|Special Issue Article
|Radioembolization for Hepatocellular Carcinoma: Evidence-Based
Answers to Frequently Asked Questions
|Bruno Sangro1,2* and Mercedes Iñarrairaegui1,2
|1Liver Unit, Clinica Universitaria de Navarra
|2Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Pamplona, Spain
||Dr. Bruno Sangro, MD
Liver Unit, Clínica Universitaria de
Avda, Pio XII 36. 31008 Pamplona, Spain
Tel: +34 948 296 637
948 296 500
|Received April 26, 2011; Accepted May 26, 2011; Published June 15, 2011
|Citation: Sangro B, Iñarrairaegui M (2011) Radioembolization for Hepatocellular
Carcinoma: Evidence-Based Answers to Frequently Asked Questions. J Nucl Med
Radiat Ther 2:110. doi:10.4172/2155-9619.1000110
|Copyright: © 2011 Sangro B, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
|Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality. Radioembolization is a form of selective internal radiation therapy that is increasingly used to treat patients with HCC, particularly those with more advanced disease. This review will try to answer some of the most frequently asked questions regarding the use of radioembolization to treat HCC patients and provide supporting evidence. Rather than a new form of transarterial chemoembolization (TACE), radioembolization is a form of brachytherapy that has a highly localized effect on liver tumors. The two devices that are available (glass and resin microspheres) are similar in size (25 to 35 microns), but differ in the amount of isotope loaded onto each microsphere and the number of spheres injected in a single treatment. Despite this, the evidence seems to indicate that the antitumor effect and safety profiles of these two devices in HCC are similar. Liver cirrhosis frequently underlies HCC. Despite the higher chance for relevant liver toxicity, there is now good evidence from large studies to show that radioembolization can be safely and effectively performed in cirrhotic patients with HCC. With no randomized controlled trials published so far, there is recent scientific evidence that allows comparison between radioembolization and other treatment options including TACE and the systemic, agent sorafenib. Radioembolization appears to have similar efficacy to TACE in patients that are ideal candidates for locoregional therapy and has shown encouraging results in patients that have failed TACE or who are poor candidates for this therapy. Survival in comparable sorafenib- and radioembolizationtreated HCC patients is quite similar. The indication for radioembolization has to be balanced against the risk of liver decompensation and the natural history of the disease, based on tumor burden and liver function. Patients with inadequate liver functional reserve and diffuse tumors affecting either lobes, or portal vein thrombosis that reaches the main trunk should probably not be treated with this procedure.
|Radioembolization; Hepatocellular carcinoma;
Chemoembolization; Sorafenib; SIRT
|Hepatocellular carcinoma (HCC) is the sixth most common cancer
in the world and the third most common cause of cancer-related
mortality . Eighty-five percent of the global burden of HCC occurs
in developing countries with 5- to 10-times higher age-standardized
incidence rates (world) in Eastern and South-Eastern Asia, and Middle
and Western Africa than Northern Europe and USA (where rates are
∼4-5 per 100,000) . Cirrhotic patients of various etiologies and
patients infected by viral hepatitis (hepatitis C virus [HCV] or chronic
hepatitis B virus [HBV]) are particularly prone to developing HCC.
Even with active HCC surveillance of high-risk groups, less than 15%
of all HCC patients are candidates for potentially curative therapies
including surgical resection, liver transplantation or percutaneous
ablation. For the majority of patients, either transarterial embolization
(TAE) or chemoembolization (TACE) for intermediate stage disease
 and/or sorafenib for more advanced stage disease has been shown
to significantly prolong survival . However, there is no universal
agreement on the best candidates for these treatment options .
|Radioembolization is a form of selective internal radiation therapy
that is increasingly used to treat patients with HCC, particularly those
with more advanced disease [5,6]. Since there is an increasing, but still
limited, body of evidence published in the medical literature on this
procedure, questions often arise. This review will try to answer some of
the most frequently asked questions and provide supporting evidence.
