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Meta-Analysis
. 2019 Feb 16;2(2):CD012244.
doi: 10.1002/14651858.CD012244.pub2.

Transcatheter arterial chemoembolisation followed by three-dimensional conformal radiotherapy versus transcatheter arterial chemoembolisation alone for primary hepatocellular carcinoma in adults

Liming Lu #  1 , Jingchun Zeng, Zehuai Wen, Chunzhi Tang #, Nenggui Xu
Affiliations
Meta-Analysis

Transcatheter arterial chemoembolisation followed by three-dimensional conformal radiotherapy versus transcatheter arterial chemoembolisation alone for primary hepatocellular carcinoma in adults

Liming Lu et al. Cochrane Database Syst Rev. .

Abstract

Background: Hepatocellular carcinoma, also called malignant hepatoma, is a primary malignancy of the liver. Despite regular surveillance conducted in high-risk populations, most people with hepatocellular carcinoma are diagnosed at an advanced stage. Consequently, only a minority of people with the disease are suitable for surgical resection when diagnosed.

Objectives: To compare the beneficial and harmful effects of transcatheter arterial chemoembolisation (TACE) followed by three-dimensional conformal radiotherapy (3-DCRT) versus TACE alone in adults with primary hepatocellular carcinoma, considered unsuitable for surgical resection.

Search methods: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index - Science up to 31 May 2018. We checked reference lists for all included studies and related reviews for further relevant articles.

Selection criteria: We included all randomised clinical trials comparing TACE followed by 3-DCRT versus TACE alone in people with primary hepatocellular carcinoma.

Data collection and analysis: We used standard methodological procedures as suggested by Cochrane. We presented the results of the fixed-effect model in the absence of statistical heterogeneity. Otherwise, we reported the results from the random-effects model meta-analysis. We assessed risk of bias of the included trials using bias risk domains and presented the review results incorporating the methodological quality of the trials using GRADE. Our main conclusions were based on the analysis up to three years' follow-up.

Main results: We identified eight randomised clinical trials (632 participants) that fulfilled our inclusion criteria. All eight trials were at high risk of bias, and we rated the evidence as low to very low certainty. The mean age ranged from 16 years to 78 years. The proportion of men ranged from 60% to 75% and the proportion of people with stage III primary hepatocellular carcinoma ranged from 22% to 85%. The median follow-up duration was 12 months (2 months to 38 months).TACE followed by 3-DCRT compared with TACE alone may have reduced all-cause mortality at three years' follow-up (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.73 to 0.88; 552 participants; 7 trials; low-certainty evidence). TACE followed by 3-DCRT compared with TACE alone may reduce the proportion of participants without tumour response (complete response plus partial response) (RR 0.49, 95% CI 0.39 to 0.61; 632 participants; 8 trials; low-certainty evidence). Data, from one trial on health-related quality of life, favoured the TACE followed by 3-DCRT group, but the provided data were ill-defined (very low-certainty evidence). None of the trials reported serious adverse events. The results on non-serious adverse events were as follows: TACE followed by 3-DCRT compared with TACE alone showed no difference in the results for proportion of participants with leukopenia (RR 1.12, 95% CI 0.92 to 1.34; 438 participants; 5 trials; very low-certainty evidence) and serum transaminases elevation (RR 1.67, 95% CI 0.66 to 4.27; 280 participants; 4 trials; very low-certainty evidence). However, the proportion of participants with total bilirubin elevation was larger in the TACE followed by 3-DCRT group than in the TACE alone group (RR 2.69, 95% CI 1.34 to 5.40; 172 participants; 2 trials; very low-certainty evidence). The rate of participants with serum alpha-fetoprotein (AFP) without decline or normalisation was significantly lower in the TACE followed by 3-DCRT group than in the TACE group, but these data were from one trial only (Chi² = 7.24, P = 0.007; very low-certainty evidence).

Authors' conclusions: TACE followed by 3-DCRT may be associated with lower all-cause mortality and increased tumour response, despite the increased toxicity expressed by a higher rise of total bilirubin. Our review findings should be considered with caution because of the methodological weaknesses in the included trials, resulting in low- to very low-certainty evidence. Data on serious adverse events and health-related quality of life are lacking. We are also very much uncertain in the results of the reported non-serious adverse events. High-quality trials are needed to assess further the role of TACE followed by 3-DCRT for unresectable hepatocellular carcinoma.

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Conflict of interest statement

