Elsevier

The Lancet Oncology

Volume 14, Issue 1, January 2013, Pages 72-80
The Lancet Oncology

Articles
Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial

https://doi.org/10.1016/S1470-2045(12)70525-9Get rights and content

Summary

Background

We compared standard adjuvant anthracycline chemotherapy with anthracycline–taxane combination chemotherapy in women with operable node-positive breast cancer. Here we report the final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety.

Methods

BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18–70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with ClinicalTrials.gov, number NCT00688740.

Findings

Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90–126), disease-free survival was 62% (95% CI 58–65) for patients in the TAC group and 55% (51–59) for patients in the FAC group (hazard ratio [HR] 0·80, 95% CI 0·68–0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72–79) for patients in the TAC group and 69% (65–72) for patients in the FAC group (HR 0·74, 0·61–0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3–4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC.

Interpretation

Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation.

Funding

Sanofi.

Introduction

Addition of a taxane to adjuvant anthracycline-based regimens improves relapse-free survival and overall survival in patients with early breast cancer.1 The Breast Cancer International Research Group (BCIRG) 001 study showed that a regimen that incorporates the taxane docetaxel reduces the risk of relapse (HR 0·72, 95% CI 0·59–0·88; p=0·001) and death (HR 0·70, 95% CI 0·53–0·91; p=0·008) compared with a standard anthracycline-based regimen in patients with node-positive, early breast cancer, as we previously reported2 after 55 months of follow-up. However, the long-term risks and benefits of adjuvant chemotherapy remain poorly understood, since many studies have not reported long-term outcomes,3 some have had substantial loss to follow-up, and most did not monitor subclinical toxic effects such as left ventricular dysfunction. Furthermore, an emerging understanding of the distinct molecular subtypes of breast cancer4 now allows for assessment of differential benefits from chemotherapy, endocrine therapy, and biologically targeted drugs.

Here we report the long-term efficacy and safety results from this large, mature, randomised study of adjuvant taxane chemotherapy, on the basis of an intention-to-treat analysis of all 1491 participants.

Section snippets

Patients and study design

As previously reported,2 women eligible for this phase 3, multicentre, open label, randomised trial were aged between 18 and 70 years, had a score on the Karnofsky performance scale of 80% or more, and had undergone primary surgery (ie, mastectomy or lumpectomy) for unilateral, operable breast cancer in which clear margins were obtained, and with axillary lymph node dissection that returned at least one positive node on histological examination (from a minimum of six nodes). A complete staging

Results

Between June 11, 1997, and June 3, 1999, 1491 women from 20 countries in Europe, North and South America, Africa, and the Middle East were enrolled in the study (figure 1). Specific demographic, clinical, and molecular phenotypic characteristics of patients were well-balanced between the group assigned to receive the TAC regimen and the group assigned to receive the FAC regimen (table 1). Compliance with the study protocol was high, with fewer than 6% of participants (43 from the TAC group and

Discussion

This 10-year analysis of the BCIRG 001 study shows that adjuvant TAC for treatment of women with node-positive, early breast cancer provides long-term disease-free survival and overall survival benefits compared with FAC, with similar long-term toxic effects (panel). However, anthracycline-induced cardiotoxicity is a serious and under-recognised complication of adjuvant anthracycline-based chemotherapy regimens that warrants further attention.

The risk-to-benefit ratio of adjuvant breast cancer

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  • Cited by (0)

    Other TRIO/BCIRG 001 investigators are listed in the appendix

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