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Cochrane Database of Systematic Reviews

Radioterapia de haz externo para el carcinoma hepatocelular no resecable

Información

DOI:
https://doi.org/10.1002/14651858.CD011314.pub2Copiar DOI
Base de datos:
  1. Cochrane Database of Systematic Reviews
Versión publicada:
  1. 07 marzo 2017see what's new
Tipo:
  1. Intervention
Etapa:
  1. Review
Grupo Editorial Cochrane:
  1. Grupo Cochrane de Hepatobiliar

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

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Autores

  • Omar Abdel‐Rahman

    Correspondencia a: Clinical Oncology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

    [email protected]

    [email protected]

  • Zeinab Elsayed

    Clinical Oncology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Contributions of authors

Omar Abdel‐Rahman: Collecting the data, performing the analyses, and writing the review.
Zeinab Elsayed: Collecting the data and revising the review.

Both authors agreed to the final version of the review submitted for publication.

Sources of support

Internal sources

  • None, Other.

External sources

  • None, Other.

Declarations of interest

Omar Abdel‐Rahman: none known.
Zeinab Elsayed: none known.

Acknowledgements

To the Cochrane Hepato‐Biliary Group and its supporting editorial team.
Special thanks go to Dr. Rouhan Wu (China) for translating the Chinese articles.

Peer Reviewers: Francesco Dionisi, Italy; Zehaui Wen, China.
Contact Editors: Rosa Simonetti, Italy; Christian Gluud, Denmark.
Sign‐off Editor: Christian Gluud, Denmark.

Cochrane Review Group funding acknowledgement: The Danish State is the largest single funder of the Cochrane Hepato‐Biliary Group through its investment in The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Denmark. Disclaimer: The views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the Danish State or The Copenhagen Trial Unit.

Version history

Published

Title

Stage

Authors

Version

2017 Mar 07

External beam radiotherapy for unresectable hepatocellular carcinoma

Review

Omar Abdel‐Rahman, Zeinab Elsayed

https://doi.org/10.1002/14651858.CD011314.pub2

2014 Sep 18

External beam radiotherapy for unresectable hepatocellular carcinoma

Protocol

Omar M Abdel‐Rahman, Zeinab Elsayed

https://doi.org/10.1002/14651858.CD011314

Differences between protocol and review

We added 'liver‐related adverse events' as a secondary outcome because we considered it to be an important additional point to clarify in any analysis of local or systemic therapies for hepatocellular carcinoma.

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.
Figuras y tablas -
Figure 1

Study flow diagram.

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.

Trial Sequential Analysis comparing external beam radiotherapy (EBRT) plus transarterial chemoembolisation (TACE) versus TACE alone on the outcome 'all‐cause mortality at one year'. A subgroup of studies used three‐dimensional conformal radiotherapy. The diversity‐adjusted required information size (DARIS) of n = 1029 patients was calculated based upon a proportion of mortality of 50.3% of patients in the TACE group, a relative risk reduction of 20% in the EBRT + TACE group, an alpha (type I error) of 5%, a beta (type II error) of 10%, and a diversity of 0%. The blue curve presents the cumulative meta‐analysis Z‐score, and the inward‐sloping dotted red curves present the adjusted threshold for statistical significance according to the two‐sided trial sequential monitoring boundaries.
Figuras y tablas -
Figure 4

Trial Sequential Analysis comparing external beam radiotherapy (EBRT) plus transarterial chemoembolisation (TACE) versus TACE alone on the outcome 'all‐cause mortality at one year'. A subgroup of studies used three‐dimensional conformal radiotherapy. The diversity‐adjusted required information size (DARIS) of n = 1029 patients was calculated based upon a proportion of mortality of 50.3% of patients in the TACE group, a relative risk reduction of 20% in the EBRT + TACE group, an alpha (type I error) of 5%, a beta (type II error) of 10%, and a diversity of 0%. The blue curve presents the cumulative meta‐analysis Z‐score, and the inward‐sloping dotted red curves present the adjusted threshold for statistical significance according to the two‐sided trial sequential monitoring boundaries.

