Methods

Randomised controlled trial
Multi‐centre (Germany), open‐label
Stratified randomisation, according to metastatic axillary lymph node involvement, hormone receptor status, and timing of adjuvant radiotherapy
Accrual September 2001 to May 2005
Baseline patient and tumour characteristics appear well balanced

Participants

Female, premenopausal and postmenopausal

Aged 18 to 70 years, median age 55 years (25 to 71)
Operable breast cancer with clear surgical margins
Axillary node positive: 100% (pN2‐3m ≥ 4 metastatic lymph nodes)
Exclusion of metastatic disease or inflammatory breast cancer
HR positive: 75% in each treatment arm
ECOG < 2

Interventions

ARM 1 (EC‐Doc):
EC × 4 21‐day cycles (epirubicin 90 mg/m², cyclophosphamide 600 mg/m²) followed by Doc × 4 21‐day cycles (docetaxel 100 mg/m²)

ARM 2 (FEC):
FEC × 6 28‐day cycles (fluorouracil 500 mg/m² and epirubicin, 60 mg/m² IV on days 1 and 8, cyclophosphamide 750 mg/m² PO on days 1 to 14)

Tamoxifen for 5 years for all patients who are ER and/or PR positive. Tamoxifen could be substituted with exemestane, letrozole, or anastrozole in postmenopausal patients with contraindications or who have tolerability issues with tamoxifen. Patients < 40 years of age with restart of menstrual bleeding within 6 months of completion of cytostatic treatment or with premenopausal hormone levels received goserelin 3.6 mg subcutaneously every 4 weeks for 2 years

All patients received adjuvant radiotherapy either following completion of chemotherapy or intermittently after completion of 50% of chemotherapy

Granulocyte colony‐stimulating factor could be used as secondary prophylaxis in cases of febrile neutropenia

Outcomes

Primary endpoint:

• Recurrence‐free survival, in 2016 revised to iDFS in line with Standardized Definitions for Efficacy End Points (STEEP), where DFS referred to all invasive ipsilateral, regional, contralateral, and distant disease recurrences, second primary tumours, and death from any cause as events, with exclusion of all non‐invasive in situ cancer events

Secondary endpoints:

• Overall survival

• Toxicity, assessed according to the Common Toxicity Criteria of the National Cancer Institute version 2.0

• Quality of life, assessed using the European Organization for Research and Treatment for Cancer Quality of Life Core Questionnaire (EORTC QLQ‐C30) and the Breast Cancer‐Specific Module (EORTC QLQ BR23)

Notes

Median follow‐up: 60.6 months in EC‐Doc and 59.5 months in FEC120
Clinical Trial Identifier: NCT00047099 (see clinicaltrials.gov/ct2/show/record/NCT00047099)

Trial supported by Sanofi‐Aventis, Astra‐Zeneca, Amgen, Wilex, and Novartis

Trial was stopped prematurely in 3.7% of participants in the EC‐Doc arm and in 8.0% in the FEC120 arm due to toxicity (P = 0.0009)
For this review update, the hazard ratio for OS was derived using Method 3 (Tierney 2007). Outcome data and numbers of participants included in the analysis for DFS were provided by trial authors and the trial publication (in 2016), and the HR was derived using Method 7 (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified randomisation based on prognostic variables, including metastatic axillary lymph node involvement, hormone receptor status, and timing of radiotherapy

Allocation concealment (selection bias)

Low risk

Trial co‐ordinated by a central office

Comment: allocation concealment probably done

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Toxicity evaluated using NCI CTC and ECG before each cycle of chemotherapy and 28 days after chemotherapy. ECG also performed 6 months after chemotherapy and whenever indicated. DFS assessment not reported

Comment: no apparent involvement of an independent adjudication committee reassessing outcomes

Blinding of outcome assessment ‐ QoL (detection bias)

High risk

Measured using QLQ‐C30 and QLQ‐BR23. Quality of life assessed at baseline, before each course of chemotherapy, and at 4 weeks, at 6 weeks, and then at 6 months after completion of chemotherapy

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

92% (689/748) of patients in the taxane arm and 91% (675/745) in the comparator arm included in the efficacy analysis. Reasons provided and appeared to be similar across groups

Selective reporting (reporting bias)

Low risk

Prespecified outcomes in Clinical Trials.gov record reported across various publications, including QoL data in the 2014 unpublished manuscript (clinicaltrials.gov/ct2/show/record/NCT00047099). Outcomes specified in methods section and results section of trial publications consistent

Other bias

Low risk

No other sources of bias identified
Quote: "Patient characteristics after randomization were well‐balanced between the two treatment arms"

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]"

Methods

Randomised controlled trial
Open‐label, multi‐centre
Randomisation method not specified, stratified to participating centre, number of nodes 1 to 3 or 4+ and age < 50 or ≥ 50
Randomisation 1:1:2:2
Accrual June 1998 to June 2001
Baseline patient and tumour characteristics well balanced

Participants

Female, premenopausal and postmenopausal
Median age 49 years (21 to 70)
Histologically proven, following surgery for operable, node‐positive breast cancer (T1 to T3)
Axillary node positive: 100%
HR positive: 76%
T4 tumours and distant metastases excluded

Interventions

ARM 1a (A‐CMF):
A × 4 21‐day cycles (doxorubicin 75 mg/m²), then CMF × 3 28‐day cycles (cyclophosphamide 100 mg/m² days 1 to 14 orally, methotrexate 40 mg/m² days 1 and 8, 5‐FU days 1 and 8)

ARM 1b (AC‐CMF):
AC × 4 21‐day cycles (doxorubicin 60 mg/m², cyclophosphamide 600 mg/m²), then CMF × 3 28‐day cycles (as in arm 1a)

ARM 2 (A‐T‐CMF):
A × 3 21‐day cycles (doxorubicin 75 mg/m²), then T × 3 21‐day cycles (docetaxel 100 mg/m²), then CMF × 3 (as in arm 1a)

ARM 3 (AT‐CMF):
AT × 4 21‐day cycles (doxorubicin 50 mg/m², docetaxel 75 mg/m²), then CMF × 3 (as in arm 1a)

Tamoxifen 20 mg/d for 5 years for ER‐ and/or PR‐positive patients

Protocol amended in 2004 to allow AI in postmenopausal women and ovarian suppression in premenopausal women

Radiotherapy when indicated following chemotherapy

No primary G‐CSF permitted

Outcomes

Primary endpoint:

• Disease‐free survival, defined as interval from the date of randomisation to the date of local, regional, or metastatic relapse or second primary cancer or death for any cause

Secondary endpoints:

• Overall survival, defined as time from date of randomisation to last follow‐up or death from any cause

• Toxicity

Notes

Median follow‐up: 121 months (max 153 months)

Clinical Trial Identifier: NCT00174655 (see clinicaltrials.gov/ct2/show/NCT00174655)
Funded by Sanofi‐Aventis; trial conducted by BIG. Analyses done entirely independent of Sanofi‐Aventis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "patients were randomly assigned"

Treatment allocation done through a "minimization procedure with stratification for centre…"

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "treatment allocation was done centrally by use of a minimisation procedure"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Quote: "clinical, haematological and biochemical assessments required before each cycle, including assessing of toxic effects according to the NCI CTC version"

Follow‐up visits every 3 months for first 2 years, every 6 months for years 3 to 5, then once a year

Comment: no independent adjudication committee involved in these assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Results analysed by intention‐to‐treat

Quote: "overall, 2.8% of patients were lost to follow‐up, with equal percentages from control and docetaxel treatment groups"

Selective reporting (reporting bias)

Low risk

All outcomes reported as specified in the ClinicalTrials.gov record (see clinicaltrials.gov/ct2/show/NCT00174655)

Other bias

Low risk

No other sources of bias identified
Quote: "baseline characteristics of enrolled patients were well balanced"

Methods

Randomised controlled trial
Multi‐centre, international, open‐label
Central randomisation by random numbers tables
Accrual April 1997 to January 2004
Baseline patient and tumour characteristics well balanced excluding tumour size

Participants

Female, premenopausal and postmenopausal
Aged 18 to 70 years. Median age not reported
Operable, unilateral breast cancer, completely resected with clear surgical margins
Axillary node positive: 100% (3 or more lymph nodes)
Exclusion of metastatic disease

HR positive: ER positive: 89% to 90% in each treatment arm

Interventions

ARM 1 (E‐CMF)
E × 4 21‐day cycles (epirubicin 100 mg/m²) followed by CMF × 4 28‐day cycles (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m²)

ARM 2 (Paclitaxel‐EV)
Paclitaxel × 4 21‐day cycles (paclitaxel 175 mg/m²) followed by EV × 4 21‐day cycles (epirubicin 75 mg/m², vinorelbine 25 mg/m²)

Tamoxifen 20 mg/d for 5 years given to all patients who were ER and/or PR positive
Radiotherapy given as mandatory following breast‐conserving surgery, and used after mastectomy according to local guidelines

Outcomes

Primary endpoint:

• Overall survival

Secondary endpoints:

• Relapse‐free survival

• Toxicity

Notes

Median follow‐up: 102 months
No trial record identified
Funding: National Research Council and University of Research Italian Minister
In the review update, O‐E and V for OS and DFS derived using Method 3 (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "randomization... was based on random number tables"

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "randomization was carried out by telephone from a central office of the coordinating center"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Clinical examinations every 3 months for 2 years, every 6 months for years 3 to 5, and annually thereafter. Chest X‐ray, liver ultrasound, and/or CT abdomen and a bone scan repeated annually during first 5 years of follow‐up. CBC and biochemistry repeated before each chemotherapy cycle. Toxicity scored using WHO criteria

Comment: no involvement of an independent adjudication committee for outcome assessment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All 244 patients randomised accounted for in results (122 per treatment arm)

Selective reporting (reporting bias)

Low risk

All outcomes reported in the methods section included in the results section of the trial publication. No trial registry record or protocol found

