Intravesical electromotive drug administration for non‐muscle invasive bladder cancer

Jae Hung Jung; Ahmet Gudeloglu; Halil Kiziloz; Gretchen M Kuntz; Alea Miller; Badrinath R Konety; Philipp Dahm

doi:10.1002/14651858.CD011864.pub2

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Postoperative MMC‐EMDA induction versus postoperative BCG induction (short term), Outcome 1 Time to recurrence.

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Analysis 1.2

Comparison 1 Postoperative MMC‐EMDA induction versus postoperative BCG induction (short term), Outcome 2 Time to progression.

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Analysis 1.3

Comparison 1 Postoperative MMC‐EMDA induction versus postoperative BCG induction (short term), Outcome 3 Serious adverse events.

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Analysis 1.4

Comparison 1 Postoperative MMC‐EMDA induction versus postoperative BCG induction (short term), Outcome 4 Disease‐specific survival.

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Analysis 1.5

Comparison 1 Postoperative MMC‐EMDA induction versus postoperative BCG induction (short term), Outcome 5 Time to death.

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Analysis 2.1

Comparison 2 Postoperative MMC‐EMDA induction versus MMC‐PD induction (short term), Outcome 1 Time to recurrence.

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Analysis 2.2

Comparison 2 Postoperative MMC‐EMDA induction versus MMC‐PD induction (short term), Outcome 2 Time to progression.

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Analysis 2.3

Comparison 2 Postoperative MMC‐EMDA induction versus MMC‐PD induction (short term), Outcome 3 Serious adverse events.

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Analysis 2.4

Comparison 2 Postoperative MMC‐EMDA induction versus MMC‐PD induction (short term), Outcome 4 Disease‐specific survival.

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Analysis 2.5

Comparison 2 Postoperative MMC‐EMDA induction versus MMC‐PD induction (short term), Outcome 5 Time to death.

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Analysis 3.1

Comparison 3 Postoperative MMC‐EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance (long term), Outcome 1 Time to recurrence.

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Analysis 3.2

Comparison 3 Postoperative MMC‐EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance (long term), Outcome 2 Time to progression.

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Analysis 3.3

Comparison 3 Postoperative MMC‐EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance (long term), Outcome 3 Serious adverse events.

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Analysis 3.4

Comparison 3 Postoperative MMC‐EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance (long term), Outcome 4 Disease‐specific survival.

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Analysis 3.5

Comparison 3 Postoperative MMC‐EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance (long term), Outcome 5 Time to death.

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Analysis 4.1

Comparison 4 Single‐dose, preoperative MMC‐EMDA versus single‐dose, postoperative MMC‐PD (long term), Outcome 1 Time to recurrence.

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Analysis 4.2

Comparison 4 Single‐dose, preoperative MMC‐EMDA versus single‐dose, postoperative MMC‐PD (long term), Outcome 2 Time to progression.

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Analysis 4.3

Comparison 4 Single‐dose, preoperative MMC‐EMDA versus single‐dose, postoperative MMC‐PD (long term), Outcome 3 Serious adverse events.

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Analysis 4.4

Comparison 4 Single‐dose, preoperative MMC‐EMDA versus single‐dose, postoperative MMC‐PD (long term), Outcome 4 Disease‐specific survival.

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Analysis 4.5

Comparison 4 Single‐dose, preoperative MMC‐EMDA versus single‐dose, postoperative MMC‐PD (long term), Outcome 5 Time to death.

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Analysis 4.6

Comparison 4 Single‐dose, preoperative MMC‐EMDA versus single‐dose, postoperative MMC‐PD (long term), Outcome 6 Minor adverse events.

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Analysis 5.1

Comparison 5 Single‐dose, preoperative MMC‐EMDA versus TURBT alone (long term), Outcome 1 Time to recurrence.

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Analysis 5.2

Comparison 5 Single‐dose, preoperative MMC‐EMDA versus TURBT alone (long term), Outcome 2 Time to progression.

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Analysis 5.3

Comparison 5 Single‐dose, preoperative MMC‐EMDA versus TURBT alone (long term), Outcome 3 Serious adverse events.