|Is radioembolization a form of transarterial (chemo)
|Much like TACE, radioembolization utilizes the well-characterized dual vasculature of the liver to selectively treat HCC lesions that are
almost exclusively supplied by blood from the hepatic arterial branches
[7,8]. However, the mechanism of these two treatment modalities is
very different. Radioembolization is in fact a form of brachytherapy
and has a highly localized effect on liver tumors. While the liver is
largely intolerant to whole liver radiation treatment, small portions
of the liver can tolerate high-dose radiation exposure without
significant complications, as long as sufficient normal liver is spared
. Commercially available microspheres for radioembolization are
made of either resin (SIR-Spheres®, Sirtex Medical Limited, Sydney,
Australia) or glass (TheraSphere®, Nordion, Ottawa, Canada). These
small inert microspheres (measuring ∼25 to 35 microns), loaded
with the radionuclide yttrium-90 (90Y), lodge within the peripheral
neovasculature of tumors, where they deliver high-energy, betaradiation
over a limited range (mean penetration of radiation into
tissues is 2.4 mm), thereby confining the tumoricidal dose to the
immediate proximity of the tumor and sparing the normal liver
parenchyma [10,11]. Bilbao and colleagues showed that resin
microspheres have little or no embolic effect on medium to small
arteries, so adequate oxygenation of the tumor tissue is maintained, increasing the lethal effect of the radiation . In contrast, the larger
TACE or bland embolization particles (100 to 500 microns in diameter)
have been designed to occlude medium to large size arteries , so
that ischemia drives the antitumor effect, with drug delivery (carried in
lipiodol or drug-eluting beads) potentially enhancing tumor cell killing
(Figure 1) .
||Figure 1: Differences in size and heterogeneity of particles used for TACE and
radioembolization and the resulting impact on the size of the occluded vessel.
|The original concept for selective internal radiation therapy in
HCC came from studies with lipiodol labeled with iodine-131 (131I), a
gamma- and beta-emitting radionuclide. Two randomized-controlled
trials were conducted. The first compared 131I-labeled lipiodol with best
supportive care in 27 patients with good liver function and multinodular
or diffuse tumors and portal vein thrombosis . Median survival
was significantly prolonged with 131I-labeled lipiodol compared with
best supportive care (24 weeks vs. 8 weeks, p<0.01) . The second
larger trial in 142 patients without portal vein thrombosis showed that
compared with TACE (70 mg cisplatin), 131I-labeled lipiodol (60 mCi;
2.2 GBq) was better tolerated with similar response rates (57% vs. 64%)
and 2-year overall survival (42% vs. 38%) . However, the clinical
development of radioactive 131I-labeled lipiodol was hindered mainly
by the need for radioprotection requiring the patient to remain isolated
during the first 7 to 10 days after therapy. By contrast, microspheres
are loaded with yttrium-90, a pure beta emitter with a short tissue
penetration, which makes post-treatment isolation for radioprotection
|In conclusion, there are important differences in the mechanism
of action between TACE/TAE and radioembolization (ischemia +
chemotherapy vs. irradiation) that account not only for the diverse
antitumor effect but also for differences in post-treatment imaging
 as well as the safety profile . Radioembolization produces
minimal or no post-embolization syndrome, but if delivered to nontarget
tissues can cause radiation-induced damage to the liver, lungs
and gastrointestinal tract [19-21].
|Are there any differences in clinical outcome between glass
and resin 90Y-loaded microspheres in HCC?
|Glass and resin microspheres, although similar in size (25 to 35
microns), differ in the amount of isotope loaded onto each microsphere
(which is lower for resin spheres) and the number of spheres injected in
a single treatment (which is typically lower for glass spheres). Despite
this, the evidence (outlined below) would seem to indicate that the antitumor effect and safety profile of these treatment modalities in
HCC are similar.
|From a hemodynamic point of view, there were no major
differences between the two microspheres in a computational model
of a representative hepatic artery system, where laminar transient 3D
particle-hemodynamics were simulated . It could be argued that
due to the higher number of microspheres typically used in a treatment
with resin microspheres, a more intense ischemic effect would result.
