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. 2017 Sep 12;2017(9):CD011864. doi: 10.1002/14651858.CD011864.pub2

Di Stasi 2006.

Methods Design: RCT, not blinded.
Randomisation: stratified‐blocked randomisation across 14 (i.e. 24‐2) strata as a results of four factors: primary versus recurrent tumours; multifocal versus unifocal tumours; grade 3 versus grade
 2 tumours; and presence versus absence of CIS.
Setting: multicentre/Italy.
Dates when study was conducted: 1 January 1994 to 30 June 2002.
Participants Inclusion criteria: people with histologically confirmed stage pT1 transitional‐cell carcinoma of the bladder, whether papillary or solid, regarded at high risk for tumour recurrence and at moderate‐ to high‐risk for progression because of: multifocal pT1, primary or recurrent, grade 2 transitional‐cell carcinoma; primary or recurrent pT1, multifocal or solitary, grade 3 transitional‐cell carcinoma; or pT1 with CIS, aged ≥ 18 years; adequate bone‐marrow reserve (i.e. white‐blood‐cell count ≥ 4000 × 106 cells/L and platelet count ≥ 120 × 109/L); normal renal function (i.e. serum creatinine ≤ 123.76 µmol/L); normal liver function (i.e. serum glutamic‐oxaloacetic transaminase ≤ 42 U/L, serum glutamic‐pyruvic transaminase ≤ 48 U/L and total bilirubin ≤ 22.23 µmol/L); and Karnofsky Performance Status between 50 and 100.
Exclusion criteria: people with previous treatment with BCG or MMC‐EMDA; treatment with any other intravesical cytostatic agent within the past 6 months; concomitant urothelial tumours of the upper urinary tract; previous muscle‐invasive (i.e. ≥ stage T2) transitional‐cell carcinoma of the bladder; bladder capacity < 2 L; untreated urinary tract infection; severe systemic infection (i.e. sepsis); urethral strictures that would prevent endoscopic procedures and repeated catheterisation; disease of upper urinary tract (e.g. vesicoureteral reflux or urinary tract stones) that would make multiple transurethral procedures a risk; previous radiotherapy to the pelvis; other concurrent chemotherapy; treatment with radiotherapy‐response or biological‐response modifiers; history of tuberculosis; other malignant diseases within 5 years of trial registration (except for basal‐cell carcinoma); pregnancy or nursing; and psychological, familial, sociological or geographical factors that would preclude study participation.
Total number of participants randomly assigned: 212.
Group A
Number of participants randomly assigned: 107.
Median age (years, interquartile range): 66.0 (56.0‐73.0).
Number of participants according to gender (male/female): 87/20.
Risk classification (number of participants):

  • primary/recurrent disease: 61/46;

  • stage Ta/T1: all T1 disease;

  • grade G1/G2/G3: 0/65/42;

  • concomitant CIS: 29;

  • multifocality: 87;

  • EAU risk classification (low/intermediate/high): not reported.


Group B
Number of participants randomly assigned: 105.
Median age (years, interquartile range): 67.0 (61.0‐73.0).
Number of participants according to gender (male/female): 86/19.
Risk classification (number of participants):

  • primary/recurrent disease: 62/43;

  • stage Ta/T1: all T1 disease;

  • grade G1/G2/G3: 0/64/41;

  • concomitant CIS: 28;

  • multifocality: 85;

  • EAU risk classification (low/intermediate/high): not reported.
Interventions Group A
MMC‐EMDA with sequential BCG induction and maintenance after TURBT.

  • BCG infusion: BCG 81 mg wet weight (10.2 ± 9.0 × 108 cfu) Connaught substrain (ImmuCyst, Alfa Wassermann SpA, Bologna, Italy) was suspended in 50 mL bacteriostatic‐free solution of 0.9% sodium chloride. After draining the bladder, suspension was infused intravesically for 120 minutes.

  • MMC infusion: MMC 40 mg (Mitomycin, Kyowa Italiana Farmaceutici, Srl, Milan, Italy) dissolved in 100 mL water was infused intravesically through the Foley catheter by gravity and retained in the bladder for 30 minutes, while 40‐60 mA per second to a maximum of 20 mA for 30 minutes pulsed electric current was given externally.


Group B
BCG induction and maintenance after TURBT: see above.
Induction therapy: about 3 weeks after TURBT.
Group A
BCG and sequential MMC‐EMDA: 3 cycles of treatment per week for 9 weeks for which 1 cycle consisted of 2 BCG infusions and 1 MMC infusion.
Group B
BCG alone: 6 intravesical treatments at weekly intervals.
Maintenance therapy (disease‐free 3 months after treatment).
Group A
BCG and sequential MMC‐EMDA: 1 infusion per month for 9 months: 3 cycles of MMC, MMC and BCG.
Group B
BCG alone: monthly infusion of BCG for 10 months.
Outcomes Primary end point:

  • Disease‐free interval.


Secondary end points:

  • Time to progression.

  • Overall survival.

  • Disease‐specific survival.


Toxic effects: local, systemic, or allergic adverse effects.
Median duration and interquartile range of follow‐up (months): 88 (63‐110).
Funding sources Not reported.
Declarations of interest No conflicts of interest.
Notes Language of article: English.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Judgement comment: computer‐generated random sequence.
Allocation concealment (selection bias) Unclear risk Judgement comment: no information given.
Blinding of participants and personnel (performance bias) 
 Time to recurrence and progression/adverse events High risk Quote: "This study was not blinded because of differences in treatment schedules and drug appearance."
Judgement comment: blinding was not done.
Blinding of participants and personnel (performance bias) 
 Disease‐specific survival/time to death Low risk Judgement comment: outcomes unlikely to be affected by lack of blinding.
Blinding of outcome assessment (detection bias) 
 Objective outcomes (time to death) Low risk Judgement comment: blinding of outcome assessor may not have affected on objective outcomes.
Blinding of outcome assessment (detection bias) 
 Subjective outcomes (time to recurrence and progression/adverse events/disease‐specific survival) High risk Judgement comment: outcome assessors were not blinded.
Incomplete outcome data (attrition bias) 
 All outcome Low risk Judgement comment: all participants randomised were included in analysis.
Selective reporting (reporting bias) Low risk Judgement comment: protocol (NCT01442519) was published and all outcomes reported well.
Other bias Low risk Judgement comment: not detected.