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Analysis 5.4

Comparison 5 Single‐dose, preoperative MMC‐EMDA versus TURBT alone (long term), Outcome 4 Disease‐specific survival.

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Analysis 5.5

Comparison 5 Single‐dose, preoperative MMC‐EMDA versus TURBT alone (long term), Outcome 5 Time to death.

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Analysis 5.6

Comparison 5 Single‐dose, preoperative MMC‐EMDA versus TURBT alone (long term), Outcome 6 Minor adverse events.

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Summary of findings for the main comparison. Postoperative MMC‐EMDA induction versus postoperative BCG induction therapy for non‐muscle invasive bladder cancer

Participants: people with non‐muscle invasive bladder cancer (multifocal carcinoma in situ or concurrent pT1, or both) Setting: multicentre study in Italy (all comparisons in the review stemmed from same study group) Intervention: initial 6 MMC‐EMDA intravesical instillations at weekly interval about 3 weeks after TURBT Control: initial 6 BCG intravesical instillations at weekly interval about 3 weeks after TURBT
Outcomes	No of participants (studies)	Quality of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with BCG	Risk difference with postoperative MMC‐EMDA
Time to recurrence Follow‐up: mean 3 months	72 (1 RCT)	⊕⊝⊝⊝ Very low^1,2	RR 1.06 (0.64 to 1.76)	Study population
				444 per 1000	27 more per 1000 (160 fewer to 338 more)
				Moderate
				500 per 1000 ³	30 more per 1000 (180 fewer to 380 more)
Time to progression Follow‐up: mean 3 months	72 (1 RCT)	⊕⊕⊝⊝ Low^1,4	Not estimable	Study population
				‐	‐
Serious adverse events Follow‐up: mean 3 months	72 (1 RCT)	⊕⊝⊝⊝ Very low^1,2	RR 0.75 (0.18 to 3.11)	Study population
				111 per 1000	28 fewer per 1000 (91 fewer to 234 more)
				High
				60 per 1000 ⁵	15 fewer per 1000 (49 fewer to 127 more)
Disease‐specific survival Follow‐up: mean 3 months	72 (1 RCT)	⊕⊕⊝⊝ Low^1,4	Not estimable	Study population
				‐	‐
Disease‐specific quality of life ‐ not reported	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BCG: Bacillus Calmette‐Guérin; CI: confidence interval; MMC‐EMDA: electromotive drug administration of mitomycin C; RCT: randomised controlled trial; RR: risk ratio; TURBT: transurethral resection of bladder tumour.
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
¹ Downgraded by one level for study limitations: unclear risk of selection bias and high risk of performance, detection and other bias. ² Downgraded by two level for imprecision: confidence interval was wide and crossed assumed clinically meaningful threshold. ³Gontero 2016: recurrence rate of bladder cancer after TURBT with postoperative six induction instillations of BCG was 50.7% on median follow‐up of 5.2 years. ⁴ Downgraded by one level for imprecision: no event. ⁵Witjes 1998: incidence of systemic adverse events after TURBT with postoperative BCG instillations for 6 consecutive weeks was 6% on a long‐term median follow‐up of more than 7 years.

Summary of findings for the main comparison. Postoperative MMC‐EMDA induction versus postoperative BCG induction therapy for non‐muscle invasive bladder cancer

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Summary of findings 2. Postoperative MMC‐EMDA induction versus MMC‐PD induction therapy for non‐muscle invasive bladder cancer