Other bias

Unclear risk

Quote: "treatment arms were well balanced with respect to major pretreatment variables, excluding tumour size (more patients in the E‐CMF arm were affected by tumours < 2 cm in size, P = 0.01)"

Methods

Randomised controlled trial
Multi‐centre, international
Randomisation stratified according to menopausal status, hormone receptor status, and HER2 status
Accrual May 2002 to July 2010
Baseline patient and tumour characteristics well balanced
2 × 2 factorial design

Participants

Female, premenopausal and postmenopausal
18 years of age and older
Operable breast cancer with clear surgical margins
90% of participants node negative; 10% with 1 to 3 positive axillary lymph nodes
Exclusion of metastatic disease

ER positive: 64% to 65% in each treatment arm

Interventions

Arm 1:
AC × 4 21/14‐day cycles (doxorubicin 60 mg/m², cyclophosphamide 600 mg/m²)

Arm 2:
AC × 6 21/14‐day cycles (as in arm 1)

Arm 3:
T × 4 21/14‐day cycles (paclitaxel 80 mg/m² when given weekly (for 12 or 18 weeks – 3 weeks equalling 1 cycle), or paclitaxel 175 mg/m² every 2 weeks)

Arm 4:
T × 6 21/14‐day cycles (as in arm 3)

Tamoxifen recommended for patients with hormone receptor‐positive tumours
Radiotherapy given as mandatory following breast‐conserving surgery, and at the discretion of physicians post mastectomy
After 2005, trastuzumab recommended to women with HER2‐positive tumours

Outcomes

Primary endpoint:

• Relapse‐free survival, as defined by STEEP (Standardized Definitions of Efficacy Endpoints) criteria, measured from study entry until local recurrence, distant relapse, or death without relapse, whichever occurred first

Secondary endpoints:

• Overall survival, defined as from study entry until death from any cause

• Toxicity, assessed using National Cancer Institute Common Toxicity Criteria (version 4.0)

• Quality of life as part of a companion trial

• Induction of menopause as part of a companion trial

Notes

Median follow‐up: approximately 73 months
Clinical Trial Identifier: NCT00041119 (see clinicaltrials.gov/ct2/show/record/NCT00041119)
Trial supported by grants from the National Cancer Institute (USA)
For the review update, 2014 full‐text publications reported HRs for RFS and OS

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "randomization used a permuted block design with fixed block size of 12 allocated patients with equal probability to one of the four possible treatment arms. Randomization was stratified by menopausal status, hormone receptor status, and after October 2005, HER2 status"

Allocation concealment (selection bias)

Low risk

Centralised system (CALGB online Patient Registration system where randomisation accepted only through CALGB main member/selected institutions using the online patient registration system)

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label study

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

Patients followed up every 6 months for the first 2 years and annually thereafter for 15 years. Adverse events reported using NCI common toxicity criteria

Comment: no apparent involvement of an independent adjudication committee for outcome assessment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "efficacy analyses used an intention‐to‐treat approach" and "at the time of reporting, 45 patients (1%) were lost to follow‐up, and 57 patients (2%) had withdrawn consent to receive follow‐up"

Selective reporting (reporting bias)

Unclear risk

All prespecified outcomes in Clinical Trials.gov record reported (clinicaltrials.gov/ct2/show/record/NCT00041119). Trial publication describes a companion trial on QoL and induction of menopause that has yet to be reported

Other bias

Low risk

No other sources of bias identified

Methods

Randomised controlled trial
Open‐label, multi‐centre (516 sites), USA
Central randomisation, stratified for number of positive axillary nodes
Accrual May 1994 to April 1999
No significant imbalance between groups
3 × 2 factorial design

Participants

Female, premenopausal and postmenopausal
Median age not provided
Operable breast cancer with clear surgical margins
Axillary node positive: 100%
HR positive: ER positive 59%; ER or PR positive 66%

Interventions

ARM 1 (AC‐T):
AC × 4 21‐day cycles (doxorubicin (60, 75, or 90 mg/m²), cyclophosphamide 600 mg/m²) followed by T × 4 21‐day cycles (paclitaxel 175 mg/m² over 3 hours)

ARM 2 (AC):
AC × 4 21‐day cycles (doxorubicin (60, 75, or 90 mg/m², cyclophosphamide 600 mg/m²) followed by NO paclitaxel

Tamoxifen 20 mg/d for 5 years given to all patients with ER and/or PR positive
Radiotherapy following chemotherapy required for all patients after breast‐conserving surgery.
Primary prophylaxis with G‐CSF and ciprofloxacin given routinely with doxorubicin 90 mg/m², but only as secondary prophylaxis for dosing of 60 or 75 mg/m² doxorubicin

Outcomes

Primary endpoint:

• Disease‐free survival

Secondary endpoints:

• Overall survival

• Toxicity

Notes

Median follow‐up: 69 months; minimum follow‐up: 12 months
98.5% of participants eligible/available for analysis

Trial protocol available (see cancer.gov/about‐cancer/treatment/clinical‐trials/search)

National Cancer Institute (USA) sponsored the trial. Bristol‐Myers Squibb provided a grant to CALGB for statistical support and for data updates

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "patients were randomly assigned at the statistical centre with equal probability to one of six treatment combinations using a stratified random permuted block design"

Allocation concealment (selection bias)

Low risk

Quote: "randomly assigned at the Statistical Centre"

Comment: central allocation probably took place

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Mammogram and chest X‐ray obtained at entry and yearly thereafter. CBC obtained twice weekly. Evaluation every 3 months during year 1, twice annually for next 2 years, then annually thereafter

Comment: no independent adjudication committee involved in outcome assessments

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "although 3170 women were randomised, 49 patients never received any protocol therapy, usually because the patient withdrew consent. Because no information is available on the treatment the cancelled patients received, their disease‐free survival, or their overall survival, all analyses in this article are based on the remaining 3,121 patients"

Selective reporting (reporting bias)

Low risk

All outcomes reported in the trial publication as outlined in the trial registry record (see cancer.gov/about‐cancer/treatment/clinical‐trials/search)

Other bias

Low risk

Quote: "there was no significant imbalances in the randomizations"

Methods

Randomised controlled trial with partial 2 × 2 factorial design
Multi‐centre (36 centres in 5 European countries)
Randomisation with computer‐generated permuted blocks. Stratified according to institution and intention‐to‐treat with tamoxifen
Accrual August 1997 to December 2005
Baseline patient and tumour characteristics well balanced
Randomised 1:1

Participants

Female, postmenopausal
Complete tumour excision with clear surgical margins
Axillary node positive: 100%
Exclusion of metastatic disease

HR positive: 77% to 78% in each treatment arm

Interventions

ARM 1 (EPI)
EPI × 6 28‐day cycles (epirubicin 50 mg/m² days 1 and 8)

ARM 2 (EPI‐Doc)
EPI × 3 28‐day cycles (epirubicin 50 mg/m² days 1 and 8) followed by Doc × 3 21‐day cycles (docetaxel 100 mg/m² on day 1)

Tamoxifen 20 mg/d for 5 years given to women with ER‐ and/or PR‐positive tumours; some centres randomising to administer concurrently or sequential to chemotherapy

Use of prophylactic G‐CSFs and antibiotics recommended in the case of febrile neutropenia

Outcomes

Primary endpoint:

• Disease‐free survival

Secondary endpoints:

• Overall survival

• Breast cancer‐free survival

• Metastasis‐free survival

• Quality of life

Notes

Intention‐to‐treat analysis
Median follow‐up 64.7 months
Clinical Trial Identifier: ISRCTN89772270 (see isrctn.com/ISRCTN89772270)

Supported by unrestricted educational trials from Pfizer and Sanofi‐Aventis, and docetaxel provided by Sanofi‐Aventis
For the review update, O‐E and V for OS and DFS derived using Method 3 (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "computer generated permuted blocks were used"

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "independent random assignment was by telephone/fax to the International Collaborative Cancer Group Data centre, London, England"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Toxicity assessed according to NCI CTC version 2. Assessed after each chemotherapy cycle, with follow‐up every 3 months for first year, every 4 months for second year, every 6 months for years 3 and 4, and annually thereafter until minimum 10 years. No other information on outcome assessment included in the report

Comment: no apparent involvement of an independent adjudication committee; therefore this domain assessed as having 'unclear' risk

Blinding of outcome assessment ‐ QoL (detection bias)

High risk

Measured by QLQ‐C30 and QLQ‐BR23. Assessed at baseline and at 9 months, 2 years, and 5 years after random assignment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "only one patient withdrew consent for additional treatment and follow‐up (in the EPI‐DOC arm) and approximately 3% were classified as lost to follow‐up; all patients were included in the intention‐to‐treat analyses"

Selective reporting (reporting bias)

Low risk

Outcomes specified in the methods section and reported in the results section consistent. Primary and secondary outcomes not provided at time of registration on ISRCTN

Other bias

Low risk

Quote: "baseline clinicopathologic characteristics of patients were evenly balanced between treatment groups"

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"

Methods

Randomised controlled trial
Open‐label, multi‐centre (31 European centres), international
Central randomisation stratified by centre, tumour size, tumour grade, and hormone receptor status
Randomised at 1:1:1
Accrual November 1996 to May 2002

Participants

Female, premenopausal and postmenopausal
Aged 18 to 70 years; median age range not reported in 2009 article
Untreated, unilateral operable breast cancer (T2 to 3, N0 to 1, M0)
Node‐positive (47%) or ‐negative (53%) breast cancer
HR positive: ER/PR positive: around 68% in each treatment arm 1 and 2
Excluded locally advanced metastatic or bilateral cancer

Interventions

ARM 1 (Surgery‐A‐CMF):
A × 4 21‐day cycles (doxorubicin 75 mg/m²) followed by CMF × 4 28‐day cycles (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m²)

ARM 2 (Surgery‐AT‐CMF):
AT × 4 21‐day cycles (doxorubicin 60 mg/m², paclitaxel 200 mg/m²) followed by CMF × 4 28‐day cycles (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m²)

