Drug delivery technique using electrical current for the treatment of non-muscle invasive bladder cancer

Review question

In people with non-muscle invasive bladder cancer (NMIBC), how do methods using electrical current to deliver a medicine compare to methods without electrical current?

Background

NMIBC is a cancer (tumour) of the inner lining of the bladder that can be removed from the inside using small instruments and a light source, so-called endoscopic surgery. These tumours can come back over time and spread into the deeper layers of the bladder wall. We know that different types of medicines that we can put into the bladder help prevent this. Investigators have looked at the use of an electrical current to make medicines work better. In this review, we wanted to discover whether using an electrical current was better or worse than not using an electrical current.

Study characteristics

The evidence is current to 7 February 2017. We found three studies that were conducted between 1994 and 2003 with 672 participants that compared five different ways of giving this treatment. Mitomycin (MMC) was the only medicine used together with electrical current. All three studies came from the same research team.

Key results

We are very unsure whether the use of an electrical current to give a course of MMC after endoscopic surgery is better or worse compared to giving a course of Bacillus Calmette-Guérin (BCG; vaccine usually used in tuberculosis) or MMC without electrical current. MMC given with electrical current together with BCG given over a long period of time may be better than BCG alone in delaying the tumour from coming back and from spreading into the deeper layer of the bladder wall. Giving one dose of MMC with electrical current before endoscopic surgery may be better than one dose of MMC without electric current after surgery or surgery alone without further treatment. We are uncertain whether people are more or less likely to have bad reactions from these treatments.

Quality of the evidence

The quality of evidence was low or very low for most of the treatments we compared, meaning that we were often uncertain about whether the findings were true. Further research will likely change these findings.

Authors' conclusions: 

While the use of EMDA to administer intravesical MMC may result in a delay in time to recurrence in select patient populations, we are uncertain about its impact on serious adverse events in all settings. Common reasons for downgrading the QoE were study limitations and imprecision. A potential role for EMDA-based administration of MMC may lie in settings where more established agents (such as BCG) are not available. In the setting of low or very low QoE for most comparisons, our confidence in the effect estimates is limited and the true effect sizes may be substantially different from those reported here.

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Background: 

Electromotive drug administration (EMDA) is the use of electrical current to improve the delivery of intravesical agents to reduce the risk of recurrence in people with non-muscle invasive bladder cancer (NMIBC). It is unclear how effective this is in comparison to other forms of intravesical therapy.

Objectives: 

To assess the effects of intravesical EMDA for the treatment of NMIBC.

Search strategy: 

We performed a comprehensive search using multiple databases (CENTRAL, MEDLINE, EMBASE), two clinical trial registries and a grey literature repository. We searched reference lists of relevant publications and abstract proceedings. We applied no language restrictions. The last search was February 2017.

Selection criteria: 

We searched for randomised studies comparing EMDA of any intravesical agent used to reduce bladder cancer recurrence in conjunction with transurethral resection of bladder tumour (TURBT).

Data collection and analysis: 

Two review authors independently screened the literature, extracted data, assessed risk of bias and rated quality of evidence (QoE) according to GRADE on a per outcome basis.

Main results: 

We included three trials with 672 participants that described five distinct comparisons. The same principal investigator conducted all three trials. All studies used mitomycin C (MMC) as the chemotherapeutic agent for EMDA.

1. Postoperative MMC-EMDA induction versus postoperative Bacillus Calmette-Guérin (BCG) induction: based on one study with 72 participants with carcinoma in situ (CIS) and concurrent pT1 urothelial carcinoma, we are uncertain (very low QoE) about the effect of MMC-EMDA on time to recurrence (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.64 to 1.76; corresponding to 30 more per 1000 participants, 95% CI 180 fewer to 380 more). There was no disease progression in either treatment arm at three months' follow-up. We are uncertain (very low QoE) about serious adverse events (RR 0.75, 95% CI 0.18 to 3.11).

2. Postoperative MMC-EMDA induction versus MMC-passive diffusion (PD) induction: based on one study with 72 participants with CIS and concurrent pT1 urothelial carcinoma, postoperative MMC-EMDA may (low QoE) reduce disease recurrence (RR 0.65, 95% CI 0.44 to 0.98; corresponding to 147 fewer per 1000 participants, 95% CI 235 fewer to 8 fewer). There was no disease progression in either treatment arm at three months' follow-up. We are uncertain (very low QoE) about the effect of MMC-EMDA on serious adverse events (RR 1.50, 95% CI 0.27 to 8.45).

3. Postoperative MMC-EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance: based on one study with 212 participants with pT1 urothelial carcinoma of the bladder with or without CIS, postoperative MMC-EMDA with sequential BCG may result (low QoE) in a longer time to recurrence (hazard ratio (HR) 0.51, 95% CI 0.34 to 0.77; corresponding to 181 fewer per 1000 participants, 95% CI 256 fewer to 79 fewer) and time to progression (HR 0.36, 95% CI 0.17 to 0.75; corresponding to 63 fewer per 1000 participants, 95% CI 82 fewer to 24 fewer). We are uncertain (very low QoE) about the effect of MMC-EMDA on serious adverse events (RR 1.02, 95% CI 0.21 to 4.94).

4. Single-dose, preoperative MMC-EMDA versus single-dose, postoperative MMC-PD: based on one study with 236 participants with primary pTa and pT1 urothelial carcinoma, preoperative MMC-EMDA likely (moderate QoE) results in a longer time to recurrence (HR 0.47, 95% CI 0.32 to 0.69; corresponding to 247 fewer per 1000 participants, 95% CI 341 fewer to 130 fewer) for a median follow-up of 86 months. We are uncertain (very low QoE) about the effect of MMC-EMDA on time to progression (HR 0.81, 95% CI 0.00 to 259.93; corresponding to 34 fewer per 1000 participants, 95% CI 193 fewer to 807 more) and serious adverse events (RR 0.79, 95% CI 0.30 to 2.05).

5. Single-dose, preoperative MMC-EMDA versus TURBT alone: based on one study with 233 participants with primary pTa and pT1 urothelial carcinoma, preoperative MMC-EMDA likely (moderate QoE) results in a longer time to recurrence (HR 0.40, 95% CI 0.28 to 0.57; corresponding to 304 fewer per 1000 participants, 95% CI 390 fewer to 198 fewer) for a median follow-up of 86 months. We are uncertain (very low QoE) about the effect of MMC-EMDA on time to progression (HR 0.74, 95% CI 0.00 to 247.93; corresponding to 49 fewer per 1000 participants, 95% CI 207 fewer to 793 more) or serious adverse events (HR 1.74, 95% CI 0.52 to 5.77).

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