E2197.

Methods	Randomised controlled trial, conducted in USA Randomisation method not specified; stratified according to nodal, hormone receptor, and menopausal status Accrual July 1998 to January 2000 Baseline patient and tumour characteristics well balanced
Participants	Female, premenopausal and postmenopausal following surgery for operable breast cancer Median age 51 years Following complete surgical excision of the primary tumour 66% lymph node negative with T > 1 cm, 34% node positive (1 to 3 N+) HR positive: approximately 68% either ER or PR positive Excluded locally advanced bilateral or metastatic cancer
Interventions	ARM 1 (AT): AT × 4 21‐day cycles (doxorubicin 60 mg/m², docetaxel 60 mg/m²) ARM 2 (AC): AC × 4 21‐day cycles (doxorubicin 60 mg/m², cyclophosphamide 600 mg/m²) Tamoxifen 20 mg/d for 5 years given to all patients with ER and/or PR positive. In June 2005, protocol changed to allow women to switch from tamoxifen to aromatase inhibitors Radiotherapy given after chemotherapy to all patients following breast‐conserving surgery and to select high‐risk patients following mastectomy at physician’s discretion
Outcomes	Primary endpoint: Disease‐free survival Secondary endpoints: Overall survival Toxicity
Notes	Intention‐to‐treat analysis Median follow‐up: 11.5 years 97.8% of randomised patients eligible and analysable Clinical Trial Identifier: NCT00003519 (see clinicaltrials.gov/ct2/show/NCT00003519) Funded by Department of Health and Human Services and National Institutes of Health (USA). Study co‐ordinated by ECOG For the review update, data on numbers of events and participants per treatment arm for OS and DFS provided by trial authors
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were randomly assigned to arm A or B… Treatments were assigned using permuted blocks within strata"
Allocation concealment (selection bias)	Unclear risk	Quote: "treatments were assigned using permuted blocks within strata with dynamic balancing within main institutions and their affiliate networks"
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	No information provided in trial publication
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	Physical examinations every 3 months for 2 years, then every 6 months for the next 3 years. Mammography and blood testing performed annually Quote: "patients were seen before each course of chemotherapy for physical and hematologic evaluations" Comment: no independent assessment committee overseeing outcome assessments
Incomplete outcome data (attrition bias) All outcomes	Low risk	Of 2952 patients randomised, 70 considered ineligible with reasons provided. 35 participants excluded from both treatment groups for similar reasons Quote: "when all patients, eligible and ineligible, were analysed. Results for this analysis were similar to the results for patients classified as eligible"
Selective reporting (reporting bias)	Low risk	All outcomes reported as specified in ClinicalTrials.gov (clinicaltrials.gov/ct2/show/NCT00003519). Methods and results sections of the trial publication also consistent
Other bias	Low risk	Quote: "patient characteristics were well balanced between treatment groups"