Description of health problem

Liver cancer is the fifth most common cancer and the second most frequent cause of cancer-related death globally.¹ Hepatocellular carcinoma (HCC) is the most common type of liver cancer, representing around 90% of primary liver cancers.¹ Around 90% of HCCs are associated with a known underlying aetiology, most frequently chronic viral hepatitis B or C, or overconsumption of alcohol (alcoholic liver disease). Long periods of chronic liver disease, characterised by hepatic inflammation, fibrosis and aberrant hepatocyte regeneration, can cause scarring of the liver (cirrhosis).² One-third of patients with cirrhosis will develop HCC during their lifetime.¹

In the UK, the underlying aetiology of HCC is commonly alcoholic liver disease and non-alcoholic fatty liver disease, with 50% of cases attributable to these factors. Hepatitis infection (hepatitis B or C) is also a common cause in the UK but, in contrast with non-Western populations, represents only 15% of cases. Viral hepatitis is the primary cause of HCC in non-Western populations, with up to 90% of cases directly attributable to the hepatitis B and C virus.³

Underlying liver cirrhosis and the burden of a growing tumour results in an often substantially reduced liver function in HCC patients, with consequences for morbidity and mortality. Liver dysfunction associated with chronic liver disease is commonly assessed using the Child–Pugh scoring system, which classifies patients into three groups: A, B or C (least severe disease, moderate liver disease and severe/end-stage liver disease). Treatment options available to HCC patients are in part dictated by liver function, with choices becoming more limited with increasing liver dysfunction. The Barcelona Clinic Liver Cancer (BCLC) staging system is used to establish prognosis and enable the selection of appropriate treatment based on both the underlying liver dysfunction and the cancer stage.¹ A modified version of the BCLC staging system is presented in Table 1. The BCLC staging system classifies patients into five stages (0, A, B, C and D) according to tumour burden, liver function and Eastern Cooperative Oncology Group (ECOG) performance status,⁴ which must all be considered when selecting appropriate treatment.¹

TABLE 1

Modified BCLC staging system and treatment strategy

Current service provision

Clinical management of HCC is complex. There are a range of treatment options available, which depend on the location and stage of the cancer and liver function. Clinical practice guidelines published by the European Association for the Study of the Liver (EASL) summarise treatment recommendations according to BCLC classification.¹ These recommendations are presented in Table 1, with some modifications, reflecting entry criteria to pivotal clinical trials.

The primary aim of therapy in patients diagnosed with early-stage HCC is typically curative, and there are a number of available treatment options with curative potential. These include radiofrequency ablation (which uses the heat generated by alternating currents to destroy solid tumour tissue), resection (in which the tumour-containing portions of the liver are removed) and liver transplantation.¹ Owing to the limited availability of suitable donors, liver transplant is typically reserved for patients with a poor prognosis owing to impaired liver function, and in whom resection is inappropriate, for example in patients with multifocal tumours. Suitability for transplant is assessed against the Milan criteria,⁹ which require patients to have a single lesion of < 5 cm, or up to three lesions of < 3 cm each, without macroscopic vascular invasion (MVI).¹ Typically, patients not meeting these criteria are ineligible for a transplant, but increasingly patients whose disease has been ‘downstaged’ may be considered for transplant. Downstaging is when patients whose tumours fall outside the limits permitted by the Milan criteria⁹ are brought within the criteria, typically through the use of conventional transarterial therapies (CTTs) (see below) to reduce tumour burden. Patients waiting for a transplant may also receive CTT as a ‘bridging therapy’, in which the intent is to control the progression of disease to keep patients within the Milan criteria.⁹ However, as transplant waiting times in the UK are typically relatively short, with a median time for HCC patients of approximately 50 days, the use of bridging therapy is limited.

Conventional transarterial therapies are the standard care in intermediate HCC if resection or other curative treatment modalities are unsuitable. CTT includes transarterial chemoembolisation (TACE), drug-eluting bead transarterial chemoembolisation (DEB-TACE) and transarterial embolisation (TAE) without chemotherapy. Blood is primarily supplied to the liver via the hepatic portal vein, whereas most tumours are supplied by the hepatic artery. All three forms of CTT work by administering an embolising agent into the hepatic artery to block blood vessels feeding the tumours within the liver. This process preferentially interrupts the blood supply to the tumours, while allowing blood to continue to reach the remaining healthy tissue. In the case of TACE, Lipiodol^® (Guerbet, Villepinte, France) is combined with a chemotherapy agent, typically doxorubicin or cisplatin, which is administered directly to the tumour, allowing for much higher concentrations of the drug to be achieved than could be tolerated systemically. In DEB-TACE, drug-eluting beads typically bound with doxorubicin or epirubicin are administered to the tumour via the hepatic artery. This allows the release of the chemotherapeutic agent over a prolonged period of time, thereby reducing systemic concentrations (and thus any side effects) compared with TACE.¹⁰ TAE, or bland TACE, involves only the physical occlusion of blood vessels, with no addition of chemotherapy. Because the primary therapeutic effect of CTT is the embolisation of the hepatic artery, the use of these techniques is typically limited to patients with good portal vein flow, so as to maintain a good blood supply to the liver. Therefore, patients with portal vein thrombosis (PVT) or tumour invasion of the portal vein are typically considered contraindicated to CTT.