Participants: people with non‐muscle invasive bladder cancer (carcinoma in situ or concurrent pT1, or both) Setting: multicentre study in Italy (all comparisons in the review stemmed from same study group) Intervention: initial 6 MMC‐EMDA intravesical instillations at weekly interval about 3 weeks after TURBT Control: initial 6 MMC‐PD intravesical instillations at weekly interval about 3 weeks after TURBT
Outcomes	No of participants (studies)	Quality of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with MMC‐PD	Risk difference with postoperative MMC‐EMDA
Time to recurrence Follow‐up: mean 3 months	72 (1 RCT)	⊕⊕⊝⊝ Low^1,2	RR 0.65 (0.44 to 0.98)	Study population
				722 per 1000	253 fewer per 1000 (404 fewer to 14 fewer)
				Moderate
				420 per 1000 ³	147 fewer per 1000 (235 fewer to 8 fewer)
Time to progression Follow‐up: mean 3 months	72 (1 RCT)	⊕⊕⊝⊝ Low^1,4	Not estimable	Study population
				‐	‐
Serious adverse events Follow‐up: mean 3 months	72 (1 RCT)	⊕⊝⊝⊝ Very low^1,5	RR 1.50 (0.27 to 8.45)	Study population
				56 per 1000	28 more per 1000 (41 fewer to 414 more)
				High
				30 per 1000³	15 more per 1000 (22 fewer to 223 more)
Disease‐specific survival Follow‐up: mean 3 months	72 (1 RCT)	⊕⊕⊝⊝ Low^1,4	Not estimable	Study population
				‐	‐
Disease‐specific quality of life ‐ not reported	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MMC‐EMDA: electromotive drug administration of mitomycin C; MMC‐PD: passive diffusion of mitomycin C; RCT: randomised controlled trial; RR: risk ratio; TURBT: transurethral resection of bladder tumour.
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
¹ Downgraded by one level for study limitations: unclear risk of selection bias, high risk of performance, detection and other bias. ² Downgraded by one level for imprecision: confidence interval crossed assumed clinically meaningful threshold. ³Witjes 1998: recurrence rate of bladder cancer after TURBT with postoperative MMC‐PD instillations (total 5 instillations) was 42.8% and incidence of systemic adverse events was 3% based on a long‐term median follow‐up of more than 7 years. ⁴ Downgraded by one level for imprecision: no event. ⁵ Downgraded by two level for imprecision: confidence interval was wide and crossed assumed clinically meaningful threshold.

Summary of findings 2. Postoperative MMC‐EMDA induction versus MMC‐PD induction therapy for non‐muscle invasive bladder cancer

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Summary of findings 3. Postoperative MMC‐EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance therapy for non‐muscle invasive bladder cancer

Participants: people with non‐muscle invasive bladder cancer (pT1 or carcinoma in situ of the bladder, or both) Setting: multicentre study in Italy (all comparisons in the review stemmed from same study group) Intervention: initial 3 cycles of MMC‐EMDA with BCG intravesical instillation (cycle: 2 BCG followed by 1 MMC‐EMDA) at weekly interval about 3 weeks after TURBT, and 3 cycles of MMC‐EMDA with BCG intravesical instillations (monthly instillation, cycle: 2 MMC‐EMDA followed by 1 BCG) for 9 months Control: initial 6 BCG intravesical instillations at weekly interval about 3 weeks after TURBT, and BCG monthly instillation for 10 months
Outcomes	No of participants (studies)	Quality of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with BCG	Risk difference with postoperative MMC‐EMDA with BCG
Time to recurrence Follow‐up: median 88 months	212 (1 RCT)	⊕⊕⊝⊝ Low^1,2	HR 0.51 (0.34 to 0.77)	Study population
				581 per 1000	223 fewer per 1000 (325 fewer to 93 fewer)
				Moderate
				430 per 1000 ³	181 fewer per 1000 (256 fewer to 79 fewer)
Time to progression Follow‐up: median 88 months	212 (1 RCT)	⊕⊕⊝⊝ Low^1,2	HR 0.36 (0.17 to 0.75)	Study population
				215 per 1000	132 fewer per 1000 (175 fewer to 49 fewer)
				Moderate
				100 per 1000 ³	63 fewer per 1000 (82 fewer to 24 fewer)
Serious adverse events Follow‐up: median 88 months	212 (1 RCT)	⊕⊝⊝⊝ Very low^4,5	RR 1.02 (0.21 to 4.94)	Study population
				28 per 1000	1 more per 1000 (22 fewer to 110 more)
				High
				70 per 1000 ³	1 more per 1000 (55 fewer to 276 more)
Disease‐specific survival Follow‐up: median 88 months	212 (1 RCT)	⊕⊕⊝⊝ Low^1,2	HR 0.31 (0.12 to 0.80)	Study population
				159 per 1000	107 fewer per 1000 (138 fewer to 30 fewer)
				Moderate
				60 per 1000 ³	41 fewer per 1000 (53 fewer to 12 fewer)
Disease‐specific quality of life ‐ not reported	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BCG: Bacillus Calmette‐Guérin; CI: confidence interval; HR: hazard ratio; MMC‐EMDA: electromotive drug administration of mitomycin C; RCT: randomised controlled trial; RR: risk ratio; TURBT: transurethral resection of bladder tumour.
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
¹ Downgrade by one level for study limitations: unclear risk of selection and attrition bias and high risk of performance and detection bias. ² Downgrade by one level for imprecision: confidence interval crossed assumed clinically meaningful threshold. ³Oddens 2013: disease recurrence, progression and disease‐specific death after TURBT with BCG maintenance therapy (once a week for 6 weeks, followed by three weekly instillations at months 3, 6 and 12) were 42.8%, 9.1% and 5.9%, respectively and stopped treatment due to local or systemic adverse events was 7% based on a long‐term median follow‐up of more than 7.1 years. ⁴ Downgrade by one level for study limitations: unclear risk of selection bias and high risk of performance and detection bias. ⁵ Downgraded by two level for imprecision: confidence interval was wide and crossed assumed clinically meaningful threshold.