Some expert users say that incomplete delivery of the prescribed 90Y
activity is more frequent with resin microspheres. In fact, an analysis
of a large cohort of 680 patients treated with resin microspheres
worldwide found that the injected activity was only slightly inferior to
prescribed activity (prescribed: 1.2 + 0.6 GBq; administered: 1.1 + 0.6)
. It could also be argued that for the same reason it would be difficult
to administer the full prescribed activity to small single lesions with
resin microspheres or that the number of radiation sources would be too small for a very large tumor to be treated with glass microspheres.
However, post-treatment imaging by SPECT or positron-emission
tomography challenges this argument .
|If there are differences in the injection procedure and intravascular
behavior, they do not seem to translate into differences in antitumor
effect. Tumor response rates vary from 20%  to 42%  for glass
microspheres, and from 23%  to 44%  for resin microspheres.
Overall survival was remarkably similar when patients were stratified
by tumor stage in two of the largest series of patients with HCC studied
so far (Figure 2) [26,29,30].
||Figure 2:Overall survival by BCLC stage with 90Y glass microspheres and 90Y
resin microspheres [5,29].
apatients in the advanced stage lacking extrahepatic disease.
|Does the presence of cirrhosis in HCC affect the outcome
|Cirrhosis, characterized by the replacement of liver tissue by fibrosis
and regenerative nodules, produces a notable distortion in the vascular
anatomy of the liver. These changes have two important consequences
for the treatment of patients with a cirrhotic liver, namely changes
in the usual distribution of the microspheres and a reduction in the
functional liver reserve. Portal triads can no longer be identified in the
cirrhotic liver and disordered vessels may traverse the fibrotic septa
that separate regenerative nodules. In the advanced stages of cirrhosis,
intrahepatic anastomosis can develop between the terminal arterioles,
portal venules and hepatic venules .
|Little data have been obtained so far from animal models or
human studies on the impact of these changes on the distribution
of microspheres to normal tissue. Certainly, lung shunting is more
prevalent in cirrhotic than non-cirrhotic livers, independent of the
volume of tumor tissue treated . This adverse event can be largely
prevented by keeping the threshold for lung irradiation below 30
Gy, although this inevitably reduces the number of microspheres
available for tumor targeting and could theoretically reduce treatment
|Of much greater 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 . Direct liver cell injury and further
compromised liver blood supply by direct damage to the vasculature
could increase the risk of clinically relevant liver toxicity in cirrhotic
compared with non-cirrhotic livers after radioembolization.
|Despite the higher chance for reduced microsphere availability and
relevant liver toxicity, there is now good evidence from large studies to
show that radioembolization can be safely and effectively performed in
cirrhotic patients with HCC. Response rates are consistently in the range
of 30% to 50%  and overall survival following radioembolization was
not significantly different in patients with cirrhotic and non-cirrhotic
livers (Hazard ratio: 1.26 [95% confidence interval [CI] 0.89 - 1.77;
|Radioembolization-induced liver disease, defined as jaundice and
ascites appearing 4 to 8 weeks after radioembolization in the absence
of clear tumor progression, was described as Grade 4 in 2.5% of HCC
patients treated in a single institution  and grade 3 increases in
bilirubin (according to CTCAE ) were described in less than 6%
of patients in a European multicenter study independent of their basal
tumor stage and treatment design .
|How does the clinical outcome for radioembolization
compare with TACE?
