Fast track — ArticlesAdjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial
Introduction
Adjuvant chemotherapy consisting of an alkylating agent, an anthracycline, and a taxane is typically administered for early breast cancer, although the regimens used can vary considerably.1, 2, 3 Results from a few large randomised trials and a meta-analysis suggest that addition of a taxane to adjuvant regimens containing an anthracycline improves disease-free and overall survival.4, 5, 6 Despite such advances in chemotherapy, many women diagnosed with early breast cancer still eventually succumb to the disease.
Capecitabine is an oral prodrug of fluorouracil, which has been used in the treatment of advanced breast cancer for a few decades. After absorption, it is metabolised in the liver and in cancerous tissue. The final step of conversion to fluorouracil is catalysed by thymidine phosphorylase, which is present in high amounts in breast tumours.7 Administration of docetaxel, paclitaxel, or cyclophosphamide boosts the concentration in tumour tissue of thymidine phosphorylase in xenograft models, suggesting that these agents might act in a synergistic manner with capecitabine.8, 9, 10 In women treated with docetaxel, or doxorubicin or epirubicin given with cyclophosphamide before surgery for breast cancer, thymidine phosphorylase was greatly stimulated in both tumour and stromal cells.11 Women with advanced breast cancer treated with an anthracycline had augmented survival when randomised to receive docetaxel plus capecitabine compared with those assigned to docetaxel alone.12
Since thymidine phosphorylase production in cancer tissue is important for capecitabine activity, in the current study (the Finland capecitabine trial [FinXX]), we administered capecitabine with agents that might enhance activity of this enzyme in tumours. Capecitabine was given for a total of 18 weeks to provide prolonged exposure, which might facilitate eradication of cancer cells with a slow cell-proliferation rate. Here, we report findings from the planned interim efficacy analysis of the trial.
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Patients
We undertook a randomised, controlled, open-label, phase 3 trial in 15 Finnish hospitals and five Swedish hospitals. We deemed women eligible for the study if they had histologically confirmed invasive breast cancer at medium-to-high risk of recurrence, defined as either: regional node-positive disease (isolated tumour-cell clusters <0·2 mm in diameter were not judged a metastasis); or node-negative disease with primary tumour diameter greater than 20 mm and negative progesterone receptor assay
Results
Between Jan 27, 2004, and May 29, 2007, 1500 patients were recruited from 15 Finnish centres (n=1199) and five Swedish centres (n=301). Four women were excluded from the modified intention-to-treat population (two withdrew informed consent before they received study treatments, two had overt distant metastases at the time of study entry; figure 1). Baseline characteristics were balanced between groups (table 1). 90% of patients had node-positive cancer, and 19% had HER2-positive disease.
The
Discussion
Our findings showed enhanced recurrence-free survival for patients who received a regimen containing capecitabine in addition to docetaxel, epirubicin, and cyclophosphamide compared with women who received docetaxel, epirubicin, cyclophosphamide, and fluorouracil. Overall survival data from FinXX are not yet mature, but we noted the hazard ratio for overall survival was similar to that for recurrence-free survival. Single-agent capecitabine has been compared with combination chemotherapy in the
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