Elsevier

The Lancet Oncology

Volume 17, Issue 1, January 2016, Pages 90-98
The Lancet Oncology

Articles
Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial

https://doi.org/10.1016/S1470-2045(15)00411-8Get rights and content

Summary

Background

Oral fluoropyrimidines are used for the first-line treatment of metastatic breast cancer to avoid severe adverse effects, although firm supporting evidence is lacking. We aimed to establish whether S-1 is non-inferior to taxanes in this setting.

Methods

We did an open-label, non-inferiority, phase 3 trial at 154 hospitals in Japan. We enrolled individuals who had HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease, and who were resistant to endocrine treatment. Patients were randomly assigned (1:1) either to taxane (docetaxel 60–75 mg/m2 at intervals of 3–4 weeks; paclitaxel 80–100 mg/m2 weekly for 3 of 4 weeks; or paclitaxel 175 mg/m2 at intervals of 3–4 weeks) or to S-1 (40–60 mg twice daily for 28 consecutive days, followed by a 14-day break). Randomisation was done centrally with the minimisation method, with stratification by institution, liver metastasis, oestrogen and progesterone receptor status, previous treatment with taxanes or oral fluorouracil, and time from surgery to recurrence. The primary endpoint was overall survival, with a prespecified non-inferiority margin of 1·333 for the hazard ratio (HR). The primary efficacy analysis was done in the full analysis set, which consisted of all patients who took at least one study treatment and who had all data after randomisation. This trial is registered with the University Hospital Medical Information Network, Japan (protocol ID C000000416).

Findings

Between Oct 27, 2006, and July 30, 2010, we enrolled 618 patients (309 assigned to taxane; 309 assigned to S-1). The full analysis set consisted of 286 patients in the taxane group and 306 in the S-1 group. Median follow-up was 34·6 months (IQR 17·9–44·4). Median overall survival was 35·0 months (95% CI 31·1–39·0) in the S-1 group and 37·2 months (33·0–40·1) in the taxane group (HR 1·05 [95% CI 0·86–1·27]; pnon-inferiority=0·015). The most common grade 3 or worse adverse events were neutropenia (20 [7%] of 307 patients in the S-1 group vs nine [3%] of 290 patients in the taxane group), fatigue (ten [3%] vs 12 [4%]), and oedema (one [<1%] vs 12 [4%]). Treatment-related deaths were reported in two patients in the taxane group.

Interpretation

S-1 is non-inferior to taxane with respect to overall survival as a first-line treatment for metastatic breast cancer. S-1 should be considered a new option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer.

Funding

Comprehensive Support Project for Oncology Research of the Public Health Research Foundation, Japan; Taiho.

Introduction

The vast majority of metastatic breast cancers are incurable.1, 2, 3 Less toxic treatments are therefore preferred, and endocrine treatment is recommended for patients with oestrogen receptor-positive tumours whenever appropriate. Patients with oestrogen receptor-negative tumours or endocrine refractory disease receive cytotoxic chemotherapy. In such patients, regimens including anthracycline or taxanes are advised because they improve overall survival.4, 5, 6 However, they often cause severe adverse effects.

Orally administered drugs are generally more convenient than intravenous drugs.7 S-1 and capecitabine are both oral fluorouracil derivatives widely used in Japan. S-1 is a combination drug, based on a biochemical modification of fluorouracil, containing tegafur, gimeracil, and oteracil in a molar ratio of 1:0·4:1.8 This combination enables the fluorouracil concentration to be increased while avoiding gastrointestinal toxic effects. It has been used to treat various solid tumours, including stomach cancer,9, 10 colorectal cancer,11, 12 pancreatic cancer,13 non-small-cell lung cancer,14, 15 and breast cancer.16 Two phase 2 studies of S-1 in previously treated and untreated patients with metastatic breast cancer have been done in Japan. 42·0% of treated patients and 40·7% of untreated patients had a tumour response, which is similar to the proportion of patients achieving a response when treated with taxane derivatives.16 We therefore did a phase 3 trial to verify the non-inferiority of S-1 to taxane in terms of overall survival, and its superiority in terms of health-related quality of life, when given as first-line chemotherapy for metastatic breast cancer.

Research in context

Evidence before this study

We searched PubMed from Nov 23, 2005, to June 1, 2015, with the terms “first-line” and either “advanced breast cancer” or “metastatic breast cancer” for full text original articles. We found no phase 2 or phase 3 trials of S-1 for metastatic breast cancer. One phase 3 trial assessed oral fluorouracil derivatives. The TURANDOT trial compared the efficacy of bevacizumab plus paclitaxel versus bevacizumab plus capecitabine. In a planned interim analysis, the predefined criterion for non-inferiority of overall survival was not met.

Added value of this study

To our knowledge, this study is the first phase 3 trial of S-1 in metastatic breast cancer. This trial showed that S-1 was non-inferior to taxane with respect to overall survival and was superior to taxane with respect to health-related quality of life. In addition, adverse events such as hair loss, peripheral neuropathy, and oedema were less common in patients treated with S-1.

Implications of all the available evidence

Our findings suggest that S-1 might provide clinical benefit as first-line treatment for patients with HER2-negative metastatic breast cancer. Our study not only provides evidence to support the use of an oral fluoropyrimidine as first-line chemotherapy, but also satisfies the need for patient choice of treatment. S-1 should be considered a new standard treatment for this setting. To support this strategy, we are doing another similar trial (SELECT BC-CONFIRM, UMIN000005449) comparing overall survival of anthracycline-containing regimens versus S-1 as first-line chemotherapy for metastatic breast cancer.

Section snippets

Study design and participants

We did this randomised phase 3 non-inferiority trial in 154 hospitals in Japan (appendix pp 7–11). We enrolled women aged 20–75 years with histologically confirmed HER2-negative and endocrine treatment-resistant breast cancer, with metastatic disease at presentation or recurrence after surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, no previous chemotherapy for their recurrent or metastatic disease (previous preoperative or postoperative adjuvant use of taxane or

Results

Between Oct 27, 2006, and July 30, 2010, we enrolled 618 patients: 309 were randomly assigned to the taxane group and 309 were randomly assigned to the S-1 group. Ten patients were ineligible for the efficacy analysis and 16 patients did not start protocol treatment; 592 patients constituted the full analysis set (figure 1). Median follow-up for the full analysis set was 34·6 months (IQR 17·9–44·4). Baseline characteristics were similar in each group (table 1). In the taxane group, 127 patients

Discussion

Our findings show that S-1 is non-inferior to taxane with respect to overall survival and better than taxane with regard to health-related quality of life as a first-line treatment for patients with metastatic breast cancer. There were no significant differences in time to treatment failure or progression-free survival between the treatment groups. The goals of treatment for metastatic breast cancer are prolonging survival and improving quality of life. The European Society of Medical Oncology

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