Summary of findings 3. Postoperative MMC‐EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance therapy for non‐muscle invasive bladder cancer

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Summary of findings 4. Single‐dose, preoperative MMC‐EMDA versus single‐dose, postoperative MMC‐PD for non‐muscle invasive bladder cancer

Participants: people with non‐muscle invasive bladder cancer (primary pTa and pT1 urothelial carcinoma) Setting: multicentre study in Italy (all comparisons in the review stemmed from same study group) Intervention: single MMC‐EMDA intravesical instillation about 30 minutes before spinal or general anaesthesia for TURBT Control: single MMC‐PD intravesical instillation immediately after TURBT
Outcomes	No of participants (studies)	Quality of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with MMC‐PD	Risk difference with preoperative MMC‐EMDA
Time to recurrence Follow‐up: median 86 months	236 (1 RCT)	⊕⊕⊕⊝ Moderate¹	HR 0.47 (0.32 to 0.69)	Study population
				588 per 1000	247 fewer per 1000 (341 fewer to 130 fewer)
				Low ²
				100 per 1000	52 fewer per 1000 (67 fewer to 30 fewer)
				High ²
				500 per 1000	222 fewer per 1000 (301 fewer to 120 fewer)
Time to progression Follow‐up: median 86 months	236 (1 RCT)	⊕⊝⊝⊝ Very low^1,3	HR 0.81 (0.00 to 259.93)	Study population
				193 per 1000	34 fewer per 1000 (193 fewer to 807 more)
				Low ²
				20 per 1000	4 fewer per 1000 (20 fewer to 975 more)
				High ²
				100 per 1000	18 fewer per 1000 (100 fewer to 900 more)
Serious adverse events Follow‐up: median 86 months	236 (1 RCT)	⊕⊝⊝⊝ Very low^1,3	RR 0.79 (0.30 to 2.05)	Study population
				76 per 1000	16 fewer per 1000 (53 fewer to 79 more)
				High ⁴
				30 per 1000	6 fewer per 1000 (21 fewer to 31 more)
Disease‐specific survival Follow‐up: median 86 months	236 (1 RCT)	⊕⊕⊝⊝ Low³	HR 0.99 (0.74 to 1.32)	Study population
				126 per 1000	1 fewer per 1000 (31 fewer to 37 more)
				Low ²
				20 per 1000	0 fewer per 1000 (5 fewer to 6 more)
				High ²
				60 per 1000	1 fewer per 1000 (15 fewer to 18 more)
Disease‐specific quality of life ‐ not reported	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio; MMC‐EMDA: electromotive drug administration of mitomycin C; MMC‐PD: passive diffusion of mitomycin C; RCT: randomised controlled trial; RR: risk ratio; TURBT: transurethral resection of bladder tumour.
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
¹ Downgraded by one level for study limitations: high risk of performance bias. ²Sylvester 2016: baseline risks of time to recurrence and progression, and disease‐specific survival were estimated from included studies in a systematic review and meta‐analysis of RCTs comparing the efficacy of a single instillation of MMC after TURBT with TURBTs alone. ³ Downgraded by two level for imprecision: confidence interval was wide and crossed clinically meaningful threshold. ⁴Witjes 1998: incidence of systemic adverse events after TURBT with postoperative MMC‐PD instillations (total 5 instillations) was 3% based on a long‐term median follow‐up of more than 7 years.

