Description of the condition
Hepatocellular carcinoma is the fifth most common cancer and the third most common cause of cancer mortality in the world (El-Serag 2007a). It has a high incidence in East and South-East Asia and in Middle and Western Africa where chronic hepatitis B viral infection is prevalent, with the exception of Japan where the major risk factor for hepatocellular carcinoma is chronic hepatitis C virus infection (Lai 2005). Hepatocellular carcinoma is less common in Europe and the US (El-Serag 1999; McGlynn 2001; El-Serag 2012), but it is on the increase in these regions because of the rising incidence of cirrhosis due to alcohol, obesity (El-Serag 2007), and especially chronic hepatitis C virus infection (Davila 2004). One-year survival for untreated patients with hepatocellular carcinoma is 17.5% and two-year survival is 7.3% (Cabibbo 2010).
Many people with hepatocellular carcinoma cannot be diagnosed at an early stage because there are no specific symptoms in early or even intermediate stage of the cancer. In countries where no systematic screening of cirrhotic patients is performed, more than 50% patients with hepatocellular carcinoma are diagnosed at an advanced stage of the carcinoma (Bruix 2005). Such patients are precluded from curative treatment options such as transplantation, surgical resection, and percutaneous ablation. Several therapies have been proposed for patients with unresectable hepatocellular carcinoma. According to the Barcelona Clinic Liver Cancer (BCLC) tumour staging system, which is endorsed by the European Association for the Study of Liver Disease (EASL) (Bruix 2001) and the American Association for the Study of Liver Disease (AASLD) (Bruix 2005). Patients at intermediate stage (BCLC stage B) may benefit from treatment with transarterial chemoembolisation, whereas patients at an advanced stage (BCLC stage C) may benefit from treatment with sorafenib (Keating 2009; Bruix 2011; Oliveri 2011). Finally, patients at end-stage (BCLC stage D) should receive palliative care (Forner 2010). Studies from Asia have evaluated the safety and survival of transarterial chemoembolisation in patients with portal vein thrombosis and have suggested that selected patients at an advanced stage (BCLC stage C) should undergo transarterial chemoembolisation (Kim 2009; Luo 2011).
Description of the intervention
Transarterial chemoembolisation is considered a mainstay of treatment for unresectable hepatocellular carcinoma. Asymptomatic patients with multinodular non-invasive tumours (BCLC stage B) are considered the best candidates for transarterial chemoembolisation, particularly in Child-Pugh A compensated cirrhosis. According to the Society of Interventional Radiology guidelines, chemoembolisation is currently defined as the infusion of a mixture of chemotherapeutic agents with or without iodised oil, followed by embolisation with particles (Brown 2007). The concept of conventional transarterial chemoembolisation is to administer a high dose of chemotherapeutic agent(s), typically emulsified in lipiodol into the hepatic arteries supplying the tumour, and, then, embolising the tumour-feeding vessels with agents such as gelfoam, polyvinyl alcohol, or acrylic copolymer gelatin particles to prolong the chemotherapeutic-to-tumour interaction time. Lipiodol acts as a carrier of chemotherapeutic agents that are released slowly from the lipiodol mixture (Nakamura 1989; Raoul 1992), but some studies argue that there is no difference in terms of pharmacokinetic parameters with intra-arterial administration of adriamycin with or without lipiodol (Johnson 1991; Dodds 1996). Transarterial chemoembolisation currently has no uniformly adopted protocol. Specifically, there are variations at different institutions in position of the catheter within the liver (selective or superselective), choice of chemotherapeutic agent, properties of the embolisation device (permanent or temporary), and schedule or interval of retreatment (Marelli 2007). This wide variety of clinical practice may lead to difficulties in the effect assessment of the various interventions. Two randomised clinical trials (Llovet 2002; Lo 2002) and two meta-analyses (Camma 2002; Llovet 2003) have demonstrated a survival benefit of transarterial chemoembolisation. However, one Cochrane review concluded that there was no firm evidence to support or refute transarterial chemoembolisation for patients with unresectable hepatocellular carcinoma (Oliveri 2011).