Trial Sequential Analysis comparing external beam radiotherapy (EBRT) versus transarterial chemoembolisation (TACE) on the outcome 'all‐cause mortality at one year'. The diversity‐adjusted required information size (DARIS) of n = 808 patients was calculated based upon a proportion of mortality of 57% of patients in the TACE group, a relative risk reduction of 20% in the EBRT group, an alpha (type I error) of 5%, a beta (type II error) of 10%, and a diversity of 0%. The blue curve presents the cumulative meta‐analysis Z‐score, and the inward‐sloping dotted red curves present the adjusted threshold for statistical significance according to the two‐sided trial sequential monitoring boundaries.
Figuras y tablas -
Figure 5

Trial Sequential Analysis comparing external beam radiotherapy (EBRT) versus transarterial chemoembolisation (TACE) on the outcome 'all‐cause mortality at one year'. The diversity‐adjusted required information size (DARIS) of n = 808 patients was calculated based upon a proportion of mortality of 57% of patients in the TACE group, a relative risk reduction of 20% in the EBRT group, an alpha (type I error) of 5%, a beta (type II error) of 10%, and a diversity of 0%. The blue curve presents the cumulative meta‐analysis Z‐score, and the inward‐sloping dotted red curves present the adjusted threshold for statistical significance according to the two‐sided trial sequential monitoring boundaries.

Trial Sequential Analysis comparing external beam radiotherapy (EBRT) plus transarterial chemoembolisation (TACE) versus TACE alone on the outcome 'complete response plus partial response ‐ subgroup of studies using three‐dimensional conformal radiotherapy'. The diversity‐adjusted required information size (DARIS) of n = 951 patients was calculated based upon a proportion of response of 52.5% of patients in the TACE group, a relative risk reduction of 20% in the TACE + EBRT group, an alpha (type I error) of 5%, a beta (type II error) of 10%, and a diversity of 0%. The blue curve presents the cumulative meta‐analysis Z‐score, and the inward‐sloping red curves present the adjusted threshold for statistical significance according to the two‐sided trial sequential monitoring boundaries.
Figuras y tablas -
Figure 6

Trial Sequential Analysis comparing external beam radiotherapy (EBRT) plus transarterial chemoembolisation (TACE) versus TACE alone on the outcome 'complete response plus partial response ‐ subgroup of studies using three‐dimensional conformal radiotherapy'. The diversity‐adjusted required information size (DARIS) of n = 951 patients was calculated based upon a proportion of response of 52.5% of patients in the TACE group, a relative risk reduction of 20% in the TACE + EBRT group, an alpha (type I error) of 5%, a beta (type II error) of 10%, and a diversity of 0%. The blue curve presents the cumulative meta‐analysis Z‐score, and the inward‐sloping red curves present the adjusted threshold for statistical significance according to the two‐sided trial sequential monitoring boundaries.

Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 1 All‐cause mortality (at 1 year).
Figuras y tablas -
Analysis 1.1

Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 1 All‐cause mortality (at 1 year).

Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 2 Complete response.
Figuras y tablas -
Analysis 1.2

Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 2 Complete response.

Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 3 Complete response + partial response.
Figuras y tablas -
Analysis 1.3

Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 3 Complete response + partial response.

Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 4 Elevated alanine aminotransferase.
Figuras y tablas -
Analysis 1.4

Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 4 Elevated alanine aminotransferase.

Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 5 Elevated total bilirubin.
Figuras y tablas -
Analysis 1.5

Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 5 Elevated total bilirubin.

Comparison 2 External beam radiotherapy versus transarterial chemoembolisation, Outcome 1 All‐cause mortality.
Figuras y tablas -
Analysis 2.1

Comparison 2 External beam radiotherapy versus transarterial chemoembolisation, Outcome 1 All‐cause mortality.