In patients who have advanced HCC, or for whom CTT has previously failed, the current standard of care consists of systemic chemotherapy. Current National Institute for Health and Care Excellence (NICE) guidance in this population recommends sorafenib (Nexavar^®; Bayer plc, Leverkusen, Germany) as an option for people with Child–Pugh class A liver impairment (TA474).¹¹ Lenvatinib (Kisplyx^®, Eisai Ltd, Tokyo, Japan) is also recommended as an option for people with Child–Pugh class A liver impairment and an ECOG performance status of 0 or 1 (TA551).¹² A recent technology appraisal on regorafenib (Stivarga^®; Bayer plc, Leverkusen, Germany) for treating advanced unresectable HCC (TA555)¹³ recommends regorafenib as an option for people who have previously been treated with sorafenib and have Child–Pugh class A liver impairment and an ECOG performance status of 0 or 1. Best supportive care (BSC) is offered to patients when CTTs or systemic therapy are not available or appropriate, including patients with terminal-stage disease.

Description of the technology under assessment

Selective internal radiation therapy (SIRT), also known as transarterial radioembolisation (TARE), is a complex intervention that delivers radiation directly to liver tumours via microspheres that are injected into the hepatic artery via a catheter inserted into the femoral artery. The most likely position for SIRT in the HCC treatment pathway is for patients with intermediate-stage (BCLC stage B) or advanced-stage (BCLC stage C) HCC as a non-curative option, as the use of SIRT is not precluded by reduced liver function as strictly as CTTs. However, SIRT is unlikely to be suitable for patients with more limited liver function (Child–Pugh class ≥ B8) or extrahepatic tumour spread. There may also be a role for SIRT as a bridging therapy for BCLC stage A patients awaiting transplant (see Current service provision) as an alternative to CTTs.

The NICE interventional procedures guidance 460¹⁴ states that current evidence on the efficacy and safety of SIRT for primary HCC was adequate to permit routine use of the technology. However, significant uncertainties remain about its comparative effectiveness relative to conventional transarterial and systemic therapeutic options.¹⁴ Clinicians have been encouraged by NICE to enter eligible patients into trials comparing the procedure against other forms of treatment and to enrol all patients into the UK SIRT registry (launched in 2013).¹⁴

The present appraisal concerns three SIRTs: SIR-Spheres^® (Sirtex Medical Ltd, Woburn, MA, USA), TheraSphere™ [BTG Ltd, London, UK (now Boston Scientific, Marlborough, MA, USA)] and QuiremSpheres^® (Quirem Medical BV, Deventer, the Netherlands). SIR-Spheres [manufactured by Sirtex Medical Ltd (hereafter Sirtex)] is a Conformité Européenne (CE)-marked class III active medical device comprising resin microspheres containing yttrium-90; SIR-Spheres is indicated for the treatment of inoperable liver tumours. TheraSphere [manufactured by BTG Ltd (hereafter BTG)] is a CE-marked class III active medical device comprising glass microspheres containing yttrium-90; TheraSphere is indicated for the treatment of hepatic neoplasia. QuiremSpheres [manufactured by Quirem Medical BV and distributed by Terumo Europe NV (Leuven, Belgium)] is a CE-marked class III active medical device comprising poly-L-lactic acid (PLLA) microspheres containing holmium-166; QuiremSpheres is indicated for the treatment of unresectable liver tumours.

In preparation for SIRT, patients undergo preliminary angiography of the hepatic artery, and protective coiling of extrahepatic branches to reduce extrahepatic radiation uptake. For TheraSphere and SIR-Spheres, technetium-99m-macroaggregated albumin is used as an imaging surrogate and injected into the hepatic artery using the same catheter position chosen for the scheduled SIRT session. Calculation of the radiation dose to the tumour and adjacent liver, hepatopulmonary shunt fraction and tracer distribution are evaluated with single-photon emission computerised tomography (SPECT) imaging. This is known as the ‘work-up’ procedure, and is ultimately what decides whether or not patients are eligible to receive SIRT. A high level of lung shunt or extrahepatic uptake contraindicate the SIRT procedure. When SIRT is not contraindicated following work-up, patients are later readmitted for the SIRT procedure, which is performed in a lobar, sectorial or segmental approach according to tumour size and location.¹ When tumours are present in both lobes, patients may receive a separate administration of SIRT to each lobe on separate occasions (often several weeks apart), to allow clinicians to monitor the liver’s response to radiation and prevent damage.

The work-up procedure for QuiremSpheres exploits the properties of holmium-166 microspheres, which, unlike yttrium-90, can be visualised with SPECT and magnetic resonance imaging (MRI) even at low concentrations. Therefore, a lower dose of holmium-166 is used for evaluating dose distribution [known as QuiremScout^® (Quirem Medical BV)], rather than a surrogate, which may allow for a more accurate assessment of radiation distribution and dosimetry.

Table 2 presents an overview of the main characteristics of each therapy.

TABLE 2

Main characteristics of SIR-Spheres, TheraSphere and QuiremSpheres