Primary liver cancer is a growing health problem worldwide. Hepatocellular carcinoma (HCC)
represents more than 90% of primary liver cancers and is considered to be the fifth most
common cancer and the second leading cause of cancer-related deaths, with the majority being
associated to cirrhosis.
Choosing the most suitable treatment option depends not only on the tumor stage, but also on
the severity of the underlying liver disease and performance status. Current guidelines
consider the Barcelona Clinic Liver Cancer (BCLC) staging system as the algorithm of choice
for tumor staging and therapeutic options, taking into account tumor burden, Child-Pugh class
and performance status (ECOG).
Surgical approach, such as resection and liver transplantation, and radiofrequency (RFA)
represent the curative treatment options. Despite screening of at-risk populations, most
patients are diagnosed with locally advanced disease (BCLC B - intermediate stage) and will
not be suitable for curative therapies. Moreover, only HCC within the "Milan" criteria (one
nodule < 5 cm or up to three nodules < 3 cm in diameter, without macroscopic vascular
invasion or extrahepatic disease) are potential candidates for transplantation. Resection can
be proposed only in case of compensated cirrhosis in the absence of portal hypertension and
RFA is only possible for small lesions (< 5 cm, < 3 cm in diameter).
Locally advanced HCC is suitable for transarterial locoregional therapies, conducted mostly
in a palliative setting. They take advantage on the double vascularization of the liver, with
75% of the parenchymas blood supply coming from the portal vein, while tumor nodules blood
supply being almost exclusively provided by the hepatic artery. When macrovascular
involvement or extrahepatic disease are discovered, but patients present a good performance
status and a compensated liver function (BCLC C), systemic therapy with the tyrosine kinase
inhibitor Sorafenib leads to a limited survival benefit, approximately 3 months advantage
compared to placebo.
Transarterial chemoembolization (TACE), either conventional (cTACE) or using drug-eluting
embolic (DEE) agents, is recommended for patients with BCLC stage B and as "bridging" therapy
for liver transplantation candidates while on the waiting list. Furthermore, it has been
shown that in selected patients, it can be successfully used as a downstaging treatment to
transplantation criteria.
Technically, TACE involves the injection of a chemotherapeutic agent (i.e. doxorubicin),
mixed with an embolic material, administered selectively into the feeding arteries of the
tumor resulting in tumoral necrosis induced by ischemia and cytotoxic effect.
During the last decade, transarterial radioembolization (TARE) with yttrium-90 microspheres
[Y90] was introduced in case of TACE failure or for patients who were not suitable for TACE
(i.e.: large tumors or macrovascular invasion). This technic consists of the intra-arterial
infusion of smaller beads that are loaded with a radioactive isotope (yttrium-90), and it
relies on the beta radiation emitted by the isotope to induce tumor necrosis, with a minor
contribution from microembolization and without risk of ischemia of the remaining liver. Its
efficacy was reported in several large patient series. Two products are commercially
available for TARE. 90Y-labelled resin microspheres (SIR-Spheres; Sirtex Medical, Sydney) and
90Y glass microspheres (TheraSphere; Boston International).
The radioembolization procedure are performed over two different sessions: work-up session
and treatment session.
The work-up evaluation starts with an angiography in order to obtain a precise map of the
patients' abdominal vascular anatomy and coil embolization might be performed if
gastro-intestinal branches arising from the hepatic arteries are found. This will prevent
radioactive microspheres, administered into the hepatic artery, from ending up in
extrahepatic organs via this route.
The second step of the work-up implies the injection of 150 MBq Technetium-99 m-labeled macro
aggregated albumin (99mTc-MAA) in order to predict the distribution pattern of
90Y-microspheres. The uptake of 99mTc-MAA will be visualized by whole body planar imaging and
single-photon emission computed tomography (SPECT-CT), including low dose computer tomography
of the abdomen. 99mTc-MAA lung shunt fraction will be calculated and lung dosage must not
exceed 30 Gy in a single treatment.
In case on an unfavorable 99mTc-MAA workup, the procedure will be repeated, if possible, to
detect the cause of the extrahepatic deposition (for example, previously undetected patent
extrahepatic vessels arising from the hepatic artery) and a solution will be searched for
(for example, more selective placement of the catheter during injection to improve the
targeting of the lesion). In the unlikely event no solution can be found and 90Y TARE cannot
be performed, the patient will be treated according to best medical practice.
If the work-up will have a favorable outcome, the patients will be re-admitted for the
treatment within 15 days.
Several retrospective studies and non-controlled prospective studies have shown higher rates
of objective tumor responses, prolonged time to progression and overall survival for TARE,
with study advocating it more effective than TACE as a downstaging tool to curative
treatment. Nevertheless its place in the treatment of HCC is still to be defined, especially
due to the non-compartmental predictive dosimetry usually performed in recent studies.
Post-treatment calculation of the radiation absorbed dose in the tumors and the healthy liver
tissue cannot be easily performed because quantitative PET imaging of the beta-emitting
90Y-microspheres is challenging. New generation microspheres may help to achieve
post-treatment dosimetry easily.
