Intravesical Bacillus Calmette‐Guérin with interferon‐alpha versus intravesical Bacillus Calmette‐Guérin for treating non‐muscle‐invasive bladder cancer

Andrew RH Shepherd; Emily Shepherd; Nicholas R Brook

doi:10.1002/14651858.CD012112.pub2

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Figure 1

Study flow diagram (searched 14 March 2016, updated 25 August 2016).

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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 Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone, Outcome 1 Time‐to‐recurrence.

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Analysis 1.2

Comparison 1 Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone, Outcome 2 Recurrence.

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Analysis 1.3

Comparison 1 Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone, Outcome 3 Progression.

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Analysis 1.4

Comparison 1 Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone, Outcome 4 Disease‐specific mortality.

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Analysis 1.5

Comparison 1 Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone, Outcome 5 Systemic or local adverse events.

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Analysis 2.1

Comparison 2 Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone, Outcome 1 Time‐to‐recurrence.

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Analysis 2.2

Comparison 2 Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone, Outcome 2 Time‐to‐progression.

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Analysis 2.3

Comparison 2 Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone, Outcome 3 Discontinuation of therapy due to adverse events.

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Analysis 2.4

Comparison 2 Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone, Outcome 4 Disease‐specific mortality.

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Analysis 2.5

Comparison 2 Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone, Outcome 5 Overall survival.

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Analysis 2.6

Comparison 2 Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone, Outcome 6 Systemic or local adverse events.

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Summary of findings for the main comparison. Intravesically administered BCG combined with IFN‐α compared to intravesically administered BCG alone for treating non‐muscle‐invasive bladder cancer

Intravesically administered BCG combined with IFN‐α compared to intravesically administered BCG alone for treating non‐muscle‐invasive bladder cancer Patient or population: patients with non‐muscle invasive bladder cancer Intervention: BCG combined with IFN‐α Comparison: BCG alone
Outcomes	№ of participants (studies)	Quality of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
				Risk with intravesically administered BCG alone	Risk difference with intravesically administered BCG combined with IFN‐α
Recurrence Follow‐up: median 38.3 to 60 months	925 (4 RCTs)	⊕⊕⊝⊝ VERY LOW ^{1 2 3}	RR 0.76 (0.44 to 1.32)	Study population
				342 per 1000	82 fewer per 1000 (191 fewer to 109 more)
Progression Follow‐up: median 38.3 to 60 months	219 (2 RCTs)	⊕⊕⊝⊝ LOW ^{4 5}	RR 0.26 (0.04 to 1.87)	Study population
				124 per 1000	92 fewer per 1000 (119 fewer to 108 more)
Discontinuation of therapy due to adverse events ‐ not measured	‐	‐	‐	‐	‐
Disease‐specific mortality Follow‐up: median 60 months	99 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{6 7}	RR 0.38 (0.05 to 3.05)	Study population
				87 per 1000	54 fewer per 1000 (83 fewer to 178 more)
Disease‐specific quality of life ‐ not measured	‐	‐	‐	‐	‐
*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; IFN‐α: interferon‐alpha; RCT: randomised controlled trial; RR: risk ratio
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.
¹Downgraded for study limitations (‐1): high risk of bias: 'blinding of participants and personnel' (Nepple 2010); 'blinding of outcome assessment' (Nepple 2010); 'selective reporting' (Bercovich 1995; Minich 2009; Nepple 2010); 'other bias' (Bercovich 1995). ²Downgraded for heterogeneity (I² = 74%). ³Downgraded for imprecision (‐1): wide 95% confidence interval around the pooled estimate which includes no effect. ⁴Downgraded for study limitations (‐1): high risk of bias: 'selective reporting' (Minich 2009). ⁵Downgraded for imprecision (‐1): wide 95% confidence interval around the pooled estimate which includes no effect. ⁶Downgraded for study limitations (‐1): unclear risk of bias overall (Chiong 2011). ⁷Downgraded for imprecision (‐2): wide 95% confidence interval around the pooled estimate which includes no effect, small sample size and few events.

