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. 2021 Jun 14;2021(6):CD009294. doi: 10.1002/14651858.CD009294.pub3

Gontero 2013.

Study characteristics
Methods Study design: multicenter, prospective, randomized, phase II study
Setting/country: multicenter (3 centers) in Italy, Germany, and the US
Dates when study was conducted: 2006–2010
Participants Ethnicity: NA
Inclusion criteria

  • People with clinical evidence of intermediate‐risk NMIBC (namely Ta‐1, G1–G2, multifocal or unique and recurrent, > 3 cm in diameter)

  • WHO performance status ≤ 2

  • Age ≤ 85 years

  • BCG naive, people not treated with intravesical chemotherapy in the last 3 months


Exclusion criteria

  • Presence of T1G3 or CIS

  • Preoperative urinary cytology positive for high‐grade atypia

  • Inadequate bone marrow reserve (white blood cells < 3 × 109/L, platelets < 100 × 109/L)

  • History of genitourinary tuberculosis

  • Presence of uncontrolled urinary infections


Total number of participants randomly assigned

  • Screened: 120

  • Eligible: 118


Disease type: primary and recurrent intermediate‐risk disease
Intervention: gemcitabine

  • Number of all participants randomly assigned: 59

  • Age: mean 67.4 (SD 9.4) years

  • Gender (men/women): 53/8

  • Tumor T stage

    • Ta: 42; T1: 19

  • Tumor grade (G1/G2)

    • 17/44

  • Tumor size (< 3 cm/≥ 3 cm): NA

  • Number of tumors (1/> 1): 25/36

  • Primary disease: 38; recurrent disease: 23

  • Prior intravesical therapy: 8 (mitomycin: 4; epirubicin: 4)


Comparator: 1/3 dose BCG

  • Number of all participants randomly assigned: 59

  • Age: mean 67.5 (SD 9.8) years

  • Gender (men/women): 50/9

  • Tumor T stage

    • Ta: 42; T1: 17

  • Tumor grade (G1/G2)

    • 20/39

  • Tumor size (< 3 cm/≥ 3 cm): NA

  • Number of tumors (1/> 1): 29/30

  • Primary disease: 31; recurrent disease: 28

  • Prior intravesical therapy: 14 (mitomycin: 6; epirubicin: 8)
Interventions Intervention: gemcitabine

  • Gemcitabine 2000 mg/50 mL saline

  • 7 to 15 days after TUR, participants received 6 weekly instillations and maintenance consisted of monthly instillations up to 1 year


Comparator: 1/3 dose BCG

  • 1/3 dose BCG (Connaught strain (ImmuCyst), 27 mg/50 mL saline)

  • 7–15 days after TUR, participants received an induction cycle of 6 weekly instillations, and maintenance consisted of 3 weekly instillations at 3, 6, and 12 months


Follow‐up: 1 year
Outcomes Primary outcomes

  • Quality of life

  • How measured: EORTC QLQ‐C30 and EORTC QLQ‐BLS 24 questionnaires

  • Time point measured: baseline, after induction (after 6 weeks), at 1 year

  • Time point reported: baseline, after induction (after 6 weeks), at 1 year


Secondary outcomes

  • Recurrence and progression at 1 year; toxicity

  • How measured

    • Recurrence: urinary cytology and cystoscopy performed every 3 months

    • Progression: biopsy or TUR

    • Toxicity: CTCAE version 3.0

  • Time point measured and time point reported

    • Recurrence, progression: at each event

    • Toxicity: baseline, after induction (after 6 weeks), at 1 year


Subgroup analysis: none
Funding Sources NA
Declarations of interest NA
Notes Protocol: NCT01697306
Language of publication: English
Baseline characteristics were based on eligible participants.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Quote from publication: "Simple 1:1 randomisation was used."
Comment: randomization stated and we received the author response "computer generate random number;" therefore, low risk of selection bias.
Allocation concealment (selection bias) Low risk Comment: we received the author response "central randomisation"; therefore, low risk of selection bias.
Blinding of participants and personnel (performance bias)
All outcomes High risk Quote from publication: in the protocol "None (open lable)" [sic: open label].
Blinding of outcome assessment (detection bias)
Subjective outcomes High risk Quote from publication: in the protocol "None (open lable)" [sic: open label].
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: no loss to follow‐up; all randomized participants were included in the analysis.
Incomplete outcome data (attrition bias)
Grade III–V adverse events High risk Comment: 41/59 (69.4%) participants in gemcitabine arm and 47/59 (79.6%) participants in 1/3 dose BCG arm were included in the analysis. The reasons for attrition were reported, but attrition rates were not balanced.
Incomplete outcome data (attrition bias)
Time to death from any cause Unclear risk Quote from publication: "At 1‐year follow up only 1 patient died of a noncancer specific cause."
Comment: author reported 1 participant died due to non‐cancer cause, but they did not report the denominator.
Incomplete outcome data (attrition bias)
Grade I or II adverse events High risk Comment: 41/59 (69.4%) participants in gemcitabine arm and 47/59 (79.6%) participants in 1/3 dose BCG arm were included in the analysis. The reasons for attrition were reported, but attrition rates were not balanced.
Incomplete outcome data (attrition bias)
Disease‐specific quality of life High risk Comment: 41/59 (69.4%) participants in gemcitabine arm and 47/59 (79.6%) participants in 1/3 dose BCG arm were included in the analysis. The reasons for attrition were reported, but attrition rates were not balanced.
Selective reporting (reporting bias) Low risk Comment: the protocol was provided (NCT01697306), but toxicity was not predefined. However, this is unlikely to introduce a bias.
Other bias Low risk Comment: treatment schedule differed between groups, but it was the same as protocol.