Guy's.

Methods	Study design: 2 RCTs Country: UK Study period: 1961‐1975 (RCT 1, 1961‐1970; RCT 2, 1971‐1975) Inclusion criteria: women with Manchester stage I or 2 (T1‐2, N0‐1 [RCT1], M0) breast cancer judged suitable for radical mastectomy or extended tylectomy (wide excision). RCT 1 included only women aged ≥ 50, whereas RCT 2 included women of any age but restricted disease classifications to T1‐2, N0‐1a, M0. Exclusion criteria: none listed Length of follow‐up: median follow up = 24.7 years
Participants	No. in trial arms: wide excision: N = 305; ALND: N = 324 Age: wide excision: mean (range) = 58 (27‐80) years; ALND: mean (range) = 56 (25‐90) years (P = 0.03) Stage distribution: not reported, but tumour size was ≤ 2 cm: N = 83 in wide excision and N = 77 in ALND group; > 2 and ≤ 5 cm: N = 190 in wide excision and N = 209 in ALND group; > 5 cm: N = 29 in wide excision and N = 28 in ALND group (P = 0.63) Proportion node positive: 46% of participants treated via radical mastectomy had pathologically involved axillary nodes. Wide excision: clinically node positive 71/304 (from Clarke 2005 meta‐analysis web figures 10A/B); ALND: clinically node positive 85/326 (from Clarke 2005 meta‐analysis web figures 10A/B) Pathological type of breast cancer: histology: grade I: N = 63 in wide excision and N = 72 in ALND; grade II: N = 169 in wide excision and N = 176 in ALND; grade III: N = 60 in wide excision and N = 64 in ALND; lobular: N = 4 in wide excision and N = 2 in ALND; other: N = 9 in wide excision and N = 10 in ALND; contralateral tumour: N = 28 in wide excision and N = 41 in ALND (P = 0.9)
Interventions	Extended tylectomy, or wide excision, of the lump, together with surrounding breast tissue within 3 cm of palpable or visible growth + thiotepa + radiotherapy vs radical mastectomy (standard Halsted operation, except that the clavicular head of the pectoralis major muscle was conserved) + synoperative thiotepa + radiotherapy
Outcomes	Overall survival, breast cancer survival, distant recurrence, local recurrence, arm function, lymphoedema, activity, attitude
Axillary node surgery	Minimum no. nodes to be removed according to protocol: not reported Nodes removed clearance arm: not reported Nodes removed wide excision arm: not reported Method of node pathological analysis: All nodes were sectioned in specimens removed at radical mastectomy. No further details were reported. Further treatment for node positive cases: no
Radiotherapy	Wide excision: same as ALND with the exception that overall treatment time to supraclavicular triangle and axilla was 12 days (i.e. 25‐27 Gy) and breast was treated with parallel opposing fields on a 6 MeV linear accelerator via “Lincolnshire bolus” to bring the peak dose to the surface. Tumour dose = 3500‐3800 rads in 3 weeks (an additional 35‐38 Gy) ALND: RT to the axilla, supraclavicular triangle and internal mammary chain via a 300 kV machine with 10 × 8 cm field sizes for the axilla and supraclavicular triangle and 15 × 7.5 cm field sizes for the internal mammary chain. Supraclavicular and axillary fields directed to cross at the apex of the axilla giving a tumour dose at this point of 2500‐2700 rads. Treatment was given 5 days a week for 18 days (25‐27 Gy). RT same in all trial arms? no
Hormone and chemotherapy	Both arms: synoperative thiotepa at doses of 2 mg per 6.4 kg body weight with premedication, 1.5 mg per 6.4 kg body weight on second postoperative day and 1 mg per 6.4 kg body weight on fourth postoperative day. However, no patient entering the trial after 1968 received thiotepa.
Notes	No. in trial arms differs slightly from that reported in the Clarke 2005 meta‐analysis (web figures 10A and B): ALND: N = 326, wide excision: N = 304 Baseline differences? With Bonferroni adjustment for multiple comparisons, the age difference is no longer statistically significant. Intention‐to‐treat analyses? Survival, disease control in the axilla and breast cancer recurrence: no details reported. Long‐term adverse events: outcomes reported only for N = 77‐92 for wide excision arm, and for N = 90‐104 for ALND arm
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was carried out by drawing a ticket from a box.
Allocation concealment (selection bias)	Unclear risk	It is unclear whether allocation could be seen on the ticket.
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	No details were provided.
Incomplete outcome data (attrition bias) Survival	Low risk	Data appear to be available for all participants.
Incomplete outcome data (attrition bias) Axillary recurrence	Unclear risk	No details were reported.
Incomplete outcome data (attrition bias) Breast cancer recurrence	Unclear risk	No details were reported.
Incomplete outcome data (attrition bias) Short term adverse events	Unclear risk	Outcome was not reported.
Incomplete outcome data (attrition bias) Long term adverse events	High risk	Outcomes were reported only for RCT 1 and only for N = 77‐92 from the wide excision arm, and for N = 90‐104 from the ALND arm.
Selective reporting (reporting bias)	Unclear risk	Short‐term adverse events were not reported, and long‐term adverse events were reported for < 1/3 of participants.