Transcatheter arterial chemoembolisation followed by three-dimensional conformal radiotherapy for primary hepatocellular carcinoma

Background

Hepatocellular carcinoma, also called malignant hepatoma, is a primary liver cancer. Despite regular surveillance conducted in high-risk populations, most people with hepatocellular carcinoma are diagnosed at an advanced stage. Consequently, a minority of the people with the disease are suitable for surgical resection (removal). Since transcatheter arterial chemoembolisation (TACE; a procedure to restrict the blood supply to a tumour) was introduced as a palliative (to relieve symptoms and improve quality of life) treatment in people with unresectable liver cancer, it has become one of the most common forms of intervention. More recently, the modern radiation technology of three-dimensional conformal radiotherapy (3-DCRT), which shapes the radiation beams to the shape of the tumour, has been used to improve the adverse effects of conventional radiotherapy. It is predicted that the combination of TACE followed by 3-DCRT could enhance the treatment effect for hepatocellular carcinoma. To date, little is known about the benefits and harms of the combination of TACE followed by 3-DCRT, and current studies are still controversial for the efficacy of the combination of TACE followed by 3-DCRT compared with TACE alone. The aim of this Cochrane systematic review was to compare the benefits and harms of TACE followed by 3-DCRT versus TACE alone in people with primary hepatocellular carcinoma, considered to be unsuitable for surgical removal.

Study characteristics

The review authors searched the medical literature in order to clarify the role of the combination of TACE followed by 3-DCRT for the treatment of primary hepatocellular carcinoma, and to compare their benefits and harms with TACE alone. We collected and analysed data from randomised clinical trials (clinical studies where people are randomly put into one of two or more treatment groups) of people with primary hepatocellular carcinoma who were able to receive TACE or 3-DCRT. Evidence is current to May 2018.

Key results and quality of evidence

The review included eight trials with 632 participants. All trials were at high risk of bias. TACE followed by 3-DCRT appeared to be superior to TACE in improving death from any cause and tumour response, despite an increased toxicity expressed by a higher rise of total bilirubin (measured by a blood test to see how well the liver is working). No trials reported serious side effects. One trial reported health-related quality of life (a measure of a person's satisfaction with their life and health), but this was ill-defined. The review findings were uncertain because the included trials had methodological weaknesses. More high-quality randomised clinical trials are needed to confirm or complete the review findings.

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.

Read the full 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 strategy: 

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).

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