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Summary of findings 2. Intravesically administered BCG alternating with IFN‐α compared to intravesically administered BCG alone for treating non‐muscle‐invasive bladder cancer

Intravesically administered BCG alternating with IFN‐α compared to intravesically administered BCG alone for treating non‐muscle‐invasive bladder cancer Patient or population: patients with non‐muscle invasive bladder cancer Intervention: BCG alternating with IFN‐α Comparison: BCG alone
Outcomes	№ of participants (studies)	Quality of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
				Risk with intravesically administered BCG alone	Risk difference with intravesically administered BCG alternating with IFN‐α
Time‐to‐recurrence Follow‐up: median 8.6 to 10.3 years	205 (1 RCT)	⊕⊕⊕⊝ LOW ^{1 2}	HR 2.86 (1.98 to 4.13)	Study population
				431 per 1000	370 more per 1000 (242 more to 471 more)
Time‐to‐progression Follow‐up: median 8.6 to 10.3 years	205 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 3}	HR 2.39 (0.92 to 6.21)	Study population
				59 per 1000	76 more per 1000 (5 fewer to 255 more)
Discontinuation of therapy due to adverse events Follow‐up: median 8.6 to 10.3 years	205 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 3}	RR 2.97 (0.31 to 28.09)	Study population
				10 per 1000	19 more per 1000 (7 fewer to 266 more)
Disease‐specific mortality Follow‐up: median 8.6 to 10.3 years	205 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 3}	HR 2.74 (0.73 to 10.28)	Study population
				29 per 1000	49 more per 1000 (8 fewer to 235 more)
Disease‐specific quality of life ‐ not measured	‐	‐	‐	‐	‐
*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; IFN‐α: interferon‐alpha; RCT: randomised controlled trial; RR: risk ratio
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.
¹Downgraded for study limitations (‐1): high risk of bias: 'blinding of participants and personnel', 'blinding of outcome assessment' (Jarvinen 2015). ²Downgraded for imprecision (‐1): wide 95% confidence interval. ³Downgraded for imprecision (‐1): wide 95% confidence interval around the pooled estimate which includes no effect.

Summary of findings 2. Intravesically administered BCG alternating with IFN‐α compared to intravesically administered BCG alone for treating non‐muscle‐invasive bladder cancer

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Comparison 1. Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time‐to‐recurrence Show forest plot	1	670	Hazard Ratio (Random, 95% CI)	1.11 [0.86, 1.43]

2 Recurrence Show forest plot	4	925	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.44, 1.32]

2.1 IFN‐α higher dose (50 MU) weekly for 6 weeks	1	670	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.93, 1.41]
2.2 IFN‐α lower dose (6 to 10 MU) weekly for 6 weeks	3	255	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.36, 0.94]
3 Progression Show forest plot	2	219	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.04, 1.87]

4 Disease‐specific mortality Show forest plot	1	99	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.05, 3.05]

5 Systemic or local adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Any (including disorientation/delirium and macro haematuria)	1	120	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.13, 0.86]
5.2 Fever	1	670	Risk Ratio (M‐H, Random, 95% CI)	2.22 [1.27, 3.91]
5.3 Constitutional symptoms	1	670	Risk Ratio (M‐H, Random, 95% CI)	1.61 [1.10, 2.36]

Comparison 1. Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone

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Comparison 2. Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time‐to‐recurrence Show forest plot	1	205	Hazard Ratio (Random, 95% CI)	2.86 [1.98, 4.13]

2 Time‐to‐progression Show forest plot	1	205	Hazard Ratio (Random, 95% CI)	2.39 [0.92, 6.21]

3 Discontinuation of therapy due to adverse events Show forest plot	1	205	Risk Ratio (M‐H, Random, 95% CI)	2.97 [0.31, 28.09]

4 Disease‐specific mortality Show forest plot	1	205	Hazard Ratio (Random, 95% CI)	2.74 [0.73, 10.28]

5 Overall survival Show forest plot	1	205	Hazard Ratio (Random, 95% CI)	1.0 [0.68, 1.47]

6 Systemic or local adverse events Show forest plot	1	205	Risk Ratio (M‐H, Random, 95% CI)	1.65 [0.41, 6.73]

Comparison 2. Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone

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