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Yttrium-90 microsphere radioembolisation for unresectable hepatocellular carcinoma. Due to a comment received and due to some other identified methodological problems, the present review is withdrawn.

Yttrium-90 microsphere radioembolisation for unresectable hepatocellular carcinoma. 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 METHODS: 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. 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.

Yttrium-90 microsphere radioembolisation for unresectable hepatocellular carcinoma. BACKGROUND: Hepatocellular carcinoma is the most common liver neoplasm and the fifth most common cancer worldwide. Moreover, its incidence has increased dramatically since the mid-2000s. 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 trans-arterial therapies in addition to the drug sorafenib. OBJECTIVES: To determine the benefits and harms of yttrium-90 microsphere trans-arterial radioembolisation either as a monotherapy or in combination with other systemic or locoregional therapies versus placebo, no treatment, or other similar systemic or locoregional therapies for people with unresectable hepatocellular carcinoma. SEARCH METHODS: We reviewed data from the Cochrane Hepato-Biliary Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index Expanded. We also checked reference lists of primary original studies and review articles manually for further related articles (cross-references) up to December 2015. SELECTION CRITERIA: Eligible studies included all randomised clinical trials comparing yttrium-90-90 microsphere radioembolisation either as a monotherapy or in combination with other systemic or locoregional therapies versus placebo, no treatment, or other systemic or locoregional therapies for unresectable hepatocellular carcinoma. DATA COLLECTION AND ANALYSIS: The two review authors independently extracted the relevant information on participant characteristics, interventions, study outcomes, and data on the outcomes for this review, as well as information on the design and methodology of the studies. The two review authors assessed risk of bias of the included trials using pre-defined risk of bias domains. We used Trial Sequential Analysis to control the risk of random errors. We assessed the methodological quality with GRADE. MAIN RESULTS: Two randomised clinical trials with 68 participants fulfilled our inclusion criteria. Both trials were at high risk of bias, and we rated the evidence as very low quality. One of the included trials compared radioembolisation versus chemoembolization for intermediate stage hepatocellular carcinoma as classified by the Barcelona Clinic Liver Cancer (BCLC) staging system, while the other included trial was an interim analysis of a randomised trial assessing radioembolisation combined with sorafenib versus sorafenib monotherapy in participants with BCLC-advanced stage hepatocellular carcinoma. The available data were insufficient to perform the planned analyses. Neither of the two trials reported data on all-cause mortality, cancer-related mortality, or time to progression of the tumour. The trial comparing radioembolisation with chemoembolization reported quality of life and serious adverse events, and there were no statistically significant differences between the trial groups with regard to these outcomes at week 12. On the basis of the two included randomised clinical trials, single-session radioembolisation appeared to be as safe as multiple sessions of chemoembolization for intermediate stage hepatocellular carcinoma and had a similar impact on quality of life, but data were too sparse to exclude even major differences. Radioembolisation followed by sorafenib appeared to be as well tolerated as sorafenib alone for advanced stage hepatocellular carcinoma, but data were too sparse to exclude even major differences. We also identified five ongoing studies evaluating the topic of our review. AUTHORS' CONCLUSIONS: There was insufficient evidence to assess the beneficial and harmful effects of yttrium-90 microsphere radioembolisation for people with unresectable hepatocellular carcinoma. Further randomised clinical trials are mandatory to better assess the potential beneficial and harmful outcomes of yttrium-90 microsphere trans-arterial radioembolisation 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.