Wildiers 2009b.

Methods	Accrual: 22 September 2005 to 18 July 2006 Multicentre, phase II randomised controlled trial conducted in Belgium Adjuvant therapy Median follow‐up: not reported
Participants	Age: mean 49.2 years (SD 10.0) (arm 1); mean 48.6 years (SD 8.5) (arm 2) 51% (in both arms) were > 50 years of age Node‐positive or other features of high risk as per St Gallen criteria Stage I: 28% (arm 1), 5% (arm 2); stage II: 51% (arm 1), 79% (arm 2); stage III: 21% (arm 1), 15% (arm 2) Axillary lymph node involvement: mean 2.8 (SD 5.3) (arm 1), mean 4.2 (SD 6.9) (arm 2) ER‐positive: 64% (arm 1), 79% (arm 2); PR‐positive: 69% (arm 1), 79% (arm 2) HER2‐positive: not reported Excluded: prior systemic anti‐cancer therapy or radiotherapy
Interventions	4‐arm study with 1 treatment comparison presented as part of Wildiers 2009a (labelled as "conventional" in trial publication) and the other treatment comparison presented in Wildiers 2009b (labelled as "dose‐dense" in trial publication). Arm 1 ('arm D' in the trial publication): docetaxel (75 mg/m²) every 2 weeks for 4 cycles followed by fluorouracil (375 mg/m²), epirubicin (75 mg/m²), cyclophosphamide (375 mg/m²) every 10 or 11 days for 4 cycles. Arm 2 ('arm C' in the trial publication): fluorouracil (375 mg/m²), epirubicin (75 mg/m²), cyclophosphamide (375 mg/m²) every 10 or 11 days for 4 cycles followed by docetaxel (75 mg/m²) every 2 weeks for 4 cycles. For both arms: pegfilgrastim allowed for secondary prophylaxis of febrile neutropenia or prolonged grade IV neutropenia
Outcomes	Primary outcome Number of participants in each arm who completed all intended cycles at any overall RDI of ≥ 85% of the global regimen. Dose intensity (percentage of reference value) was defined as the dose intensity achieved in arm 1 or 2 for a participant who received all intended doses with no cycle delay or dose reduction Secondary outcomes Incidence of dose delays (≥ 1 day) and dose reductions due to adverse events (haematological or non‐haematological) Toxicity and tolerability (e.g. neutropenia and febrile neutropenia, grade 3–4); toxicity assessed before each cycle using the NCI CTC version 3.0
Notes	Clinical trial registration record not found Funding considerations: study and trial publication were supported by an Amgen grant.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were randomized…(1:1:2:2)." Comment: this process involved stratified randomisation for age (< or > 50 years of age). Baseline characteristics were similar across groups and no major imbalances were noted (e.g. for age, white blood cell count, tumour parameters).
Allocation concealment (selection bias)	Low risk	Central allocation Quote: "…Randomisation of patients was carried out centrally via email or fax…"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Open‐label study. Participants in both groups received the same drugs though in different order. Therefore, it was unlikely that this would lead to material bias in participants' and physicians' behaviours even when unblinded.
Blinding of outcome assessment (detection bias) Toxicity and treatment adherence	Low risk	Study used formalised toxicity criteria (NCI CTC) and the limited number of toxicity outcomes reported (i.e. neutropenia) were based on objective measures from blood tests. Dose‐reductions/delays were based on this toxicity assessment. Given the types of toxicities assessed in this study, unblinding was unlikely to influence the physicians' assessments.
Incomplete outcome data (attrition bias) All outcomes	Low risk	92% (36/39) of participants in dose‐dense Doc → FEC (docetaxel → fluorouracil, epirubicin, cyclophosphamide) arm and 97% (38/39) of participants in dose‐dense FEC → Doc (fluorouracil, epirubicin, cyclophosphamide → docetaxel) arm completed the study. 3 withdrawals related to adverse events and 1 due to the physician’s decision.
Selective reporting (reporting bias)	Low risk	Could not identify clinical trial registry record (trial started recruitment in September 2005 and completed in July 2006). However, all outcomes reported in the Methods section had the corresponding results in the publication.
Other bias	Low risk	None identified

ANC: absolute neutrophil count; DFS: disease‐free survival; ER: oestrogen receptor; FACT‐B: Functional Assessment of Cancer Therapy – Breast Cancer; G‐CSF: granulocyte‐colony stimulating factor; HER2: human epidermal growth factor receptor 2; ITT: intention to treat; LVEF: left ventricular ejection fraction; NCI CTC: National Cancer Institute Common Toxicity Criteria for Adverse Events; OS: overall survival; pCR: pathological complete response; PR: progesterone receptor; RDI: relative dose intensity; SD: standard deviation.