Yttrium-90 microsphere radioembolisation for advanced hepatocellular carcinoma (primary liver cancer)

Review question

What are the benefits and harms of yttrium-90 microsphere radioembolisation compared with placebo, no intervention, or other available interventions in people with advanced liver cancer?

Background
Hepatocellular carcinoma (i.e. primary liver cancer) is the most common malignant tumour of the liver and the fifth most common malignant tumour worldwide. In the majority of people, hepatocellular carcinoma is diagnosed at an advanced stage. For these people, treatment options include ablation therapy (which destroys the tumour), embolisation therapy (which uses substances to block or decrease the flow of blood through the hepatic artery to the tumour), radiotherapy, and sorafenib (targeted therapy that uses a substance to identify and attack cancer cells while avoiding normal cells). Yttrium microsphere radioembolisation involves injection into the blood supply of the tumour very small spheres that have radioactive material attached to them. The radioactivity is supposed to destroy the liver tumour without affecting other parts of the body.

Study characteristics
Review authors searched for published medical articles to clarify the role of yttrium microsphere radioembolisation in the treatment of people with advanced liver cancer. Review authors looked for randomised clinical trials (where people were allocated at random to one of two or more treatments groups) to perform statistical analysis on which they could form conclusions about the intervention. Evidence is current to September 2019.

Funders and funding collaborators of these studies were Bayer, Sirtex Medical, Johannes Gutenberg University Mainz, and Northwestern University.

We also identified two ongoing randomised trials evaluating the topic of our review. One of them compared radioembolisation with chemoembolisation in intermediate-stage hepatocellular carcinoma, and the other compared radioembolisation plus sorafenib versus sorafenib alone in advanced hepatocellular carcinoma.

Key results
Review authors found six randomised clinical trials, in which 1340 people with advanced liver cancer were randomised. One trial compared radioembolisation plus sorafenib versus sorafenib alone. This trial suggested that combination treatment for this disease seems to be associated with similar risk of death compared with use of sorafenib alone. Two trials compared radioembolisation with sorafenib. There seems to be no difference in the risk of death between these interventions. Three trials compared radioembolisation with chemoembolisation. There seems to be no difference in serious toxicities between these interventions. Review authors identified two ongoing randomised clinical trials, the results of which have not been finalised.

Certainty of the evidence and conclusions

Evidence for the benefits and harms of radioembolisation with or without sorafenib and compared with sorafenib alone in people with unresectable hepatocellular carcinoma is highly insufficient. We cannot determine if radioembolisation plus sorafenib compared with sorafenib alone affects the occurrence of adverse events. Radioembolisation compared with sorafenib seemed to achieve equivalent survival and to cause fewer adverse effects, but our certainty is very low. Evidence for the benefits and harms of radioembolisation versus chemoembolisation in people with unresectable hepatocellular carcinoma is also highly insufficient. Radioembolisation did not seem to differ from chemoembolisation in terms of serious adverse events and health-related quality of life, but the certainty of evidence was very low. Additional well-performed and high-quality placebo-controlled randomised clinical trials are needed to assess patient-centred outcomes.

Authors' conclusions: 

Evidence showing effects of radioembolisation with or without sorafenib compared with sorafenib alone in people with unresectable hepatocellular carcinoma is highly insufficient. We cannot determine if radioembolisation plus sorafenib compared with sorafenib alone affects all-cause mortality or the occurrence of adverse events. Radioembolisation compared with sorafenib seemed to achieve equivalent survival and to cause fewer adverse effects, but our certainty was very low. Evidence showing effects of radioembolisation versus chemoembolisation in people with unresectable hepatocellular carcinoma is also highly insufficient. Radioembolisation did not seem to differ from chemoembolisation in terms of serious adverse events and quality of life, but the certainty of evidence was very low. Further high-quality placebo-controlled randomised clinical trials are needed to assess patient-centred outcomes.

Read the full abstract...
Background: 

Hepatocellular carcinoma is the most common liver neoplasm and the sixth most common cancer worldwide. Its incidence has increased dramatically since the mid-2000s. Although surgical resection and liver transplantation are the main curative treatments, only about 20% of people with early hepatocellular carcinoma may benefit from these interventions. Treatment options for unresectable hepatocellular carcinoma include ablative and transarterial interventions - selective yttrium-90 microsphere transarterial radioembolisation - in addition to the drug sorafenib.

Objectives: 

To determine the benefits and harms of yttrium-90 (Y-90) microsphere transarterial radioembolisation given as monotherapy or in combination with other systemic or locoregional interventions versus placebo, no treatment, or other similar systemic or locoregional interventions for people with unresectable hepatocellular carcinoma.

