Trans-arterial radioembolization with yttrium-90 of unresectable and systemic chemotherapy resistant hepatoblastoma in three toddlers

Abstract The aim of this short communication was to report
the results of transarterial radioembolization (TARE) with
Yttrium-90 (Y90) loaded resin microspheres in three toddlers
with unresectable and systemic chemotherapy-resistant HB
hepatoblastoma (HB). Six TARE procedures were performed
on the patients. The dose required for treatment was calculated
using partition model. Administered doses of Y90 were
1.369, 0.851, and 1.147 GBq.Complete radiological response
in two patients and partial response enabling liver resection in
one patient were achieved. Neither life-threatening nor minor
complications developed after the treatment. These results
demonstrates that HB is a radiosensitive neoplasm, and
TARE-Y90 can be used as the primary, neoadjuvant and
palliative treatment method in patients with unresectable and
systemic chemotherapy-resistant HBs. However, studies with
higher number of patients and long-term results are required.
Keyword Hepatoblastoma Toddlers Transarterial
Radioembolization Yttrium-90
Introduction
Hepatoblastoma (HB) is the most common primary
malignant liver tumour in paediatric patients [1]. Surgical
resection and liver transplantation are proven curative
treatments for HB [2, 3]. However, only one-third of
patients can receive surgical treatment as the first choice
[4, 5]. In patients with HBs who are not suitable for surgery,
systemic chemotherapy is performed [6]. Multi-drug
resistance developing in some patients constitutes a
& Ferhat Can Piskin
ferhatcpiskin@gmail.com
Huseyin Tugsan Balli
tugsanballi@gmail.com
Kairgeldy Aikimbaev
aikimbaev@gmail.com
Isa Burak Guney
isaburak@gmail.com
Begul Yagci-Kupeli
drbegul@yahoo.com
Serhan Kupeli
serhankupeli@cu.edu.tr
Turan Kanmaz
turan.kanmaz@memorial.com.tr
1 Department of Radiology, Cukurova University Medical
School, Balcali Hospital, Adana, Turkey
2 Department of Nuclear Medicine, Cukurova University
Medical School, Balcali Hospital, Adana, Turkey
3 Department of Pediatric Hematology and Oncology,
University of Health Sciences, Adana Education and
Research Center, Adana, Turkey
4 Department of Pediatric Oncology, Cukurova University
Medical School, Balcali Hospital, Adana, Turkey
5 Department of Pediatric Surgery, Organ Transplantation
Center, Koc University Hospital, Istanbul, Turkey
123
Cardiovasc Intervent Radiol
https://doi.org/10.1007/s00270-021-03026-6
significant problem [7]. There are promising reports of
transarterial treatments for unresectable HBs in paediatric
patients whose treatment options are nearly exhausted
[8–10]. Although most reports on the treatment of HBs
relate to transarterial chemoembolization (TACE), there
are two recently published case series describing the
treatment of paediatric HB patients using transarterial
radioembolization (TARE) with Yttrium-90 (Y90) [11, 12].
The aim of this short communication was to report the
results of Y90-TARE in three toddlers with unresectable
and systemic chemotherapy-resistant HB.
Materials and Methods
Between March 2016 and May 2020, three toddlers, 14, 8,
and 9 months old, were treated with Y90-TARE based on
the decision of the multidisciplinary tumour board. All
diagnostic and interventional radiological procedures performed
were in accordance with the ethical standards of the
1964 Declaration of Helsinki, and a signed informed consent
form was obtained from all patients’ parents in
advance. Due to the retrospective character of this short
communication, the approval for publishing from the
Institutional Ethics Committee for Clinical Research was
waived. The patients’ demographic and clinical characteristics
with main radiological findings regarding tumour
response to TARE are presented in Table 1. Briefly, the
diagnosis of HB was confirmed by tru-cut needle biopsy in
all patients. The PRE-Treatment EXTent of tumour
(PRETEXT) stages [4] of the tumours were determined as
III (P (portal venous involvement) ? , V (hepatic venous/
inferior vena cava involvement) ? , M (distant metastases)
-), and multiple cycles of chemotherapy (in accordance
with the PLADO-SIOPEL-4 (cisplatin plus doxorubicin-
International Childhood Liver Tumours Strategy Group)
protocol) [13] were administered for the tumours, which
were considered unresectable. With respect to the results of
published studies [14, 15], drug-eluting bead TACE with
40 micron microspheres (Embozene TANDEM, Boston
Scientific) containing 50 mg of doxorubicin was performed
in patient one due to the lack of radiological response to
treatment according to Modified Response Evaluation
Criteria in Solid Tumours (mRECIST) [16]. During clinical
and radiological follow-ups, tumours were considered
chemotherapy resistant, while a diagnosis of doxorubicininduced
cardiotoxicity was made in one patient. As a result,
the multidisciplinary tumour board decided to administer
TARE due to exhaustion of treatment options.