|Rough comparisons of survival between retrospective series of patients treated with TACE or radioembolization are meaningless
if the target populations differ. At least in Western countries,
radioembolization is in most cases indicated for patients who are
considered poor candidates for TACE. Typical candidates for
radioembolization are either:
|i. patients with advanced stage disease with portal vein invasion but
no extrahepatic metastases;
|ii. patients with intermediate stage disease but too many nodules
involving both lobes to be treated by TACE in a selective fashion; or
|iii. patients with intermediate stage disease who have failed to respond
to TACE and have ongoing disease progression in the liver or active
tumor following TACE.
|The ratio of each of these three subgroups differs with each
published series [18,36,37]. Any blind comparison with TACE is
basically irrelevant because TACE cohorts usually include patients
that have early stage disease and tumors that cannot be treated with
radical therapies because of age, tumor size and location, cirrhosis or
comorbidities, or intermediate-stage disease with a limited number of
tumors that can be selectively embolized (avoiding occlusion of the
main lobar arteries) . However, the inclusion criteria for TACE in
some centers has broadened beyond the evidence base in intermediatestage
disease  to include patients with more advanced disease. In a
randomized controlled trial of 138 patients by Doffoël and colleagues
 which included advanced cases (48% had an ECOG >0, 49% had
bilobar disease and 9% had segmental portal vein thrombosis), median
overall survival was 13.8 months (95% CI, 7.6-16.8) with conventional
TACE plus tamoxifen and 11.0 months (95% CI, 7.3-15.1) with
|Over the last 12 months, three different groups have published
outcomes of patients treated in routine clinical practice using TACE or
radioembolization in cohorts with either early or intermediate tumors
, or a mixture of patients with more advanced tumors [36,37].
Each analysis found equivalent or better survival for patients receiving radioembolization compared with broadly matched patients allocated
to TACE (Table 1). In other case series evaluations analyzed by BCLC
(Barcelona Clinic Liver Cancer) stage of disease for treatment using
TACE (n=172) , 90Y-glass microspheres (n=291)  or 90Y-resin
microspheres (n=325) , the following median overall survivals
in months (95% CI) were reported in early (BCLC stage A) disease:
40 (15-46), 26.9 (17-30.2) and 24.4 (18.6-38.1); intermediate (BCLC
stage B) disease: 17.4 (13.9-18.8), 17.2 (13.5-29.6) and 16.9 (12.8-22.8)
and advanced (BCLC stage C) disease: 6.6 (4-9.3), 7.3 (6.5-10.1) for
glass microspheres in patients with no extra-hepatic disease and 5.4
(2.7-7.5) in those with extra-hepatic disease, and 10.0 (7.7-10.9),
respectively. The overlapping confidence intervals indicate that
radioembolization and TACE have broadly similar benefits in terms
of overall survival. According to Salem and colleagues , a trial of
more than 1,000 patients would be required in order to demonstrate
equivalence between these therapies. Therefore a head-to-head
comparison between radioembolization and TACE is impractical in
this disease setting.
||Table 1: Results from comparative series of HCC patients treated by TACE and
|Importantly, the ability to down-stage patients that are beyond those
criteria used for the indication of radical therapies (transplantation,
resection or ablation) and are finally treated with these options was
superior for radioembolization than for TACE  and results in longterm
survival in most patients successfully down-staged .
|In summary, radioembolization appears to have similar efficacy to
TACE in patients that are ideal candidates for local-regional therapy
and has shown encouraging results in patients that have failed TACE
or who are poor candidates for this therapy.
|How does radioembolization compare with sorafenib?
|The comparisons with the multi-tyrosine kinase inhibitor
sorafenib are more straightforward. Most radioembolization series
include patients who have progressed or relapsed after locoregional
therapies, such as TACE or bland embolization, or were considered
poor candidates for these locoregional therapies due to the presence
of portal vein invasion or bulky tumors. The finding that the multityrosine
kinase inhibitor sorafenib prolonged survival in a very similar
population of patients with mixed intermediate and advanced stage
HCC  has led to its increasing use since 2008. The main difference
between radioembolization series and sorafenib trials is the higher
percentage of patients with extrahepatic disease in the sorafenib clinical
trials, particularly in the Asia-Pacific trial .