In an attempt to simplify and standardise the embolisation and chemotherapy delivery aspects of transarterial chemoembolisation, drug-eluting beads were developed. To date, there are two different types of drug-eluting beads: polyvinyl alcohol (PVA)-based microspheres (DC Bead®) and superabsorbent polymer (SAP) microspheres (HepaSphere® (Europe)/QuadraSphere® (USA)) (Grosso 2008; Lewis 2009; van Malenstein 2011). Both types of drug-eluting beads can lead to persistent and sustained drug elution (Sottani 2012). Drug-eluting beads have two functions in transarterial chemoembolisation, one as an embolic material and the other as an anticancer drug delivery vehicle that can elute the agent in a sustained and controlled manner. Drug-eluting bead transarterial chemoembolisation represents a relatively new dimension to the field of chemoembolisation. It is performed using similar materials (microcatheter, beads, and drug), similar technique (superselective), and with similar retreatment time intervals as conventional transarterial chemoembolisation (Poon 2007; Varela 2007; Lewandowski 2011). Drug-eluting beads add to the standardisation of transarterial chemoembolisation and may reduce the heterogeneity of the transarterial chemoembolisation procedure (Lewandowski 2011).
The main adverse effects of conventional transarterial chemoembolisation include post-embolisation syndrome, which is characterised by nausea, vomiting, fever, and right upper quadrant pain. In addition, there are other adverse effects such as bone marrow aplasia, renal failure, and cardiac toxicity. A minority of patients may develop severe infectious complications such as hepatic abscess or cholecystitis (Meza-Junco 2012). Drug-eluting bead transarterial chemoembolisation is better than conventional transarterial chemoembolisation in reducing the incidence and severity of adverse events including liver function parameters and cardiac function (Vogl 2011).
How the intervention might work
The main difference between drug-eluting bead transarterial chemoembolisation and conventional transarterial chemoembolisation is the drug-delivery mechanism (Varela 2007). Beads preloaded with anticancer drugs can be trapped within the hepatocellular carcinoma vascular network, blocking the supply of nutrition and oxygen, and inducing ischaemic necrosis (Lewis 2006). At the same time, anticancer drugs can be released in a sustained and controlled manner, achieve higher intratumoural levels of the chemotherapeutic compared with conventional transarterial chemoembolisation, and allow for prolonged contact time with cancer cells (Hong 2006; Lewis 2006). In addition, the high intratumoural concentrations of the chemotherapeutic do not result in diffusion of chemotherapeutic in the systemic circulation as opposed to conventional transarterial chemoembolisation, and so may lead to less systemic and liver toxicity (Poon 2007; Varela 2007).
Why it is important to do this review
Many studies on drug-eluting bead transarterial chemoembolisation including retrospective studies and randomised clinical trials have shown a good local response, lower number of complications without systemic toxicity, and better results in patients with more advanced hepatocellular carcinoma patients compared with conventional transarterial chemoembolisation (Varela 2007; Malagari 2008; Lammer 2010; Malagari 2010). An assessment of drug-eluting bead transarterial chemoembolisation on survival benefit is underway (Malagari 2010). Drug-eluting bead transarterial chemoembolisation is more expensive than conventional transarterial chemoembolisation and it is important for policy makers to find out whether drug-eluting bead transarterial chemoembolisation surpasses no intervention, sham intervention, or conventional transarterial chemoembolisation for unresectable hepatocellular carcinoma. During our search, we could not find any meta-analyses or systematic reviews of randomised clinical trials evaluating the beneficial and harmful effects of drug-eluting bead transarterial chemoembolisation for unresectable hepatocellular carcinoma. Thus, we consider it important to study the effects of drug-eluting bead transarterial chemoembolisation for patients with unresectable hepatocellular carcinoma.