BCIRG006.

Study characteristics
Methods	Accrual time: April 2001 to March 2004 Multicentre, international Baseline comparability: balanced
Participants	N = 3222 female Age: information about the age range of the patients not available; median age: 49 years Diagnosis: axillary node‐positive or high risk node‐negative breast cancer with HER2‐positive confirmed by central FISH Inclusion criteria: definitive surgery of the breast cancer (either mastectomy with axillary lymph node involvement assessment, or breast conserving surgery with axillary lymph node involvement assessment); Karnofsky Performance status index > 80%; normal cardiac, hepatic and renal function, normal values of the haemochrome; negative pregnancy test; normal audiology assessment Exclusion criteria: prior systemic anti‐cancer therapy or radiation therapy for breast cancer or prior anthracycline therapy, for any malignancy; bilateral invasive breast cancer; pregnancy; pre‐existing motor or sensory neurotoxicity; any T4 or N2 or known N3 or M1 breast cancer; cardiac diseases; other serious illness or medical condition (neurologic or psychiatric disorders, dementia or seizures, uncontrolled infection, active peptic ulcer, unstable diabetes mellitus, impaired hearing); past or current history of neoplasm other than breast carcinoma (except for: curatively treated non‐melanoma skin cancer, in situ carcinoma of the cervix, other cancer curatively treated and with no evidence of disease for at least 10 years); current therapy with any hormonal agent such as Raloxifene, Tamoxifen, or other selective ER modulators, with corticosteroids, with ovarian hormonal replacement therapy; definite contraindications for the use of corticosteroids; and concurrent treatment with other experimental drugs or with any other anti‐cancer therapy Note: 6% of patients had a tumour diameter larger than 5 cm; 9% had more than 10 nodes affected by the disease HER2‐positive: 100%
Interventions	Adjuvant setting Arm A (AC→T) (N = 1073): doxorubicin plus cyclophosphamide (60mg/sm and 600mg/sm, every three weeks, four cycles) followed by docetaxel (100mg/sm, every three weeks, 4 cycles) Arm B (AC→TH) (N = 1074): doxorubicin plus cyclophosphamide (60mg/sm and 600mg/sm, every three weeks, four cycles) followed by docetaxel (100mg/sm, every three weeks, four cycles) plus trastuzumab (weekly, 52 cycles). Trastuzumab doses are not reported anywhere Arm C (TCH) (N = 1075): docetaxel plus carboplatin (75mg/sm and 75 mg/sm, every three weeks, six cycles) plus trastuzumab (weekly, 52 cycles). Trastuzumab doses are not reported anywhere Other adjuvant therapies: hormonal therapy for five years after chemotherapy in patients with hormone‐receptor‐positive tumours
Outcomes	Primary: DFS Secondary: OS; adverse events; and QoL
Notes	Median follow‐up: 65 months Third interim analysis After the first interim analysis 17 patients (1.6%) in the observation group switched to trastuzumab Not reported if it is a multicentre study
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Patients were prospectively stratified by number of positive lymph nodes (0, 1 to 3 versus 4+) and hormone‐receptor status
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not reported
Selective reporting (reporting bias)	High risk	The study protocol is available but largely incomplete (http://clinicaltrials.gov/ct2/show/NCT00021255?term=bcirg006&rank=1). The results have been reported only as meeting abstracts or presentations. It is likely that not all the prespecified outcomes have been reported