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Microspheres and radioembolisation in HCC

Bruno Sangro and Mercedes I
1 July, 2013  
The role of radioembolisation, relative to sorafenib and trans-arterial chemoembolisation, as part of the multidisciplinary treatment of hepatocellular carcinoma is discussed
Bruno Sangro MD PhD
Mercedes Iñarrairaegui MD PhD
Liver Unit,
Clinica Universidad de Navarra and
Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD),
Pamplona, Spain
Liver disease (secondary to hepatitis B or C or a lifetime of chronic alcohol abuse) often develops silently, with no signs or symptoms, until presenting with potentially fatal complications of cirrhosis and/or hepatocellular carcinoma (HCC). Cirrhosis, which is present in 90% of all cases of HCC, complicates all aspects of the management of HCC: it hampers the diagnosis of early HCC, restricts the choice of treatment, limits those potentially eligible for resection, and is an independent determinant of prognosis.
At time of diagnosis, 80% of HCC cases are inoperable and/or have progressed beyond the early stages of HCC and are no longer suitable for liver transplantation or ablation. For patients with metastatic disease that has progressed beyond the liver or portal vein invasion, systemic therapy with sorafenib is the standard of care in most health systems. However, for patients with inoperable liver-dominant HCC, both sorafenib and liver-directed treatments, including either trans-arterial (chemo)embolisation (TAE/TACE) or radioembolisation can be recommended in the absence of a recognised first-line treatment. In this review, the role of radioembolisation, relative to sorafenib and TACE, as part of the multidisciplinary treatment of HCC is discussed. 
Introduction to radioembolisation
Radioembolisation is a form of brachytherapy in which intra-arterially injected microspheres loaded with yttrium-90 (90Y) serve as a local source for the selective delivery of internal radiation to highly vascular HCC lesions.(1) The microspheres (measuring approximately 25–35 micrometres in diameter) lodge within the distal arterioles of tumours, thereby confining the tumourcidal dose of beta-radiation to the immediate proximity of the tumour.1 Within six months of the procedure, histological analyses of explanted livers show evidence of complete necrosis in 89% of treated lesions (1–2.9cm) and 65% of lesions (3–5cm in diameter).(2)
A correlation between complete necrosis (from histological findings) and radiological features (a decrease in enhancement and size of the target lesion) is evident, with a partial response by World Health Organization (WHO) criteria, for example, associated with a complete histologic necrosis in 78% of the lesions. The radiologic response (European Association for the Study of the Liver (EASL) and WHO) after radioembolisation evolves over time, with the median time to EASL response of 34 days and the median time to WHO response of 126 days.(2) Unlike TACE, repeat radioembolisation is rarely deemed necessary for patients with HCC.(1) 
Data now published on radioembolisation from three large series totalling over 700 patients with HCC suggest that this procedure, whether delivered by glass or resin microspheres, confers similar outcomes. As shown in Figure 1, overall survival was remarkably similar when patients were stratified by tumour stage in three of the largest series of patients with HCC studied so far.(3–5)
 
In the hours following the procedure, several generally mild and transient procedure-related symptoms may ensue, including fatigue (54–61%), abdominal pain (23–56%), nausea and vomiting (20–32%) and low-grade fever (3–12%).(3–5) Mild-to-moderate lymphopenia is commonly reported after radioembolisation but is not associated with increased susceptibility to infections.(1)
In contrast to reports with TACE, radioembolisation also appears to be an acceptable treatment options for patients with portal vein thrombosis,(1) probably as a consequence of the lack of significant ischaemia, as observed in animal models. Although radioembolisation has the advantage of causing minimal or no post-embolisation syndrome, if in the rare event that 90Y microspheres are inadvertently distributed to non-target tissues, they can cause radiation-induced cholecystitis, gastrointestinal ulceration, pneumonitis and, most importantly for HCC patients, liver toxicity.(1)
Impact of cirrhosis and liver functional reserve on radioembolisation
Cirrhosis is characterised by the replacement of liver tissue by fibrosis and regenerative nodules, as well as by notable distortions in the vascular anatomy of the liver. These changes have two important consequences for the treatment of patients using radioembolisation, namely, changes in the usual distribution of the microspheres and a reduction in the functional liver reserve. 
Although arteriovenous lung shunting is more prevalent in cirrhotic than in non-cirrhotic livers, independent of the volume of tumour treated,(1) this adverse event can be largely prevented by keeping the threshold for lung irradiation below 30Gy. Of much greater clinical importance is the reduced functional reserve and impaired regenerative ability of the cirrhotic liver. Both these factors increase the risk of liver failure, especially for patients who have had prior extensive resection, or liver insult from toxins, acute viral hepatitis or external irradiation.(1)
Despite the higher likelihood of relevant liver toxicity, there is now good evidence from a 325-patient European multicentre evaluation to show that radioembolisation can be safely and effectively performed in cirrhotic patients with HCC.(4) Objective response rates range between 30% and 50%,(3) and overall survival  rates following radioembolisation do not differ significantly in patients with cirrhotic and non-cirrhotic livers (hazard ratio: 1.26; 95% CI 0.89–1.77; p=0.19).(4) 
Radioembolisation-induced liver disease (REILD), defined as jaundice and ascites appearing four-to-eight weeks after the procedure in the absence of clear tumour progression, was described as grade 4 in 2.5% of HCC patients treated in a single institution.(1) Grade 3 increases in bilirubin (according to CTCAE) were described in <6% of patients in the European multicentre study and were independent of basal tumour stage and treatment approach (whole liver vs lobar).(4)
Radioembolisation or TACE?
Typical candidates for radioembolisation have either advanced- or intermediate-stage HCC and are generally considered poor candidates for TACE. By contrast, the core data supporting the efficacy and safety of TACE are primarily from randomised controlled trials in early and intermediate HCC (that is, unilobar disease and/or a limited number (one-to-five) of nodules) and include patients who cannot be treated with radical therapies because of either age, tumour size and location, cirrhosis or comorbidities.
There are, however, some small single-centre cohort studies that have analysed the long-term outcome of patients with UNOS stage T3 HCC (one nodule >5cm, or two-to-three nodules with at least one >3cm, without vascular invasion), who after treatment with radioembolisation or TACE for palliative intent were down-staged for radical treatment (resection, ablation, transplantation). In all of these studies, down-staging after radioembolisation was associated with favourable long-term survival, superior to TACE in one study(6) and comparable with early-stage disease treated radically at diagnosis in another study.(7)
In addition, there are several series with TACE that include patients with intermediate- and even advanced-stage disease. In a recent case series evaluation analysed using the Barcelona Clinic Liver Cancer (BCLC) staging system, TACE (n=172)(8) was found to be broadly equivalent to radioembolisation (n=291),(3) with median overall survivals of 17.4 months (95% CI 13.9–18.8) and 17.2 months (95% CI 13.5–29.6 months), respectively, in patients with intermediate (BCLC) stage B disease. 
 
