ICCG 2005.

Methods	Randomised controlled trial Number of women randomised: 281 (143 high dose, 138 standard dose) Number of women analysed: 279 Number of women not analysed: 2 (lost to follow‐up) Number of breaches of protocol/failure to receive prescribed treatment: 68 (30 in high‐dose arm, due to toxicity (5), centre error (1), refusal of treatment (10), recurrence (2), death (2), other reasons (10); 38 in control arm, due to toxicity (13), intercurrent illness (2), centre error (2), refusal of treatment (2), recurrence (3), death (2), other reasons (14)) Intention‐to‐treat analysis: 279 women analysed by intention‐to‐treat Number of centres: 8 Source of funding: Cancer Research UK, Pharmacia, Amgen Years: 1993 ‐ 2001 Countries: UK, Italy, Spain, Australia
Participants	INCLUDED: Women with primary breast cancer, T1 ‐ T4, aged 60 or less, with at least 4 positive axillary nodes after complete surgical resection and no metastatic disease on bone scan EXCLUDED: Women with overt metastatic disease or abnormal bone marrow, hepatic or renal function or WHO performance status > 1
Interventions	All women had 1 3‐week cycle of FEC (cyclophosphamide 600 mg/m², epirubicin 50 mg/m², fluorouracil 600 mg/m²) followed by 2 4‐week cycles of FEC (as above but 2 doses per cycle) Women randomised to the HDC arm then received cyclophosphamide 6 gm/m², epirubicin 50 mg/m² and carboplatin 800 mg/m² with PBSC support Women randomised to the control arm had a further 3 4‐week cycles of FEC as above Women who had had conservative surgery and some who had had a mastectomy received radiotherapy. All received tamoxifen for 5 years
Outcomes	Disease‐free survival Overall survival Toxicity
Notes	Power calculation: 300 participants would show an improvement from 30% ‐ 45% in 5‐year survival with 80% power (α = 0.05) Accrual failed following early reports from other trials Data immature: 5‐year data in our tables based on 5‐year estimates by trialists at median 50 months follow‐up
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Centres randomised their patients by telephoning the ICCG Data Centre. The randomisation method used was adapted minimisation, where the weighted probabilities ensure a random component to the allocation. Stratification factors were centre, menopausal status and number of axillary nodes involved (4–9, 10+)".
Allocation concealment (selection bias)	Low risk	By telephone to central data centre
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Blinding not mentioned; however this appears unlikely to influence primary review outcomes
Incomplete outcome data (attrition bias) All outcomes	Low risk	279/281 (99%) randomised women included in analysis
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Low risk	No other potential bias identified