New Holmium-166 (166Ho) loaded poly(L-lactic acid) microspheres have been developed at the
Department on Radiology and Nuclear Medicine of the University Medical center (UMC) Utrecht
and are commercialized by Terumo Europe (QuiremSpheres®). Just like 90Y, 166Ho relies on the
emitted beta radiation to induce tumor necrosis. The advantage provided by this isotope is
its gamma radiation emission, which allows for quantitative SPECT imaging (166Ho: T1/2 of 27
hours, gamma-radiation 81 keV, beta-radiation 1.8 MeV) and the assessment of the radiation
absorbed dose delivered in both the tumor(s) and the remaining part of the liver (i.e.
dosimetry). Besides, holmium is a highly paramagnetic metal, and as such may be visualized by
MRI. This is useful because quantitative analysis of the MRI scans is possible, including R2*
relaxometry for microsphere concentration, and especially useful for medium- and long-term
monitoring of the intra-hepatic behavior of the microspheres.
TARE using 166Ho -microspheres underwent a first evaluation in a clinical phase I safety
study with an administration system specifically designed for 166Ho radioembolization (HEPAR
I, METC 08-450). Fifteen patients with unresectable, chemorefractory liver metastases were
enrolled, using a standard dose escalation protocol. They were treated in cohorts of 3
(target absorbed dose 20 Gy, 40 Gy, 60 Gy and 80 Gy). The maximum tolerable radiation dose
was 60 Gy. In the 80 Gy cohort, dose-limiting toxicity occurred in two patients: grade four
thrombocytopenia, grade three leukopenia, and grade three hypoalbuminaemia in one patient,
and grade three abdominal pain in another patient. The most frequently encountered laboratory
toxicities (including grade one) were lymphocytopenia, hypoalbuminaemia, raised alkaline
phosphatase, raised aspartate aminotransferase, and raised gamma-glutamyltransferase, which
were all noted in 12 of 15 patients (80%). Stable disease or partial response regarding
target lesions was achieved in 14 of 15 patients (93%, 95% CI 70-99) at 6 weeks and 9 of 14
patients (64%, 95% CI 39-84) at 3 months after TARE. It was concluded that 166Ho
radioembolization is feasible and safe for the treatment of patients with unresectable and
chemorefractory liver metastases and enables image-guided treatment.
This was followed by a non-randomized single-arm phase II study that included 56 patients
with unresectable, chemorefractory liver metastases (HEPAR II METC 11-538). 166Ho
radioembolization was performed with a mean liver absorbed dose of 60 Gy. The primary outcome
was tumor response of two target lesions on triphasic liver CT scans, 3 months after therapy
using modified RECIST criteria as evaluated by three blinded readers. After treatment of 38
eligible patients, the target lesions showed disease control in 73% after 3 months (95%
confidence interval [CI], 57 to 85%). The median overall survival was 15.3 months (95% CI,
9.1 to ∞ months). Grade three or four toxic events (according to CTCAE version 4.03 criteria)
after treatment included abdominal pain (in 18% of patients), nausea (9%), ascites (3%),
gastric stenosis (3%), liver abscesses (3%), paroxysmal atrial tachycardia (3%), REILD (3%),
thoracic pain (3%), upper gastrointestinal hemorrhage (3%), and vomiting (3%). Laboratory
examination after treatment showed grade three or four toxicities in alkaline phosphatase
(70%), γGT (78%), lymphocytes (11%), and ALAT (4%). From the results of this study it was
concluded that 166Ho radioembolization induced a favorable tumor response with an acceptable
toxicity profile in patients with liver metastases.
The University Medical center (UMC) of Utrecht is currently conducting a third study for
patients with HCC (HEPAR Primary, NCT03379844). The primary objective is to evaluate safety
and toxicity profile of 166Ho-TARE. HCC patients were not included in previous studies,
because underlying liver disease in HCC patients puts a higher demand on safety issues, which
should be studied separately.
The investigators aim to evaluate the efficacy and safety of TARE using the newly developed
166Ho-microspheres in our HCC population, at ERASME Hospital. Using 166Ho has distinctive
advantages over the existing 90Y-microspheres, making quantitative individualized dose
planning possible by means of SPECT and MRI. Accurate dosimetry in radiation treatment is a
prerequisite for optimal safety and efficacy evaluation. This is particularly relevant in
patients with hepatocellular carcinoma and underlying chronic liver disease, which limits the
maximum tolerated absorbed dose that can be applied to the liver.
Regarding this underlying chronic liver disease, assessment of hepatic function with
99mTc-IDA hepatobiliary scintigraphy is routinely performed at Erasme hospital before TARE.
However, in classical 90Y TARE workflow, because both MAA and IDA are labeled with 99mTc the
predictive dosimetry and the evaluation of the hepatic function with IDA cannot be performed
on the same day. The management of the patient and the planning of TARE may be greatly
optimized if both predictive dosimetry and evaluation of hepatic function can be performed on
the same day. And it becomes possible with the use of 166Ho.
