ADEBAR.

Methods	Randomised controlled trial Multi‐centre (Germany), open‐label Stratified randomisation, according to metastatic axillary lymph node involvement, hormone receptor status, and timing of adjuvant radiotherapy Accrual September 2001 to May 2005 Baseline patient and tumour characteristics appear well balanced
Participants	Female, premenopausal and postmenopausal Aged 18 to 70 years, median age 55 years (25 to 71) Operable breast cancer with clear surgical margins Axillary node positive: 100% (pN2‐3m ≥ 4 metastatic lymph nodes) Exclusion of metastatic disease or inflammatory breast cancer HR positive: 75% in each treatment arm ECOG < 2
Interventions	ARM 1 (EC‐Doc): EC × 4 21‐day cycles (epirubicin 90 mg/m², cyclophosphamide 600 mg/m²) followed by Doc × 4 21‐day cycles (docetaxel 100 mg/m²) ARM 2 (FEC): FEC × 6 28‐day cycles (fluorouracil 500 mg/m² and epirubicin, 60 mg/m² IV on days 1 and 8, cyclophosphamide 750 mg/m² PO on days 1 to 14) Tamoxifen for 5 years for all patients who are ER and/or PR positive. Tamoxifen could be substituted with exemestane, letrozole, or anastrozole in postmenopausal patients with contraindications or who have tolerability issues with tamoxifen. Patients < 40 years of age with restart of menstrual bleeding within 6 months of completion of cytostatic treatment or with premenopausal hormone levels received goserelin 3.6 mg subcutaneously every 4 weeks for 2 years All patients received adjuvant radiotherapy either following completion of chemotherapy or intermittently after completion of 50% of chemotherapy Granulocyte colony‐stimulating factor could be used as secondary prophylaxis in cases of febrile neutropenia
Outcomes	Primary endpoint: Recurrence‐free survival, in 2016 revised to iDFS in line with Standardized Definitions for Efficacy End Points (STEEP), where DFS referred to all invasive ipsilateral, regional, contralateral, and distant disease recurrences, second primary tumours, and death from any cause as events, with exclusion of all non‐invasive in situ cancer events Secondary endpoints: Overall survival Toxicity, assessed according to the Common Toxicity Criteria of the National Cancer Institute version 2.0 Quality of life, assessed using the European Organization for Research and Treatment for Cancer Quality of Life Core Questionnaire (EORTC QLQ‐C30) and the Breast Cancer‐Specific Module (EORTC QLQ BR23)
Notes	Median follow‐up: 60.6 months in EC‐Doc and 59.5 months in FEC120 Clinical Trial Identifier: NCT00047099 (see clinicaltrials.gov/ct2/show/record/NCT00047099) Trial supported by Sanofi‐Aventis, Astra‐Zeneca, Amgen, Wilex, and Novartis Trial was stopped prematurely in 3.7% of participants in the EC‐Doc arm and in 8.0% in the FEC120 arm due to toxicity (P = 0.0009) For this review update, the hazard ratio for OS was derived using Method 3 (Tierney 2007). Outcome data and numbers of participants included in the analysis for DFS were provided by trial authors and the trial publication (in 2016), and the HR was derived using Method 7 (Tierney 2007)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Stratified randomisation based on prognostic variables, including metastatic axillary lymph node involvement, hormone receptor status, and timing of radiotherapy
Allocation concealment (selection bias)	Low risk	Trial co‐ordinated by a central office Comment: allocation concealment probably done
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Open‐label
Blinding of outcome assessment ‐ OS (detection bias)	Low risk	Assessment of overall survival unlikely to be influenced by no or incomplete blinding
Blinding of outcome assessment ‐ DFS & Toxicity (detection bias)	Unclear risk	Toxicity evaluated using NCI CTC and ECG before each cycle of chemotherapy and 28 days after chemotherapy. ECG also performed 6 months after chemotherapy and whenever indicated. DFS assessment not reported Comment: no apparent involvement of an independent adjudication committee reassessing outcomes
Blinding of outcome assessment ‐ QoL (detection bias)	High risk	Measured using QLQ‐C30 and QLQ‐BR23. Quality of life assessed at baseline, before each course of chemotherapy, and at 4 weeks, at 6 weeks, and then at 6 months after completion of chemotherapy
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	92% (689/748) of patients in the taxane arm and 91% (675/745) in the comparator arm included in the efficacy analysis. Reasons provided and appeared to be similar across groups
Selective reporting (reporting bias)	Low risk	Prespecified outcomes in Clinical Trials.gov record reported across various publications, including QoL data in the 2014 unpublished manuscript (clinicaltrials.gov/ct2/show/record/NCT00047099). Outcomes specified in methods section and results section of trial publications consistent
Other bias	Low risk	No other sources of bias identified Quote: "Patient characteristics after randomization were well‐balanced between the two treatment arms"