Capecitabine in stage IV breast cancer

Questions: What is the role of capecitabine as second-, third-, or fourth-line chemotherapy in stage IV (metastatic) breast cancer? What is the role of capecitabine in anthracycline failure or taxane failure? What is the role of capecitabine as first-line chemotherapy in metastatic breast cancer? Perspectives: A previous evidence summary from the Breast Cancer Disease Site Group (DSG) suggested that available evidence did not allow a firm clinical recommendation to be made for the use of capecitabine in metastatic breast cancer. Since the development of the original evidence summary, additional evidence, including results from randomised trials, has been published. The new information merits further examination to answer the contemporary clinical questions identified by the Breast Cancer DSG. Outcomes: Survival, time to disease progression, tumour response, quality of life, and adverse effects were the outcomes of interest. Methods: A systematic search of the MEDLINE (Ovid; 1995-2003) and Cochrane Library (Issue 1, 2003) databases was undertaken. In addition, the Physician Data Query database, conference proceedings from the American Society of Clinical Oncology (ASCO, 1998-2002) and the San Antonio Breast Cancer Symposium (2000, 2001), and relevant bibliographies were also searched. The Canadian Medical Association Infobase, the National Guidelines Clearinghouse, and other Web sites were searched for existing evidence-based practice guidelines. Randomised controlled trials of capecitabine were of primary interest, but reports of uncontrolled phase II studies were eligible when evidence from randomised trials was not available. Results: Evidence was available from one randomised phase III trial of capecitabine plus docetaxel versus docetaxel alone in patients who had prior anthracycline-containing chemotherapy. Two relevant randomised phase II trials were also found: one of capecitabine versus cyclophosphamide/methotrexate/fluorouracil (CMF) in patients receiving first-line chemotherapy for metastatic disease, and one of capecitabine versus paclitaxel following prior anthracycline therapy. Two non-comparative phase II trials evaluated the activity of capecitabine in women with heavily pretreated, paclitaxel- or docetaxel-refractory metastatic breast cancer. Practice Guideline: In selected patients (for example, those with good performance status, less than 70 years of age, and with no other major comorbidities) who are anthracycline-resistant or who have previously received an anthracycline as adjuvant therapy, the combination of docetaxel and capecitabine is an appropriate therapeutic option. If docetaxel and capecitabine are used in combination, the recommended starting dose for most patients is capecitabine 950 mg/m² twice daily (75% of the full dose) on days 1-14, plus docetaxel 75 mg/m² given intravenously on day 1 of a 21-day cycle. In patients who have been pretreated with anthracyclines or taxanes, or both, capecitabine alone (1250 mg/m² twice daily for 21 days) is a reasonable treatment option. Evidence is insufficient for the use of capecitabine as first-line chemotherapy in metastatic breast cancer. Warnings: Patients receiving concomitant capecitabine and coumarin-derivative therapy should be monitored for anticoagulant response, because coagulant response time is significantly increased in patients stabilised on anticoagulants at the time of capecitabine introduction. In patients with renal impairment, capecitabine therapy can increase systemic exposure to alpha-fluoro-beta-alanine (FBAL) and 5′-deoxy-5-fluorouridine (5′-DFUR). Systemic exposure to capecitabine was approximately 25% in patients with renal impairment. Qualifying Statements: In patients who have been heavily pretreated, a reduction in the starting dose of single-agent capecitabine (75% of full dose) may be considered. Available data are limited and do not allow a firm clinical recommendation to be made for optimal use of capecitabine in metastatic breast cancer. Further studies are needed to evaluate its role in combination and sequential therapies. Capecitabine needs to be further evaluated as an alternative to paclitaxel or docetaxel in patients whose tumour has progressed on an anthracycline-based regimen and in selected women as first-line therapy as an alternative to more toxic standard combination-chemotherapy regimens.