Addeo 2010.

Study characteristics
Methods	Study design: randomized phase III trial (1:1) Setting/country: single center in Italy Dates when study was conducted: March 2003 to November 2005
Participants	Ethnicity: NA Inclusion criteria People with superficial bladder cancer (Ta and T1 of any grade) whose disease had progressed or relapsed after BCG intravesical infusion or were ineligible for BCG treatment Exclusion criteria Prior radiation to the pelvis and intractable urinary tract infections Total number of participants randomly assigned Screened: 120 Eligible: 109 Disease type: recurrent disease Intervention: gemcitabine Number of all participants randomly assigned: 54 Mean age: 64.9 (SD 10.55) years Gender (men/women): 46/8 Tumor T stage Ta: 37; T1: 17 Tumor grade (G1/G2/G3) 11/28/15 Tumor size (< 3 cm/≥ 3 cm) NA but < 2 cm/> 2 cm = 36/18 Number of tumors (1/> 1): 29/25 Prior intravesical therapy: 54 (BCG: 46, epirubicin: 8) Comparator: mitomycin C Number of all participants randomly assigned: 55 Mean age: 67.9 (SD 10.2) years Gender (men/women): 47/8 Tumor T stage Ta: 35; T1: 20 Tumor grade (G1/G2/G3) 14/27/14 Tumor size (< 3 cm/≥ 3 cm) NA but < 2 cm/> 2 cm = 33/22 Number of tumors (1/> 1): 34/21 Prior intravesical therapy: 55 (BCG: 45, epirubicin: 10)
Interventions	Intervention: gemcitabine Gemcitabine 2000 mg/50 mL saline 6‐week induction course of infusion after TURBT. For the initial responders who remained free of recurrences, maintenance therapy consisted of 10 monthly treatments during first year Comparator: mitomycin C Mitomycin C 40 mg/50 mL saline Early infusion of the diluted drug within 2 days after TURBT, followed by 4 weekly treatments. For the initial responders who remained free of recurrences, maintenance therapy consisted of 10 monthly treatments during first year Follow‐up: median 36 months
Outcomes	Study did not separate the outcomes as primary and secondary Main endpoints Time of first recurrence (disease‐free survival) Relative risk of recurrence estimated by the life‐table method Recurrence rate per 100 patient‐months Cumulative rates of tumor progression How measured: recurrence; cystourethroscopy Time point measured: every 6 months Time point reported: cumulative Subgroup analysis Recurrence‐free survival in high‐grade disease (G3)
Funding Sources	Supported by grants from Lega Italiana per la Lotta contro i Tumori (LILT; Italian League for the Fight against Cancer; non‐profit organization and has oncologic prevention as its primary institutional task): organization information is available at www.lilt.it
Declarations of interest	None
Notes	Protocol: NA Language of publication: English
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "Random" only. Comment: randomization stated, but no information on method used; therefore, unclear risk of selection bias.
Allocation concealment (selection bias)	Unclear risk	Comment: no information given.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: no information given.
Blinding of outcome assessment (detection bias) Subjective outcomes	Unclear risk	Comment: no information given.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Comment: objective outcomes not likely affected by lack of blinding.
Incomplete outcome data (attrition bias) Time to recurrence	Low risk	Comment: no loss to follow‐up; all randomized participants were included in the analysis.
Incomplete outcome data (attrition bias) Time to progression	Low risk	Comment: study did not investigate this outcome, but reported several progressions from all randomized participants in each arm. We approximated the effect estimates (HR) using an indirect method (Parmar 1998). Thus, low risk of bias.
Incomplete outcome data (attrition bias) Grade III–V adverse events	Low risk	Comment: no loss to follow‐up; all randomized participants were included in the analysis.
Incomplete outcome data (attrition bias) Grade I or II adverse events	Low risk	Comment: no loss to follow‐up; all randomized participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Comment: no protocol available, but all objectives defined in the method section were reported.
Other bias	High risk	Comment: treatment schedule differed between groups; mitomycin C was given within 2 days of TURBT followed by 4 weekly treatment, but gemcitabine was given as a 6‐week induction course. If the schedule of mitomycin C was considered as standard treatment at that time, should we rate this domain as high.