulation, the need for in-dwelling central venous catheters and toxicity have proved to be major impediments. Capecitabine (Xeloda, N4-pentyloxycarbonyl-5'-deoxy-5-fluoro-cytidine), an oral fluoropyrimidine, has been synthesized in the laboratory as an inactive precursor that passes intact through the intestinal mucosa and is sequentially converted to 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR) and finally 5-FU in the liver and tumour tissues selectively. Preclinical studies provided evidence of preferential conversion of inactive 5'-DFUR to active 5-FU in solid tumours due to the relative overexpression of the final anabolising enzyme, thymidine phosphorylase (TP), in neoplastic tissues more than in normal counterparts. Phase I/II studies exploring toxicity and the appropriate dosing resulted in the evaluation of the intermittent schedule (2510 mg/m2/day for 14 days every 3 weeks) in subsequent trials. Two large phase III studies in patients with metastatic colon cancer established at least equivalent efficacy and improved tolerability for capecitabine compared to the Mayo Clinic bolus 5-FU/folinic acid regimen. Phase II studies established remarkable activity in women with heavily pretreated metastatic breast cancer. Moreover the combination with a taxane yielded a unique survival benefit compared to the previous gold standard of taxane monotherapy in a phase III trial of women with anthracycline resistant breast cancer. The commonest side-effects are hand and foot syndrome, diarrhoea and stomatitis with serious adverse events occurring in a minority of patients. Myelosuppression was minimal or absent. Toxic manifestations are easily managed with a significant reduction in the frequency of hospitalizations and medical resource use, as shown in appropriate studies. Capecitabine is expected to find a role in the treatment of other tumour types as well as adjuvant administration. It represents an advance in modern drug development, stressing the current shift towards rational development of new agents and home-based outpatient regimens.