Usefulness of a novel transarterial chemoinfusion plus external‐beam radiation therapy for advanced hepatocellular carcinoma with tumor thrombi in the inferior vena cava and right atrium: Case study

Abstract Background Invasion beyond inferior vena cava (IVC) to right atrium (RA) is a rare complication in patients with advanced hepatocellular carcinoma (HCC), and results in fatal oncologic emergencies, including pulmonary embolism and right heart failure. Aim As there is no gold standard treatment for unresectable HCC with tumor thrombi involving IVC and RA, we considered it valuable to assess safety and efficacy of a combination of hepatic arterial infusion chemoembolization (HAIC) therapy and external‐beam radiation therapy (EBRT). Methods and results The “New FP” was chosen as the HAIC therapy, in which the enhanced permeation and retention effect was achieved using a cisplatin‐Lipiodol suspension combined with continuous infusion of 5‐fluorouracil (5‐FU). Sixteen patients with HCC with tumor thrombi in IVC, RA, and pulmonary arteries were enrolled. modified response evaluation criteria in solid tumors‐based evaluation of response to the combination treatment was as follows: complete response, 6.2% (1 patient); partial response, 81.3% (13 patients); stable disease, 12.5% (2 patients); progressive disease, 0%. The median overall survival time (MST) was 19.0 months. Notably, MST of patients receiving sequential sorafenib monotherapy (39.0 months) was significantly longer than that of the rest (15.3 months). Conclusion The combination of New FP and EBRT is an efficacious treatment option for unresectable HCC involving IVC and RA, complicated with pulmonary embolism. Sequential administration of molecular‐targeted drugs may prolong survival in such patients.


Vascular invasion is a common complication in patients with
advanced-stage hepatocellular carcinoma (HCC). The presence of tumor thrombi in portal vein (PV) or inferior vena cava (IVC) is common in patients with HCC and has been reported in 44%-84% during autopsy. 1 However, tumor extension beyond the IVC to the right atrium (RA) is rare, and RA invasion is usually associated with extremely poor prognosis due to oncologic emergencies such as fatal pulmonary embolism and right heart failure. 2,3 Given that there is no gold standard treatment for aggressive HCC, it is empirically treated with surgery, 4,5 external-beam radiation therapy (EBRT), 6 transarterial chemoembolization (TACE), 7 and systemic chemotherapy 8 in selected patients. TACE is a guideline-recommended treatment procedure for advanced HCC globally, but its therapeutic effect on RA tumor thrombi remains discouraging. 7 Under such circumstances, a limited number of reports suggest that a challenging combination of TACE with EBRT might potentially improve the therapeutic response in aggressive HCCs. 9 However, the clinical benefit of this treatment outcome is marginal; therefore, the combination has not been widely accepted. In this regard, it is valuable to assess whether another treatment modality, such as hepatic arterial infusion chemoembolization (HAIC), could complement EBRT better than the existing modalities in the treatment of HCC with tumor thrombi involving IVC and RA.
The high efficacy and safety of our novel HAIC regimen called the New FP has previously been reported, 10,11 and it demonstrated unprecedented periods of progression-free survival (PFS) (8.9 months) and overall survival (OS) (27.0 months) in patients with HCC macroscopically invading the PV. 11 The "New FP" therapy consisting of a cisplatin-Lipiodol suspension and continuous infusion of 5-fluorouracil (5-FU) via a reservoir system exerts an enhanced permeation and retention (EPR) effect, 12 and its unique combinatorial administration provides robust efficacy on HCC with macroscopic vascular invasion compared with the multi-tyrosine kinase inhibitor (TKI) sorafenib monotherapy. 13 In the present study, we retrospectively evaluated the efficacy and safety of the combination of New FP and EBRT in 16 patients with HCC with IVC and RA tumor thrombi. In the combination strategy, the New FP was used to treat intrahepatic HCC lesions and tumor thrombi, and EBRT was exclusively applied to the tumor thrombi in IVC and RA.

| Criteria for treatments
In this multicenter retrospective cohort study of patients with HCC, the following criteria were set for the use of the New FP therapy: (1) tumor thrombosis invading the PV (portal vein invasion [Vp]2-4),

| External-beam radiation therapy
Conventional EBRT was performed using a linear accelerator. Computed tomography (CT) scans of the abdomen were used for three-dimensional conformal radiation therapy (3D-CRT) planning. The patients were immobilized in the supine position using thermoplastic casts. The helical CT images were transferred to the treatment planning system (Xio, CMS. Inc, USA). 3D-CRT was designed to target only the IVC and RA tumor thrombi. The total radiation dose was determined based on the location and burden of each tumor thrombus, hepatic functional reserve of the patient, and the irradiation-related AEs. 3D-CRT was administered either concurrently or sequentially with the New FP.

| Assessment of response to therapy
The primary efficacy endpoint was objective tumor response, while the secondary endpoint was patient survival. The primary endpoint was assessed at 1-3 months after the initial treatment and every 2 months thereafter. Tumors were measured using dynamic CT or dynamic magnetic resonance imaging (MRI). The response to treatment was classified into four categories according to the mRECIST criteria, 15 together with the European Association for the Study of the Liver (EASL) amendments that take into account the amount of necrotic tumor 16 : as complete response (CR), representing disappearance of all measurable lesions for more than 4 weeks; partial response (PR), representing a decrease in the sum of the longest diameter by more than 30%, and lack of any new lesion for more than 4 weeks; progressive disease (PD), representing an increase in the sum of the longest diameter by more than 25% or appearance of new lesion(s); and stable disease (SD), representing cases categorized as neither PR nor PD for more than 8 weeks.

| Statistical analysis
Baseline data were expressed as median and range values. Survival was con-

| OVERALL SURVIVAL
The median overall survival time (MST) of patients enrolled in this study was 19.0 months (Figure 3). Of note, the MST of the patients who sequentially received the multi-tyrosine kinase inhibitor sorafenib (39.0 months) was significantly longer than that of those not receiving the drug (15.3 months) (P = .012, log-rank test) (Figure 4).

| Adverse effects
Grade 3 AEs, such as thrombocytopenia, liver injury, and constrictive pericarditis, were observed in one patient each. Grade   In the era of molecular-targeted drugs for the treatment of HCC, we should consider the standpoint of the combination treatment of the New FP and EBRT. Recently, the novel treatment regimen "atezolizumab plus bevacizumab" was approved as the first immunooncology therapy for unresectable HCC. In the setting of its phase 1b clinical trial (GO30140), the regimen exhibited an ORR of 35.5% (CR 11.5% and PR 24%, evaluated by RECIST v1.1), although 53% of the enrolled patients with HCC had MVI. 17 Thus, immuno-oncology therapy may be promising in controlling far-advanced HCC with extrahepatic tumor thrombi invading the IVC or RA, as in our patients.
However, to date, there is no definite biomarker to predict the responsiveness or time to response to novel treatments. Therefore, such immuno-oncology therapy should be applied after efficacious and manageable treatments, such as the combination of the New FP and EBRT, in patients under a state of pre-oncologic emergency with unresectable HCC invading the IVC, RA, and pulmonary arteries.
Although the current study was retrospective, and the number of patients was small, the combination of the New FP and EBRT would be feasible in cases where oncologic emergencies must be treated using speedy and effective procedures.

ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing.

CONFLICT OF INTEREST
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

DATA AVAILABILITY STATEMENT
Clinical data are stored in an institutional database and will be shared upon request to the corresponding author.

ETHICAL STATEMENT
The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the ethics review committee of Kurume University (Approval No. 20164). Written informed consent was obtained from each patient before enrollment in the study.