Summary of findings 4. Single‐dose, preoperative MMC‐EMDA versus single‐dose, postoperative MMC‐PD for non‐muscle invasive bladder cancer

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Summary of findings 5. Single‐dose, preoperative MMC‐EMDA versus TURBT alone for non‐muscle invasive bladder cancer

Participants: people with non‐muscle invasive bladder cancer (primary pTa and pT1 urothelial carcinoma) Setting: multicentre study in Italy (all comparisons in the review stemmed from same study group) Intervention: single MMC‐EMDA intravesical instillation about 30 minutes before spinal or general anaesthesia for TURBT Control: TURBT alone
Outcomes	No of participants (studies)	Quality of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with TURBT alone	Risk difference with preoperative MMC‐EMDA
Time to recurrence Follow‐up: median 86 months	233 (1 RCT)	⊕⊕⊕⊝ Moderate¹	HR 0.40 (0.28 to 0.57)	Study population
				638 per 1000	304 fewer per 1000 (390 fewer to 198 fewer)
				Low ²
				400 per 1000	215 fewer per 1000 (267 fewer to 147 fewer)
				High ²
				700 per 1000	318 fewer per 1000 (414 fewer to 203 fewer)
Time to progression Follow‐up: median 86 months	233 (1 RCT)	⊕⊝⊝⊝ Very low^1,3	HR 0.74 (0.00 to 247.93)	Study population
				207 per 1000	49 fewer per 1000 (207 fewer to 793 more)
				Low ²
				20 per 1000	5 fewer per 1000 (20 fewer to 973 more)
				High ²
				100 per 1000	25 fewer per 1000 (100 fewer to 900 more)
Serious adverse events Follow‐up: median 86 months	233 (1 RCT)	⊕⊝⊝⊝ Very low^1,3	RR 1.74 (0.52 to 5.77)	Study population
				34 per 1000	26 more per 1000 (17 fewer to 164 more)
				Moderate ⁴
				30 per 1000	22 more per 1000 (14 fewer to 143 more)
Disease‐specific survival Follow‐up: median 86 months	233 (1 RCT)	⊕⊕⊕⊝ Moderate⁵	HR 1.06 (0.80 to 1.40)	Study population
				129 per 1000	7 more per 1000 (24 fewer to 47 more)
				Low ²
				20 per 1000	1 more per 1000 (4 fewer to 8 more)
				High ²
				100 per 1000	6 more per 1000 (19 fewer to 37 more)
Disease‐specific quality of life ‐ not reported	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio; MMC‐EMDA: electromotive drug administration of mitomycin C; RCT: randomised controlled trial; RR: risk ratio; TURBT: transurethral resection of bladder tumour.
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
¹ Downgraded by one level for study limitations: high risk of performance bias. ²Sylvester 2016: baseline risks of time to recurrence and progression, and disease‐specific survival were estimated from included studies in a systematic review and meta‐analysis of RCTs comparing the efficacy of a single instillation of MMC after TURBT with TURBT alone. ³ Downgraded by two level for imprecision: confidence interval was wide and crossed assumed clinically meaningful threshold. ⁴Matulewicz 2015: rates of death and overall adverse events rate after TURBT were 2.8% and 5.8%. ⁵ Downgraded by one level for imprecision: confidence interval crossed assumed clinically meaningful threshold.

