HOlmium radioembolization as adjuvant treatment to Radiofrequency Ablation for Early STage Hepatocellular carcinoma (HORA EST HCC): a dose-finding study

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related
death in the world. Surgical resection is the first line treatment for patients
with solitary HCC and a well-preserved liver function. Unfortunately, many
patients with HCC are not surgical candidates due to tumor location,
comorbidity or underlying liver disease, i.e. cirrhosis with portal
hypertension. Radiofrequency ablation (RFA) is an effective alternative for
surgical resection. Yet, local tumor recurrence rates in HCC * 2cm are higher
than after surgical resection. Local tumor recurrence most frequently occurs as
a result of incomplete tumor necrosis or growth of pre-existent satellite
nodules. Most tumor recurrences occur in the hyperaemic zone surrounding the
area of coagulation necrosis. Radioembolization is a type of brachytherapy and
an effective treatment for intermediate or advanced stage HCC. Using a
transarterial approach small microspheres loaded with Holmium-166 are infused
into the hepatic artery. By super-selective infusion of microspheres radiation
can be delivered to a segment with low toxicity to the non-tumorous liver
parenchyma. It is generally recommended to deliver a dose of * 120Gy to the
target area. Our study aims to establish the treatment area dose that will
result in delivery of a radiation dose of * 120Gy to the target area.

Establishment of treatment area dose at which 90% technical success is
achieved. Technical success will be defined as * 120Gy calculated radiation
absorbed dose to the target area, i.e. the hyperaemic zone surrounding the area
of post-RFA coagulation necrosis.

In this multi-center, dose-finding study, patients with early stage
hepatocellular carcinoma according to the Barcelona Clinic Liver Cancer (BCLC)
staging system will be included to receive percutaneous radiofrequency ablation
in combination with RFA with adjuvant segmental radioembolization.

Radiofrequency ablation
Patients will be admitted to the hospital one day before the procedure or on
the day of the procedure. The procedure will be performed under general
anesthesia or deep sedation. Ultrasonography and/ or CT will be used to target
the tumor with a single 3cm Cooltip electrode or a 3 or 4 cm exposed tip
multi-electrode Cooltip RFA probe with switch-control system (Covidien, Gosport
Hamspire, United Kingdom). Ablation will be performed for 12 minutes (single
electrode) or 16 minutes (multi-electrode) using standard impedance controlled
ablation. Upon removal of the RFA probe the needle tract will be ablated to
reduce the chance of post-procedural hemorrhage or tumor seeding. Contrast
enhanced computed tomography (CECT) will be performed immediately after
ablation to confirm adequate tumor ablation. If CECT shows residual tumor
enhancement, re-ablation will immediately be performed. Peri-procedural care
will be in accordance with the protocol of the institution.

Radioembolization
Radioembolization consists of two sessions: pre-treatment planning and the
actual treatment.
Part 1. Pre-treatment planning
Part 1 will be performed 1 day after RFA and in the same hospital admission.
The first part of the radioembolization consists of an angiographic study and
*test-injection* of 99m-technitium labelled macro-aggregated albumin
(99mTc-MAA). The angiographic study is performed using a common femoral artery
approach. Angiographic images of the celiac trunc and hepatic arteries are
obtained. The vascular liver anatomy is meticulously skeletonized to identify
hepatico-enteric anastomoses. If present, coil-embolization of such anastomoses
will be performed if deemed necessary to enable safe radioembolization. If the
planned location of infusion is distal and distant to hepatico-enteric
anastomoses, these anastomoses do not need to be coiled. Coil-embolization is
likely to be unnecessary in the majority of patients in the study as the
injection will be super-selective, i.e. distal to the gastroduodenal artery
(GDA) and right gastric artery (RGA). Using a 2.4F/ 2.7F microcatheter the
segmental artery is catheterized and angiography and cone-beam computed
tomography (CBCT) are performed. The CBCT will be used to verify that the
segmental artery supplies the entire hyperaemic marginal zone surrounding the
area of coagulation necrosis. If there is only partial opacification of the
marginal zone, a second segmental artery may need to be catheterized. 99mTc-MAA
is then injected into the segmental hepatic artery/ arteries feeding the tumor.
Alternatively, the injection may be performed from a more proximal position, if
the tumor is located at the border of two different segments. After the
angiographic study with injection of 99mTc-MAA, planar scintigraphy and
SPECT/CT are performed to visualize the distribution of the 99mTc-MAA. Also,
SPECT imaging is performed using the handheld declipse®SPECT gamma probe.
In patients with arterio-hepatovenous tumor shunting a portion of the 99mTc-MAA
will bypass the hepatic capillary bed and accumulate in the lungs. If shunting
to the lungs is more than 20%, there is a risk of radiation pneumonitis.
Patients with a lung shunt exceeding these limits will be excluded from
treatment with 166Ho. The activity of 99mTc-MAA itself is too low to cause
radiation pneumonitis.

