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Использование внутрипузырной вакцины БЦЖ с интерфероном‐альфа и без него для лечения рака мочевого пузыря без инвазии в мышечный слой

Información

DOI:
https://doi.org/10.1002/14651858.CD012112.pub2Copiar DOI
Base de datos:
  1. Cochrane Database of Systematic Reviews
Versión publicada:
  1. 08 marzo 2017see what's new
Tipo:
  1. Intervention
Etapa:
  1. Review
Grupo Editorial Cochrane:
  1. Grupo Cochrane de Urología

Copyright:
  1. Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

  • Andrew RH Shepherd

    Correspondencia a: Department of Urology, Royal Adelaide Hospital, Adelaide, Australia

    [email protected]

    School of Medicine, The University of Adelaide, Adelaide, Australia

  • Emily Shepherd

    ARCH: Australian Research Centre for Health of Women and Babies, Robinson Research Institute, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, Australia

  • Nicholas R Brook

    Department of Urology, Royal Adelaide Hospital, Adelaide, Australia

    School of Medicine, The University of Adelaide, Adelaide, Australia

Contributions of authors

All review authors (Andrew RH Shepherd (ARHS), Emily Shepherd (ES), and Nicholas R Brook (NRB)) contributed to the design, development, and drafting of the protocol, and search strategy development.

ARHS and ES acquired trial reports and conducted trial selection and data extraction

NRB was consulted to resolve discrepancies or disagreements

ARHS led the data analysis, and ES and NRB assisted with data interpretation

All review authors contributed to review drafting, with ARHS in the leading role

All review authors will contribute to future review updates

Sources of support

Internal sources

  • None, Other.

External sources

  • None, Other.

Declarations of interest

ARHS: none known

ES: none known

NRB: none known

Acknowledgements

We thank the Cochrane Urology Group for their support, including the editors for their feedback on this review. We also thank the referees for their valuable feedback: Ashish Kamat, Jonathan Izawa, Bastian Keck, Maximilian Burger, and Stefanie Schmidt.

We would like to acknowledge Eduard Bercovich for his assistance in the procurement of manuscripts of two of the included studies, and Alexander Minich for the provision of the manuscript for one of the included studies. We thank Giorgio Maria Agazzi and Alexander Troelnikov for their kind assistance in the translation of included studies from Italian and Russian into English.

Version history

Published

Title

Stage

Authors

Version

2017 Mar 08

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

Review

Andrew RH Shepherd, Emily Shepherd, Nicholas R Brook

https://doi.org/10.1002/14651858.CD012112.pub2

2016 Mar 05

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

Protocol

Andrew RH Shepherd, Emily Shepherd, Nicholas R Brook

https://doi.org/10.1002/14651858.CD012112

Differences between protocol and review

This review was based on a published protocol (Shepherd 2016), with differences as described here.

We included a second comparison, 'intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone', which we believed was important and relevant to our review objective. We did not consider it appropriate for studies assessing alternating BCG and IFN‐α to be pooled with those assessing co‐administration of BCG and IFN‐α.

As for our first comparison, 'intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone', we were unable to obtain time‐to‐event information for the outcomes time‐to‐recurrence and time‐to‐progression, assessing the dichotomous outcomes recurrence and progression instead; we thus included these outcomes in the 'Summary of findings' table. For both comparisons, we were unable to obtain information for the outcome disease‐specific survival, assessing the outcome disease‐specific mortality instead; we thus included this outcome in the 'Summary of findings' tables.

Notes

Parts of the Methods section of this review were based on a standard template developed by the Cochrane Metabolic and Endocrine Disorders Group that has been modified and adapted for use by the Cochrane Urology Group.

Keywords

MeSH

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Study flow diagram (searched 14 March 2016, updated 25 August 2016).
Figuras y tablas -
Figure 1

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

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

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

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 3

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

Comparison 1 Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone, Outcome 1 Time‐to‐recurrence.
Figuras y tablas -
Analysis 1.1

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

Comparison 1 Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone, Outcome 2 Recurrence.
Figuras y tablas -
Analysis 1.2

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

Comparison 1 Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone, Outcome 3 Progression.
Figuras y tablas -
Analysis 1.3

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

Comparison 1 Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone, Outcome 4 Disease‐specific mortality.
Figuras y tablas -
Analysis 1.4

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

Comparison 1 Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone, Outcome 5 Systemic or local adverse events.
Figuras y tablas -
Analysis 1.5

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

Comparison 2 Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone, Outcome 1 Time‐to‐recurrence.
Figuras y tablas -
Analysis 2.1

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

Comparison 2 Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone, Outcome 2 Time‐to‐progression.
Figuras y tablas -
Analysis 2.2

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

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

Comparison 2 Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone, Outcome 4 Disease‐specific mortality.
Figuras y tablas -
Analysis 2.4

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

Comparison 2 Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone, Outcome 5 Overall survival.
Figuras y tablas -
Analysis 2.5

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

Comparison 2 Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone, Outcome 6 Systemic or local adverse events.
Figuras y tablas -
Analysis 2.6

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

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.

Figuras y tablas -
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
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.

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

Figuras y tablas -
Comparison 1. Intravesically administered BCG combined with IFN‐α versus intravesically administered BCG alone
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]

Figuras y tablas -
Comparison 2. Intravesically administered BCG alternating with IFN‐α versus intravesically administered BCG alone