Search strategy: 

We performed electronic searches in the Cochrane Hepato-Biliary Group (CHBG) Controlled Trials Register, CENTRAL, MEDLINE, Embase, Latin American Caribbean Health Sciences Literature (LILACS), Science Citation Index - Expanded, and Conference Proceedings Citation Index – Science until September 2019. We manually checked the reference lists of primary studies and review articles.

Selection criteria: 

We searched for randomised clinical trials.

Data collection and analysis: 

We used standard Cochrane methods. We extracted information on participants, interventions, outcomes, trial design, and trial methods. We assessed risk of bias of the included trials using pre-defined domains and the certainty of evidence using GRADE. Our primary review outcomes were all-cause mortality, quality of life, and serious adverse events; our secondary outcomes were cancer-related mortality, time to progression of the tumour, tumour response, non-serious adverse events, and liver transplantation. For dichotomous variables, we calculated risk ratio (RR), and for continuous variables, we planned to calculate mean difference (MD) or standardised mean difference (SMD), with 95% confidence intervals (CIs). We based time-to-event data analyses on hazard ratios (HRs).

Main results: 

Six randomised trials with 1340 participants in total fulfilled the review inclusion criteria and provided data for one or more of our analysed outcomes. All trials were at high risk of bias. We assessed the certainty of evidence as low to very low.

One trial compared radioembolisation plus sorafenib versus sorafenib alone in people with advanced hepatocellular carcinoma. All-cause mortality, health-related quality of life, cancer-related mortality, time to progression, and tumour response rates were not reported. Serious adverse events were reported in 63 trial participants (39.6%) in the radioembolisation plus sorafenib group versus 70 trial participants (38.5%) in the sorafenib group (very low-certainty evidence). Hyperbilirubinaemia was approximately three times more common in the radioembolisation plus sorafenib group versus the sorafenib group (14.5% versus 4.4%; very low-certainty evidence). Fatigue was more common in the radioembolisation plus sorafenib group than in the sorafenib group, at 35.2% versus 24.2% of trial participants.

Two trials compared radioembolisation versus sorafenib for unresectable hepatocellular carcinoma in people with locally advanced hepatocellular carcinoma. From the data we could extract, one-year all-cause mortality was 62.7% in the radioembolisation group versus 53.0% in the sorafenib group (1 trial; n = 360; very low-certainty evidence). There were no differences in the quality of life between radioembolisation and sorafenib groups (1 trial). Global health status subscore was better in the radioembolisation group than in the sorafenib group (P = 0.0048; 1 trial). Fewer participants had serious adverse events in the radioembolisation group than in the sorafenib group (27 (20.8%) in the radioembolisation group versus 57 (35.2%) in the sorafenib group; 1 trial). Median time to progression of the tumour in the radioembolisation group was 6.1 months versus 5.4 months in the sorafenib group (1 trial). The RR for disease control rate was 0.94 (95% CI 0.84 to 1.05; n = 748; 2 trials; very low-certainty evidence), favouring neither radioembolisation nor sorafenib. In two trials with 734 participants, radioembolisation seemed to be less likely to be associated with hand-foot skin reaction (RR 0.02, 95% CI 0.00 to 0.06; P < 0.001; low-certainty evidence), skin rash (RR 0.11, 95% CI 0.04 to 0.34; low-certainty evidence), diarrhoea (RR 0.11, 95% CI 0.04 to 0.34; low-certainty evidence), and hypertension (RR 0.10, 95% CI 0.01 to 0.88; low-certainty evidence). No trial reported cancer-related mortality.

Three trials compared radioembolisation versus chemoembolisation in people with intermediate-stage hepatocellular carcinoma. From the data we could extract, none of these trials reported all-cause mortality and cancer-related mortality. The RR for serious adverse events was 1.41 (95% CI 0.63 to 3.14; n = 97; very low-certainty evidence), favouring neither radioembolisation nor chemoembolisation. One trial reported quality of life and noted no differences between intervention groups with regard to this outcome at week 12 (very low-certainty evidence). Median time to progression was not reached in the radioembolisation group and was 6.8 months in the chemoembolisation group (HR 0.122, 95% CI 0.027 to 0.557; 1 trial). Median time to progression of the tumour in the radioembolisation group was 371 days versus 336 days in the chemoembolisation group (P = 0.5764; 1 trial). Disease control rates (complete response + partial response + stable disease) were 73.3% with radioembolisation versus 76.9% with chemoembolisation (1 trial). According to World Health Organization (WHO) criteria, tumour response was reported in 52% of participants who received radioembolisation versus 63% of those who received chemoembolisation (1 trial). Patients in the chemoembolisation group experienced diarrhoea (P = 0.031; 1 trial) and hypoalbuminaemia (P < 0.001; 1 trial) more frequently.

Four trials were sponsored by industry, and two by University.

We found two ongoing trials.

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