Summary of findings for the main comparison. External beam radiotherapy (EBRT) plus transarterial chemoembolisation (TACE) versus TACE alone for unresectable hepatocellular carcinoma

External beam radiotherapy (EBRT) plus transarterial chemoembolisation(TACE) versus TACE alone for unresectable hepatocellular carcinoma

Patient or population: people with unresectable hepatocellular carcinoma
Setting: specialist hospitals
Intervention: EBRT + TACE
Comparison: TACE

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with TACE

Risk with EBRT + TACE

All‐cause mortality (at maximum 1‐year follow‐up)

Study population

RR 0.51
(0.41 to 0.62)

786
(9 RCTs)

⊕⊕⊝⊝
LOW 1

456 per 1000

233 per 1000
(187 to 283)

Health‐related quality of life

No data were available for this outcome.

Serious adverse events

No data were available for this outcome.

Complete response plus partial response

Length of follow‐up: 1 year

Study population

RR 1.58
(1.40 to 1.78)

620
(7 RCTs)

⊕⊕⊝⊝
LOW 1

518 per 1000

819 per 1000
(726 to 923)

Elevated alanine aminotransferase

Length of follow‐up: 1 year

Study population

RR 1.41
(1.08 to 1.84)

232
(3 RCTs)

⊕⊝⊝⊝
VERY LOW 2

319 per 1000

449 per 1000
(344 to 586)

Elevated total bilirubin

Length of follow‐up: 1 year

Study population

RR 2.69
(1.34 to 5.40)

172
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 3

108 per 1000

292 per 1000
(145 to 586)

*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; RR: risk ratio; RCT: randomised clinical trial

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 two levels (‐2) due to: i) within‐study risk of bias: high risk of bias in all included trials; ii) publication bias: cannot be assessed.
2Downgraded three levels (‐3) due to: i) within‐study risk of bias: high risk of bias in all included trials; ii) publication bias: cannot be assessed; iii) heterogeneity: large heterogeneity index (93%); iv) imprecision: small number of trials.
3Downgraded three levels (‐3) due to: i) within‐study risk of bias: high risk of bias in all included trials; ii) publication bias: cannot be assessed; iii) imprecision: small number of trials.

Figuras y tablas -
Summary of findings for the main comparison. External beam radiotherapy (EBRT) plus transarterial chemoembolisation (TACE) versus TACE alone for unresectable hepatocellular carcinoma
Summary of findings 2. External beam radiotherapy (EBRT) versus transarterial chemoembolisation (TACE) for unresectable hepatocellular carcinoma

External beam radiotherapy (EBRT) versus transarterial chemoembolisation(TACE) for unresectable hepatocellular carcinoma

Patient or population: people with unresectable hepatocellular carcinoma
Setting: specialist hospitals
Intervention: EBRT
Comparison: TACE

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with TACE

Risk with EBRT

All‐cause mortality (at 1 year)

Study population

RR 1.21
(0.97 to 1.50)

152
(3 RCTs)

⊕⊝⊝⊝
VERY LOW1

570 per 1000

689 per 1000
(553 to 854)

Serious adverse events

No data were available for this outcome.

Complete response plus partial response

Length of follow‐up: 1 year

10 out of 20 trial participants attained partial response in the TACE arm.

3 out of 21 trial participants attained a response in the EBRT arm.

41 (1 RCT)

⊕⊝⊝⊝
VERY LOW1

Elevated alanine aminotransferase

No data were available for this outcome.

Elevated total bilirubin

No data were available for this outcome.

*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; RR: risk ratio; RCT: randomised clinical trial

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 three levels (‐3) due to i) within‐study risk of bias: high risk of bias in all included trials; ii) publication bias: cannot be assessed; iii) imprecision: small number of trials.

Figuras y tablas -
Summary of findings 2. External beam radiotherapy (EBRT) versus transarterial chemoembolisation (TACE) for unresectable hepatocellular carcinoma
Table 1. Explanations for the 'Summary of findings' table

Examples from table

Explanation

Outcomes

The tables provide the findings for the most important outcomes for someone making a decision. These include potential benefits and harms, whether the included studies provide data for these outcomes or not. Additional findings may be reported elsewhere in the review.