Part 2. Radioembolisation with 166Ho
Part 2 consists of the actual treatment and will be performed within 5-10 days
after part 1, providing that the lung shunt is less than 20%. On the morning of
the procedure baseline non-contrast enhanced MRI will be performed. Using a
common femoral artery approach, angiographic images of the hepatic arteries are
obtained. A 2.4/2.7F microcatheter is placed in the exact same position as
where 99mTc-MAA was administered. 166Ho microspheres (QuiremSpheres®; Quirem
Medical) will be used for the treatment. The required activity is calculated
according to the partition model. The volume of liver segment to be treated is
calculated by measurements using cone-beam CT and/or the pre-procedural CT or
MRI. The activity is chosen to deliver the desired radiation dose to the
treatment zone (see 5.3). With the microcatheter in place, the catheter is
connected to the microspheres delivery set. The microspheres are then delivered
using a slow injection. The injection is interrupted at the discretion of the
radiologist to check whether blood flow remains unobstructed by injecting a
contrast medium through the microcatheter under fluoroscopic imaging. If
arterial spasm occurs, boluses of 100-200 micrograms nitroglycerine may be
administrated intra-arterially at the discretion of the interventional
radiologist. The end-point of treatment will be the delivery of the calculated
dose. If vascular stasis occurs before the entire dose has been delivered, the
procedure may be ended before all microspheres have been delivered.
If no complications occur, patients will be discharged from the hospital on the
day following radioembolization. No antibiotics are required. Patients are
fasted at least three hours before the procedure and should have a well running
peripheral venous access. Peri-procedural care and pain management will be in
accordance with the protocol of the institution.

Surgical treatment is the treatment of choice for patients with early stage HCC
according to the BCLC staging system. Unfortunately, many patients are not
surgical candidates either due to tumor location, co-morbidity or cirrhosis
with portal hypertension. The EASL recommends RFA as an alternative to
resection in patients with limited disease (single tumor < 5cm or * 3 lesions
of * 3cm each) and a Child Pugh A or B status. Local tumor progression rates
after RFA tend to be higher than after resection, especially in tumors larger
than 2 cm. Study patients are ineligible for surgical resection and will have
tumors > 2cm. They are thus at an increased risk of local tumor progression.
Adjuvant treatment with transarterial segmental radioembolization may
potentially result in lower local tumor progression rates and thus may improve
long-term prognosis.
Study patients will be subjected to a pre-procedural angiography and *test-
injection* of 99mTc-MAA as well as transarterial segmental radioembolization.
Percutaneous transarterial angiography and radioembolization both carry the
risk of mild complications like haematoma of the inguinal region or an
aneurysma spurium as a result of the femoral artery puncture. With the use of a
vascular closure device, the risk of puncture site complications is
approximately 1%. In rare cases a dissection of the femoral or iliac artery can
occur. Although according to literature the chance is less than 2%, there is
also a risk of a dissection or thrombosis of the hepatic artery.
During the pre-procedural angiography, coil-embolization of hepatic-enteric
anastomosis may be deemed necessary to avoid inadvertent flow of 166Ho
microspheres to the stomach or duodenum. The chance of dislocation of coils
during the procedure is about 2%. In most of these cases a dislocated coil can
be removed without further problems. Rarely, a dislocated coil can cause
reduction of flow in the hepatic artery, which impedes the procedure.
Radioembolization is generally well tolerated and most complications are mild.
In a large European multicentre analysis of 325 patients, common
procedure-related adverse events were grade 1/2 according to CTCAE v 3.0 and
included nausea/vomiting (32.0% all grades) and abdominal pain (27.1% all
grades), with very few grade 3 events. Fatigue was reported in 54.5% of
patients (all grades), typically occurring in the first few weeks after
radioembolization and lasting 1-2 weeks, with few (2.5%) grade 3 events. The
percentage of patients experiencing such complications is expected to be much
lower in our study. In multcenter study mentioned above, 92.6% of patient
received either whole liver or lobar radiation with a median administrated
activity of 1.6 GBq. In our study, treatment will be limited to one or two
liver segments and the administrated activity is therefore also expected to be
lower.
Events related to radiation of non-target tissues include gastrointestinal
ulcerations and liver-related events. In the European multicentre study,
gastrointestinal ulceration occurred in 3.7% of patients with a related
mortality of 0.3%. Radiation-induced liver toxicity grade 3 occurred in 5.8% of
patients. Gastro-intestinal ulceration and radiation-induced liver disease are
associated with whole liver treatment and infusion of microspheres from a
proximal location. These complications are therefore expected to occur less
frequently in our study, as a segmental approach will be used in all patients.
In a study of 84 patients treated with ultra-high dose segmental
radioembolization, none of the patients developed gastro-intestinal ulcers or
radiation-induced liver disease.