The splanchnic angiographies under cone beam computed
tomography guidance were performed before TARE
in accordance with reported recommendations [17]. The
tumour-feeding arteries were selectively catheterized, and
four mCi 99 m Technetium-macroaggregate albumin
(99mTc-MAA) particles were injected. Single-photon
emission computed tomography detected lung shunt fractions
as 7%, 6%, and 10%, and the patients were found to
be suitable for TARE. The Y90 dose required for treatment
was calculated using the partition model in all patients [18]
with the Dosimetry and Activity Visualizer for 90Y
Table 1 Demographic and clinical characteristics with main radiological findings regarding tumour response to TARE of the patients group
Patient 1 Patient 2 Patient 3
Initial tumour diameter, cm 10.0 8.0 8.5
PRETEXT, stage III III III
Pre-treatment therapies Six cycles of systemic
chemotherapy, one TACE
Three cycles of systemic
chemotherapy
Four cycles of systemic
chemotherapy
Age at TARE, months 14 8 9
MAA lung shunt fraction, % 6 10 7
TARE, number of sessions 2 2 2
Total administered dose of Yttrium-90, GBq 1.369 0.851 1.147
The estimated total radiation absorbed doses for
tumour, Gray
518 307 506
The estimated total radiation absorbed doses for
healthy liver, Gray
0 0 0
Final tumour diameter, cm 3.0 2.7 4.0
Tumour shrinkage, % 70.0 66.2 53.0
Radiological response to TARE Complete response Complete response Partial response
Local tumour control after TARE, months 12 5 6
PRETEXT PRE-Treatment EXTent of tumour staging system, TACE transarterial chemoembolization, TARE transarterial embolization, MAA
macroaggregate albumin, GBq gigabecquerel
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Radioembolization (DAVYR) software. 90Y-loaded resin
microspheres (SIR-Spheres; Sirtex Medical) at doses of
1.369 GBq, 0.851 GBq, and 1.147 GBq were injected into
the tumour-feeding arteries without any procedural complications.
Six TARE procedures were performed on the
patients for following reasons: tumour’s recurrence at the
sixth month follow-up in patient one with partial response,
tumour’s dual feeding from left and right hepatic arteries
(two separate TARE sessions with one month interval) in
patient two, and tumour’s dual feeding from left hepatic
and inferior phrenic arteries (two separate TARE sessions
with ten days apart) in patient three. A tumour-feeding
vessel in patient one was a left hepatic artery. Embolization
of the right hepatic artery branches with two coils to protect
non-tumour liver parenchyma, and embolization of the
diaphragmatic branches of the inferior phrenic artery with
two coils with the aim to protect the patient’s diaphragm
was performed in last two patients.
All investigated patients were evaluated by dynamic
contrast-enhanced computed tomography (CECT) before
and after TARE at the sixth week, third month, and then in
three-month intervals. Radiological response assessment of
the treated tumours was conducted in accordance with the
mRECIST, and a-fetoprotein (AFP) levels were obtained at
the same scheduled intervals.
Results
Before TARE AFP levels were 172 ng/mL, 21 541 ng/mL,
and 24 333 ng/mL, while after TARE AFP levels
decreased to 28 ng/mL, 16 ng/mL, and 2 373 ng/mL. At
the third month of follow-up after second TARE, the
radiological findings of the first patient consistent with
complete response according to the mRECIST were registered
(Fig. 1B). Unfortunately, in September 2017, the
patient was diagnosed with acute myeloblastic leukaemia,
after that the patient died at 29 months old. In this patient,
local tumour control with the complete eradication of HB
was achieved for 12 months without side effects related to
TARE. In patient two, in the sixth week after TARE, the
results of CECT (Fig. 1D) were consistent with a complete
response according to mRECIST. Local tumour control of
patient two was achieved for five months with tumour
eradication without side effects after TARE. The patient’s
follow-ups are ongoing and the patient is waiting a suitable
donor for liver transplantation. In patient three, during
the sixth week of follow-up, the tumour component was
enhanced in accordance with the partial response according
to mRECIST, and decrease in size and larger diameter was
measured as four cm (Fig. 1F). Six months later, the patient
underwent successful left hepatectomy. In the postoperative
pathological material, although malignant tissue was
not observed in the surgical material, significant
Fig. 1 Radiological assessment of patients with hepatoblastoma
before and after TARE with Yttrium-90 A, CECT of 14-month-old
boy (patient 1) with partially calcified and hypervascular HB (10 cm
diameter) in the left lobe of the liver. B, CECT of the same patient
from panel A demonstrating avascular character of the tumour
compatible with complete radiological response after two procedures
of TARE. C, CECT of 8-month-old boy (patient 2) with hepatoblastoma
(8 cm diameter) in the right lobe of the liver. D, CECT of the
same patient from panel C demonstrating avascular character of the
tumour compatible with complete radiological response after two
procedures of TARE. E, CECT of 9-month-old girl (patient 3) with
hepatoblastoma (8.5 cm diameter) in the both lobes of the liver. F,
CECT of the same patient from panel E demonstrating decreased
contrast enhancement of the tumour compatible with partial radiological
response after two procedures of TARE. Arrow = tumour;
