Capecitabine

Publisher Website
Google Scholar
Abstract
Capecitabine is an orally administered prodrug of fluorouracil which is indicated in the US and Europe, in combination with docetaxel, for the treatment of patients with metastatic breast cancer failing anthracycline therapy, and as monotherapy for metastatic breast cancer resistant to paclitaxel and anthracycline therapy (US) or failing intensive chemotherapy (Europe). Capecitabine is also approved for use in metastatic colorectal cancer. Capecitabine is metabolically activated preferentially at the tumour site, and shows antineoplastic activity and synergy with other cytotoxic agents including cyclophosphamide or docetaxel in animal models. Bioavailability after oral administration is close to 100%. In patients with pretreated advanced breast cancer, capecitabine is effective as monotherapy and also in combination with other agents. Combination therapy with capecitabine 1250 mg/m2 twice daily for 2 weeks of every 3-week cycle plus intravenous docetaxel 75 mg/m2 on day one of each cycle was superior to intravenous monotherapy with docetaxel 100 mg/m2 on day one of each cycle. Capecitabine plus docetaxel significantly reduced the risks of disease progression and death by 35% (p = 0.0001) and 23% (p < 0.05), respectively, and significantly increased median survival (p < 0.05) and objective response rates (p < 0.01). Efficacy has also been demonstrated with capecitabine monotherapy and combination therapy in previously untreated patients in preliminary trials. The most common adverse effects occurring in patients receiving capecitabine monotherapy include lymphopenia, anaemia, diarrhoea, hand-and-foot syndrome, nausea, fatigue, hyperbilirubinaemia, dermatitis and vomiting (all >25% incidence). While gastrointestinal events and hand-and-foot syndrome occurred more often with capecitabine than with paclitaxel or a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF), neutropenic fever, arthralgia, pyrexia and myalgia were more common with paclitaxel, and nausea, stomatitis, alopecia and asthenia were more common with CMF. The incidence of adverse effects and hospitalisation was similar in patients receiving capecitabine plus docetaxel and those receiving docetaxel monotherapy. In conclusion, capecitabine, an oral prodrug of fluorouracil which is activated preferentially at the tumour site, is an effective and convenient addition to the intravenous polychemotherapeutic treatment of advanced breast cancer in pretreated patients, and also has potential as a component of first-line combination regimens. Combined capecitabine plus docetaxel therapy resulted in similar rates of treatment-related adverse effects and hospitalisation to those seen with docetaxel monotherapy. Capecitabine is also effective as monotherapy in pretreated patients and phase II data for capecitabine as first-line monotherapy are also promising. While gastrointestinal effects and hand-and-foot syndrome occur often with capecitabine, the tolerability profile was comparatively favourable for other adverse effects (notably, neutropenia and alopecia). Capecitabine is an oral fluoropyrimidine which undergoes several metabolic changes in vivo, ultimately yielding fluorouracil. This occurs preferentially in tumour tissue and leads to subsequent formation of fluorodeoxyuridine mono-phosphate and fluorouridine triphosphate. Capecitabine demonstrates antineoplastic activity in human mammary tumour xenograft models, with synergistic effects when used in combination with other cytotoxic agents including cyclophosphamide and docetaxel. Pharmacokinetic studies with capecitabine have been performed in patients with solid tumours, many of which were colorectal but including some breast tumours. The oral bioavailability of capecitabine is nearly 100%. Maximum plasma concentrations and area under the plasma concentration-time curve (AUC) of capecitabine showed linear increases with dosage and were decreased when capecitabine was administered with food. Elimination of capecitabine is primarily renal; in patients with severe renal impairment, use of capecitabine is contraindicated. Capecitabine increased the AUC and decreased clearance of a single dose of warfarin. Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy therefore require frequent monitoring of their anticoagulant response. The pharmacokinetics of capecitabine are not significantly affected by paclitaxel or docetaxel. Oral capecitabine 1250 or 1255 mg/m2 twice daily for 2 weeks in every 3 has shown efficacy in prospective trials as monotherapy in patients with pretreated advanced breast cancer. Objective response rates with capecitabine monotherapy were 36% (vs a similar rate of 26% with intravenous paclitaxel 175 mg/m2 every 3 weeks) in women with disease resistant to or failing anthracycline therapy, 18 to 41% in those with disease resistant to or failing taxane therapy, and 43, 57 and 70% in those with relapsed disease after high-dose chemotherapy plus autologous stem cell support. A randomised nonblind phase III trial has demonstrated the efficacy of capecitabine as part of a combination regimen in women with advanced breast cancer resistant to or failing anthracycline therapy. Capecitabine 1250 mg/m2 twice daily for 2 weeks of every 3-week cycle plus intravenous docetaxel 75 mg/m2 administered over a 1-hour infusion on day one of each cycle was superior to intravenous docetaxel 100 mg/m2 monotherapy on day one of each cycle in women with advanced breast cancer refractory to previous anthracycline therapy. The risks of disease progression and death were reduced by 35% (p = 0.0001) and 23% (p < 0.05) with capecitabine plus docetaxel. Median survival was longer with the combination than with docetaxel alone (14.5 vs 11.5 months, p < 0.05) and objective response rates were higher (42% vs 30%, p < 0.01)....