Until recently, the management of breast cancer with chemotherapeutic agents has led to modest benefits. Hence, there is an urgent need to introduce new active agents into the management of this disease. The demonstration of a superior tumor response rate, time to disease progression, and overall survival with the combination of capecitabine(Drug information on capecitabine) (Xeloda) and docetaxel(Drug information on docetaxel) (Taxotere) compared with single-agent docetaxel in anthracycline-pretreated patients indicates the important role of capecitabine in the treatment of advanced breast cancer.
The use of this agent in combination therapy in breast cancer patients, however, has only begun to be explored, as the agent has a unique mode of action and can be combined safely with a variety of agents. Potential for improvement in the therapeutic index of treatment with capecitabine-containing combinations is suggested by (1) activity of other treatments (eg, taxanes, cyclophosphamide(Drug information on cyclophosphamide) [Cytoxan, Neosar], irinotecan(Drug information on irinotecan) [Camptosar], and vinorelbine [Navelbine], as well as radiation therapy) in increasing tumor levels of thymidine phosphorylase, the activating enzyme for capecitabine; (2) early-phase studies showing activity of combinations with a variety of different agents; and (3) preclinical data indicating potential for synergistic effects with a number of combinations.
In North America, cyclophosphamide/doxorubicin combinations at full conventional dosages have been the basis of breast adjuvant treatment.[5-7] Based upon the enhanced response rates of phase III trials in the neoadjuvant setting (National Surgical Adjuvant Breast and Bowel Project trial B-27) and in the adjuvant setting (the Aberdeen trial), cyclophosphamide/doxorubicin followed by docetaxel may offer a new standard approach in the management of early-disease patients.[8-10] As capecitabine/taxane combinations demonstrate a higher response rate and better survival than docetaxel alone in metastatic disease, the combination is being advanced into treatment of earlier disease. The current US Oncology Adjuvant Trial (XEL242) addresses the question of whether or not the use of capecitabine/docetaxel following classical cyclophosphamide/doxorubicin (Adriamycin) (AC) offers any benefit over single-agent docetaxel following AC. Additional similar studies are in development.
Weekly taxanes may offer a therapeutic advantage over traditional every-3-week schedules of administration and are being actively studied. Because of the ease of administration of taxanes on a weekly schedule and the possibility of repetitively up-regulating thymidine phosphorylase, additional studies are exploring the feasibility of weekly taxane treatment in combination with capecitabine.
Preliminary findings using this approach in 19 anthracycline-pretreated patients with metastatic breast cancer demonstrated activity with acceptable toxicity in an ongoing phase I/II study. The recommended dose was identified as intermittent oral capecitabine at 900 mg/m² twice daily on a 14-day schedule every 3 weeks plus weekly docetaxel at 30 mg/m². There was a low incidence of severe myelosuppression, with only one grade 4 event (neutropenia) being observed; the most common grade 3 toxicity was palmar-plantar erythrodysesthesia (in 3 of 19 patients). Objective tumor response was observed in two patients, with seven patients demonstrating stable disease.
Meza et al have reported findings in a phase II study of paclitaxel(Drug information on paclitaxel) at 175 mg/m² every 3 weeks, plus capecitabine at 825 mg/m² twice daily on days 1 to 14, as first- or second-line treatment of metastatic breast cancer. The patients had a median age of 52 years (range: 35-76 years) and a median Karnofsky performance status of 90. Among 47 evaluable patients, 34 patients received this therapy as first-line treatment, and 13 patients as second-line treatment. Of these patients, 13% (five patients with first-line treatment, and one with second-line treatment) achieved a complete response; 30% of patients achieved a partial response; and 38% had stable disease. Because of the small number of patients, there is some variation in the partial responses in patients receiving first- or second-line treatment (Figure 1). Overall, median time to disease progression was 44 weeks.