ARM 3 (AT‐CMF‐Surgery):
Neoadjuvant AT‐CMF dosed as per arm 2 followed by surgery

All patients undergoing either mastectomy or breast‐conserving surgery with clear margins. All patients who received breast‐conserving surgery undergoing postoperative irradiation. All patients with pT4 disease given chest wall irradiation following mastectomy

Tamoxifen 20 mg/d for 5 years to all patients before June 2000, then protocol amended and limited to ER‐ and/or PR‐positive group

Outcomes

Primary endpoint:

• Disease‐free survival (freedom from progression)

Secondary endpoints:

• Overall survival

• Toxicity

• Response rate (CR, PR, SD)

• Rate of breast‐conserving therapy

• Rate of pathological nodal status to identify pretreatment variables likely to predict clinical and pathological response to neoadjuvant chemotherapy

Notes

Only arms 1 and 2 used in this review

Median follow‐up: 43 months

Trial identifier not retrieved
Supported by an “unrestricted grant from Bristol‐Myers Squibb”. Data collection, analysis, and interpretation independent of sponsors and completed by ECTO Group

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "treatment was allocated centrally using a minimization algorithm"

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "treatment was allocated centrally"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Assessed by physical exam before each cycle of chemotherapy and 2, 6, 12, 18, and 24 months after completion of treatment, then yearly thereafter. Mammography performed yearly after completion of radiotherapy. Cardiac function assessed by physical examination, ECG, and measurement of LVEF at baseline, at completion of chemotherapy, and every 6 months for 2 years followed by yearly

Comment: no involvement of an independent assessment committee

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "all randomly assigned patients were included in the intention‐to‐treat analyses"

Selective reporting (reporting bias)

Low risk

All outcomes in the trial publication reported as specified in ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00003013?term=european+cooperative+trial+in+operable+breast+cancer&rank=1). All prespecified outcomes in the methods section reported in the results section of the trial publication

Other bias

Low risk

Quote: "baseline characteristics were well balanced between the three treatment arms"

Methods

Randomised controlled trial
Multi‐centre, international
Central randomisation, using a minimisation procedure with centre, pT and pN category, planned number of chemotherapy cycles, age as strata
Open‐label study
Accrual July 2003 to April 2011
Baseline tumour characteristics well balanced although slight imbalance in distribution of comorbidities (e.g. no comorbidity in 7% and 13%, and previous cerebrovascular disease in 1% and 6% in docetaxel and CMF groups, respectively)

Participants

Female, postmenopausal
Aged 65 to 79 years (median 70)
Operable breast cancer with clear surgical margins
Axillary node positive or high risk node negative
ECOG performance status ≤ 2
HR positive: ER positive/PgR positive: 74% to 76% in each treatment group
Exclusion of metastatic disease

Interventions

ARM 1 (CMF)
CMF × 4 to 6 28‐day cycles (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m² on days 1 and 8)

ARM 2 (Doc)
Doc × 4 to 6 28‐day cycles (docetaxel 35 mg/m² on days 1, 8, and 15)
6 cycles planned for tumours < 10% positive for both ER and PgR, 4 cycles for those with ER or PR ≥ 10%

Tamoxifen or aromatase inhibitors according to standard schedules given after chemotherapy to patients with tumour positive for ER/PR in at least 1% of cells

Patients with HER2‐positive tumour given adjuvant trastuzumab for 1 year after chemotherapy. Radiotherapy performed when indicated after the end of chemotherapy and within 6 months after surgery

Outcomes

Primary endpoint:

• Disease‐free survival, defined as interval between randomisation and locoregional or distant relapse or contralateral invasive breast cancer or second primary invasive non‐breast cancer or ipsilateral or contralateral in situ ductal carcinoma or death without cancer, whichever occurred first

Secondary endpoints:

• Toxicity, using National Cancer Institute Common Toxicity Criteria (NCI CTC) version 2.0

• Compliance

• Quality of life, using EORTC C‐30 and BR‐23 questionnaires

• Overall survival

Notes

Median follow‐up 70 months (95% confidence interval 66 to 73 months)
Clinical Trial Identifier: NCT00331097 (see clinicaltrials.gov/ct2/show/NCT00331097)

Sponsored by the Clinical Trials Unit of the National Cancer Institute of Naples

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “randomization was carried out centrally at the Clinical Trials Unit of the NCI Naples, with a computer‐based minimization procedure…”

Allocation concealment (selection bias)

Low risk

Central randomisation

Quote: “…clinicians contacted the Clinical Trials Unit by telephone or by fax”

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label study

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

Assessment including clinical visits with biochemistry and haematological tests every 3 months for 3 years, then every 6 months for 2 years, then annually for 5 years. Chest X‐ray, ultrasonography, and mammography included. Treatment toxicity graded according to National Cancer Institute Common Toxicity Criteria

Comment: no involvement of an independent adjudication committee for outcome assessment

Blinding of outcome assessment ‐ QoL (detection bias)

High risk

Patients completing EORTC QLQ‐C30a and BR23 at baseline, and at end of first, second, and third cycles of chemotherapy

Incomplete outcome data (attrition bias)
All outcomes

Low risk

302 patients randomised (docetaxel: 150; CMF: 152) and 299 patients included in modified intention‐to‐treatment analysis (99.1%)

Selective reporting (reporting bias)

Low risk

Methods consistent with trial registry record (clinicaltrials.gov/ct2/show/NCT00033683). Outcomes reported in the methods and results sections of the trial publication consistent. Primary and secondary outcomes not listed at the time of registration

Other bias

Low risk

No other sources identified

Methods

Randomised controlled trial
Multi‐centre (17 Finnish centres), open‐label
Central randomisation stratified for HER2 status and institution
Accrual October 2000 to September 2003
Baseline patient and tumour characteristics well balanced

Participants

Female premenopausal and postmenopausal (age < 66 years) within 12 weeks following surgery for operable unilateral invasive breast cancer
Performance score 0 or 1
Median age 51 years (range 25.5 to 65.8)
89% lymph node positive; 11% lymph node negative with T > 20 mm and PR negative
72.2% of cancers were ER positive

Interventions

ARM 1 (T‐FEC):
T × 3 21‐day cycles (docetaxel 100 mg/m² (changed to 80 mg/m² in Feb 2002 by independent study monitoring committee)), then FEC × 3 21‐day cycles (fluorouracil 600 mg/m², epirubicin 60 mg/m², cyclophosphamide 600 mg/m²)

ARM 2 (V‐FEC):
V × 3 21‐day cycles (vinorelbine 25 mg/m² days 1, 8, and 15), then FEC × 3 21‐day cycles (fluorouracil 600 mg/m², epirubicin 60 mg/m², cyclophosphamide 600 mg/m²)

HER2‐positive patients randomised to receive trastuzumab or not (weekly dose for 9 weeks commencing with first cycle of docetaxel or vinorelbine, first dose 4 mg/kg, then 2 mg/kg)

Tamoxifen 20 mg/d for 5 years given to all patients with ER and/or PR positive until protocol amendment in 2005, which allowed postmenopausal women to switch to aromatase inhibitors to complete 5 years of hormonal therapy

Radiotherapy as per institution’s guidelines

G‐CSF not recommended unless 1 or more episodes of febrile neutropenia or severe infection

Outcomes

Primary endpoint:

• Recurrence‐free survival (in 2006 publication); DDFS (distant disease‐free survival) in 2009 publication

Secondary endpoints:

• Overall survival

• Toxicity

• Effects of treatment on LVEF in trastuzumab‐treated patients only

• Time to distant recurrence

Notes

Intention‐to‐treat analysis
Median follow‐up 62 months
No patients lost to follow‐up

Clinical Trial Identifier: ISRCTN76560285 (see isrctn.com/ISRCTN76560285)

Supported by Sanofi‐Aventis, Pierre Fabre, Phamacia, Roche, and state of Finland

For the review update, we received clarification on the unadjusted hazard ratio for RFS from trial authors

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "permuted blocks were used to randomly assign all participants"

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "participants were randomly assigned (central and with computer‐assisted blinding)"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Quote: "patients were scheduled for follow‐up for a minimum of five years. Mammography was performed at one‐to‐two‐year intervals, but otherwise follow‐up was carried out according to institution's guidelines. Patients were assessed for adverse effects of therapy on day 21 of each cycle, and 12 and 36 months after completing chemotherapy" Comment: no independent adjudication committee providing oversight

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote from Joensuu 2006: "No patient was lost to follow up. Two women who did not receive the study treatments because of abnormal results on liver‐function tests were excluded from the safety analyses, and one patient ... With overt distant metastases at randomisation was excluded from the survival analyses"

Efficacy analyses based on intention‐to‐treat principle

Selective reporting (reporting bias)

Unclear risk

All outcomes reported in the trial registry reported in 1 or more trial publications. Primary endpoint changed from recurrence‐free survival in 2006 to distant disease‐free survival (DDFS) in the 2009 publication, whereby DDFS did not include contralateral breast cancers. Trialists stated in 2009: "DDFS was preferred to time to any recurrence as the primary endpoint because it allowed a longer follow‐up time and collection of more endpoints before final analysis and distant recurrences are more closely associated with mortality than local ones"

Other bias

Unclear risk

Quote: "the baseline characteristics of the patients in the treatment groups were balanced, except that larger breast tumours (> 20 mm in diameter) were more common in the docetaxel group than in the vinorelbine group"

Methods

Randomised controlled trial
Open‐label, multi‐centre trial involving 67 Spanish institutions
Centralised randomisation in blocks of 4. Stratified according to institution, menopausal status, node status diagnostic method, hormone receptor status
Accrual September 2003 to October 2008
Baseline patient and tumour characteristics well balanced

Participants

Female, premenopausal and postmenopausal
Age 18 to 70 years
Median age 50 years
Operable breast cancer with clear surgical margins
High risk, lymph node negative (St Gallen criteria)
Exclusion of metastatic disease
Exclusion of HER2‐positive patients after 2005. Overall 9.4% HER2 positive

