BCIRG 001.

Methods	Randomised controlled trial Multi‐centre, international (20 countries participated) Computer‐generated randomisation lists balanced with a block size of 4, stratified according to institution, and number of involved nodes Accrual June 1997 to June 1999 Baseline patient and tumour characteristics well balanced
Participants	Female, premenopausal and postmenopausal Median age 49 years (23 to 70) Unilateral, operable breast cancer with clear surgical margins Axillary node positive: 100% HR positive: 76% in each treatment arm Exclusion of T4, N2/3, and M1 disease
Interventions	ARM 1: TAC × 6 21‐day cycles (doxorubicin 50 mg/m², cyclophosphamide 500 mg/m², docetaxel 75 mg/m²) ARM 2: FAC × 6 21‐day cycles (doxorubicin 50 mg/m², fluorouracil 500 mg/m², cyclophosphamide 500 mg/m²) Primary prophylaxis with G‐CSF not permitted. Tamoxifen 20 mg/d for 5 years given to all patients with ER‐ and/or PR‐positive tumours. Radiotherapy given as mandatory following breast‐conserving surgery
Outcomes	Primary endpoint: Disease‐free survival Secondary endpoints: Overall survival Toxicity Quality of life
Notes	Intention‐to‐treat analysis Median follow‐up: 124 months Clinical Trial Identifier: NCT00688740 (see clinicaltrials.gov/ct2/show/NCT00688740) Funded by Sanofi. Interim efficacy analysis done by a statistician as part of an independent DMC; final efficacy analysis completed by Sanofi’s statistician
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Block randomisation Quote: "computer‐generated randomisation lists were used for each stratum (centre and number of nodes) and were balanced with a block size of four"
Allocation concealment (selection bias)	Unclear risk	Quote: "Random assignment was done with an interactive voice response system and treatment allocation was immediately communicated to the investigator" Comment: methods not described in sufficient detail
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Unblinded Quote: "patients and treating physicians could not be masked to allocation because of the nature of the interventions"
Blinding of outcome assessment ‐ OS (detection bias)	Low risk	Quote: "investigators were not masked since the outcomes (relapse, death) were objective"
Blinding of outcome assessment ‐ DFS & Toxicity (detection bias)	Unclear risk	Chest radiography and mammography performed every year of follow‐up. Blood counts, general biochemical and clinical assessments each cycle and every 6 months for 5 years, then annually Comment: no independent assessment committee overseeing assessment of outcomes
Blinding of outcome assessment ‐ QoL (detection bias)	High risk	Assessed using European Organisation for Research and Treatment of Cancer QoL Questionnaire (QLQ‐C30, version 2.0) and the Breast‐cancer‐specific QLQ‐BR21 (version 1.0). Patients asked to complete both at baseline, before cycles 3 and 5, and at 1, 6, 12, and 24 months after last cycle
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Intention‐to‐treat efficacy and safety analyses were done as originally and prospectively defined in the study protocol" "fewer than 6% of participants... lost to 10‐year follow up" 43/745 in the TAC group and 39/746 in the FAC group
Selective reporting (reporting bias)	Low risk	Prespecified outcomes in Clinical Trials.gov record ‐ clinicaltrials.gov/ct2/show/NCT00688740 ‐ and in methods section of the trial publication the same. All outcomes reported in 5‐year follow‐up data. All outcomes (excluding quality of life) reported in 10‐year follow‐up data
Other bias	Low risk	Quote: "specific demographic, clinical, and molecular phenotypic characteristics of patients were well‐balanced between the group[s]"