VACURG.

Methods	Design: 3 prospective randomised clinical trials Setting: multicentric Recruiting period: 1960 to 1975 (study 1: 1960 to 1967; study 2: 1967 to 1969; study 3: 1969 to 1975) Sample size: 3433 patients (study 1: 1902; study 2: 508; study 3: 1023) Follow‐up (months): not reported
Participants	Population description: patients with histologically confirmed prostate cancer stage I to IV whose condition had been newly diagnosed Inclusion criteria: stage I: Incidentally found microscopic cancer stage II: palpable cancer by rectal examination not extended beyond the prostatic capsule stage III: patients with local extension beyond the prostate capsule as detected by digital examination but without evidence of distant metastasis and with normal acid phosphatase stage IV: patients with distant metastasis and/or elevated acid phosphatase No patients had staging laparotomies and bone scans were not used in staging. Exclusion criteria: not reported Tumour stage: stage I to IV Previous treatment: no previous treatment reported Number randomised: 3433 patients Withdrawals and exclusions: study 2 had to stop after a few years because 5.0 mg oestrogens were too hazardous Subgroup measured: not reported Subgroup reported: not reported Age: not reported Baseline imbalances: no baseline imbalances reported
Interventions	VACURG study consisted of 3 prospective randomised clinical trials that were analysed separately (we included only study 1): STUDY 1 Early ADT (intervention group): route of administration: surgical intervention plus oral frequency, dose: orchiectomy plus placebo (469 patients); other interventions not included in this review: 5.0 mg diethylstilbestrol (DES) (475 patients), orchiectomy plus 5.0 mg DES (474 patients) number of patients randomised: 484 patients (all randomised participants in study 1: 1902 patients) Deferred ADT (control group): route of administration: oral frequency, dose: placebo without orchiectomy (484 patients) definition of deferred ADT: If patients showed progression of the disease, then the clinicians treating them were free to change their therapy. Definition of time to progression: defined as time until first metastases or first increase in acid phosphatase or death from prostate cancer. Patients in the placebo group were able to change their therapy so they could receive oestrogens later. The comparison can be thought of as an orchiectomy vs delayed endocrine therapy number of patients randomised: 484 patients (all randomised participants in study 1: 1902 patients) STUDY 2 (not included in this review) Early ADT (intervention group) route of administration: oral frequency, dose: 0.2 mg DES (125 patients) or 1.0 mg DES (128 patients) or 5.0 mg DES (127 patients) number of patients randomised: 508 patients (all participants of study 2) Deferred ADT (control group): route of administration: oral frequency, dose: placebo (128 patients) definition of deferred ADT: If patients showed progression of the disease, then the clinicians treating them were free to change their therapyDefinition of time to progression: defined as time until first metastases or first increase in acid phosphatase or death from prostate cancer number of patients randomised: 508 patients (all participants of study 2) STUDY 3 (not included in this review) Early ADT (intervention group) route of administration: oral frequency, dose: premarin 2.5 (263 patients) or provera 30 (255 patients) or provera 30 + 1.0 mg DES (251 patients) or 1.0 mg DES (254 patients) number of patients randomised: 1023 patients Deferred ADT (control group): route of administration: ‐ frequency, dose: No group with deferred ADT
Outcomes	Primary outcome(s): overall/ cancer‐specific survival cardiovascular death deaths from other causes
Funding sources	Grant R10 CA12443 from the National Cancer Institute, National Institutes of Health, Public Health Service, Bethesda, MD.
Declaration of interest	not reported
Notes	for time to death of any cause, we included only data from study 1 for prostate cancer patients with metastatic disease (M1 = stage IV) treated with placebo or with orchiectomy + placebo. For time to death of any cause, we did not include patients receiving oestrogens (study 1, 2, 3) or patients with locally advanced disease (T3‐4 M0 = stage III) because it was unclear if these patients received also local therapy (e.g. prostatectomy) for death from heart or vascular disease, we included data from study 1 for prostate cancer patients with locally advanced (T3‐4 M0 = stage III) or metastatic disease (M1 = stage IV) treated with placebo or with orchiectomy + placebo. we did not include data for time‐to‐progression, time to death from prostate cancer because the analyses of these outcome included locally advanced and metastatic patients (stage III and IV) and it is unclear if stage III patients also had local therapy. study 1: The study was stopped early because a pattern of excess cardiovascular death in the 5.0 mg DES arm was beginning to emerge
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information from publication: Information was not reported. Comment: Unclear random sequence generation.
Allocation concealment (selection bias)	Unclear risk	Information from publication: Information was not reported. Comment: Unclear allocation concealment.
Blinding of participants and personnel (performance bias) Time to death of any cause	Unclear risk	Information from publication: "Patients received a placebo treatment" (placebo with orchiectomy vs. placebo without orchiectomy). Comment: However, there was no blinding regarding orchiectomy (such as a placebo operation). It might be conceivable that even time to death of any cause is influenced by lack of blinding. We finally judge that there is an unclear risk of bias.
Blinding of participants and personnel (performance bias) All other outcomes	High risk	Information from publication: "Patients received a placebo treatment" (placebo with orchiectomy vs. placebo without orchiectomy). Comment: However, there was no blinding regarding orchiectomy (such as a placebo operation). Patients received a placebo treatment (orchiectomy + placebo vs. placebo). However, blinding was not reported and there was no blinding for orchiectomy. We judge that adverse events are likely to be influenced by lack of blinding.
Blinding of outcome assessment (detection bias) Time to death from any cause	Low risk	Information from publication: There was no blinding of outcome assessment (or it was not reported). Comment: Blinding of outcome assessment could have been expected. However, we judge that it is not likely that outcome assessment for time to death of any cause is influenced by lack of blinding.
Blinding of outcome assessment (detection bias) All other outcomes	High risk	Information from publication: There was no blinding of outcome assessment (or it was not reported). Comment: Blinding of outcome assessment could have been expected. We judge that outcome assessment of adverse events is likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias) Oncological outcomes (Time‐to‐death of any cause, Time‐to‐disease progression, Time‐to‐death from prostate cancer)	Unclear risk	There is no evidence for missing outcome data for time to death of any cause. However, we included only prostate cancer patients from study 1 with metastatic disease treated with placebo or with orchiectomy + placebo. We did not include patients from study 2 or 3 or patients receiving oestrogens for treating prostate cancer. There is therefore unclear risk of bias.
Incomplete outcome data (attrition bias) Adverse events (Serious and other adverse events)	Unclear risk	Not applicable (outcome not measured/reported). Only death due to heart or vascular disease was reported.
Incomplete outcome data (attrition bias) Quality of life	Unclear risk	Not applicable (outcome not measured/reported).
Selective reporting (reporting bias)	High risk	There was no assessment of adverse events (only for death due to heart or vascular disease) but it could have been expected or adverse events were measured but not reported.
Other bias	Unclear risk	We identified no other sources of bias.

p.o. = per os

s.c. = subcutaneous