HR positive: 73% in each treatment arm

Interventions

ARM 1 (FAC)
FAC × 6 21‐day cycles (5‐fluorouracil 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²)

ARM 2 (FAC‐wP)
FAC × 4 21‐day cycles (doxorubicin 50 mg/m², fluorouracil 500 mg/m², cyclophosphamide 500 mg/m²) followed by wP × 8 weekly cycles (paclitaxel 100 mg/m²)

Premenopausal women with hormone receptor‐positive tumours given tamoxifen 20 mg/d for 5 years post chemotherapy. Postmenopausal women with hormone receptor‐positive tumours allowed to receive aromatase inhibitors as initial adjuvant therapy or after tamoxifen

Radiotherapy given as mandatory following breast‐conserving surgery

Outcomes

Primary endpoint:

• Disease‐free survival

Secondary endpoints:

• Overall survival

• Toxicity

• Quality of life

• Prognostic gene profile

Notes

Median follow‐up: 63.3 months
Clinical Trial Identifier: NCT00129389 (see clinicaltrials.gov/ct2/show/record/NCT00129389?term=GEICAM)
Supported partially by Bristol‐Myers Squibb; company not involved in trial design, data collection, data analysis, manuscript writing, or decisions related to publication of results
For the review update, O‐E and V for OS and DFS derived using Method 3 (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified randomisation

Quote: "patients were randomly assigned" and "patients were stratified... In blocks of four"

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "random assignment was centralized at GEICAM headquarters"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Follow‐up visits every 3 months for first 2 years, every 6 months for years 3 to 5, annually for years 6 to 10. For first 5 years, haematology and biochemistry performed every 6 months, and chest radiography and mammograms performed annually

Quote: "toxicities were assessed after each chemotherapy cycle and graded according to the NCI CTC version 2.0. ECG and LVEF were repeated as clinically indicated" Comment: no independent adjudication committee involved in assessing outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "we performed the primary analysis on the intention‐to‐treat population, whereas safety analyses were performed on all patients who received at least one dose of chemotherapy according to the treatment received"

Selective reporting (reporting bias)

Unclear risk

Primary and secondary outcomes reported as consistent with trial registry 2009 update (clinicaltrials.gov/ct2/show/record/NCT00129389?term=GEICAM). Methods section and results section in the trial publication consistent. The original secondary outcome measure of QoL listed in the 2005 trial registry record not reported

Other bias

Low risk

Quote: "baseline patient and tumor characteristics were well balanced between arms"

Methods

Randomised controlled trial
Multi‐centre international (49 centres in Spain, 2 in Poland, 4 in Germany), open‐label
Central, block randomisation. Stratified according to institution and menopausal status
Accrual from July 1999 to March 2003

Baseline patient and tumour characteristics well balanced

Participants

Female, premenopausal and postmenopausal
18 to 70 years of age
Median age 50 years (23 to 74)
Operable breast cancer, resected with clear surgical margins
High risk for recurrence (according to 1998 St Gallen criteria), axillary lymph node negative
Exclusion of T4 tumours or metastatic disease

HR positive: 64% to 67% in each treatment arm

Interventions

ARM 1 (TAC)
TAC × 6 21‐day cycles (docetaxel 75 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²)

ARM 2 (FAC)
FAC × 6 21‐day cycles (fluorouracil 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²)

Primary prophylactic antibiotics for all TAC patients. Primary prophylactic G‐CSF for TAC after protocol amended July 2000
Tamoxifen 20 mg/d for 5 years given to all patients with ER and/or PR positive

Radiotherapy given as mandatory following breast‐conserving surgery, and given according to individual institutional guidelines for post‐mastectomy patients

Outcomes

Primary endpoint:

• Disease‐free survival

Secondary endpoints:

• Overall survival

• Toxicity

• Quality of life

• Biological markers

Notes

Median follow‐up: 77 months
Clinical Trial Identifier: NCT00121992 (see clinicaltrials.gov/ct2/show/NCT00121992)

Trial sponsored by GEICAM and Sanofi‐Aventis
For the review update, O‐E and V for OS and DFS derived using Method 3 (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified randomisation

Quote: "patients underwent randomization... According to a center‐specific randomization block"

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "randomization was centralized and stratified for the participating institution and for menopausal status"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Chest radiography and mammography performed yearly during first 5 years of follow‐up. Toxic effects assessed before each chemotherapy cycle and graded according to the NCICTC version 2.0. CBC mandatory on days 7 to 10 and 20 to 21. No independent adjudication committee involved in outcome assessment

Blinding of outcome assessment ‐ QoL (detection bias)

High risk

EORTC QLQ‐C30 and QLQ‐BR23 used. Self‐administered to patients at baseline and at size prospective time points corresponding to chemotherapy cycles

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "the primary analysis was performed for the intention‐to‐treat population"

< 1% of the participant population not included in the safety analyses, with reasons provided

Selective reporting (reporting bias)

Low risk

Primary and secondary outcomes reported as consistent with study protocol (clinicaltrials.gov/ct2/show/NCT00121992). Outcomes specified in the methods and results sections consistent

Other bias

Low risk

Quote: "baseline characteristics were well balanced between the treatment groups"

Methods

Randomised controlled trial
Multi‐centre, Spain, open‐label
Randomisation by a computer programme
Stratified for institution, menopausal status, affected lymph nodes (1 to 3 or > 3)
Accrual November 1999 to June 2002
Baseline patient and tumour characteristics well balanced, except for HR‐positive tumours; FEC‐paclitaxel with higher percentage of HR‐positive tumours compared to FEC alone (P = 0.024)

Participants

Female, premenopausal and postmenopausal following primary curative surgery for operable node‐positive breast cancer
Age 18 to 70 years. Median age: 50 years

Axillary node positive: 100%
HR positive: > 63% in each treatment arm
Exclusion of advanced disease (T4, N2/3, M1)

Interventions

ARM A (FEC):
FEC × 6 21‐day cycles (fluorouracil 600 mg/m², epirubicin 90 mg/m², cyclophosphamide 600 mg/m²)

ARM B (FEC‐T):
FEC × 4 21‐day cycles followed by T × 8 weekly cycles (paclitaxel 100 mg/m²)

Tamoxifen 20 mg/d for 5 years for all ER‐ and/or PR‐positive patients
An amendment in 2005 allowed administration of aromatase inhibitors to menopausal women

Radiotherapy mandatory after breast‐conserving surgery and recommended for patients with > 4 axillary lymph nodes and tumours > 5 cm

Outcomes

Primary endpoint:

• Disease‐free survival

Secondary endpoints:

• Overall survival

• Prognostic and predictive values of hormone receptor status and HER2/neu status

• Toxicity

• Unplanned distant relapse‐free survival

Notes

Median follow‐up: 66 months
Intention‐to‐treat analysis
Clinical Trial Identifier: NCT00129922 (see clinicaltrials.gov/ct2/show/NCT00129922)

Supported by unrestricted grants for the conduct of this trial by Bristol‐Myers Squibb and Pharmacia
For the review update, we received clarification on the unadjusted hazard ratio for OS from trial authors

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified randomisation used

Quote: "eligible patients were stratified according to....and randomly assigned to the control or experimental arms by means of a computer program"

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Quotes: "haematologic and biochemical tests, chest X‐ray and mammography for first 5 years of follow up" and "blood counts, biochemical and clinical assessments performed each cycle of chemotherapy and continued after completion of therapy every 3 months for 2 years, then every 6 months in years 3‐5 followed by annually thereafter"

Comment: no independent adjudication committee involved in assessing these outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "the primary analysis was conducted according to the intention‐to‐treat principle"

Selective reporting (reporting bias)

Low risk

All prespecified outcomes in Clinical Trials.gov record (clinicaltrials.gov/ct2/show/NCT00129922) reported with the addition of distant relapse‐free survival in the 2008 publication. Methods and results sections of the trial publication also consistent

Other bias

Unclear risk

Quote: "two treatment arms were well balanced in terms of demographic and tumour characteristics, except for hormone receptor status"

Methods

Randomised controlled trial
Multi‐centre, 20 Italian centres
Centralised, computer‐generated randomisation. Stratified according to institution, number of metastatic lymph nodes, age, and hormone receptor status
Accrual April 1999 to October 2005
Baseline patient and tumour characteristics well balanced

Participants

Female, premenopausal and postmenopausal
Age 18 to 70 years
Median age 50 years (range 43 to 60)
Operable breast cancer with clear surgical margins
Axillary node positive: 100%
Exclusion of metastatic disease
Performance status 0 to 1

HR positive: 77% in each treatment arm

Interventions

ARM 1 (EC)
EC × 4 21‐day cycles (epirubicin 120 mg/m², cyclophosphamide 600 mg/m²)

ARM 2 (D‐EC)
D × 4 21‐day cycles (docetaxel 100 mg/m²) followed by EC × 4 21‐day cycles (epirubicin 120 mg/m², cyclophosphamide 600 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. From January 2003, postmenopausal women given anastrozole for 5 years

Radiotherapy given following breast‐conserving surgery and in cases of > 4 positive lymph nodes

Outcomes

Primary endpoint:

• Disease‐free survival

Secondary endpoints:

• Overall survival

• Safety

Notes

Median follow‐up: 64 months

Trial registration record not retrieved

GOIM 9902 funded by Sanofi‐Aventis and the Gruppo Oncologica Italia Meridionale
For the review update, O‐E and V for OS and DFS derived using Method 3 (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "randomisation procedures were computer generated... And patients assigned according to the minimization technique"

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "randomisation procedures were computer generated, centralized at the Regina Elena National Cancer Institute"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information provided in the 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

Imaging studies (chest X‐ray, liver ultrasound) carried out every 6 months for 5 years and yearly thereafter. Mammography and bone scan performed every year. Toxicity evaluated each cycle, graded according to NCI CTC (version 3.0) criteria. LVEF evaluated with MGAS or echocardiography at baseline, after for EC cycles, and during follow‐up

