Transarterial Radioembolization for the Treatment of Advanced Hepatocellular Carcinoma Invading the Right Atrium

Hepatocellular carcinoma (HCC) has the tendency to invade the portal and/or hepatic venous system. The invasion of the right atrium is uncommonly observed and constitutes a treatment challenge. We report the case of a patient with HCC invading the right atrium treated with 90Yttrium-transarterial radioembolization (90Y-TARE). Following the treatment, organizing pneumonia secondary to nivolumab occurred, raising the question of an interaction between 90Y-TARE and nivolumab. Electronic supplementary material The online version of this article (10.1007/s00270-020-02605-3) contains supplementary material, which is available to authorized users.

We report the case of a patient with HCC invading the right atrium who benefited from 90 Yttrium-transarterial radioembolization ( 90 Y-TARE). We discuss the rationale and risks of 90 Y-TARE in this subgroup of patients.

Case
Patient's specific consent was obtained for this report. A 71-year-old male with alcoholic cirrhosis (Child-Pugh A5) presented in the emergency department with abdominal pain and hemodynamic instability. CT scan showed multifocal HCC involving segments II, VII, VIII, with spontaneous rupture of a 9-cm tumor (segment VII), and hemoperitoneum. The patient was successfully treated with superselective Gelfoam embolization, with complete tumor necrosis on follow-up imaging. Several locoregional treatments of the remaining lesions were performed over an 18-month period; conventional TACE (cTACE) of left liver and segments VII/VIII, and radiofrequency ablation of tumor in segment VIII. The a-fetoprotein dropped from 182 to 15.3 ng/ml.
Five months after the last treatment, follow-up imaging showed a tumor thrombus invading the right hepatic vein, inferior vena cava (IVC) and right atrium, arising from a small tumor infiltrating segment VII. The patient was Pre-treatment angiography and CT demonstrated exclusive tumor arterial supply via the right inferior phrenic artery (rIPA) (Fig. 1B-D). Microcoil embolization was performed in the posterior branch of rIPA to protect the diaphragm and prioritize the blood flow to the tumor (Fig. 1E).
99m Technetium-macroaggregated albumin ( 99m Tc-MAA) scintigraphy showed a 30% lung shunt fraction (LSF) with an estimated calculated dose of 216.7 Gy to the tumor and 19.4 Gy to the lungs, for an administered activity of 1.

Discussion
The main finding of our report is that 90 Y-TARE of HCC invading the right atrium was feasible and effective in a rapidly growing tumor.
HCC invading the right atrium is a treatment challenge, and efficacy of available treatments is yet to be proven. Conventional TACE is the most frequently utilized catheter-based treatment for HCC invading the right atrium with dismal outcomes [4,5]. The largest series reported the outcomes of 26 patients with invasion of the IVC including 5 patients with coexisting tumor extension into the right atrium who were treated with cTACE. The median overall survival was 4.2 months [5]. HCC rupture following TACE is a rare but feared complication. Risk factors include male sex, large tumor size, subcapsular location and exophytic outgrowth [6]. These factors need to be considered in light of predictors of spontaneous rupture, such as arterial hypertension, cirrhosis, tumor size [ 5 cm, vascular thrombus and extrahepatic invasion [7]. Taken together, the absence of substantial demonstrated efficacy of TACE, and TACE-induced risk of tumor edema/rupture in this fast-growing mass (per se at risk of cardiopulmonary embolism/collapse) prompted us to favor 90 Y-TARE.
In our patient, the 99m Tc-MAA-scintigraphy showed a 30% LSF. Published upper limit for resin 90 Y-microspheres shunt fraction is 20%, and treatment is not recommended beyond this limit [8]. To avoid radiation-induced lung injury (RILI), a mean lung absorbed dose up to 30 Gy for one radioembolization and a cumulative mean lung absorbed dose up to 50 Gy for repeated radioembolizations are empirically recommended for resin and glass 90 Y-microspheres [9]. For resin 90 Y-microspheres, this 30 Gy lung dose maximum is used for establishing the [ 20% LSF contraindication threshold, should the entire 3 GBq-vial be administered. For glass 90 Y-microspheres, no LSF contraindication threshold is specified. A recent study analyzed 103 HCC patients treated with glass 90 Y-micropsheres with LSF [ 15%. The median LSF was 24.4%. The median lung dose per session and cumulative lung dose were 22.9 and 29.5 Gy. Twenty patients (19%) developed nonspecific pulmonary complaints in the first year, none attributable to 90 Y-TARE, and no RILI was observed [10].
Collectively, these data show that both LSF percentage and the absolute dose delivered to the lungs are important factors. The LSF percentage per se as a unique variable should not prevent selected patients from being treated with 90 Y-TARE, and the absolute dose delivered to the lungs should be the main limiting factor in treating those patients. In our patient, the balance between benefits of 90 Y-TARE and risk of RILI favored treatment, especially since 99m Tc-MAA-based dose calculation estimated a lung absorbed dose of 19.4 Gy. Thus, no prophylactic measures were taken to decrease the hepatopulmonary shunting (such as bland embolization, [11]), and we aimed for an atrial tumor dose of [ 200 Gy, as a dose reduction would imply decreased efficacy and potential futility of 90 Y-TARE itself.
In conclusion, 90 Y-TARE is a palliative treatment option for patients with advanced HCC extending up to the right atrium. An increased LSF per se should not prevent 90 Y-TARE from being performed and is not as important as the lungs absolute absorbed dose. Further research is needed to investigate the safety of 90 Y-TARE performed shortly after immune checkpoint inhibitor therapy.
Acknowledgements Open access funding provided by University of Lausanne. The authors thank Silvano Gnesin, Ph.D., for his technical support.
Funding This study was not supported by any funding.

Compliance with Ethical Standards
Conflict of interest The authors declare that they have no conflict of interest related to this work.
Ethical Approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendment or comparable ethical standards. Patient's specific consent was obtained for this report, and consent by the Institutional Review Board was not required.
Informed Consent Informed consent was obtained from all individual participants included in the study.

Consent for Publication Consent for publication was obtained for every individual person's data included in the study.
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