title: Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial.
abstract: BACKGROUND
  Anthracyclines and taxanes have been the standard neoadjuvant chemotherapies for breast cancer in the past decade. We aimed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide, and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel (with or without gemcitabine).
  
  
  METHODS
  In our randomised, open-label, 2×2 factorial phase 3 trial (Neo-tAnGo), we enrolled women (aged >18 years) with newly diagnosed breast cancer (tumour size >20 mm) at 57 centres in the UK. Patients were randomly assigned via a central randomisation procedure to epirubicin and cyclophosphamide then paclitaxel (with or without gemcitabine) or paclitaxel (with or without gemcitabine) then epirubicin and cyclophosphamide. Four cycles of each component were given. The primary endpoint was pathological complete response (pCR), defined as absence of invasive cancer in the breast and axillary lymph nodes. This study is registered with EudraCT (2004-002356-34), ISRCTN (78234870), and ClinicalTrials.gov (NCT00070278).
  
  
  RESULTS
  Between Jan 18, 2005, and Sept 28, 2007, we randomly allocated 831 participants; 207 received epirubicin and cyclophosphamide then paclitaxel; 208 were given paclitaxel then epirubicin and cyclophosphamide; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine; and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide. 828 patients were eligible for analysis. Median follow-up was 47 months (IQR 37-51). 207 (25%) patients had inflammatory or locally advanced disease, 169 (20%) patients had tumours larger than 50 mm, 413 (50%) patients had clinical involvement of axillary nodes, 276 (33%) patients had oestrogen receptor (ER)-negative disease, and 191 (27%) patients had HER2-positive disease. Addition of gemcitabine did not increase pCR: 70 (17%, 95% CI 14-21) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared with 71 (17%, 14-21) of 408 patients who received additional gemcitabine (p=0·98). Receipt of a taxane before anthracycline was associated with improved pCR: 82 (20%, 95% CI 16-24) of 406 patients who received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR compared with 59 (15%, 11-18) of 406 patients who received epirubicin and cyclophosphamide first (p=0·03). Grade 3 toxicities were reported at expected levels: 173 (21%) of 812 patients who received treatment and had full treatment details had grade 3 neutropenia, 66 (8%) had infection, 41 (5%) had fatigue, 41 (5%) had muscle and joint pains, 37 (5%) had nausea, 36 (4%) had vomiting, 34 (4%) had neuropathy, 23 (3%) had transaminitis, 16 (2%) had acute hypersensitivity, and 20 (2%) had a rash. 86 (11%) patients had grade 4 neutropenia and 3 (<1%) had grade 4 infection.
  
  
  CONCLUSIONS
  Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy does not improve pCR, sequencing chemotherapy so that taxanes are received before anthracyclines could improve pCR in standard neoadjuvant chemotherapy for breast cancer.
  
  
  BACKGROUND
  Cancer Research UK, Eli Lilly, Bristol-Myers Squibb.
authors.affiliation: University of Cambridge, Department of Oncology, Addenbrooke's Hospital, Hills Road, Cambridge, UK; National Institute for Health Research, Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Hills Road, Cambridge, UK; Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK. Electronic address: hme22@cam.ac.uk.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Earl
authors.affiliation: Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Vallier
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry, UK. Electronic address: L.Hiller@warwick.ac.uk.
authors.forename: Louise
authors.initials: L
authors.lastname: Hiller
authors.affiliation: Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Fenwick
authors.affiliation: Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Jennie
authors.initials: J
authors.lastname: Young
authors.affiliation: University of Melbourne, Shepparton, VIC, Australia.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Iddawela
authors.affiliation: National Institute for Health Research, Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Hills Road, Cambridge, UK; Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK; CancerResearch UK Cambridge Institute, Cambridge, UK.
authors.forename: Jean
authors.initials: J
authors.lastname: Abraham
authors.affiliation: Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Hughes-Davies
authors.affiliation: CancerResearch UK Cambridge Institute, Cambridge, UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gounaris
authors.affiliation: Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK; Peterborough and Stamford Hospitals NHS Foundation Trust and Cambridge University Hospital NHS Foundation Trust, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: McAdam
authors.affiliation: Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Houston
authors.affiliation: Royal Bournemouth Hospital, Castle Lane East, Bournemouth, UK.
authors.forename: Tamas
authors.initials: T
authors.lastname: Hickish
authors.affiliation: Department of Surgery, Royal Bournemouth Hospital, Castle Lane East, Bournemouth, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Skene
authors.affiliation: Nottingham City Hospital, Hucknall Road, Nottingham, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.affiliation: Dorset Cancer Centre, Poole Hospital NHS Trust, Poole, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Dean
authors.affiliation: Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Ritchie
authors.affiliation: Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Laing
authors.affiliation: Breast Oncology Unit, Thomas Guy House, Guys Hospital, St Thomas Street, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Harries
authors.affiliation: Department of Medical Oncology, St Bartholomew's Hospital, West Smithfield, London, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gallagher
authors.affiliation: Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Wishart
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry, UK.
authors.forename: Janet
authors.initials: J
authors.lastname: Dunn
authors.affiliation: National Institute for Health Research, Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Hills Road, Cambridge, UK; Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Provenzano
authors.affiliation: University of Cambridge, Department of Oncology, Addenbrooke's Hospital, Hills Road, Cambridge, UK; National Institute for Health Research, Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Hills Road, Cambridge, UK; Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK; CancerResearch UK Cambridge Institute, Cambridge, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008207:Lymphatic Metastasis; D008875:Middle Aged; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000008:administration & dosage; D016016:Proportional Hazards Models; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden; D006113:United Kingdom; D000093542:Gemcitabine
chemical_list: D014408:Biomarkers, Tumor; D003841:Deoxycytidine; D015251:Epirubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D000093542:Gemcitabine