Summary of findings 5. Single‐dose, preoperative MMC‐EMDA versus TURBT alone for non‐muscle invasive bladder cancer

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Table 1. Baseline characteristics of included studies

Study name	Trial period (year to year)	Setting	Participants	Intervention(s) and comparator(s)	Description of intervention	Median age (years, interquartile range)	Disease characteristics (n)	Median follow‐up (months, interquartile range)
Di Stasi 2003	June 1994 to March 2001	Multicentre/Italy	People with histologically confirmed multifocal CIS of the bladder and most had concurrent pT1 papillary transitional‐cell carcinoma (all primary disease).	MMC‐EMDA induction after TURBT	6 intravesical instillation at weekly intervals.	64.5 (not reported)	Ta/T1: 0/32 Grade: not reported CIS: 36	43 (not reported)
				MMC‐PD induction after TURBT		68.5 (not reported)	Ta/T1: 0/33 Grade: not reported CIS: 36
				BCG induction after TURBT		66.5 (not reported)	Ta/T1: 0/33 Grade: not reported CIS: 36
Di Stasi 2006	1 January 1994 to 30 June 2002	Multicentre/Italy	People with histologically confirmed stage pT1 transitional‐cell carcinoma of the bladder were regarded as being 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.	MMC‐EMDA with sequential BCG induction and maintenance after TURBT	Induction: 3 cycles of treatment per week for 9 weeks for which 1 cycle consisted of 2 BCG infusions and 1 MMC infusion Maintenance: 1 infusion per month for 9 months: 3 cycles of MMC, MMC and BCG.	66.0 (56.0‐73.0)	Ta/T1: all T1 disease Grade: 0/65/42 CIS: 29	88 (63‐110)
				BCG induction and maintenance after TURBT	Induction: 6 intravesical treatments at weekly intervals Maintenance: monthly infusion of BCG for 10 months.	67.0 (61.0‐73.0)	Ta/T1: all T1 disease Grade: 0/64/41 CIS: 28
Di Stasi 2011	1 January 1994 to 31 December 2003	Multicentre/Italy	People with pTa and pT1 urothelial carcinoma.	Single‐dose, MMC‐EMDA before TURBT	Single intravesical instillation about 30 minutes before spinal or general anaesthesia.	67.0 (63.0‐74.0)	Ta/T1: 63/54 Grade: 22/62/33 CIS: not reported	86 (57‐125)
				Single‐dose, MMC‐PD immediately after TURBT	Single intravesical instillation within 6 hours of TURBT.	67.0 (61.0‐72.0)	Ta/T1: 64/55 Grade: 23/64/32 CIS: not reported
				TURBT alone	No intravesical instillation.	66.5 (60.0‐73.0)	Ta/T1: 63/53 Grade: 21/63/32 CIS: not reported
BCG: Bacillus Calmette‐Guérin; CIS: carcinoma in situ; MMC‐EMDA: electromotive drug administration of mitomycin C; MMC‐PD: passive diffusion of mitomycin C; TURBT: transurethral resection of bladder tumour.

Table 1. Baseline characteristics of included studies

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Table 2. Participants' disposition of included studies

Study name	Intervention(s) and comparator(s)	Screened/eligible (n)	Randomised (n)	Treatment completion (n (%))	Analysed (n (%))
Di Stasi 2003	MMC‐EMDA induction after TURBT	Not reported/117	36	36 (100)	36 (100)
	MMC‐PD induction after TURBT		36	36 (100)	36 (100)
	BCG induction after TURBT		36	36 (100)	36 (100)
	Total		108	108 (100)	108 (100)
Di Stasi 2006	MMC‐EMDA with sequential BCG induction and maintenance after TURBT	241/212	107	96 (89)	107 (100)
	BCG induction and maintenance after TURBT	241/212	105	94 (89)	105 (100)
	Total		212	190 (89)	212 (100)
Di Stasi 2011	Single‐dose, MMC‐EMDA before TURBT	398/374	124	117 (94)	117 (94)
	Single‐dose, MMC‐PD immediately after TURBT		126	119 (94)	119 (94)
	TURBT alone		124	116 (93)	116 (93)
	Total		374	352 (94)	352 (94)
Grand total			694	650 (93)	672 (96)
BCG: Bacillus Calmette‐Guérin; MMC‐EMDA: electromotive drug administration of mitomycin C; MMC‐PD: passive diffusion of mitomycin C; n: number of participants; TURBT: transurethral resection of bladder tumour.

