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Integrating SIR-spheres into the treatment of HCC

Kiruthikah Thillai, Praveen Peddu and Paul J Ross
9 June, 2014  
Recent years have seen the emergence of radio-embolisation with Yttrium 90 as a potential treatment for patients with inoperable hepatocellular carcinoma
Kiruthikah Thillai MBBS MRCP
Department of Oncology, Guy’s and 
St Thomas’ NHS Foundation Trust, London, UK
Praveen Peddu MBBS MRCS FRCR
Department of Radiology, King’s College Hospital NHS Foundation Trust, London, UK
Paul J Ross PhD FRCP
Department of Oncology, Guy’s and St Thomas’ NHS Foundation Trust; Department of Oncology, King’s College Hospital NHS Foundation Trust, London, UK
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide and, with a rising incidence, it is an important global health issue. Despite the implementation of surveillance strategies and improved diagnostic techniques, the majority of patients still present late with inoperable disease. Progressive HCC often remains confined to the liver, highlighting the need for therapeutic modalities that achieve loco-regional control without compromising liver function. Transarterial chemoembolisation (TACE) and radiofrequency ablation are now established treatment modalities. The past few years has seen the emergence of radio-embolisation with Yttrium 90 (Y90RE) as yet another potential treatment for patients with inoperable HCC. 
Current treatments for HCC
The Barcelona Clinic Liver Clinic (BCLC)(1) is currently the most widely used staging system and considers the extent of tumour, the presence or absence of portal vein thrombosis (PVT) and performance status. Patients with intermediate stage (Barcelona Stage B) are conventionally offered TACE or trans-arterial embolisation without chemotherapy (TAE). Patients with advanced stage C disease but without distant metastases are offered loco-regional treatment. TACE/TAE exploits the predominant hepatic arterial supply to the tumour, as the non-tumour liver receives 75% of its supply from the portal vein. A variety of techniques are now in use, most recently doxorubicin-eluting beads have been introduced, reducing first-pass effect. There remains uncertainty as to whether TACE offers an advantage over TAE, but a recent Phase II/III trial comparing sequential TACE and TAE demonstrated differing response rates of 13.2% with TAE and 32.6% with TACE (p=0.04) but no statistically significant difference in survival.(2)
There is increasing evidence to support the use of radioembolisation with Y90RE, a technique known as selective internal radiation therapy. HCC is a highly radiosensitive tumour, as is liver parenchyma; consequently, the use of traditional external beam radiotherapy results in unacceptable toxicities and is therefore not routinely used. In Y90RE, the arterial supply to the tumour is targeted by injecting small radioactive microspheres directly into the vessels thereby leading to a more targeted delivery of radiotherapy to the tumour and minimising toxicities.
There are currently two microspheres available constructed of either resin (SIR-Spheres® Sirtex, Australia) or glass (TheraSphere®, Nordion, Canada). Both microspheres are pre-loaded with Y90, a pure beta emitter, which is a high-energy radiation source with a relatively short half life (2.67 days) and short tissue penetration (2.5mm): characteristics that lend itself to administering focused high dose radiation with limited parenchymal damage. Within two weeks of injection, >95% of the radiation has been deposited.(3)
Evidence for the efficacy of Y90RE
Several small studies have demonstrated efficacy with Y90RE. The largest prospective study to date was a single-centre longitudinal cohort study of 291 patients with inoperable HCC.(4) Response rates as measured by the European Study of the Liver and World Health Organisation criteria were 42% and 57%, respectively. The overall time to progression was 7.9 months (95% confidence interval 6–10.3). 
A sub-group analysis of patients by Child-Pugh status demonstrated a difference in median overall survival (mOS) of 17.2 months versus 7.7 months (p=0.02) in patients with Child-Pugh A and B, respectively. Patients with PVT and Child-Pugh B had a survival of 5.6 months (4.5–6.7). A smaller prospective Phase II trial of 52 patients treated with Y90RE demonstrated a mOS of 11 months, with an objective response of 40% and disease control rate of 78.8%.(5) 
A retrospective study analysed 325 patients with inoperable HCC treated with Y90 resin microsphere radioembolisation across eight European centres.(6) Patients had good performance status, and the majority had preserved liver function (82.5% Child-Pugh class A). The mOS was 12.8 months and outcomes varied significantly by disease stage, performance status, hepatic function, tumour burden and the presence of extra-hepatic disease (see Table 1). Common adverse events were fatigue, nausea, vomiting, and abdominal pain (Table 2). An increase in bilirubin to grade 3 or more was seen in a minority of patients (5.8%)
Another proposed use of Y90RE is to downstage inoperable tumours to resectable disease. A non-randomised analysis of 86 patients with stage T3 disease, as classified by the united network of organ sharing staging system, assessed the use of TACE compared with Y90RE using glass micro-spheres to downstage tumours from T3 to T2 and thereby rendering patients potentially operable.(7)
Forty-three patients were treated with TACE and 43 were treated with Y90RE with a median tumour size of 5.6cm. Partial response rates favoured Y90RE compared to TACE (61% versus 37%) and down-staging to T2 was achieved in 31% of TACE and 58% of Y90RE patients. Eleven (26%) patients treated with TACE went on to transplantation compared to nine (21%) with Y90RE. One patient in each group underwent subsequent resection following embolisation. A further eight (23%) patients had RFA following TACE versus 18 (42%) following Y90RE treatment.