Assumed control group risk

Assumed control group risks can be based either on the control group risks reported in the included studies or on epidemiological data from elsewhere. When only one control group risk is provided, it is normally the median control group risk across the studies that provided data for that outcome.

Risk is the probability of an outcome occurring. The control group risk is the risk of an outcome occurring in the comparison group (without the intervention).

Corresponding intervention group risk

Risk is the probability of an outcome occurring. The intervention group risk is the risk of an outcome occurring in the group receiving the intervention.

Relative effect

Relative effect or RR (risk ratio)

Relative effects are ratios. Here the relative effect is expressed as a risk ratio.

Risk is the probability of an outcome occurring. A RR is the ratio between the risk in the intervention group and the risk in the control group. If the risk in the control group is 10% (100 per 1000) and the risk in the intervention group is 1% (10 per 1000), the RR is 10/100 or 0.10.

If the RR is exactly 1.0, this means that there is no difference between the occurrence of the outcome in the intervention and the control group. It is unusual for the RR to be exactly 1.0, and understanding what it means if it is above or below this value depends on whether the outcome being counted is judged to be good or bad.

If the RR is greater than 1.0, the intervention increases the risk of the outcome. If it is a good outcome (e.g. the birth of a healthy baby), a RR > 1.0 indicates a desirable effect for the intervention, whereas if the outcome is bad (e.g. death), a RR > 1.0 indicates an undesirable effect.

If the RR is less than 1.0, the intervention decreases the risk of the outcome. This indicates a desirable effect if it is a bad outcome (e.g. death) and an undesirable effect if it is a good outcome (e.g. birth of a healthy baby).

What is the difference between absolute and relative effects?

The effect of an intervention can be described by comparing the risk of the intervention group with the risk of the control group. Such a comparison can be made in different ways.

One way to compare two risks is to calculate the difference between the risks. This is the absolute effect.

Consider the risk for blindness in a person with diabetes over a five‐year period. If the risk for blindness is found to be 20 in 1000 (2%) in a group of people treated conventionally and 10 in 1000 (1%) in people treated with a new drug, the absolute effect is derived by subtracting the intervention group risk from the control group risk: 2% ‐ 1% = 1%. Expressed in this way, it can be said that the new drug reduces the five‐year risk for blindness by 1% (absolute effect is 10 fewer per 1000).

Another way to compare risks is to calculate the ratio of the two risks. Given the data above, the relative effect is derived by dividing the two risks, with the intervention risk being divided by the control risk: 1% ÷ 2% = ½ (0.50). Expressed in this way, as the 'relative effect', the five‐year risk for blindness with the new drug is 1/2 the risk with the conventional drug.

Here the table presents risks as x per 1000 (or 100, etc.) instead of %, as this tends to be easier to understand. Whenever possible, the table presents the relative effect as the RR.

The absolute effect is usually different for groups that are at high and low risk, whereas the relative effect is often the same, therefore, when it is relevant, we have reported indicative risks for groups at different levels of risk. Two or three indicative control group risks and the corresponding intervention group risks are presented when there are important differences across different populations.

Mean difference

The mean difference (MD) is the average difference between the intervention group and the control group across studies. Here a weighted MD is used, which means the results of some of the studies make a greater contribution to the average than the results of others. Studies with more precise estimates for their results (narrower confidence intervals) are given more weight.

This way of measuring effect is used when combining or comparing data for continuous outcomes such as weight, blood pressure, or pain measured on a scale. When different scales are used to measure the same outcome, e.g. different pain scales, a standardised mean difference (SMD) may be provided. This is a weighted mean difference standardised across studies giving the average difference in standard deviations for the measures of that outcome.