Comment: no independent adjudication committee involved in outcome assessments

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "data on treatment and follow‐up were completely lacking from 14 (arm A) and 8 (arm B) patients"

ITT analysis carried out on remaining patients for whom treatment and follow‐up data were available

Selective reporting (reporting bias)

Low risk

Primary and secondary outcomes reported in the results section consistent with study methods section

Other bias

Low risk

Quote: "in general, the two treatment arms were well balanced in terms of demographics and tumour characteristics"

Methods

Randomised controlled trial
Multi‐centre (30 sites), Italy
Randomisation method not specified
Accrual November 1996 to January 2001

Participants

Female, premenopausal and postmenopausal
Aged under 70 years
Operable, unilateral breast cancer, stage IIa, IIb, or III, completely resected with clear surgical margins
Axillary node positive: 100% with at least 1 and fewer than 10 involved nodes
Exclusion of metastatic disease
ECOG performance status 0

HR positive: 76% in CEF and 81% in ET

No prior chemotherapy. Surgery performed not more than 5 weeks before randomisation

Interventions

Arm 1 (CEF)
CEF × 6 21‐day cycles (cyclophosphamide 600 mg/m², epirubicin 60 mg/m², 5‐fluorouracil 600 mg/m²)

Arm 2 (ET)
ET × 4 21‐day cycles (epirubicin 90 mg/m², paclitaxel 175 mg/m²)

Tamoxifen 20 mg/d for 5 years to women with ER‐ and/or PR‐positive tumours

Postoperative radiotherapy given to patients who received breast‐conserving surgery. For those who had a mastectomy, radiotherapy done according to local guidelines

Outcomes

Primary endpoint:

• Overall survival, defined as date of randomisation to date of death from any cause

Secondary endpoints:

• Event‐free survival/DFS, defined as date of randomisation to date of local recurrence, distant metastases, second primary cancer, or death from any cause, whichever came first

• Tolerability

• Toxicity, graded as per World Health Organization criteria

• Quality of life

Notes

Median follow‐up: 12.8 years

Clinical Trial Identifier: NCT00005581 (see clinicaltrials.gov/ct2/show/record/NCT00005581) and NCT02450058 (see clinicaltrials.gov/ct2/show/NCT02450058)

Funded by National Institute for Cancer Research Italy
For the review update, numbers of events for OS and EFS, as well as unadjusted hazard ratio and confidence interval for each analysis, provided by trial authors and confirmed in a follow‐up trial publication in 2016. O‐E and V for OS and EFS derived using Method 3 (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "eligible patients were randomly allocated 1:1 to one of the two study arms by telephone or fax at the central operation office …Patients were assigned to a treatment arm according to stratified random lists that were balanced in blocks of various sizes in random sequence”

Allocation concealment (selection bias)

Low risk

Quote: “…randomly allocated 1:1 to one of the two study arms by telephone or fax at the central operational office of the Trials Center of National Cancer Research Institute”

Comment: central allocation

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label study

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

Assessment including clinical visits every 3 months for first 3 years, then every 6 months during the fourth and fifth years, followed by annual visits. Mammography and blood count performed yearly. Toxicity graded according to WHO toxicity criteria

Comment: no involvement of an independent adjudication committee for outcome assessment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Analyses conducted according to intention‐to‐treat principle. At median follow‐up of 12.8 years, 3.2% of patients lost to follow‐up

Selective reporting (reporting bias)

Unclear risk

Trial registry record specifies OS, DFS, and QoL; abstract and trial publication report on DFS, OS, and toxicity but not quality of life (clinicaltrials.gov/ct2/show/record/NCT00005581)

Other bias

Low risk

No other sources of bias identified

Methods

Randomised controlled trial
Multi‐centre, Greece
Stratified randomisation balanced by centre for number of positive nodes, hormonal receptor status, and menopausal status
Accrual June 1997 to November 2000
Baseline patient and tumour characteristics well balanced except for tumour grade (significantly higher tumour grade in group A)
Treatment delays and dose reductions similar in each group

Participants

Female, premenopausal and postmenopausal following surgery for operable breast cancer, pathological stage T1 to 3 N1 M0 or T3 N0 M0

Axillary node positive: 98%
Postmenopausal women with 1 to 3 positive nodes and hormone receptor positive excluded
Median age: 50 years (22 to 78)
HR positive: 75% to 76% in each group

Interventions

ARM A (E‐T‐CMF):
E × 3 14‐day cycles (epirubicin 110 mg/m²) then T × 3 14‐day cycles (paclitaxel 250 mg/m² over 3 hours) followed by intensified CMF × 3 14‐day cycles (cyclophosphamide 840 mg/m², methotrexate 57 mg/m², fluorouracil 840 mg/m²). G‐CSF (5 mcg/kg) days 3 to 10 of each cycle

ARM B (E‐CMF):
E × 4 14‐day cycles, then intensified CMF × 4 14‐day cycles. Doses and G‐CSF given as in arm A

Tamoxifen 20 mg/d for 5 years for all ER‐ and/or PR‐positive patients
All premenopausal patients given ovarian suppression for 1 year (IM triptorelin)

Radiotherapy for all patients with breast‐conserving therapy and/or T > 5 cm

Outcomes

Primary endpoint:

• Disease‐free survival

Secondary endpoints:

• Overall survival

• QoL

• Acute toxicity

Notes

Intention‐to‐treat analysis
Median follow up 61.7 months (Group A) and 62 months (Group B)
Clinical Trial Identifier: ACTRN12611000506998 (see anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336915)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "stratified randomisation balanced by centre"

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "...randomisation... was performed at the HeCOG Data Office in Athens"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information provided in trial publication or trial registry record

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

Chest X‐ray, abdominal US, and bone scan done every 6 months for 3 years, then annually. Blood count and biochemistry repeated before each cycle. CBC, biochemistry, and physical exams repeated every 3 months for 2 years, then every 6 months thereafter

Comment: no independent adjudication committee involved in assessing these outcomes

Blinding of outcome assessment ‐ QoL (detection bias)

High risk

Completed by participants at baseline and at completion of chemotherapy using QLQ‐C30 questionnaire

Incomplete outcome data (attrition bias)
All outcomes

Low risk

At 5‐year follow‐up, 4/298 in the E‐T‐CMF group and 7/297 in the E‐CMF group lost to follow‐up. Analyses conducted according to intention‐to‐treat principle

Selective reporting (reporting bias)

Low risk

All outcomes reported as specified in ANZCTR (anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336915) and in trial publications reported consistently

Other bias

Unclear risk

Quote: "no significant differences in major characteristics between the two treatment groups with the exception of tumour grade"

E‐T‐CMF group had 36% II, 57% III vs E‐CMF group with 52% II and 45% III

Methods

Randomised controlled trial
Multi‐centre, 9 centres in Greece and Cyprus
Central randomisation, stratified according to number of positive lymph nodes and menopausal status
Accrual June 1995 to October 2004
Baseline patient and tumour characteristics well balanced

Participants

Female, premenopausal and postmenopausal
Aged 18 to 75 years
Median age 56 years (26 to 73)
Operable early stage (II to IIIa) breast cancer with clear surgical margins
Axillary node positive: 100%
ECOG performance status: 0 to 2
Exclusion of metastatic disease

HR positive: 68% to 74% in each treatment arm

Interventions

ARM 1 (FEC)
FEC × 6 21‐day cycles (5‐fluorouracil 700 mg/m², epirubicin 75 mg/m², cyclophosphamide 700 mg/m²)

ARM 2 (D‐EC)
D × 4 21‐day cycles (docetaxel 100 mg/m²) followed by EC × 4 21‐day cycles (epirubicin 75 mg/m², cyclophosphamide 700 mg/m²)

Tamoxifen 20 mg/d for 5 years given to all patients with ER‐ and/or PR‐positive tumours
Postoperative radiotherapy given after chemotherapy to all patients after breast‐conserving surgery and to high‐risk patients following mastectomy
No prior chemotherapy, no endocrine or radiation therapy allowed
Prophylactic G‐CSF not permitted

Outcomes

Primary endpoint:

• Disease‐free survival

Secondary endpoints:

• Overall survival

• Toxicity

Notes

Median follow‐up: 62.5 months

Conducted by the Hellenic Cooperative Oncology Group (HeCOG)

No record of trial registration found
For the review update, number of events per treatment arm for DFS and unadjusted hazard ratio and confidence intervals for OS and DFS provided by trial authors. O‐E and V for OS and DFS derived using Method 3 (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified randomisation for number of lymph nodes and menopausal status

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "treatment allocation was done centrally"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described

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

History, physical exam, and routine bloods performed every 3 months for first 2 years, every 6 months for following 3 years, and yearly thereafter. Imaging (mammography, chest X‐ray, liver ultrasound) performed 1 year post surgery and yearly for 5‐year follow‐up. Physical examination, full blood count, and biochemistry performed before each course of chemotherapy. Toxicity graded according to NCI CTC version 2.0. LVEF measured by radio‐isotopic or echocardiographic methods at baseline, after completion of chemotherapy, and at 1‐year follow‐up

Comment: no independent adjudication committee involved in outcome assessment

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "there were 16 (4.2%) patients in the D/EC arm and 27 (7.1%) in the FEC who were lost to follow‐up (P=0.084); all these patients were censored in DFS and OS analyses"

Efficacy analyses based only on participants who received treatment

Selective reporting (reporting bias)

Low risk

Outcomes specified in the methods and results sections in the trial publication consistent. No record of trial registration found

Other bias

Low risk

Quote: "baseline patient characteristics were well balanced between the two treatment arms"

Methods

Randomised controlled trial
Multi‐centre (63 sites), Germany (part of German Breast Group), open‐label
Randomisation performed centrally and stratified by participating centre, risk assessment method (pT3/4, pN2/3, or clinicopathological, or high urokinase plasminogen activator (uPA) or high plasminogen activator inhibitor 1 (PAI‐1)), age, oestrogen receptor/progesterone receptor/HER2 status
Accrual April 2009 to April 2013
Baseline characteristics balanced between treatment groups