|In the absence of survival data from direct comparative trials with
radioembolization and sorafenib, a recent retrospective analysis has
compared radioembolization as first-line treatment with a control
group matched for liver function and tumor burden, treated with
conventional or experimental therapies or no therapy . In this
well-matched comparison, survival was significantly better with
radioembolization than the control arm (16 vs. 8 months; p < 0.05)
even when adjusted for cirrhosis, vascular invasion, multinodularity,
or bilobar involvement. This preliminary evidence illustrates that
radioembolization can prolong survival over no specific therapy in a
population of patients not amenable for TACE. This is supported by
numerous studies reporting survivals in the range of 9 to 16 months
with radioembolization [5,25,27,29,30,45] among patients who had
similar characteristics to the patients who were randomized to placebo
in the SHARP trial and who had a median survival of 7.9 months
. Figure 3 illustrates overall survival of the patients following
radioembolization within a European multicenter series ,
approximately 60% of whom met the inclusion criteria for SHARP, the sorafenib and placebo arms of the SHARP trial , and the
sorafenib arm of a phase II trial conducted in the US . The Figure
illustrates the significant overlap in 95% confidence intervals between
the sorafenib- and radioembolization-treated groups. Phase III trials
comparing sorafenib and radioembolization or their combination are
||Figure 3:Overall survival reported for similar patients treated with
radioembolization, sorafenib and placebo.
90Y-radioembolization: consecutive patients identified with Child-Pugh class
A and advanced stage disease (BCLC stage C) or had intermediate stage
disease (BCLC stage B) and had failed prior vascular procedures (TACE;
TAE) or were poor candidates for TACE .
Sorafenib (SHARP): patients randomized to the sorafenib arm in the SHARP
trial . Sorafenib (US phase II): patients with Child-Pugh class A class that
received sorafenib in the US phase II study .
Placebo (SHARP): patients randomized to the placebo arm in the SHARP
|When should patients not be treated with radioembolization?
|A recent European series has provided an in-depth analysis of
the prognostic factors among 325 consecutive patients with mostly
advanced-stage HCC who received radioembolization at eight centers
between September 2003 and December 2009 . Prognosis was
driven by liver function (as measured by individual variables such
as INR or bilirubin levels or by composite variables such as the
Child-Pugh score) and tumor burden (as measured by nodularity,
portal vein thrombosis, alpha-fetoprotein levels, distant metastases
or performance status) . Individual predictors of survival in a
multivariate model were: an INR level greater than 1.2, an Eastern
Cooperative Oncology Group (ECOG) score higher than '0', more than
5 nodules and extrahepatic disease . Not surprisingly, subgroups of
patients from a different series  with Child-Pugh class B, portal vein
thrombosis, advanced (BCLC stage 'C') disease and / or extrahepatic
disease were also found to have a very poor prognosis (median overall
survival less than 6 months). Similar findings were reported by Kulik et
al.  among patients with portal vein thrombosis of the main trunk
who had a median survival of 6 months .
|The importance of tumor burden and liver function in predicting
poor survival following radioembolization accords with the early
experience in North America where 3-month mortality was associated
with infiltrative tumors, bulky disease, highly increased transaminases
(5xUNL), tumor volume > 50% with albumin < 3 g/dL, and bilirubin
> 2 mg/dL . As a result, although this is not level 1 evidence coming
from controlled trials, treatment with radioembolization is probably
not appropriate for those patients that have a bilirubin higher than
1.5 mg/dL or an INR higher than 1.2 (that reflect a reduced functional
liver reserve) and also have either diffuse, ill-defined tumors affecting
both lobes, or portal vein thrombosis that reaches the main trunk.
Radioembolization should be formally contraindicated for those
patients with decompensated cirrhosis (Child-Pugh score higher than
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