CECT = contrast-enhanced computed tomography, TARE = transarterial
radioembolization
H. T. Balli et al.: Trans-arterial Radioembolization with Yttrium-90 of Unresectable and...
123
hyalinization, embolizing material, and surrounding foreign
body type giant cell reaction were observed. In summary,
two patients achieved complete response and one
partial response according to mRECIST.
Discussion
The most effective treatment modalities for HB are liver
transplantation or surgical resection [1, 2]. Pham et al. [19]
reported one-, five-, and 10-year disease-free survival after
liver transplant as 93, 82, and 82%, respectively, for
patients with HB. However, surgical treatments can only be
applied to a limited number of patients [3]. A significant
increase in survival rates in HB has been observed with the
use of adjuvant or neoadjuvant chemotherapy. Illiano et al.
[20] reported 10-year event-free survival and overall survival
probabilities as 95.5% and 98.7%, respectively, for
hepatoblastoma survivors treated with SIOPEL risk-adapted
strategies. Cisplatin is the most effective chemotherapy
agent in hepatoblastoma and provides a curative effect
even when used as a single agent in low risk patients [4]. In
patients unsuitable for surgical resection, recurrent or
metastatic patients, doxorubicin is the most commonly
added agent to cisplatin [5, 6]. Significant side effects such
as myelosuppression and cardiotoxicity can be seen at the
end of these long-term systemic chemotherapies. Moreover,
some patients develop resistance to systemic
chemotherapy and tumour control is lost [7].
In recent years, TACE treatment, which has less side
effects compared to systemic chemotherapy, has been
applied as the first treatment option in patients with unresectable
HB, due to its local effect on the liver [8–10]. Oue
et al. [8] applied TACE treatment to eight patients with
unresectable HB and achieved a significant reduction in
tumour size and a significant reduction in AFP values
compared to pre-treatment. All of these tumours treated
with TACE regressed to the resectable stage and were
surgically resected. Xianliang et al. [21] reported curative
treatment by applying only TACE treatment in a sixmonth-
old patient with HB in the unresectable stage and
achieved a tumour-free survival period of 33 months. In
these reports, it has been stated that, with all these positive
results, multisession-repetitive TACE treatment is required
for disease control in patients with HB [8–10].
Although TARE is a safe and effective treatment
modality for adult liver tumours [22], there is limited
information about TARE for paediatric patients with HB.
Aguado et al. [11] applied TARE to ten patients with primary
liver tumours including two paediatric patients with
unresectable HB. Later the same authors [12] reported
successful use of TARE in two patients with unresectable
HB when curative treatment by performing
surgical resection after the tumours shrank in size and the
stage was declined. In the current short communication,
three toddlers with unresectable and systemic chemotherapy-
resistant HB were treated with TARE. In patient one,
the patient’s tumour was eradicated (Fig. 1B) and the
patient survived 12 months. This patient died due to acute
myeloblastic leukaemia, which probably developed as a
side effect of systemic chemotherapy. Similar situation was
reported by Hirakawa et al. [23]. In current short communication,
TARE was applied as the first transarterial
therapy in patient two and patient three. In both patients,
Y90 injections were performed twice for safety as the
tumour had two different tumour-supplying arteries. As a
result, the tumour was eradicated in two patient (Fig. 1B
and Fig. 1D); tumour size was reduced (Fig. 1F) and surgical
resectability were achieved in one patient, in which
malignant tissue was not observed in the surgical material
in the postoperative pathological examination. No lifethreatening
complications developed in any of the three
patients after TARE treatment.
In conclusion, the results show that HB is a radiosensitive
tumour, and TARE can be used as the primary,
neoadjuvant, and palliative treatment method in patients
with unresectable and systemic chemotherapy-resistant
HB. However, in order to reach a definite conclusion and to
determine the advantages and disadvantages compared to
other treatment methods, studies with higher number of
patients and long-term results are required.
Acknowledgements The authors did not receive support from any
organization for the submitted work.
Declarations
Conflict of interest The authors have no conflicts of interest to
declare that are relevant to the content of this article.
Ethical Approval The study was performed in accordance with the
ethical standards of the 1964 Declaration of Helsinki, and a signed
informed consent form was obtained from all patients’ parents in
advance. Due to the retrospective character of this short communication,
the approval for publishing from the Institutional Ethics
Committee for Clinical Research was waived.
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