Participants

Female or male patients aged ≥ 65 years with Charlson co‐morbidity index ≤ 2
Median age 72 (range 65 to 84)
Two‐thirds of patients had clinopathologically medium‐ to high‐risk pT1/2 pN0/1 breast cancer
65.5% hormone receptor‐positive/HER2‐negative disease; 16.9% HER2‐positive disease; 17.6% triple‐negative breast cancer
Exclusion of metastatic disease
Prior chemotherapy for any malignancy and concurrent or previous systemic investigational or established anti‐tumour treatment not permitted

Interventions

ARM 1 (EC or CMF)
EC × 4 21‐day cycles (epirubicin 90 mg/m², cyclophosphamide 600 mg/m²) or CMF × 6 28‐day cycles (cyclophosphamide 500 mg/m², methotrexate 40 mg/m², 5‐fluorouracil 600 mg/m² on days 1 and 8) based on investigators’ decision

ARM 2 (nPX)
nPX × 6 21‐day cycles (nab‐paclitaxel 100 mg/m² on days 1, 8, and 15 every 3 weeks with a week of rest every 6 weeks) plus capecitabine (1000 mg/m²) twice daily on days 1 to 14 every 3 weeks

Sequential radiotherapy, anti‐HER2 therapy, and endocrine treatment recommended as per national guidelines

Primary prophylaxis with granulocyte colony‐stimulating factor not recommended

Outcomes

Primary endpoint:

• Compliance and safety

Secondary endpoints:

• Invasive disease‐free survival (iDFS) and distant disease‐free survival (DDFS), defined as any local invasive or distant recurrence of breast cancer, any contralateral breast cancer, any second malignancy, and any death irrespective of its cause for iDFS

• Overall survival, defined as any cause of death

• Efficacy of treatment in subgroups according to clinical stratification factors

• Prognostic factors on tumour tissue collected from primary surgery and for correlation with study treatment effects

• Geriatric assessment scores at baseline and at completion of therapy

Toxicity, assessed using Common Terminology Criteria for Adverse Events (version 3.0)

Notes

Median follow‐up: 22.8 months
Clinical Trial Identifier: NCT01204437 (see clinicaltrials.gov/ct2/show/NCT01204437)
Funded: supported received from Celgene and Roche; sponsored/collaborators were the German Breast Group

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “…randomization at a 1:1 ratio was performed centrally and stratified according to participating center, risk assessment method, age, and estrogen receptor/progesterone receptor/HER2 status…”

Allocation concealment (selection bias)

Low risk

Randomisation performed centrally

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label study

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

Assessment including clinical visits and breast imaging techniques every 3 months for 2 years, then every 6 months from year 2 to 5 for the diagnosis of local, locoregional, ipsilateral, or contralateral recurrence; distant metastasis, or death. Toxicity graded according to National Cancer Institute Common Toxicity Criteria

Comment: no involvement of an independent adjudication committee for outcome assessment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All efficacy analysis intention‐to‐treat; safety analysis including patients who received treatment

Selective reporting (reporting bias)

Low risk

Trial registry record outcomes reported in the trial publication

Other bias

Low risk

No other sources identified

Methods

Randomised controlled trial, 3‐arm trial
Multi‐centre, international
Central randomisation by minimisation procedure
Stratified according to number of positive nodes, type of surgery, ER status
Accrual December 2000 to May 2005
Baseline patient and tumour characteristics well balanced

Participants

Female, premenopausal and postmenopausal
Age 60 years or younger. Median age not provided
Operable breast cancer, resected with clear surgical margins
Approximately 72% axillary node positive and 28% high risk node negative
Exclusion of metastatic disease

HR positive: ER positive: 59% to 60% in each treatment arm

Interventions

ARM 1 (CEF):
CEF × 6 28‐day cycles (cyclophosphamide 75 mg/m² orally days 1 to 14, epirubicin 60 mg/m² days 1 and 8, fluorouracil 500 mg/m² days 1 and 8)

ARM 2 (EC‐T):
EC with G‐CSF × 6 14‐day cycles (epirubicin 120 mg/m², cyclophosphamide 830 mg/m²) followed by paclitaxel × 4 21‐day cycles (paclitaxel 175 mg/m²)

Tamoxifen 20 mg/d for 5 years given to all patients with ER‐positive tumours. After October 2004, aromatase inhibitors allowed
After June 2005, trastuzumab for 1 year allowed for patients with HER2‐positive cancer
Radiotherapy given to all women following breast‐conserving surgery, and given following mastectomy according to institutional practice

Outcomes

Primary endpoint:

• Relapse‐free survival

Secondary endpoints:

• Overall survival

• Toxicity

• Quality of life (data not yet reported; QoL to be released shortly as per 2012 abstract)

Notes

Median follow‐up: 30.4 months
Clinical Trial Identifier: NCT00014222 (see clinicaltrials.gov/ct2/show/NCT00014222)

Supported in part by the Canadian Cancer Society, National Institutes of Health, and the following companies; Pfizer, Bristol‐Myers Squibb

For the review update, O‐E and V for DFS derived using Method 3 (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "patients were assigned using a minimization procedure to one of three regimens"

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "patients were assigned... by the NCIC CTG central office"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Patients undergoing history, physical exam, CBC count, platelet count, and liver function tests at each follow‐up every 3 months for first year, every 4 months in second year, every 6 months to the end of 5 years, and yearly thereafter. Mammography performed yearly. Toxicity evaluations by NCI CTC Version 2.0, performed on day 1 of each cycle of chemotherapy

Comment: no independent adjudication committee involved for outcome assessment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "all 2,104 patients randomly assigned to the study are included in the efficacy analysis"

ITT principle used

Selective reporting (reporting bias)

Low risk

Method consistent with trial registry record (clinicaltrials.gov/ct2/show/NCT00014222). To date, only RFS, OS, and toxicity outcomes presented, DFS and QoL data yet to be published

Other bias

Low risk

Quote: "baseline characteristics were similar among treatments"

Methods

See details in NCIC‐CTG MA21a

Participants

See details in NCIC‐CTG MA21a

Interventions

Three‐arm trial. For MA21b:

ARM 1 (CEF):
CEF × 6 28‐day cycles (cyclophosphamide 75 mg/m² orally days 1 to 14, epirubicin 60 mg/m² days 1 and 8, fluorouracil 500 mg/m² days 1 and 8)

ARM 3 (AC‐T):
AC × 4 21‐day cycles (doxorubicin 60 mg/m², cyclophosphamide 600 mg/m²) followed by T × 4 21‐day cycles (paclitaxel 175 mg/m²)

Outcomes

See details in NCIC‐CTG MA21a

Notes

See details in NCIC‐CTG MA21a

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

See NCIC‐CTG MA21a

Allocation concealment (selection bias)

Low risk

See NCIC‐CTG MA21a

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

See NCIC‐CTG MA21a

Blinding of outcome assessment ‐ OS (detection bias)

Low risk

See NCIC‐CTG MA21a

Blinding of outcome assessment ‐ DFS & Toxicity (detection bias)

Unclear risk

See NCIC‐CTG MA21a

Incomplete outcome data (attrition bias)
All outcomes

Low risk

See NCIC‐CTG MA21a

Selective reporting (reporting bias)

Low risk

See NCIC‐CTG MA21a

Other bias

Low risk

See NCIC‐CTG MA21a

Methods

Randomised controlled trial
Multi‐centre
Central randomisation, stratified for number of positive nodes, type of surgery, and tamoxifen use
Accrual August 1995 to May 1998
Baseline patient and tumour characteristics well balanced between treatment arms

Participants

Female, premenopausal and postmenopausal
Operable breast cancer with free surgical margins
Axillary node positive: 100%
HR positive: 66% in each treatment arm
Exclusion of metastatic disease

Interventions

ARM 1 (AC):
AC × 4 21‐day cycles (doxorubicin 60 mg/m², cyclophosphamide 600 mg/m²)

ARM 2 (AC‐T):
AC × 4 21‐day cycles (as per control arm) followed by T × 4 21‐day cycles (paclitaxel 225 mg/m²)

Tamoxifen 20 mg/d for 5 years given to all patients over 50 years and to those younger than 50 years with ER and/or PR positive
Whole‐breast irradiation given to patients treated with breast‐conserving surgery

Outcomes

Primary endpoints:

• Disease‐free survival

• Overall survival

Secondary endpoints:

• Toxicity

Post‐hoc analyses presented in 2005 publication but not part of the trial protocol (as described in the publication):

• Treatment effectiveness in hormone receptor positive vs hormone receptor negative

• Recurrence‐free survival

Notes

Intention‐to‐treat analysis
Median follow‐up: 64.6 months
79% continuing follow‐up at 5 years
Trial identifier not retrieved

Supported by Public Health Service grants from NCI and NIH (USA)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "patient assignment to the two treatment arms was balanced… using a biased‐coin minimisation algorithm"

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "random assignment was performed centrally" at the NSABP Biostatistical Centre in Pittsburgh, PA

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described

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

Gynaecological exam (where applicable), chest X‐ray, and bilateral/unilateral mammogram yearly for first 5 years. Physical exam, gynaecological exam, and mammogram annually after 5‐year follow‐up. History, physical exam, and haematological studies and chemistries on day 1 before each cycle and every 6 months for first 5 years Comment: no independent adjudication committee involved in assessing these outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Intention‐to‐treat analysis. 79% of participants continuing follow‐up at 64.6 months. Only 1 patient contributing no follow‐up in the non‐taxane treatment arm

Selective reporting (reporting bias)

Low risk

Outcomes listed in methods and results sections of the trial publications consistent with trial listing at the NCI (cancer.gov/about‐cancer/treatment/clinical‐trials/search/)

Other bias

Low risk

Quote: "patient and tumour characteristics were distributed evenly between the two groups"