Confidence interval

A confidence interval (CI) is a range around an estimate that conveys how precise the estimate is; in this example the result is the estimate of the intervention group risk. The CI is a guide to how sure we can be about the quantity we are interested in (here the true absolute effect). The narrower the range between the two numbers, the more confident we can be about what the true value is; the wider the range, the less sure we can be. The width of the CI reflects the extent to which chance may be responsible for the observed estimate (with a wider interval reflecting more chance).

95% confidence interval

As explained above, the CI indicates the extent to which chance may be responsible for the observed numbers. In the simplest terms, a 95% CI means that we can be 95% confident that the true size of effect is between the lower and upper confidence limit (e.g. 0 and 3 in the blindness drugs example mentioned above). Conversely, there is a 5% chance that the true effect is outside of this range.

Not statistically significant

Statistically significant means that a result is unlikely to have occurred by chance. The usual threshold for this judgement is that the results, or more extreme results, would occur by chance with a probability of less than 0.05 if the null hypothesis (no effect) was true. When results are not statistically significant, as in this example, this is stated to alert users to the possibility that the results may have occurred by chance.

No. of participants (studies)

The table provides the total number of participants across studies and the number of studies that provided data for that outcome. This indicates how much evidence there is for the outcome.

Quality of the evidence

The quality of the evidence is a judgement about the extent to which we can be confident that the estimates of effect are correct. These judgements are made using the GRADE system, and are provided for each outcome. The judgements are based on the type of study design (randomised trials versus observational studies), the risk of bias, the consistency of the results across studies, and the precision of the overall estimate across studies.

For each outcome, the quality of the evidence is rated as high, moderate, low, or very low using the following definitions:

  • high quality: further research is very unlikely to change our confidence in the estimate of effect;

  • moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate;

  • low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate;

  • very low quality: we are very uncertain about the estimate.

A "‐" indicates that the information is not relevant.

Figuras y tablas -
Table 1. Explanations for the 'Summary of findings' table
Comparison 1. External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All‐cause mortality (at 1 year) Show forest plot

9

786

Risk Ratio (M‐H, Fixed, 95% CI)

0.51 [0.41, 0.62]

1.1 Studies using three dimensional conformal radiation therapy

8

527

Risk Ratio (M‐H, Fixed, 95% CI)

0.54 [0.43, 0.68]

1.2 Studies using stereotactic radiotherapy

1

259

Risk Ratio (M‐H, Fixed, 95% CI)

0.40 [0.25, 0.64]

2 Complete response Show forest plot

7

620

Risk Ratio (M‐H, Fixed, 95% CI)

2.14 [1.47, 3.13]

2.1 Studies using three dimensional conformal radiation therapy

6

361

Risk Ratio (M‐H, Fixed, 95% CI)

2.13 [1.34, 3.37]

2.2 Studies using stereotactic radiotherapy

1

259

Risk Ratio (M‐H, Fixed, 95% CI)

2.17 [1.12, 4.21]

3 Complete response + partial response Show forest plot

7

620

Risk Ratio (M‐H, Fixed, 95% CI)

1.58 [1.40, 1.78]

3.1 Studies using three dimensional conformal radiation therapy

6

361

Risk Ratio (M‐H, Fixed, 95% CI)

1.53 [1.31, 1.79]

3.2 Studies using stereotactic radiotherapy

1

259

Risk Ratio (M‐H, Fixed, 95% CI)

1.65 [1.36, 1.99]

4 Elevated alanine aminotransferase Show forest plot

3

232

Risk Ratio (M‐H, Fixed, 95% CI)

1.41 [1.08, 1.84]

5 Elevated total bilirubin Show forest plot

2

172

Risk Ratio (M‐H, Fixed, 95% CI)

2.69 [1.34, 5.40]

Figuras y tablas -
Comparison 1. External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE
Comparison 2. External beam radiotherapy versus transarterial chemoembolisation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All‐cause mortality Show forest plot

3

152

Risk Ratio (M‐H, Fixed, 95% CI)

1.21 [0.97, 1.50]

Figuras y tablas -
Comparison 2. External beam radiotherapy versus transarterial chemoembolisation