Radiotherapy administered externally for advanced hepatocellular carcinoma (primary liver cancer)

Review question

What are the benefits and harms of radiotherapy administered externally in people with advanced liver cancer compared with other available therapies or no therapy?

Background

Hepatocellular carcinoma (primary liver cancer) is the most common cancerous tumour of the liver and the sixth most common cancerous tumour worldwide. In the majority of people with hepatocellular carcinoma, the disease is diagnosed at the advanced stage. Treatment options for these people include ablation (which destroys the tumour), embolisation (the use of substances to block or decrease the flow of blood through the hepatic artery to the tumour), radiotherapy, or sorafenib, which is a targeted drug therapy (a treatment that uses a substance to identify and attack cancer cells while avoiding normal cells).

Study characteristics

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.

Key results

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.

Quality of the evidence and conclusions

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.

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.

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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 strategy: 

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.

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