Methods

Randomised controlled trial
Multi‐centre (85 centres across France and Belgium)
Central randomisation and balanced per block
Stratification by age, number of positive nodes, and centre
Accrual June 1997 to March 2000
Baseline characteristics well balanced between treatment arms, except for combined HR status and ER status

Participants

Female, premenopausal and postmenopausal, ages 18 to 64
Median age: 50 years (25 to 67)
Following surgery for operable node‐positive unilateral breast cancer (all had axillary dissection)

Axillary node positive: 100%
WHO performance status: < 2
HR positive: 81% in FEC‐D and 77% in FEC arm
Exclusion of metastatic disease

Interventions

ARM A (FEC):
FEC × 6 21‐day cycles (fluorouracil 500 mg/m², epirubicin 100 mg/m², cyclophosphamide 500 mg/m² day 1)

ARM B (FEC‐D):
FEC × 3 21‐day cycles (as in arm A), then docetaxel (D) × 3 21‐day cycles (docetaxel 100 mg/m² day 1)

Tamoxifen 20 mg/d for 5 years for all ER‐ and/or PR‐positive patients and at investigators' discretion for ER/PR‐negative women

Radiotherapy mandatory for all women following breast‐conserving surgery. Chest wall, supraclavicular fossa (SCF), and internal mammary chain radiotherapy recommended following mastectomy. Irradiation to axilla prohibited

Outcomes

Primary endpoints:

• 5‐year disease‐free survival

Secondary endpoints:

• Overall survival

• Toxicity

• Cost‐effectiveness (as per supplementary information provided with 2012 publication)

• Quality of life (as per supplementary information provided with 2012 publication)

Notes

Intention‐to‐treat analysis
Median follow‐up: 92.8 months
Trial identifier not retrieved

Supported by Ligue Nationale Contre le Cancer, Sanofi‐Aventis, and Amgen

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified randomisation.

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "randomisation procedures were centralized"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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 examination performed every 4 months from 2 years then 6 monthly for the next 3 years. Imaging studies (mammography, chest X‐ray, liver ultrasound, and bone scan) performed 1 year post surgery then annually for 5 years

Quote: "ECG and absolute blood count were performed on day 21... Toxicity was graded according to WHO criteria"

Comment: no independent adjudication committee involved in assessing these outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Results analysed by intention‐to‐treat principle. No apparent loss to follow‐up

Selective reporting (reporting bias)

Unclear risk

Data on prespecified outcomes reported as outlined in the NCI trial registry record (see cancer.gov/about‐cancer/treatment/clinical‐trials/search/) except for QoL

Other bias

Unclear risk

Quote: "baseline characteristics were well balanced between treatment arms, except for combined hormone‐receptor status (HR) and estrogen‐receptor status"

Methods

Randomised controlled trial
Multi‐centre (11 French centres)
Central randomisation using computerised random number generator. Stratified according to centre, node status, and proliferation
Accrual June 1999 to January 2003
Baseline patient and tumour characteristics well balanced
Closed prematurely for toxicity in 2003

Participants

Female, premenopausal and postmenopausal
Age 18 to 70 years
Median age: 52 years (range 26 to 70)
Unilateral, operable breast cancer with clear surgical margins
57% limited axillary node positive (≤ 3); 43% high risk node negative
Exclusion of metastatic disease

HR positive: 80% to 81% in each treatment arm

Interventions

ARM 1 (AT):
AT × 4 21‐day cycles (doxorubicin 50 mg/m², docetaxel 75 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
Radiotherapy given as mandatory following breast‐conserving surgery
Chemotherapy delivered without primary G‐CSF prophylaxis

Outcomes

Primary endpoint:

• Disease‐free survival (as stated in 2005 toxicity full‐text article but listed as time to recurrence (TTR) in 2009 abstract)

Secondary endpoints:

• Overall survival

• Toxicity

Notes

Median follow‐up: 64 months
Trial registry record not identified
Rene Huguenin Cancer Centre sponsored the trial supported in part by Aventis‐Oncology France and Ligue Regionale Contre le Cancer due Department des Yvelines
For the review update, O‐E and V for DFS derived using Method 3 (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified randomisation

Quote: "using a computerized random‐number generator"

Allocation concealment (selection bias)

Low risk

Central allocation

Quote: "central randomization was performed by fax or telephone in the Biostatistics Department of Rene Huguenin Cancer Center (Saint‐Cloud, France)"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described

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

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No information provided

Selective reporting (reporting bias)

High risk

Not all outcomes reported as outlined in the methods section of the trial publication. Primary outcome listed as DFS in 2005 full‐text article but reported as TTR in the 2009 abstract, and data related to overall survival not reported (although listed as a secondary outcome measure)

Other bias

Low risk

Quote: "the patients' characteristics were well balanced between the two treatment groups"

Methods

Randomised controlled trial
Open‐label, single institution
Computer‐based randomisation procedure, 1:1
Accrual July 2007 to January 2010
Baseline patient and tumour characteristics well balanced

Participants

Female, premenopausal and postmenopausal
Median age: 47 years (18 to 66)
Operable, unilateral breast cancer, stage II
Post modified radical mastectomy with clear surgical margins

Axillary node positive: 100%
Exclusion of metastatic disease
Karnofsky performance status: > 70

HR positive: 60% AC‐T and 58% AC

Interventions

ARM 1 (AC)
AC × 6 21‐day cycles (doxorubicin 60 mg/m², cyclophosphamide 600 mg/m²)

ARM 2 (AC‐T)
AC × 3 21‐day cycles (doxorubicin 60 mg/m², cyclophosphamide 600 mg/m²) followed by T × 3 21‐day cycles (paclitaxel 175 mg/m²)

Tamoxifen 20 mg/d for 5 years to women with ER‐ and/or PR‐positive tumours, or tumours with unknown hormone receptor status
Surgical treatment of mastectomy
All patients given locoregional external beam radiotherapy post chemotherapy

Outcomes

Primary endpoint:

• Disease‐free survival

Secondary endpoints:

• Toxicity

• Overall survival

Notes

Median follow‐up: 24 months
Trial registry record not found in Clinical Trials Registry ‐ India
Funding source: not reported in trial publication
For the review update, O‐E and V for OS and DFS derived using Method 3 (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "the patient[s] were randomly assigned into two treatment arms by a computer‐based randomization procedure"

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Mammography, CXR, and in patients receiving tamoxifen, pelvic and rectal examination with Pap smear performed annually. Examination and evaluation before the start of each chemotherapy cycle; CBC, liver and kidney function tests. Follow‐up performed 3 weeks after chemotherapy, then 2 monthly for the first year, followed by 3 monthly until end of the study. LVEF evaluated at baseline and at 18 months

Comment: no involvement of an independent adjudication committee for outcome assessment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "there was no loss of patients in any of the arms due to 'lost to follow‐up'"

Selective reporting (reporting bias)

Low risk

Outcomes specified in the methods and results sections of the trial publication consistent. No trial registry or protocol found on Clinical Trials Registry ‐ India

Other bias

Unclear risk

Baseline patient and tumour characteristics appearing well balanced, excluding tumour status with 28% T2 and 44% T3 in AC‐T treatment group vs 44% T2 and 24% T3 in AC treatment group

Methods

Randomised controlled trial
Randomisation method not specified
Accrual January 2006 to January 2010
Baseline patient and tumour characteristics well balanced

Participants

Female, premenopausal and postmenopausal
Aged 18 to 65. Median age: 45 years (24 to 69)
Operable, unilateral breast cancer, completely resected with clear surgical margins
Axillary lymph node positive or high risk (T3/4) node negative

Axillary node positive: 100%
Exclusion of metastatic disease
ECOG performance status: 0 to 1

HR positive: 81% FEC‐D and 77% FEC

Interventions

ARM 1 (FEC)
FEC × 6 21‐day cycles (fluorouracil 500 mg/m², epirubicin 100 mg/m², cyclophosphamide 500 mg/m²)

ARM 2 (FEC‐D)
FEC × 3 21‐day cycles (fluorouracil 500 mg/m², epirubicin 100 mg/m², cyclophosphamide 500 mg/m²) followed by D × 3 21‐day cycles (docetaxel 100 mg/m²)

Tamoxifen 20 mg/d for 5 years to women with ER‐ and/or PR‐positive tumours
Radiotherapy mandatory following breast‐conserving surgery, and used after mastectomy according to local guidelines

Outcomes

Primary endpoint:

• Disease‐free survival

Secondary endpoints:

• Toxicity

• Overall survival

• Prognostics

• Predictive values (i.e. age, nodal status, and tamoxifen)

Notes

Median follow‐up: 61 months
No trial record identified
Funding source: not reported in the trial publication
For the review update, O‐E and V for OS derived using Method 3; Method 7 used for DFS (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "the randomisation scheme was a permuted block design with an equal probability of assignment to either treatment arms"

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described

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 exam and metastatic work‐up (mammogram, chest X‐ray, abdominal ultrasound) performed 3 weeks after completion of chemotherapy, then every 3 months for first year, then yearly thereafter. Toxicity graded according to WHO criteria. Assessed with ECG, absolute blood count, and tolerability before each cycle

Comment: no involvement of an independent adjudication committee for outcome assessment

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "data of three patients who did not receive treatment (2 FEC, 1 FEC‐D) were deleted list wise from the study"

Not apparent that ITT analyses were conducted

Selective reporting (reporting bias)

Low risk

Outcomes specified in the methods and results sections of the trial publication consistent. No trial registry or protocol found

Other bias

Low risk

Quote: "baseline characteristics... were well balanced among the both treatment groups"

Methods

Randomised controlled trial
Multi‐centre, open‐label
Computer programme allocation via dynamic balancing algorithm
Balancing factors: centre, number of lymph nodes involved, ER status, menopausal status
Accrual from July 1998 to July 2002

Participants

Female, premenopausal and postmenopausal
Median age: 51 years (range 23 to 74)
Following surgery for operable breast cancer
Axillary node positive: 100%