Table 2. Participants' disposition of included studies

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Comparison 1. Postoperative MMC‐EMDA induction versus postoperative BCG induction (short term)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to recurrence Show forest plot	1	72	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.64, 1.76]

2 Time to progression Show forest plot	1	72	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

3 Serious adverse events Show forest plot	1	72	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.18, 3.11]

4 Disease‐specific survival Show forest plot	1	72	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

5 Time to death Show forest plot	1	72	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. Postoperative MMC‐EMDA induction versus postoperative BCG induction (short term)

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Comparison 2. Postoperative MMC‐EMDA induction versus MMC‐PD induction (short term)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to recurrence Show forest plot	1	72	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.44, 0.98]

2 Time to progression Show forest plot	1	72	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

3 Serious adverse events Show forest plot	1	72	Risk Ratio (M‐H, Random, 95% CI)	1.5 [0.27, 8.45]

4 Disease‐specific survival Show forest plot	1	72	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

5 Time to death Show forest plot	1	72	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 2. Postoperative MMC‐EMDA induction versus MMC‐PD induction (short term)

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Comparison 3. Postoperative MMC‐EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance (long term)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to recurrence Show forest plot	1	212	Hazard Ratio (Random, 95% CI)	0.51 [0.34, 0.77]

2 Time to progression Show forest plot	1	212	Hazard Ratio (Random, 95% CI)	0.36 [0.17, 0.75]

3 Serious adverse events Show forest plot	1	212	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.21, 4.94]

4 Disease‐specific survival Show forest plot	1	212	Hazard Ratio (Random, 95% CI)	0.31 [0.12, 0.80]

5 Time to death Show forest plot	1	212	Hazard Ratio (Random, 95% CI)	0.59 [0.35, 1.00]

Comparison 3. Postoperative MMC‐EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance (long term)

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Comparison 4. Single‐dose, preoperative MMC‐EMDA versus single‐dose, postoperative MMC‐PD (long term)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to recurrence Show forest plot	1	236	Hazard Ratio (Random, 95% CI)	0.47 [0.32, 0.69]

2 Time to progression Show forest plot	1	236	Hazard Ratio (Random, 95% CI)	0.81 [0.00, 259.93]

3 Serious adverse events Show forest plot	1	236	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.30, 2.05]

4 Disease‐specific survival Show forest plot	1	236	Hazard Ratio (Random, 95% CI)	0.99 [0.74, 1.32]

5 Time to death Show forest plot	1	236	Hazard Ratio (Random, 95% CI)	0.89 [0.62, 1.28]

6 Minor adverse events Show forest plot	1	236	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.42, 0.72]

Comparison 4. Single‐dose, preoperative MMC‐EMDA versus single‐dose, postoperative MMC‐PD (long term)

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Comparison 5. Single‐dose, preoperative MMC‐EMDA versus TURBT alone (long term)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to recurrence Show forest plot	1	233	Hazard Ratio (Random, 95% CI)	0.40 [0.28, 0.57]

2 Time to progression Show forest plot	1	233	Hazard Ratio (Random, 95% CI)	0.74 [0.00, 247.93]

3 Serious adverse events Show forest plot	1	233	Risk Ratio (M‐H, Random, 95% CI)	1.74 [0.52, 5.77]

4 Disease‐specific survival Show forest plot	1	233	Hazard Ratio (Random, 95% CI)	1.06 [0.80, 1.40]

5 Time to death Show forest plot	1	233	Hazard Ratio (Random, 95% CI)	1.07 [0.73, 1.57]

6 Minor adverse events Show forest plot	1	233	Risk Ratio (M‐H, Random, 95% CI)	1.68 [1.11, 2.53]

Comparison 5. Single‐dose, preoperative MMC‐EMDA versus TURBT alone (long term)

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