There is good evidence from the European series showing that radioembolisation appears to be particularly promising for the subset of patients with intermediate-stage HCC who are considered poor candidates for TACE (that is, those with bilobar and/or multiple (>five) tumours; median survival: 15.4–16.(6) months), as well as for those who had failed prior TACE/TAE (median survival: 15.4 months) (Table 1).(4)
Radioembolisation and systemic treatment
Advanced (BCLC) stage C HCC is defined by the presence of ECOG performance status of 1–2, portal vein occlusion (PVO) and/or extra-hepatic (N1, M1) disease. In this cohort, median overall survivals following radioembolisation are in the range of 6–10 months,(3,4) which is broadly equivalent to the overall survival of 6.5–10.7 months reported in the phase III clinical trials of sorafenib in a similar group of patients.(9,10) As mentioned previously, PVO is not a contraindication for radioembolisation and overall survival are 10.2 (95% CI 7.7–11.8) and 9.3 months (7.4–11.4) in patients with and without PVO, respectively.(4)
However, with advancing disease and occlusion of the main portal vein, overall survival significantly diminishes (median overall survival three months)(1) in contrast to patients with branch (segmentary or lobar) portal vein thrombosis, which achieve median survivals of 10–14 months(1) after radioembolisation.
Overall survival rates following radioembolisation also reflect the severity of symptomatic disease (ECOG 0 versus 1 versus 2: 10.8 (6.5–11.9) versus 10.0 (7.7–11.8) versus 6.6 months (5.5–20.8)) and the presence or otherwise of disease beyond the liver (no EHD versus EHD: 10.2 (8.2–11.7) versus 7.4 months (4.3–13.1)).(4) Radioembolisation clearly outperforms sorafenib in terms of tolerance and safety profile. Randomised controlled trials are now ongoing to directly compare the relative efficacy and safety of sorafenib and radioembolisation across the spectrum of patients with advanced HCC (clinicaltrials.gov NCT01135056 and NCT01482442), as well as assessing the possible synergism that might be achieved with these two different treatments in combination (clinicaltrials.gov NCT001126645). 
Conclusions
The current evidence to support the use of radioembolisation in HCC is based on retrospective series or non-controlled prospective studies (level 2 evidence). Nevertheless, when compared with TACE and sorafenib in well-defined cohorts of patients, the current evidence suggests that radioembolisation achieves similar survival rates in patients with intermediate or advanced HCC. Potential indications for radioembolisation include the treatment of patients who are typical candidates for TACE and for whom downstaging could open the door to radical treatment, patients who are poor candidates for TACE, patients who have previously failed TACE/TAE, and patients progressing to TACE/TAE. The ongoing programme of clinical trials will help further define the roles for radioembolisation in the treatment of HCC. 
References
  1. Sangro B, Iñarrairaegui M, Bilbao JI. Radioembolization for hepatocellular carcinoma. J Hepatol 2012;56:464–73.
  2. Riaz A et al. Radiologic–pathologic correlation of hepatocellular carcinoma treated with internal radiation using Yttrium-90 microspheres. Hepatology 2009;49:1185–93.
  3. Salem R et al. Radioembolization for hepatocellular carcinoma using yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 2010;138:52–64.
  4. Sangro B et al on behalf of European Network on Radioembolization with yttrium-90 resin microspheres (ENRY). Survival after 90Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: A European evaluation. Hepatology 2011;54:868–78.
  5. Hilgard P et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology 2010;52:1741–9.
  6. Lewandowski RJ et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant 2009;9:1920–8.
  7. Iñarrairaegui M et al. Response to radioembolization with yttrium-90 resin microspheres may allow surgical treatment with curative intent and prolonged survival in previously unresectable hepatocellular carcinoma. Eur J Surg Oncol 2012;Mar 20 [Epub ahead of print].
  8. Lewandowski RJ et al. Chemoembolization for hepatocellular carcinoma: comprehensive imaging and survival analysis in a 172-patient cohort. Radiology 2010;255:955–65.
  9. Llovet J et al for the SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90.
  10. Cheng AL et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25–34.