NSABP B‐04.

Methods	Study design: RCT Country: USA and Canada Study period: 1971‐1974 Inclusion criteria: women with primary operable potentially curable breast cancer, with tumours confined to breast or breast and axilla, with tumours moveable in relation to underlying muscle and chest wall, with axillary nodes moveable in relation to chest wall and neuromuscular bundle, with no arm oedema Exclusion criteria: pregnancy, lactation previous treatment for current neoplasm, prior or concomitant cancer other than an effectively managed basal or squamous cell skin tumour, bilateral breast cancer, tumour other than a carcinoma, inflammatory tumour, skin ulceration > 2 cm, peau d’orange involving more than one‐third of the skin of the breast, satellite or parasternal nodules, fixation of axillary lymph nodes (> 2 cm), lymph nodes elsewhere suspected of containing tumour unproved by biopsy to be negative, poor surgical risks precluding any treatment options, presence of non‐malignant systemic disease making prolonged follow‐up unlikely Length of follow‐up: 25 years
Participants	No. in trial arms: clinically node negative: ALND: N = 389; total mastectomy + RT: N = 386; total mastectomy alone: N = 384. Clinically node positive: ALND: N = 301; total mastectomy + RT: N = 305 Age: clinically node negative: ALND: 56.5 years; total mastectomy + RT: 55.6 years; total mastectomy alone: 56.4 years. Clinically node positive: ALND: 55.3 years; total mastectomy + RT: 55.3 years Stage distribution: not reported, but Pathologic size of tumour was (for 1599/1665 participants): clinically node negative: ALND: 3.2 (SD 1.99) cm; total mastectomy + RT: 3.4 (SD 2.25) cm; total mastectomy alone: 3.1 (SD 1.73) cm. Clinically node positive: ALND: 3.7 (SD 2.02) cm; total mastectomy + RT: 3.7 (SD 1.95) cm Proportion node positive: See No. in trial arms entry above. Pathological type of breast cancer (for 1578/1665 participants): clinically node negative: ALND: infiltrating duct not otherwise stated (NOS) pure 46.3%, infiltrating duct NOS combinations 35.1%, medullary 3.5%, lobular 5.6%, mucoid 2.9%, tubular 0.9%, other 5.6%. Total mastectomy + RT: infiltrating duct NOS pure 48.5%, infiltrating duct NOS combinations 31%, medullary 3.3%, lobular 5.4%, mucoid 3.3%, tubular 1.5%, other 6.9%. Total mastectomy alone: infiltrating duct NOS pure 41.2%, infiltrating duct NOS combinations 37.2%, medullary 6%, lobular 7.1%, mucoid 2%, tubular 1.1%, other 5.4%. Clinically node positive: ALND: infiltrating duct NOS pure 57.1%, infiltrating duct NOS combinations 25.6%, medullary 8.4%, lobular 4.4%, mucoid 1.5%, tubular 0.4%, other 2.6%. Total mastectomy + RT: infiltrating duct NOS pure 62.1%, infiltrating duct NOS combinations 23.4%, medullary 3.9%, lobular 4.3%, mucoid 1.1%, tubular 0.7%, other 4.6%
Interventions	Participants were clinically assessed to be axillary node positive or axillary node negative before randomisation, then were randomly assigned to the following treatments:  If node negative: radical mastectomy (see below) vs total mastectomy (see below) + regional radiation vs total mastectomy alone. Participants designated as having clinically negative axillary nodes who had a total mastectomy and subsequently developed clinical evidence of axillary node involvement in the absence of other manifestations of disease were managed as follows. biopsy of involved nodes was performed to determine their status. If such nodes were reported as tumour positive, an axillary dissection was performed. If node positive: radical mastectomy vs total mastectomy + regional radiation. Radical mastectomy: removal of breast, pectoral muscles and axillary content en bloc. Total (simple) mastectomy: total removal of breast tissue in that area bounded by the midline of the sternum extending superiorly to the supraclavicular space, posteriorly along the lateral edge of the latissimus dorsi and inferiorly to the costal margin. Removal of the nipple was included. The pectoral fascia but not the pectoral muscles, together with an adequate excision of skin affected by tumour, was removed. No operative intervention was permissible in the axilla beyond the border of the pectoral muscle per protocol.
Outcomes	Disease‐free survival, overall survival, arm oedema
Axillary node surgery	Minimum no. nodes to be removed according to protocol: axillary clearance: see Interventions  Nodes removed ALND arm: median = 15.5 nodes, mean = 17.7 nodes (range, 3‐63) Nodes removed total mastectomy: two‐thirds of participants having a total mastectomy had no nodes in the specimen; in 90%, ≤ 5, in 97%, ≤ 10. Median = 0 nodes, mean = 2 nodes (range, 0‐31) Method of node pathological analysis: not reported Further treatment for histological node‐positive cases: no (but in the clinical node negative arm ‐ ALND was done if nodes became clinically involved and histological evidence showed node metastasis on biopsy)
Radiotherapy	Participants in the total mastectomy + RT arm Clinically negative axillary node: Both internal mammary and supraclavicular nodes received a tumour dose of 45 Gy in 25 fractions. Both chest wall and mid‐axilla received a tumour dose of 50 Gy in 25 fractions. Clinically positive axillary node: as for clinically node‐negative participants + an additional 10‐20 Gy boost to the mid‐axilla RT same in all trial arms? no
Hormone and chemotherapy	None received adjuvant systemic therapy.
Notes	68/365 node‐negative women who received total mastectomy alone subsequently had pathological confirmation of positive ipsilateral nodes. Positive nodes were identified within 2 years of surgery in 51/68, > 2‐5 years after surgery in 10/68, > 5‐10 years after surgery in 6/68 and > 10 years after surgery in 1/68. Median (range) time from mastectomy to identification of positive axillary nodes = 14.8 (3‐134.5) months. Baseline differences? Groups appear to be comparable at baseline. Intention‐to‐treat analyses? not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details were reported.
Allocation concealment (selection bias)	Unclear risk	No details were reported.
Blinding of outcome assessment (detection bias) Disease control in the axilla	Unclear risk	No details were provided.
Blinding of outcome assessment (detection bias) Breast cancer recurrence	Unclear risk	No details were provided.
Blinding of outcome assessment (detection bias) Short term adverse events	Unclear risk	Outcome was not reported.
Blinding of outcome assessment (detection bias) Long term adverse events	Unclear risk	Outcome was not reported.
Incomplete outcome data (attrition bias) Survival	Unclear risk	Data were reported for clinically node negative: ALND: N = 362/389; total mastectomy + RT: N = 352/386; total mastectomy alone: N = 365/384. Clinically node positive: ALND: N = 292/301; total mastectomy + RT: N = 294/305
Incomplete outcome data (attrition bias) Axillary recurrence	Unclear risk	Data were reported for clinically node negative: ALND: N = 362/389; total mastectomy + RT: N = 352/386; total mastectomy alone: N = 365/384. Clinically node positive: ALND: N = 292/301; total mastectomy + RT: N = 294/305
Incomplete outcome data (attrition bias) Breast cancer recurrence	Unclear risk	Data were reported for clinically node negative: ALND: N = 362/389; total mastectomy + RT: N = 352/386; total mastectomy alone: N = 365/384. Clinically node positive: ALND: N = 292/301; total mastectomy + RT: N = 294/305
Incomplete outcome data (attrition bias) Short term adverse events	Unclear risk	Outcome was not reported.
Incomplete outcome data (attrition bias) Long term adverse events	Unclear risk	Outcome was not reported.
Selective reporting (reporting bias)	Unclear risk	Short‐term and long‐term adverse events were not reported.