, Volume 63, Issue 2, pp 217-236
Date: 17 Sep 2012

Capecitabine

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Summary

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).

Overview of Pharmacology|

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.

Therapeutic Efficacy|

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). Smaller non-comparative trials demonstrated objective response rates of 52–63% in women pretreated with anthracyclines and/or taxanes who received therapy combining capecitabine with intravenous paclitaxel 175 mg/m2 every 3 weeks, intravenous vinorelbine 2530 mg/m2/week or (tumour overexpressing HER2) intravenous trastuzumab 2 mg/kg/week.

First-line monotherapy with capecitabine 1255 mg/m2 twice daily for 2 weeks in every 3 resulted in an objective response rate of 30% in women aged ≥55 years versus 16% in those receiving intravenous cyclophosphamide 600 mg/m2 plus methotrexate 40 mg/m2 and fluorouracil 600 mg/m2 (CMF) once every 3 weeks. Objective response rates of 49, 67 and 76% were seen with combination first-line therapy of capecitabine 825 to 1000 mg/m2 twice daily for 2 weeks in every 3 plus paclitaxel 175 mg/m2 once every 3 weeks, vinorelbine 25 mg/m2 on days 1 and 8 of each cycle, or epirubicin plus docetaxel, both 75 mg/m2 every 3 weeks in noncomparative trials.

Dosage reduction for adverse effects does not appear to compromise the efficacy of capecitabine.

Two pharmacoeconomic studies have suggested that there may be cost savings associated with treatment of patients with locally advanced or metastatic breast cancer with capecitabine and docetaxel compared with docetaxel alone. Incremental cost-effectiveness ratios of $CAN4254 per life-year gained and $US5520 per quality-adjusted life year gained were reported.

Tolerability|

Adverse effects associated with administration of capecitabine monotherapy 1255 mg/m2 twice daily for 2 weeks in every 3, in six clinical trials in patients with breast or colorectal cancer (n = 570) and occurring at an incidence of ≥5%, were lymphopenia, anaemia, diarrhoea, hand-and-foot syndrome, nausea, fatigue, hyperbilirubinaemia, dermatitis and vomiting (all >25% incidence). Adverse effects graded level 4 included lymphopenia (10% incidence), hyperbilirubinaemia (3%), neutropenia (2%), diarrhoea (2%), dehydration (1%), thrombocytopenia (1%) and anaemia (1%), while those graded level 3 were lymphopenia (36%), gastrointestinal effects (27%), hyperbilirubinaemia (14%), hand-and-foot syndrome (13%), and fatigue, neutropenia, anorexia, dehydration, anaemia, dermatitis, headache, and thrombocytopenia (all ≤5%).

Adverse effects were reported by most patients receiving oral capecitabine monotherapy or comparative agents in randomised nonblind clinical trials. Gastrointestinal effects and hand-and-foot syndrome occurred more often with oral capecitabine than with either intravenous paclitaxel or intravenous CMF, while neutropenic fever, arthralgia, pyrexia and myalgia were more common with paclitaxel, and nausea, stomatitis, alopecia and asthenia were more common with the CMF regimen.

In patients receiving combination therapy, median delivered capecitabine and docetaxel doses were 77% and 87% of the planned doses. Doses were mainly reduced because of hand-and-foot syndrome, diarrhoea or stomatitis. Treatment-related adverse effects occurred in 98% of patients in the combination therapy group compared with 94% of patients receiving docetaxel monotherapy. The incidences of gastrointestinal adverse effects and hand-and-foot syndrome were higher among capecitabine plus docetaxel recipients, while neutropenic fever, arthralgia and pyrexia occurred more frequently among recipients of docetaxel monotherapy.

Dosage and Administration|

In the US and Europe, capecitabine in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy. Capecitabine monotherapy is indicated in patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or in those resistant to paclitaxel and for whom further anthracycline therapy is not indicated (US) or failing intensive chemotherapy (Europe). The recommended dosage is 1250 mg/m2 administered twice daily (equivalent to 2500 mg/m2/day) for 14 days followed by a 7-day rest. Capecitabine tablets should be taken within 30 minutes after a meal. Capecitabine is also approved for use in metastatic colorectal cancer.

Capecitabine is contraindicated in patients with a known hypersensitivity to fluorouracil and in those with severe renal impairment; in Europe it is also contraindicated in those with severe hepatic impairment, dihydropyrimidine dehydrogenase deficiency, or severe leucopenia, neutropenia or thrombocytopenia. Dosages should be reduced in patients with moderate renal impairment. Patients taking coumarin anticoagulants or phenytoin concomitantly with capecitabine should be regularly monitored; in the US, there is a boxed warning recommending frequent monitoring with the use of capecitabine and coumarin anticoagulants. Concomitant use with allopurinol should be avoided. Capecitabine toxicity occurring during monotherapy can be managed with symptomatic treatment or dose modification.

Various sections of the manuscript reviewed by: D.R. Budman, Don Monti Division of Oncology, North Shore University Hospital, New York, New York, USA; F.M. Muggia, Kaplan Cancer Center, New York, New York, USA; D. Papamichael, Department of Medical Oncology, BOC Oncology Centre, Strovolos, Nicosia, Cyprus; P.N. Plowman, Department of Radiotherapy, St. Bartholomew’s Hospital, London, England; C. Twelves, Department of Medical Oncology, Cancer Research UK, Glasgow, Scotland.

Data Selection

Sources: Medical literature published in any language since 1980 on capecitabine, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘capecitabine’ and ‘breast-neoplasms’. EMBASE search terms were ‘capecitabine’ and ‘breast cancer’. AdisBase search terms were ‘capecitabine’ and ‘breast-cancer’. Searches were last updated 12 December, 2002.
Selection: Studies in patients with advanced breast cancer who received capecitabine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: capecitabine, breast cancer, advanced breast cancer, pharmacodynamics, pharmacokinetics, therapeutic use.