Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial

Research output: Contribution to journalArticlepeer-review

Authors

  • tAnGo trial collaborators
  • Helena M. Earl
  • Louise Hiller
  • Helen C. Howard
  • Janet A. Dunn
  • Jennie Young
  • Sarah Bowden
  • Michelle McDermaid
  • Anna K. Waterhouse
  • Gregory Wilson
  • Rajiv Agrawal
  • Susan O'Reilly
  • Angela Bowman
  • Diana M. Ritchie
  • Andrew Goodman
  • Tamas Hickish
  • Karen McAdam
  • David Cameron
  • David Dodwell
  • Daniel Rea
  • Carlos Caldas
  • Elena Provenzano
  • Jean E. Abraham
  • Peter Canney
  • John P. Crown
  • M. John Kennedy
  • Robert Coleman
  • Robert C. Leonard
  • James A. Carmichael
  • Andrew M. Wardley
  • Christopher J. Poole

Colleges, School and Institutes

External organisations

  • Cambridge Breast Unit
  • University of Warwick
  • University of Leeds
  • St. George's Healthcare National Health Service Trust
  • Gloucestershire Hospitals NHS Foundation Trust
  • Clatterbridge Cancer Centre
  • Western General Hospital
  • Beatson West Scotland Cancer Centre
  • Royal Devon & Exeter NHS Foundation Trust
  • Poole Hospital NHS Trust
  • Peterborough and Stamford Hospitals NHS Foundation Trust
  • University of Edinburgh
  • St James' Hospital
  • NIHR Cambridge Biomedical Research Centre
  • St Vincent's University Hospital
  • Cancer Trials Ireland
  • Weston Park Hospital
  • Charing Cross Hospital
  • CELGENE CORPORATION
  • NIHR/CRUK Christie Clinical Research Facility
  • University Hospitals Coventry and Warwickshire NHS Trust

Abstract

Background

The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel.

Methods

tAnGo was an international, open-label, randomised, phase 3 superiority trial that enrolled women aged 18 years or older with newly diagnosed, early-stage breast cancer who had a definite indication for chemotherapy, any nodal status, any hormone receptor status, Eastern Cooperative Oncology Group performance status of 0–1, and adequate bone marrow, hepatic, and renal function. Women were recruited from 127 clinical centres and hospitals in the UK and Ireland, and randomly assigned (1:1) to one of two treatment regimens: epirubicin, cyclophosphamide, and paclitaxel (four cycles of 90 mg/m2 intravenously administered epirubicin and 600 mg/m2 intravenously administered cyclophosphamide on day 1 every 3 weeks, followed by four cycles of 175 mg/m2 paclitaxel as a 3 h infusion on day 1 every 3 weeks) or epirubicin, cyclophosphamide, and paclitaxel plus gemcitabine (the same chemotherapy regimen as the other group, with the addition of 1250 mg/m2 gemcitabine to the paclitaxel cycles, administered intravenously as a 0·5 h infusion on days 1 and 8 every 3 weeks). Patients were randomly assigned by a central computerised deterministic minimisation procedure, with stratification by country, age, radiotherapy intent, nodal status, and oestrogen receptor and HER-2 status. The primary endpoint was disease-free survival and the trial aimed to detect 5% differences in 5-year disease-free survival between the treatment groups. Recruitment completed in 2004 and this is the final, intention-to-treat analysis. This trial is registered with EudraCT (2004-002927-41), ISRCTN (51146252), and ClinicalTrials.gov (NCT00039546).

Findings

Between Aug 22, 2001, and Nov 26, 2004, 3152 patients were enrolled and randomly assigned to epirubicin, cyclophosphamide, paclitaxel, and gemcitabine (gemcitabine group; n=1576) or to epirubicin, cyclophosphamide, and paclitaxel (control group; n=1576). 11 patients (six in the gemcitabine group and five in the control group) were ineligible because of pre-existing metastases and were therefore excluded from the analysis. At this protocol-specified final analysis (median follow-up 10 years [IQR 10–10]), 1087 disease-free survival events and 914 deaths had occurred. Disease-free survival did not differ significantly between the treatment groups at 10 years (65% [63–68] in the gemcitabine group vs 65% [62–67] in the control group), and median disease-free survival was not reached (adjusted hazard ratio 0·97 [95% CI 0·86–1·10], p=0·64). Toxicity, dose intensity, and a detailed safety substudy showed both regimens to be safe, deliverable, and tolerable. Grade 3 and 4 toxicities were reported at expected levels in both groups. The most common were neutropenia (527 [34%] of 1565 patients in the gemcitabine group vs 412 [26%] of 1567 in the control group), myalgia and arthralgia (207 [13%] vs 186 [12%]), fatigue (207 [13%] vs 152 [10%]), infection (202 [13%] vs 141 [9%]), vomiting (143 [9%] vs 108 [7%]), and nausea (132 [8%] vs 102 [7%]).

Interpretation

The addition of gemcitabine to anthracycline and taxane-based adjuvant chemotherapy at this dose and schedule confers no therapeutic advantage in terms of disease-free survival in early breast cancer, although it can cause increased toxicity. Therefore, gemcitabine has not been added to standard adjuvant chemotherapy in breast cancer for any subgroup.

Funding

Cancer Research UK core funding for Clinical Trials Unit at the University of Birmingham, Eli Lilly, Bristol-Myers Squibb, and Pfizer.

Details

Original languageEnglish
Pages (from-to)755-769
JournalThe Lancet Oncology
Volume18
Issue number6
Early online date4 May 2017
Publication statusPublished - Jun 2017

Keywords

  • EC-T, gemcitabine, tAnGo, early breast cancer, adjuvant chemotherapy

ASJC Scopus subject areas

Sustainable Development Goals