Quantity of Research Available
The literature search yielded 46 citations. The full text for 10 studies was reviewed and one randomized controlled trial6 was included (Appendix 1). A further seven grey literature sources were identified, none of which were included. Additional references of potential interest (some of which pre-dated the inclusion criteria of 2009) are included in Appendix 2. No studies on cost-effectiveness were identified.
Summary of Study Characteristics
Setting
The parallel group randomized control trial was conducted at three centres in Italy.6
Patient population
Eligible patients were >18 years old with confirmed diagnosis of pTa or pT1 urothelial carcinoma of the bladder, without previous history of bladder cancer or history of intravesical chemo/immunotherapy. The participants were stratified based on unifocal versus multifocal tumours, and by cancer grade (1, 2 or 3) before randomization.
Intervention
117 patients were treated with 40 mg intravesical EDMA mitomycin dissolved in 100mL sterile water about 30 minutes before TURBT. The solution was retained in the bladder for 30 minutes with a simultaneous external pulsed electric current.
Comparators
The control groups in this study received either passive diffusion of mitomycin within 6 hours after TURBT (n=119) or TURBT alone (n=116) Passive diffusion patients received a mitomycin dose of 40 mg in 50mL of sterile water, retained in the bladder for 60 minutes with catheter clamping.
Outcomes
The primary outcomes were recurrence and disease-free interval.
The secondary outcomes included time to disease progression (to muscle invasive disease), overall survival and disease-specific survival. The outcomes were assessed with abdominal ultrasonography, cystoscopy and urinary cytology.
Summary of Critical Appraisal
The included study6 was deemed high quality. The treatment and comparison groups showed similar baseline characteristics, the study exceeded the sample size required to detect a 20% increase in time to recurrence (n=297 required as per power calculation versus n=352 included in analysis) and analysis was completed by intention to treat. The randomization method was described in detail and the authors did not report any censoring due to loss to follow up. Staff conducting outcome assessments and data analysis were blinded to treatment assignment, though patients and physicians were not (presumably because this would not have been possible for this intervention).
Summary of Findings
Tumour Recurrence
Patients receiving EDMA treatment had 60% (Hazard Ratio [HR] 0.40, 95% confidence interval [CI] 0.28 to 0.59) lower hazard of recurrence relative to those receiving only TURBT over median 86 months follow up. There was no significant difference between patients receiving passive diffusion mitomycin versus TURBT alone (HR 0.84; 95% CI 0.61 to 1.17).
Disease-free interval
Patients receiving EDMA treatment had median 52 months disease free interval (interquartile range [IQR] 32 to 184 months) versus 16 months (IQR 12 to 168) in patients receiving passive diffusion and 12 months (IQR 12 to 37) for those only receiving TURBT.
Secondary outcomes
There were no statistically significant differences in progression to muscle-invasive disease, overall survival, or disease-specific survival between the treatment groups.
Adverse effects
99% of patients receiving EDMA treatment completed the instillation compared to 76% in the passive diffusion group. In the passive diffusion group, the instillation was stopped in the remaining 24% of patients due to pain, bladder spasm and solution leakage.
After TURBT, 6% of EDMA patients, 8% of passive diffusion patients and 4% of TURBT-only patients experienced overt bladder perforation, while 16%, 31% and 21% reported irritative bladder symptoms in the EDMA, passive diffusion and TURBT-only groups, respectively. Irritative bladder symptoms were longest lasting in the passive diffusion group.
Limitations
This study was conducted at three centres in Italy so generalizability beyond this context is unclear. Further, the study did not stratify results by centre, which would have provided insight into whether the setting affects the outcome.
The study compared EDMA before TURBT to passive diffusion just after TURBT, so a comparison of both treatments post-TURBT, or a combination of before and after treatment may yield different results. Furthermore, testing for statistical significance was conducted relative to the TURBT-only intervention rather than comparing EDMA versus passive diffusion directly. The statistical significance comparing the disease-free interval between these groups was also unclear.
No evidence on cost-effectiveness was identified.
