Boccon‐Gibod 1997.

Methods	Start date, end date of recruitment: April 1989 to June 1991 Follow‐up period: minimum follow‐up of 36 months Design: randomised controlled trial
Participants	Population/Inclusion criteria: newly diagnosed hormone‐naive metastatic prostate cancer; histologically proven prostate cancer with documented metastatic disease beyond pelvic lymph nodes, no prior hormonal manipulation, chemotherapy or radiation therapy outside of the primary tumour, normal liver function test, ECOG performance status 0 to 2 and absence of any previous malignant disease except skin cancer Setting: multi‐centre (7 institutions) Geographical location: France Exclusion criteria: not reported Total number randomly assigned: 104 Baseline imbalances: balanced Number of participants with non‐metastatic disease: 0 Number of participants with metastatic disease: 104 Age (mean ± SD): intervention: 72.3 ± 8.5 years; control: 73.8 ± 8 years PSA (mean ± SD): intervention: 666 ± 961 ng/mL; control: 681 ± 1073 ng/mL Subgroup measured: no
Interventions	Intervention Description/Timing: flutamide 250 mg 3 times daily; tablets were taken after each meal Number randomly assigned to this group: 54 Control Description/Timing: orchiectomy (formal or subcapsular orchiectomy at the discretion of each urologist) Number randomly assigned to this group: 50
Outcomes	Overall survival Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: minimum follow‐up of 36 months; at 69 months Time points reported: at 69 months Number of participants randomly assigned: intervention: 54; control: 50 Number of participants in evaluation for ITT: unclear Cancer‐specific mortality Outcome not reported/measured Treatment discontinuation due to adverse events Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: minimum follow‐up of 36 months Time points reported: minimum follow‐up of 36 months Number of participants randomly assigned: intervention: 54; control: 50 Number of participants in evaluation for ITT: intervention: 54; control: 50 Clinical progression Not measured/reported Biochemical progression Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: minimum follow‐up of 36 months Time points reported: minimum follow‐up of 36 months Outcome definition in report: defined by an increase in serum PSA > 50% of its nadir value confirmed over 2 months or a PSA rise > 50% over the nadir in association with another objective parameter (newly proven metastasis) Number of participants randomly assigned: intervention: 54; control: 50 Number of participants in evaluation for ITT: intervention 44; control: 42 Note: This outcome was named as clinical progression by the primary investigators. However, because of the outcome definition reported, we classified it as biochemical progression. The primary investigators reported that at progression, treatment was left to the discretion of the urologist. Participants treated by orchiectomy could receive flutamide or another antiandrogen. Participants receiving flutamide were treated with orchiectomy or medical castration using an LHRH agonist. Continuation of flutamide was done at the urologist's discretion. Also investigators reported no significant differences whether the progression‐free survival plot concerned only follow‐up participants or all included participants Treatment failure Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: minimum follow‐up of 36 months Time points reported: minimum follow‐up of 36 months Outcome definition in report: not reported Number of participants randomly assigned: intervention: 54; control: 50 Number of participants in evaluation for ITT: intervention: 44; control: 42 Adverse events Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: minimum follow‐up of 36 months Time points reported: minimum follow‐up of 36 months Number of participants randomly assigned: intervention: 54; control: 50 Number of participants in evaluation for ITT: intervention: 54; control: 50 Other outcomes reported Serum testosterone, salvage therapy by second‐line flutamide
Notes	Sexual function was not assessable because of advanced age of participants. Study authors reported no data on overall survival at 69 months but noted an "identical" survival, irrespective of second‐line treatment. They reported no definition of hepatic enzyme increase Study funding source: not reported Possible conflict of interest: Co‐author is a member of Schering‐Plough
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Low risk	Participants centrally randomly assigned after signing the informed consent form
Blinding of participants and personnel (performance bias) overall survival, cancer‐specific mortality, biochemical progression	Unclear risk	No blinding for overall survival and biochemical progression. Blinding was not possible because of different interventions provided. It might be conceivable that outcomes such as overall survival, cancer‐specific mortality or biochemical progression are influenced by lack of blinding. We finally judge that risk of bias regarding these outcomes is unclear
Blinding of participants and personnel (performance bias) treatment discontinuation due to adverse events, clinical progression, treatment failure, adverse events	High risk	No blinding for treatment discontinuation due to adverse events, adverse events and treatment failure. Blinding was not possible because of different interventions provided. We judge that outcomes such as treatment discontinuation due to adverse events, adverse events and treatment failure are likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) overall survival, cancer‐specific mortality, biochemical progression	Low risk	No blinding for overall survival and biochemical progression. Blinding was not possible because of different interventions provided, and study authors reported insufficient information only. However, we judge that it is not likely that outcome assessment for overall survival and biochemical progression are influenced by lack of blinding
Blinding of outcome assessment (detection bias) treatment discontinuation due to adverse events, clinical progression, treatment failure, adverse events	High risk	No blinding for treatment discontinuation due to adverse events, adverse events and treatment failure. Blinding was not possible because of different interventions provided, and study authors reported insufficient information only. We judge that it is likely that outcome assessment for clinical progression, treatment failure, adverse events and treatment discontinuation due to adverse events is influenced by lack of blinding
Incomplete outcome data (attrition bias) overall survival, cancer‐specific mortality	High risk	Data on overall survival were reported incompletely (Boccon‐Gibod et al reported only "identical" survival in both groups)
Incomplete outcome data (attrition bias) treatment discontinuation due to adverse events, adverse events	Low risk	Intention‐to‐treat analysis for adverse events and treatment discontinuation due to adverse events
Incomplete outcome data (attrition bias) clinical progression, biochemical progression	High risk	'As‐treated' analysis on biochemical progression done with substantial departure of the intervention received from that assigned at randomisation
Incomplete outcome data (attrition bias) treatment failure	High risk	'As‐treated' analysis on treatment failure done with substantial departure of the intervention received from that assigned at randomisation
Selective reporting (reporting bias)	High risk	Data on overall survival were reported incompletely and could not be entered into the meta‐analysis
Other bias	Unclear risk	Unclear risk for conflict of interest