Although this was a non-randomised trial in a single institution, it suggests the potential use of Y90RE as a technique to downstage inoperable tumours, but its benefits clearly need to be confirmed in larger, randomised clinical trials. As well as down-staging disease, Y90RE has been used as a bridging treatment for patients awaiting liver transplantation and disease stability and sustained responses have been described in patients with intermediate HCC. 
Radiation segmentectomy using Y90 has also demonstrated efficacy as demonstrated in a single centre analysis of 84 patients treated over five years. Response by size and necrosis guidelines were seen in 59% and 81% of patients, respectively, with high-response explained by increased doses of radiation delivered directly to the tumour. Fatigue was seen in 52% of patients with other toxicities, including pain (18%) and nausea/vomiting (13%). Median time to progression was 13.6 months with a median survival of 26.9 months. 
Portal vein thrombosis
One potential advantage of radio-embolisation is its use in the presence of PVT. A significant number of patients with HCC and underlying liver cirrhosis have portal vein occlusion or thrombus at presentation. The presence of this feature results in an increase risk of ischaemic hepatic decompensation with TACE if both arterial and portal flows are compromised.(3) A Phase II trial reported the outcomes of 108 patients with or without the presence of PVT complicating HCC treated with Y90 microspheres.(8) 37/108 patients had PVT, 12 of which occluded the main portal vein. While survival was shorter in patients with PVT, this was not thought to be a contributing survival determinant, as was usually an accompanying feature of underlying cirrhosis.
There was no significant difference in toxicities in patients without PVT compared to those with thrombi in the portal vein branches. However, in patients with main PVT, there was a higher incidence of bilirubin adverse events but, again, these patients had more advanced underlying hepatic damage. A smaller analysis of 20 patients with inoperable HCC and branch or main PVT showed that liver function was maintained in the majority of patients when treated with Y90RE. A further Phase II study of patients treated with Y90RE showed no statistical difference in toxicities in patients with or without PVT and survival outcomes were similar irrespective of thrombotic status.(5) The results from these trials suggest that, in patients with branch or main PVT, Y90RE treatment appears to be safe, whereas TACE remains contra-indicated. 
Ongoing clinical trials
Several larger prospective clinical trials assessing the use of Y90RE are currently recruiting patients and aim to determine the benefits of SIRT compared to other available therapies in non-resectable disease. These include a prospective open-label, multi national Phase II non-inferiority study assessing the combination of sorafenib with RFA or Y90RE with a sub-group study of contrast enhanced computed tomography imaging versus Primovist® enhanced MRI. Two further large Phase III prospective, open-label, multi-national trials are currently randomising patients with unresectable liver disease and preserved hepatic function to SIRT or sorafenib, with a primary end point of overall survival.(9–11)
Radio-embolisation with Y90 microspheres for liver-limited, inoperable HCC appears to offer favourable outcomes, comparable with other loco-regional treatments such as TACE, but with a broader application as demonstrated by its safety and efficacy in patients with PVT. Efficacy has been confirmed in intermediate disease, but SIRT also appears to be an effective modality to down-stage inoperable HCC or as bridging treatment prior to transplantation. Recent studies have led to its proposed addition to the HCC management algorithm and the outcomes of ongoing Phase III trials may determine the role of Y90RE in the management of HCC.
  1. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLCstaging classification. Semin Liver Dis 1999;19:329–38.
  2. Meyer T et al. A randomised phase II/III trial of 3-weekly cisplatin-based sequential transarterial chemoembolisation vs embolisation alone for hepatocellular carcinoma. Br J Cancer 2013;108:1252–9.
  3. Sangro B et al. Radioembolization for hepatocellular carcinoma: a review of the evidence and treatment recommendations. Am J Clin Oncol 2011;34:422–31.
  4. Salem R et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 2010;138:52–64.
  5. Mazzaferro V et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study. Hepatology 2013;57:1826–37.
  6. Sangro B et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 2011;54:868–78.
  7. Lewandowski RJ et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant 2009;9:1920–8.
  8. Kulik LM. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology 2008;47:71–81.
  9. SorAfenib Versus Radioembolization in Advanced Hepatocellular Carcinoma (SARAH) NCT01482442.
  10. Sorafenib and Micro-therapy Guided by Primovist Enhanced MRI in Patients With Inoperable Liver Cancer (SORAMIC) NCT01126645.
  11. Study to Compare Selective Internal Radiation Therapy (SIRT) Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma (HCC) NCT01135056.