Abstract: 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. 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.

Plain-language summary: We searched the medical literature for randomised clinical trials (where people are allocated at random to one of two or more treatment groups) in order to perform an analysis of the role of radiotherapy administered externally for advanced liver cancer. We found nine randomised clinical trials including a total of 879 people with advanced liver cancer. All of the included trials were conducted in China. The average age in most of the included studies was around 52 years, and most trial participants were male. The average follow-up duration ranged from one to three years. All trials were at high risk of bias, and we rated the evidence as low to very low quality. Most of the included trials compared combined radiotherapy and chemoembolisation versus chemoembolisation alone. We also identified seven ongoing randomised clinical trials. The evidence is current to October 2016. When compared with chemoembolisation alone, combined radiotherapy plus chemoembolisation may be associated with fewer deaths and more tumour size reduction, despite being associated with an increased risk for non-life-threatening adverse effects such as a higher rise of bilirubin and alanine aminotransferase. Combined radiotherapy and chemoembolisation may be associated with fewer deaths and increased overall response, but also an increased risk of adverse effects, when compared with chemoembolisation alone. The low quality of evidence suggests that these results should be considered cautiously and that high-quality randomised trials should be performed to assess further the role of external beam radiotherapy for unresectable hepatocellular carcinoma.