HR status reported; 66% ER positive

Interventions

ARM 1 (E‐CMF):
E × 4 21‐day cycles (epirubicin 120 mg/m² day 1) followed by CMF × 4 28‐day cycles (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², and fluorouracil 600 mg/m² all IV days 1 and 8)

ARM 2 (E‐T‐CMF):
E × 4 21‐day cycles (dose as per arm 1) followed by T × 4 21‐day cycles (docetaxel 100 mg/m² on day 1) followed by CMF × 4 28‐day cycles (dose as in arm 1)

Radiation therapy mandatory after breast‐conserving surgery and commencing after completion of chemotherapy
Tamoxifen 20 mg/d recommended after chemotherapy for ER‐positive premenopausal women and for all postmenopausal women irrespective of ER status

Outcomes

Primary endpoint:

• Disease‐free survival, then reclassified as Invasive DFS (which excluded DCIS from events)

Secondary endpoints:

• Overall survival

• Recurrence‐free survival

• Toxicity

Notes

Median follow‐up: 62 months
Trial identifier not retrieved

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "treatment allocation was performed by a computer program using a dynamic balancing algorithm"

Allocation concealment (selection bias)

Low risk

Quote: "randomization was done centrally by fax at the coordinating center (University of Naples Federico II, Italy)"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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 exam and blood chemistry every 3 weeks and haematology weekly during chemotherapy. Follow‐up every 3 months for 2 years, every 6 months for years 3 to 5, and annually for years 6 to 10

Comment: no independent adjudication committee involved in assessing these outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Efficacy analyses done as per intention‐to‐treat principle. All participants apparently included in efficacy and safety analysis (i.e. no withdrawals)

Selective reporting (reporting bias)

Low risk

All prespecified outcomes in the methods section reported in the results section of the thesis

Other bias

Low risk

Baseline characteristics well balanced

Methods

Randomised controlled trial
Multi‐centre (66 sites), USA, open‐label
Randomisation method (using web system) stratified according to number of involved axillary notes (0, 1 to 3, 4, more)
Accrual December 2008 to January 2011
Baseline characteristics well balanced between treatment groups

Participants

Females > 18 years, 70% postmenopausal
Median age: 54 years
Unilateral or synchronous bilateral, operable breast cancer with clear surgical margins, < pT4
Triple negative (ER/PR negative < 10% IHC, HER2 negative)
Axillary node positive: 33% (pN0 to pN3a eligible)
Exclusion of metastatic disease

Prior anthracycline exposure not permitted
ECOG: 0 to 2

Interventions

ARM 1 (AC‐Ixa)
AC × 4 21‐day cycles (doxorubicin 60 mg/m², cyclophosphamide 600 mg/m²) followed by Ixa × 4 21‐day cycles (ixabepilone 40 mg/m²)

ARM 2 (AC‐T)
AC × 4 21‐day cycles (doxorubicin 60 mg/m², cyclophosphamide 600 mg/m²) followed by T × 12 weekly (paclitaxel 80 mg/m²)

Colony‐stimulating growth factor allowed as per American Society of Clinical Oncology (ASCO) guidelines or at discretion of the treating physician

MammoSite Brachytherapy radiation permitted if immediately following surgery and before study treatment. Radiotherpy following BCS or postmastectomy radiotherapy as per institutional guidelines except to those who had MammoSite Brachytherapy

Outcomes

Primary endpoint:

• Disease‐free survival, defined as time between randomisation and date of first documented disease recurrence or death from any cause

Secondary endpoints:

• Overall survival, assessed using National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE v3.0)

• Safety

Notes

Median follow‐up: 48 months
Clinical Trial Identifier: NCT00789581 (see clinicaltrials.gov/ct2/show/NCT00789581)
Funded: supported in part by a grant from Bristol‐Myers Squibb; sponsored also by SCRI Development Innovations, LLC

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “…randomized …using an Interactive Web Response System and stratified according to the number of involved axillary lymph nodes (0, 1‐3, 4, or more)…”

Allocation concealment (selection bias)

Low risk

Randomisation via a web‐based system

Comment: central randomisation

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label study

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

Assessment including clinical visits every 3 months for 2 years, then every 6 months for 3 years; breast imaging performed annually. Toxicity graded according to National Cancer Institute Common Toxicity Criteria

Comment: no involvement of an independent adjudication committee for outcome assessment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All efficacy analysis intention‐to‐treat; safety analysis including patients who received treatment

Selective reporting (reporting bias)

Low risk

Trial registry record outlining disease‐free survival and overall survival as outcomes (clinicaltrials.gov/ct2/show/NCT00789581); trial publication adding toxicity data, which are considered important outcome data

Outcomes reported in the methods and results sections of the trial publication consistent

Other bias

Low risk

No other sources identified

Methods

Randomised controlled trial
Multi‐centre (103 centres in the UK and 1 in Belgium), open‐label
Computer‐generated permuted block randomisation
1:1 taxane regimen or control regimen
Accrual February 2001 to July 2003

Participants

Female, premenopausal and postmenopausal
Aged over 18 years. Median age not reported
Operable, unilateral breast cancer, completely resected with clear surgical margins
80% axillary node positive; 20% high risk node negative
Exclusion of metastatic disease
WHO performance status: 0 to 1

HR positive: ER positive: 69% in each treatment group

Interventions

ARM 1 (FEC‐D)
FEC × 4 21‐day cycles (fluorouracil 600 mg/m², epirubicin 60 mg/m², cyclophosphamide 600 mg/m²) followed by D × 4 21‐day cycles (docetaxel 100 mg/m²)

ARM 2a (Control)
Regimen a (FEC)
FEC × 8 21‐day cycles (fluorouracil 600 mg/m², epirubicin 60 mg/m², cyclophosphamide 600 mg/m²)

ARM 2b (Control)
Regimen b (E‐CMF)
E × 4 21‐day cycles (epirubicin 100 mg/m²) followed by CMF × 4 28‐day cycles (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m² all IV on days 1 and 8)

Tamoxifen 20 mg/d for 5 years given to all patients with ER and/or PR positive. From 2005, aromatase inhibitors could be used as an alternative to tamoxifen
Radiotherapy given as mandatory following breast‐conserving surgery, and used after mastectomy according to local guidelines
Patients with HER2‐positive tumours allowed to enter clinical trials for trastuzumab

Outcomes

Primary endpoint:

• Invasive disease‐free survival

Secondary endpoints:

• Metastasis‐free survival

• Overall survival

• Tolerability

• Quality of life (at selected centres)

Notes

Median follow‐up: 97.5 months
Clinical Trial Identifier: NCT00033683 (see clinicaltrials.gov/ct2/show/NCT00033683)
Funded by Cancer Research UK, Sanofi‐Aventis, Pfizer, and Roche
For the review update, O‐E and V for OS and DFS derived using Method 3 (Tierney 2007)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "randomly assigned by computer‐generated permuted block randomization"

Allocation concealment (selection bias)

Low risk

Quote: "independent randomisation was by telephone to the ICR‐CTSU or one of four regional clinical trial units"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label

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

Clinical follow‐up as per local policy with relevant details forwarded to the clinical trials unit. Adverse events assessed after every cycle of chemotherapy and every 3 months for 2 years of follow‐up. Graded according to NCI CTC criteria

Comment: no involvement of an independent adjudication committee for outcome assessment

Blinding of outcome assessment ‐ QoL (detection bias)

High risk

Patients completing EORTC QLQ‐C30, BR23, HADS questionnaires before randomisation, before fifth and after eighth cycles of chemotherapy, and at 9, 12, 18, and 24 months of follow‐up

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "complete follow‐up data available for 3191 (94%) of 3410 alive patients"

Analyses using ITT principle

Selective reporting (reporting bias)

Low risk

Methods consistent with the trial registry record (clinicaltrials.gov/ct2/show/NCT00033683). Outcomes reported in the methods and results sections of the trial publication consistent. Primary and secondary outcomes not listed at the time of registration

Other bias

Low risk

Baseline characteristics apparently balanced

Methods

Randomised controlled trial
Randomisation method not specified
Patients stratified by age and nodal status
Accrual July 1997 to December January 2000
Baseline characteristics well balanced between treatment arms

Participants

Female, premenopausal and postmenopausal
Patients aged 18 to 75 years. Median age: 52 years (28 to 78)
Following surgery for operable breast cancer, stage I to III
Approximately 48% node negative and 52% node positive included
Locally advanced tumours excluded
HR positive: 71% of patients

Interventions

ARM 1 (AC):
AC × 4 21‐day cycles (doxorubicin 60 mg/m², cyclophosphamide 600 mg/m² day 1)

ARM 2 (TC):
TC × 4 21‐day cycles (docetaxel 75 mg/m², cyclophosphamide 600 mg/m² day 1)

Tamoxifen 20 mg/d for 5 years given to all patients with ER and/or PR positive
Radiotherapy as indicated

Outcomes

Primary endpoints:

• Disease‐free survival

• Overall survival

Secondary endpoints:

• Toxicity

Notes

Median follow‐up: 84 months
Trial identifier not retrieved

Supported by Sanofi‐Aventis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients were randomly assigned"

No further details provided in the trial report

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described

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

Quote: "follow‐up was done at 6‐month intervals for 5 years and annually thereafter to 7 years. Lab work, annual chest X‐rays, mammograms (if indicated), and assessments of health status occurred at these visits"

Quote: "toxicity was assessed at each patient visit and for 30 days after the last dose"

Graded according to NCI CTC

Comment: no independent adjudication committee involved in assessing these outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All patients reported as randomised (1016) accounted for in the results presented: 506 in the TC group and 510 in the AC group. Efficacy analyses conducted as intention‐to‐treat and safety analyses including patients who had received at least 1 dose of study drug

Selective reporting (reporting bias)

Low risk

All prespecified outcomes in the methods section reported in the results section of the trial publication

Other bias

Low risk

Quote: "patient characteristics were well balanced between treatment arms"