Proton Beam Therapy for Hepatocellular Carcinoma after the Fontan Procedure

Background: Hepatocellular carcinoma (HCC) is more likely to occur in patients with a history of Fontan surgery, possibly due to long-term liver congestion. Proton beam therapy (PBT) may be effective for HCC that develops after Fontan surgery. Methods: Six lesions in 5 patients (3 females, 2 males) received PBT. The median age of the patients was 33 (range 21 - 42) years, and the median age at the time of the Fontan procedure was 6 (5 - 13) years. Four patients had multiple HCC at the time of PBT. The median tumor size was 57 (22 - 80) mm and 4 patients were classified as Child-Pugh B. Two patients received transcatheter arterial chemoembolization before PBT. The schedule of PBT was 66 Gy (RBE) in 10 fractions for 2 lesions, 72.6 Gy (RBE) in 22 fractions for 2 lesions, and 74 GyE (RBE) in 37 fractions for 2 lesions. Results: The median follow-up period was 31 (10 - 46) months, and the numbers of survivors, deaths from primary diseases, and deaths from other diseases were 3, 1, and 1, respectively. There were no local recurrences, one intrahepatic metastasis, one lung metastasis, and one intrathoracic metastasis. Conclusion: Although experiences on a small number of patients cannot conclude things, we believe that PBT can be a reasonable choice of radical treatment for HCC occurring after the Fontan procedure.


Introduction
A Fontan procedure is a palliative operation for patients with single ventricle congenital heart disease (CHD). Since it was first described in 1971, the Fontan procedure has been widely accepted for use in children [1] [2]. However, many reports have shown that Fontan-associated liver disease (FALD) occurs due to hepatic venous congestion and ischemia [2] [3] [4] [5], and some recent reports have suggested that the risk of hepatocellular carcinoma (HCC) is higher after a Fontan procedure [6] [7] [8] [9] [10].
The standard curative treatments for HCC are surgery, liver transplantation, radiofrequency ablation (RFA) and transarterial chemoembolization (TACE). However, these are often difficult to perform for HCC after a Fontan procedure because of low heart function, hypohepatic function, and liver congestion. We have shown that proton beam therapy (PBT) can be performed for patients with a poor general condition [11] [12] [13] [14]. Herein, we describe the first use of PBT for HCC after a Fontan procedure.

Methods
From 2016 to 2018, we performed PBT for 5 patients (3 females, 2 males) with HCC after a Fontan procedure. This retrospective study was approved by the institutional review board and written informed consent was obtained from all patients. The median age of the patients was 33 (range 21 -42) years, and the median age at the time of the Fontan procedure was 6 (range 5 -13) years. The Fontan procedure was performed for double outlet right ventricle (n = 3) and tricuspid atresia (n = 2). Four patients needed anticoagulation therapy after the Fontan procedure.
At the time of PBT, 4 patients had multiple HCC. Two patients had received TACE before PBT. The median time from the Fontan procedure to PBT was 26 (15 -33) years. Six lesions in 5 patients received PBT because standard treatment was considered to be difficult. The median tumor size was 57 (22 -80) mm and 4 patients were classified as Child-Pugh B. Three treatment schedules were used: 66 Gy (RBE) in 10 fractions for 2 lesions, 72.6 Gy (RBE) in 22 fractions for 2 lesions, and 74 GyE (RBE) in 37 fractions for 2 lesions. These were selected based on the tumor location.

Results
The backgrounds of the patients and the tumor characteristics are shown in Table 1. Each PBT schedule was performed without interruption. One patient had grade 4 hyperkalemia, which was probably a side effect of a diuretic. No other grade 3 or higher acute toxicity was observed. At the time of analysis, three patients are alive, one died due to heart failure, and one died due to bleeding from intrathoracic metastasis. The median follow-up period was 31 months (range: 10 -46 months). There has been no local recurrence, but one case has had intrahepatic recurrence outside the irradiated field, one developed lung metastasis, and one had intrathoracic metastasis. As an illustrative example, we describe the case of a 33-year-old Asian female who was born with tricuspid atresia. At the age of 6, she underwent a Fontan procedure followed by a total cavopulmonary connection at age 23. She had been under observation by abdominal US and CT from her twenties, and a dynamic CT image revealed multiple HCC in segment 7 at age 32 ( Figure 1(b), Figure   1(c)). The HCCs were 5.5 cm and 2.9 cm in diameter and both protruded on the liver surface, but there was no vascular invasion. Her serum alpha-fetoprotein level increased to 9883 ng/ml and PIVKAII also increased to 33

Discussion
In 1971, Fontan reported the basic surgery in the Fontan procedure [1]. Subse- quently, the surgical technique has been improved, and since the extracardiac conduit method using an artificial blood vessel was reported in 1990, stable postoperative management has become possible and the number of treated cases has increased [2]. However, the number of reports of postoperative complications has also increased since the 1990s [3] [4] and various measures for complications and follow-up methods have been proposed [5] [15] [16]. One complication after Fontan surgery is an increased incidence of HCC, which several reports since 2010 have described [7] [8] [17] [18] [19] ( Table 2). In these reports, the incidence of HCC after Fontan surgery is 0.18% to 1.4%, which is higher than the prevalence of HCC in the general population of Japan.  years indicates that this disease mainly affects young people. After Fontan surgery, patients often need to take anticoagulants or have a pacemaker in place to maintain cardiac function or normal blood flow, and thus, the treatment methods for HCC are limited. Of the 34 reported cases, 11 had difficulty with curative treatment. PBT has been established as a radical treatment for HCC, and can be used as a radical therapeutic method even in cases with low liver function or those in which the inferior vena cava or portal vein has a tumor plug. All 5 cases in which we used PBT were judged to be difficult to cure radically, but in all cases, radical PBT was completed according to the protocol and without any serious adverse events to date. In addition, PBT reduces the risk of secondary cancer in pediatric cases, and this effect can be expected in patients with a young onset age of HCC after a Fontan procedure.
HCC is a heterogeneous population that can be triggered by several clinical backgrounds.
Therefore, depending on the etiology of each, the HCCs that develop may have different cytological and oncological characteristics. It is not yet clear what the cytological characteristics of HCC after Fontan surgery are, and whether proton therapy is advantageous for these characteristics. However, it may be a relatively reasonable treatment to receive, at least for those with poor liver and circulatory system conditions.

Conclusion
This is the first report of the use of PBT for HCC after a Fontan procedure. The results show that PBT has potential as a radical treatment in the special circumstances present in this population of patients.

Conflicts of Interest
The authors declare that they have no competing interests.

Financial Disclosure
All authors have no financial relationships associated with the content of the manuscript.

Availability of Data and Materials
Please contact the corresponding author for data requests.

Ethics Approval and Consent to Participate
The patients signed a consent form prior to initiation of treatment and collection of data.

Authorization Number of This Study
H28-152; authorized by Ethics Committee University of Tsukuba Hospital.