Hepatocellular carcinoma (HCC), a primary malignant tumor of the liver, is the sixth most common cancer worldwide with an incidence of 626,000 new patients a year, and the third most common cause of cancer-related death . HCC is a heterogeneous disease in terms of etiology and clinical behavior. It usually develops in the setting of chronic liver disease, mostly related to infection with hepatitis B or C, excessive alcohol intake and, today, also more as a consequence of non-alcoholic steatohepatitis (NASH) . Cure can only be achieved by hepatic resection, liver transplantation and in certain cases by radiofrequency ablation (RFA) . Although there is no universally accepted HCC staging system, many have adopted the Barcelona Clinic Liver Cancer (BCLC) staging classification, which links the stage of the disease to a specific treatment strategy [4, 5].
Only 10% to 15% of all patients with HCC are eligible for treatment with curative intent, and local ablative treatment is limited by strict criteria on the stage of the disease (that is, disease confined to the liver and limited number of lesions with relatively small dimensions (maximum of three lesions <3 cm in size) according to the BCLC staging classification). However, the majority of patients present at more advanced stages and are not eligible for such treatment.
For patients with locally advanced, liver restricted disease (BCLC intermediate stage), transarterial loco regional treatment modalities offer palliative treatment options. These therapies exploit the dual blood supply to the liver. HCC derives its blood supply almost entirely from the hepatic artery, while liver parenchyma derives >75% of its blood supply from the portal vein . This anatomical fact provides the basis for the development of intra-arterial therapies for the treatment of HCC, with the potential of selectively inducing tumor necrosis while sparing surrounding liver parenchyma. Antitumoral agents, such as cytotoxic drugs or radionuclides, can be delivered at the site of the tumor, as they lodge in the peritumoral vascular bed after intra-arterial injection.
This randomized controlled trial is designed to compare two transarterial loco regional therapies applied for the treatment of patients with intermediate stage HCC: transarterial chemoembolization (TACE), the current standard treatment, and Yttrium-90 radioembolization (90Y-RE), a newer treatment modality.
Transarterial chemoembolization (TACE) is a procedure in which a catheter is advanced into the branches of the hepatic artery supplying the tumor, and a combination of embolic material and chemotherapeutics is delivered through the catheter directly into the tumor. This way arterial inflow to the tumor is reduced, resulting in ischemic tumor necrosis, and washout of the chemotherapeutic agent is diminished, thereby prolonging contact time between cancer cells and the drug .
According to the BCLC staging classification and treatment schedule, TACE can be considered the current standard treatment for patients with intermediate stage HCC with compensated liver disease, with a reported median survival of around 17 months [8–10].
Two randomized, controlled trials [11, 12] and two systematic reviews [13, 14] demonstrated a survival benefit of TACE in this selected patient group. A more recent Cochrane review and meta-analysis concluded that there is no firm evidence to support or refute TACE in patients with unresectable HCC . However, this review is controversial since some studies included in the meta-analysis included patients that are no longer consistent with the more stringent selection criteria currently applied for TACE (BCLC intermediate stage B with compensated liver disease) and there are discrepancies in treatment application between the studies. The lack of standardization accompanied with the application of conventional TACE (mostly performed with a mixture of chemotherapeutics, lipiodol and an occluding agent) is no longer an issue with the arrival of drug-eluting beads (DEBs). DEBs act as both an occluding agent as well as a drug-loaded carrier, achieving local ischemia and cytotoxic death of the tumor with one device, enabling standardization . Several clinical trials reported DEBs to be effective for treatment of intermediate stage HCC [16–20], with objective response (complete plus partial response) rates ranging from 60% to 85.5%, which is substantially higher compared to the mean objective response of 35% (range 16% to 61%) stated in a meta-analysis of RCTs for conventional TACE . The complication rates are considered acceptable, although post-embolization syndrome is observed in 37% to 100% of the treated patients. This is a condition in which the patient experiences abdominal pain, fever, ileus and nausea, self-limiting hours to days after the procedure, probably due to damage of hepatocytes . Most importantly, these trials report no systemic toxicity despite the high doses of doxorubicin loaded on the DEBs [16–20]. The PRECISION V trial compared conventional TACE with TACE-DEB in a large, randomized study . The TACE-DEB group showed higher rates of complete response, objective response and disease control when compared with conventional TACE at six months (27% vs. 22%, 52% vs. 44%, 63% vs. 52%); however, the difference was not statistically significant. Subgroup analysis showed that TACE-DEB results in a higher tumor control rate in patients with Child-Pugh B cirrhosis, bilobar disease or reduced performance score compared to conventional TACE. This was achieved without an increased risk of adverse events .
Yttrium-90 radioembolization (90Y-RE) is a relatively recently developed technique which involves the transarterial administration of minimally embolic microspheres loaded with Yttrium-90, a β-emitting isotope, delivering selective internal radiation to the tumor. This brachytherapy device is approved by the Food and Drug Administration for HCC with and without portal vein thrombosis (PVT). Several prospective and retrospective studies demonstrated the safety and efficacy of 90Y-RE treatment for unresectable HCC, all documented in a recent review . An earlier structured meta-analysis describes a response rate of 78% (glass microspheres) and 89% (resin microspheres) . The largest prospective study to date included 291 HCC patients that were treated with 90Y-RE . In intermediate stage patients (BCLC stage B) median time to progression was 13.3 months (Child-Pugh A, 13.3 months and Child-Pugh B, 17.4 months) and median survival was 17.2 months (Child-Pugh A, 17.3 months and Child-Pugh B, 13.5 months).
Although 90Y-RE is increasingly used in clinical practice, there is no high quality clinical evidence to justify this. Lewandowsky et al.  retrospectively analyzed HCC patients with disease beyond the Milan criteria for liver transplantation and concluded that radioembolization outperforms TACE for down-staging HCC to within transplant criteria. The results of a single-center study carried out by Kooby et al. , in which patients treated with chemoembolization or radioembolization were retrospectively compared, suggests that both treatment modalities have similar effectiveness and safety profiles in patients with unresectable HCC. Carr et al.  carried out a similar retrospective analysis and concluded that chemoembolization or radioembolization appeared to be equivalent regional therapies for patients with unresectable, nonmetastatic HCC. Recently Salem et al.  retrospectively compared 122 HCC patients who received chemoembolization with 123 patients who received radioembolization and concluded both patient groups had similar survival times. Radioembolization resulted in longer time-to-progression and less toxicity than chemoembolization.
To date, no prospective studies have been performed comparing both treatment modalities in a randomized setting. This randomized controlled trial is designed to prospectively compare TACE and 90Y-RE for treatment of patients with unresectable (BCLC intermediate stage) HCC.