Elsevier

The Lancet Oncology

Volume 10, Issue 12, December 2009, Pages 1145-1151
The Lancet Oncology

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Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial

https://doi.org/10.1016/S1470-2045(09)70307-9Get rights and content

Summary

Background

Standard adjuvant chemotherapy regimens for patients with moderate-to-high-risk early breast cancer typically contain a taxane, an anthracycline, and cyclophosphamide. We aimed to investigate whether integration of capecitabine into such a regimen enhances outcome.

Methods

In this open-label trial, we randomly assigned (centrally by computer; stratified by node status, HER2 status, and centre) 1500 women with axillary node-positive or high-risk node-negative breast cancer to either three cycles of capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (capecitabine group, n=753), or to three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (control group, n=747). The primary endpoint was recurrence-free survival. A planned interim analysis was done after 3 years' median follow-up. Efficacy analyses were by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT00114816.

Findings

Two patients in each group were excluded from efficacy analyses because of withdrawal of consent or distant metastases. After a median follow-up of 35 months (IQR 25·5–43·6), recurrence-free survival at 3 years was better with the capecitabine regimen than with control (93% vs 89%; hazard ratio 0·66, 95% CI 0·47–0·94; p=0·020). The capecitabine regimen was associated with more cases of grade 3 or 4 diarrhoea (46/740 [6%] vs 25/741 [3%]) and hand-foot syndrome (83/741 [11%] vs 2/741 [<1%]) and the control regimen with more occurrences of grade 3 or 4 neutropenia (368/375 [98%] vs 325/378 [86%]) and febrile neutropenia (65/741 [9%] vs 33/742 [4%]). More patients discontinued planned treatment in the capecitabine group than in the control group (178/744 [24%] vs 23/741 [3%]). Four patients in the capecitabine group and two in the control group died from potentially treatment-related causes.

Interpretation

The capecitabine-containing chemotherapy regimen reduced breast cancer recurrence compared with a control schedule of standard agents. Capecitabine administration was frequently discontinued because of adverse effects.

Funding

Roche, Sanofi-Aventis, AstraZeneca, Cancer Society of Finland.

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.

Section snippets

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

References (30)

  • H Roché et al.

    Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 trial

    J Clin Oncol

    (2006)
  • M De Laurentiis et al.

    Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials

    J Clin Oncol

    (2008)
  • M Endo et al.

    Induction of thymidine phosphorylase expression and enhancement of efficacy of capecitabine or 5′-deoxy-5-fluorouridine by cyclophosphamide in mammary tumor models

    Int J Cancer

    (1999)
  • K Fujimoto-Ouchi et al.

    Schedule dependency of antitumor activity in combination therapy with capecitabine/5′-deoxy-5-fluorouridine and docetaxel in breast cancer models

    Clin Cancer Res

    (2001)
  • N Sawada et al.

    Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts

    Clin Cancer Res

    (1998)
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