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Meta-Analysis
. 2017 Mar 7;3(3):CD011314.
doi: 10.1002/14651858.CD011314.pub2.

External beam radiotherapy for unresectable hepatocellular carcinoma

Omar Abdel-Rahman  1 , Zeinab Elsayed  1
Affiliations
Meta-Analysis

External beam radiotherapy for unresectable hepatocellular carcinoma

Omar Abdel-Rahman et al. Cochrane Database Syst Rev. .

Abstract

Background: Hepatocellular carcinoma is the most common liver neoplasm, the sixth most common cancer worldwide, and the third most common cause of cancer mortality. Moreover, its incidence has increased dramatically in the past decade. While surgical resection and liver transplantation are the main curative treatments, only around 20% of people with early hepatocellular carcinoma may benefit from these therapies. Current treatment options for unresectable hepatocellular carcinoma include various ablative and transarterial therapies in addition to the drug sorafenib.

Objectives: To assess the benefits and harms of external beam radiotherapy in the management of localised unresectable hepatocellular carcinoma.

Search methods: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE (OvidSP), Embase (OvidSP), Science Citation Index Expanded (Web of Science), and clinicaltrials.gov registry. We also checked reference lists of primary original studies and review articles manually for further related articles (cross-references) up to October 6, 2016.

Selection criteria: Eligible studies included all randomised clinical trials comparing external beam radiotherapy either as a monotherapy or in combination with other systemic or locoregional therapies versus placebo, no treatment, or other systemic or locoregional therapies for people with unresectable hepatocellular carcinoma.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. We used a random-effects model as well as a fixed-effect model meta-analysis but in case of discrepancy between the two models (e.g. one giving a significant intervention effect, the other no significant intervention effect), we reported both results; otherwise, we reported only the results from the fixed-effect model meta-analysis. We assessed risk of bias of the included trials using predefined risk of bias domains; assessed risks of random errors with Trial Sequential Analysis; and presented the review results incorporating the methodological quality of the trials using GRADE.

Main results: Nine randomised clinical trials with 879 participants fulfilled our inclusion criteria. All trials were at high risk of bias, and we rated the evidence as low to very low quality. All of the included trials compared combined external beam radiotherapy plus chemoembolisation versus chemoembolisation alone in people with unresectable hepatocellular carcinoma; moreover, three of the trials compared external beam radiotherapy alone versus chemoembolisation alone. All trials were conducted in China. The median age in most of the included trials was around 52 years, and most trial participants were male. The median follow-up duration ranged from one to three years. None of the trials reported data on cancer-related mortality, quality of life, serious adverse events, or time to progression of the tumour. For the comparison of radiotherapy plus chemoembolisation versus chemoembolisation alone, the risk ratio for one-year all-cause mortality was 0.51 (95% confidence interval (CI) 0.41 to 0.62; P < 0.001; 9 trials; low-quality evidence); for complete response rate was 2.14 (95% CI 1.47 to 3.13; P < 0.001; 7 trials; low-quality evidence); and for overall response rate defined as complete response plus partial response was 1.58 (95% CI 1.40 to 1.78; P < 0.001; 7 trials; low-quality evidence), all in favour of combined treatment with external beam radiotherapy plus transarterial chemoembolisation and seemingly supported by our Trial Sequential Analysis. Additionally, the combined treatment was associated with a higher risk of elevated total bilirubin and elevated alanine aminotransferase. The risk ratio for the risk of elevated alanine aminotransferase was 1.41 (95% CI 1.08 to 1.84; P = 0.01; very low-quality evidence), while for elevated total bilirubin it was 2.69 (95% CI 1.34 to 5.40; P = 0.005; very low-quality evidence). For the comparison of radiotherapy versus chemoembolisation, the risk ratio for one-year all-cause mortality was 1.21 (95% CI 0.97 to 1.50; 3 trials; I2 = 0%; very low-quality evidence) which was not supported by our Trial Sequential Analysis.In addition, we found seven ongoing randomised clinical trials evaluating different external beam radiotherapy techniques for people with unresectable hepatocellular carcinoma.

Authors' conclusions: We found very low- and low-quality evidence suggesting that combined external beam radiotherapy and chemoembolisation may be associated with lower mortality and increased complete and overall response rates, despite an increased toxicity as expressed by a higher rise of bilirubin and alanine aminotransferase. A high risk of systematic errors (bias) as well as imprecision and inconsistency suggest that these findings should be considered cautiously and that high-quality trials are needed to assess further the role of external beam radiotherapy for unresectable hepatocellular carcinoma.

PubMed Disclaimer

Conflict of interest statement

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

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 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.
5
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.
6
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.
1.1
1.1. Analysis
Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 1 All‐cause mortality (at 1 year).
1.2
1.2. Analysis
Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 2 Complete response.
1.3
1.3. Analysis
Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 3 Complete response + partial response.
1.4
1.4. Analysis
Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 4 Elevated alanine aminotransferase.
1.5
1.5. Analysis
Comparison 1 External beam radiotherapy plus transarterial chemoembolisation (TACE) versus TACE, Outcome 5 Elevated total bilirubin.
2.1
2.1. Analysis
Comparison 2 External beam radiotherapy versus transarterial chemoembolisation, Outcome 1 All‐cause mortality.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD011314

References

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