LL: none ZJ: none WZ: none CT: none NX: none

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Trial Sequential Analysis of transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE for primary hepatocellular carcinoma with the primary outcome of one‐year all‐cause mortality. The blue line (Z‐curve) shows the cumulative meta‐analysis adding the results of individual trials based on the year of publication. The horizontal green line represents the 2.5% level of significance. The monitoring boundaries (inward sloping red lines) show the significance level after adjusting for the cumulative analysis. The vertical red line shows the required information size (the number of participants needed to determine if firm evidence was established). We conducted the Trial Sequential Analysis with the alpha set to 2.5%, power to 80%, control group event proportion to 50%, relative risk reduction to 20%, and heterogeneity correction based on model variance. The diversity‐adjusted required information size was 941 participants. The cumulative Z‐curve crossed the monitoring boundary before reaching the heterogeneity‐adjusted information size. In total, the cumulative meta‐analysis included 319 participants in the TACE followed by 3‐DCRT group and 313 in the TACE alone group. The cumulative Z‐curve also crossed the monitoring boundary before reaching the adjusted information size when we increased the power to 90%. DARIS: Distributed and Reflective Informatics System.
5
5
Trial Sequential Analysis of transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone for primary hepatocellular carcinoma with the primary outcome of two‐year all‐cause mortality. The blue line (Z‐curve) shows the cumulative meta‐analysis adding the results of individual trials based on the year of publication. The horizontal line represents the 2.5% level of significance. The monitoring boundaries (inward sloping red lines) show the significance level adjusting for the cumulative analysis. The vertical red line shows the required information size (the number of participants needed to determine if firm evidence was established). We conducted the Trial Sequential Analysis with the alpha set to 2.5%, power to 80%, control group event rate to 70%, relative risk reduction to 20%, and heterogeneity correction based on model variance. The diversity‐adjusted required information size was 1155 participants (diversity adjusted). The cumulative Z‐curve crossed the monitoring boundary before reaching the diversity‐adjusted required information size. In total, the cumulative meta‐analysis included 295 participants in the TACE followed by 3‐DCRT group and 289 in the TACE alone group. The cumulative Z‐curve also crossed the monitoring boundary before reaching the heterogeneity adjusted information size when we increased the power to 90%. DARIS: Distributed and Reflective Informatics System.
6
6
Trial Sequential Analysis of transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT)T versus TACE alone for primary hepatocellular carcinoma with the primary outcome of three‐year all‐cause mortality. The blue line (Z‐curve) shows the cumulative meta‐analysis adding the results of individual trials based on the year of publication. The horizontal green line represents the 2.5% level of significance. The monitoring boundaries (inward sloping red line) show the significance level adjusting for the cumulative analysis. The vertical red line shows the required information size (the number of participants needed to determine if firm evidence was established). We conducted the Trial Sequential Analysis with the alpha set to 5%, power to 80%, control group event rate to 85%, relative risk reduction to 20%, and heterogeneity correction based on model variance. The diversity‐adjusted required information size was 237 participants. The cumulative Z‐curve crossed the monitoring boundary before reaching the heterogeneity‐adjusted information size. In total, the cumulative meta‐analysis included 279 participants in the TACE followed by 3‐DCRT group and 273 in the TACE alone group. The cumulative Z‐curve also crossed the monitoring boundary before reaching the heterogeneity adjusted information size when we increased the power to 90%. DARIS: Distributed and Reflective Informatics System.
7
7
Trial Sequential Analysis of transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone for participants with primary hepatocellular carcinoma without complete or partial tumour response. The blue line (Z‐curve) shows the cumulative meta‐analysis adding the results of individual trials based on the year of publication. The horizontal green line represents the 2.5% level of significance. The monitoring boundary (inward sloping red line) shows the significance level after adjusting for the cumulative analysis. The vertical red line shows the required information size (the number of participants needed to determine if firm evidence was established). We conducted the Trial Sequential Analysis with the alpha set to 2.5%, power to 80%, control group event rate to 50%, relative risk reduction to 25%, and heterogeneity correction based on model variance. The estimated required information size was 599 participants (diversity adjusted). The cumulative Z‐curve crossed the monitoring boundary before reaching the heterogeneity adjusted information size. In total, the cumulative meta‐analysis included 319 participants in the TACE followed by 3‐DCRT group and 313 in the TACE alone group. The cumulative Z‐curve also crossed the monitoring boundary before reaching the heterogeneity adjusted information size when we increased the power to 90%. DARIS: Distributed and Reflective Informatics System.
1.1
1.1. Analysis
Comparison 1 Transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone, Outcome 1 All‐cause mortality: at 1 year.
1.2
1.2. Analysis
Comparison 1 Transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone, Outcome 2 All‐cause mortality: at 2 years.
1.3
1.3. Analysis
Comparison 1 Transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone, Outcome 3 All‐cause mortality: at 3 years.
1.4
1.4. Analysis
Comparison 1 Transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone, Outcome 4 Proportion of participants without complete and partial tumour response.
1.5
1.5. Analysis
Comparison 1 Transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone, Outcome 5 Proportion of participants with leukopenia.
1.6
1.6. Analysis
Comparison 1 Transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone, Outcome 6 Proportion of participants with serum transaminases elevation.
1.7
1.7. Analysis
Comparison 1 Transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone, Outcome 7 Proportion of participants with total bilirubin elevation.
1.8
1.8. Analysis
Comparison 1 Transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone, Outcome 8 All‐cause mortality: at 1 year (sensitivity analysis).
1.9
1.9. Analysis
Comparison 1 Transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone, Outcome 9 All‐cause mortality: at 2 years (sensitivity analysis).
1.10
1.10. Analysis
Comparison 1 Transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone, Outcome 10 All‐cause mortality: at 3 years (sensitivity analysis).
1.11
1.11. Analysis
Comparison 1 Transcatheter arterial chemoembolisation (TACE) followed by three‐dimensional conformal radiotherapy (3‐DCRT) versus TACE alone, Outcome 11 Proportion of participants without complete and partial tumour response (sensitivity analysis).
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Update of

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References to studies included in this review

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