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 [email protected] Huseyin Tugsan Balli [email protected] Kairgeldy Aikimbaev [email protected] Isa Burak Guney [email protected] Begul Yagci-Kupeli [email protected] Serhan Kupeli [email protected] Turan Kanmaz [email protected] 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 H. T. Balli et al.: Trans-arterial Radioembolization with Yttrium-90 of Unresectable and... 123 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. References 1. Darbari A, Sabin KM, Shapiro CN, Schwarz KB. Epidemiology of primary hepatic malignancies in US Children. 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