ANTI-TUMOUR TREATMENT Contemporary issues and the potential uses of capecitabine in metastatic breast cancer Peter Barrett-Lee a,d , François-Clément Bidard b , Jean-Yves Pierga b,c, * a Velindre Cancer Centre, Velindre Road, Cardiff CF14 2TL, UK b Institut Curie Hospital, 26 rue d’Ulm, Paris 75248, France c Université Paris Descartes,12, rue de l’Ecole de Médecine, 75270 Paris Cedex 06, France article info Article history: Received 26 March 2009 Received in revised form 10 June 2009 Accepted 12 June 2009 Keywords: Metastatic breast cancer Capecitabine HER2 Brain Targeted therapy summary Since its first regulatory approval more than 10 years ago, oncologists have gained wide experience in using the oral fluoropyrimidine, capecitabine, as monotherapy or in combination with other agents and the body of evidence supporting these approaches continues to grow. Alongside this increasing expe- rience has been the appearance of new challenges in patient management. We now recognise several dif- ferent biological subtypes of breast cancer, such as HER2-positive disease. The standard of care in these tumours comprises anti-HER2 therapy, and phase III data show that capecitabine can be effectively com- bined with such agents. Another increasingly prominent and currently unresolved issue resulting from more effective treatment of metastatic disease is the management of patients with brain metastases. The introduction of new, well-tolerated, oral chemotherapies also provides the opportunity for longer duration of therapy. These new clinical scenarios are discussed in the current review. Ó 2009 Elsevier Ltd. All rights reserved. Introduction The oral fluoropyrimidine, capecitabine (Xeloda Ò ; F. Hoffmann- La Roche, Basel, Switzerland), is widely used in metastatic breast cancer (MBC) as monotherapy or combination therapy, especially in HER2-negative and/or pretreated disease, supported by the re- sults of phase II studies and randomised, phase III trials. As mono- therapy, first-line capecitabine (n = 214) significantly improves overall survival (OS) compared with classical cyclophosphamide, methotrexate and 5-fluorouracil (CMF; n = 109) (hazard ratio 0.72 [95% confidence interval (CI): 0.55–0.94]; p = 0.02). 1 The addi- tion of capecitabine to docetaxel (n = 255) significantly improves OS versus docetaxel alone (n = 256) (hazard ratio 0.775 [95% CI: 0.634–0.947]; p = 0.0126). 2 However, there is less information about three more contemporary issues relating to the use of cape- citabine: the role of capecitabine in combination with targeted therapy, particularly in HER2-positive disease; the potential value of capecitabine in patients with brain metastases; and the optimal duration of capecitabine therapy. In this paper we will review cur- rently available data in these therapeutic areas. Capecitabine in combination with targeted therapy Capecitabine/anti-HER2 combination therapy Initially, many oncologists were reluctant to use capecitabine in patients with HER2-positive disease. The standard of care for these patients is trastuzumab-based therapy, and early preclinical data reported by Pegram et al. 3 suggested that trastuzumab and 5-fluo- rouracil (5-FU) (capecitabine not tested) were antagonistic when combined in vitro. Results of subsequent studies of capecitabine and trastuzumab in human breast cancer models contradicted this finding, showing at least additive efficacy with the combination, 4 but by then, many clinicians were favouring vinorelbine as an alternative to taxanes in combination with trastuzumab, supported by results of several single-arm, phase II studies. 5–10 Individual case studies and a small retrospective study 11–14 sug- gested that the combination of capecitabine and trastuzumab (HX) was active in the clinical setting of HER2-positive MBC. Subsequent data from five single-arm, phase II studies and two large, random- ised trials have confirmed the high activity of HX, with or without docetaxel, in HER2-positive MBC in both the first-line setting and pretreated disease and in patients with or without prior trast- uzumab exposure (Table 1). 15–21 0305-7372/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2009.06.003 * Corresponding author. Address: Institut Curie Hospital, 26 rue d’Ulm, Paris 75248, France. Tel.: +33 1 4432 4207; fax: +33 1 53104041. E-mail addresses: Peter.Barrett-Lee@velindre-tr.wales.nhs.uk (P. Barrett-Lee), francois-clement.bidard@curie.fr (F.-C. Bidard), jean-yves.pierga@curie.net (J.-Y. Pierga). d Tel.: +44 2920 316914; fax: +44 2920 316267. Cancer Treatment Reviews 35 (2009) 582–589 Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv