INTRODUCTION
Hepatocellular carcinoma with portal vein invasion is currently
classified as stage C according to the Barcelona Liver
Cancer Clinic (BCLC) classification; the proposed standard
treatment is sorafenib.1
However, combined treatments in-cluding local treatment such as external beam radiation therapy
(EBRT) are commonly used,2 because the tumor response and
survival benefit owing to sorafenib alone are unsatisfactory.3 The Asia-Pacific Primary Liver Cancer consensus recommends
combined radiotherapy in patients with BCLC stage C tumors.4 Transarterial chemoembolization (TACE) and hepatic arterial
injection chemotherapy (HAIC) can be used combined
with EBRT for HCC with portal vein invasion.5,6 Stereotactic
body radiotherapy (SBRT) is a novel technique that delivers a
high radiation dose to lesions over a short period of time,
usually 1–2 weeks. SBRT also treats lesions in major vessels
such as the portal vein.7
However, grade ≥3 biliary toxicities
have been reported after SBRT for HCC with portal vein invasion.8,9 We report a patient with HCC exhibiting portal vein
invasion who maintained complete response status after SBRT
and HAIC; he ultimately died owing to the aggravation of a
liver abscess with unknown etiology.
CASE REPORT
1. Clinical presentation
A 67-year-old man experienced upper-right abdominal pain
for 3 weeks and was referred from a private clinic after HCC
was suspected following computed tomography (CT) and ultrasonography.
The patient was unaware of any viral hepatitis
history and had not undergone regular screening. He consumed
1.5 bottles of Soju (Korean distilled liquor with an alcohol
content of 15–20%) daily until 3 months prior. He also
smoked a pack of cigarettes daily for 35 years, and was on medications
for hypertension and diabetes. He had undergone an
appendectomy 40 years ago. Blood analyses revealed white blood cells at 12,900/mm3, hemoglobin of 14.7 g/dL, and platelets at 308,000/mm3. Biochemical
analyses showed total protein 8.6 g/dL, albumin 4.6
g/dL, blood urea nitrogen 9.4 mg/dL, creatinine 1.08 mg/dL,
aspartate aminotransferase/alanine aminotransferase 24/19
IU/L, alkaline phosphatase 103 IU/L, total cholesterol 32 mg/
dL, total bilirubin 0.49 mg/dL (direct bilirubin 0.12 mg/dL),
and prothrombin time/international normalized ratio 0.99.
Viral hepatitis serologic tests showed HBsAg (+), anti-HBs
Ab (+), anti-HCV Ab (-), IgG anti-HBc (+), and HBV DNA
232,634 IU/mL. As for tumor markers, alpha-fetoprotein (AFP)
was 598.4 ng/mL and protein induced by vitamin K absenceII
(PIVKA-II) was 51 mAU/mL.
2. Diagnosis
Primovist magnetic resonance imaging (MRI) showed a 4.7
cm mass with arterial enhancement and delayed washout in
segment 6. This lesion formed a tumor thrombus in the main
portal vein up to the right 2nd-ordered and left 1st-ordered
branches (Fig. 1). Ascites was not evident, and the liver surface
was smooth. At diagnosis, the patient’s Child-Pugh score was 5, and he
was classified as class A; his Eastern Cooperative Oncology
Group performance status score was 1. The tumor was considered
BCLC stage C (advanced) owing to portal vein invasion.

Figure 1. Imaging studies at initial diagnosis and follow-up visits. (A) Liver MRI at initial diagnosis. A 4.7 cm-sized mass was noted at the porta hepatis, extending
up to the right 2nd ordered branch and left 1st ordered branch. The tumor showed arterial enhancement and a delayed washout pattern. (B) One
month post-SBRT and after 2 cycles of HAIC, the tumor size decreased from 4.7 cm to 4 cm, and the patency of the left portal vein was almost fully restored.
(C) Seven months post-SBRT and after 6 cycles of HAIC (i.e., HAIC completion), the tumor size was further decreased (to 2.5 cm) and the enhanced
portion of the tumor disappeared. (D) Eleven months post-SBRT, common hepatic duct enhancement and intrahepatic duct dilatation were noted. The total
bilirubin was elevated to 17.45 mg/dL. (E) Thirteen months post-SBRT, a liver abscess of 8.1 cm was noted at the left lateral lobe of the liver. (F) Fifteen
months post-SBRT, severe ascites with multiple liver abscesses were observed. (G) Temporal change of AFP and CP score after SBRT. MRI, magnetic resonance
imaging; SBRT, stereotactic body radiotherapy; HAIC, hepatic arterial chemotherapy; AFP, alpha-fetoprotein; CP score, Child-Pugh score.
3. Treatment and progress
We planned a combination therapy of HAIC and SBRT.
HAIC was performed with the following protocol every 4
weeks; 5-FU 750 mg on day 1, 5-FU 750 mg and cisplatin 90
mg on day 2, and 5-FU 750 mg on day 3. For SBRT planning,
gross tumor volume (GTV) was drawn using planning CT and
3 minute delayed MRI images, which are fused with rigid registration
method. Abdominal compressor was applied at umbilical
area to diminish respiratory movement, and internal
target volume (ITV) was designed considering the respiratory
movement tracked by Real-Time Position Management system
(Varian Medical System, Palo Alto, CA). Then, a planning
target volume (PTV) was expanded by 3 mm from ITV. We
followed the guidelines of Korean Liver Cancer Study Group,
having a mean normal liver dose of <28 Gy (in equivalent dose
of 2 Gy per fraction), and more than 700 cc of normal liver
volume received the dose of <15 Gy.10 The planned dose of 48
Gy was divided into 4 fractions and delivered to PTV every
other day. The duodenum D1cc (the largest dose received by at
least 1 cc of duodenum) was 23.5 Gy, and the mean PTV dose
was 48.1 Gy. The planning was performed using Eclipse 8.9
(Varian Medical System, Palo Alto, CA). The SBRT plan and
dose-volume histogram are shown in Fig. 2. One month after SBRT and after 2 cycles of HAIC, the longest
diameter of the tumor decreased from 4.7 cm to 4 cm, and
left portal vein patency was almost fully restored. AFP levels
significantly dropped from 598.4 ng/mL to 14.5 ng/mL and
normalized. PIVKA-II levels also normalized at 32 mAU/mL.
At 7 months post-SBRT and 6 cycles of HAIC, the longest tumor
axis was further reduced to 2.5 cm, and the enhanced portion
of the tumor lesion disappeared. AFP and PIVKA-II levels
were 5.3 ng/mL and 36 mAU/mL, respectively. The Child-Pugh
score was 5 (class A). This was considered complete response
according to the modified Response Evaluation Criteria in
Solid Tumors.11 At 11 months post-SBRT and after 6 cycles of HAIC,
common hepatic duct enhancement and intrahepatic duct
dilation were noted on follow-up CT. The total bilirubin was
elevated to 17.45 mg/dL, and the Child-Pugh score was 8
(class B). The AFP level was within normal range (5 ng/mL),
but PIVKA-II was elevated to 277 mAU/mL. After pigtail
plastic stent insertion, the total bilirubin normalized to 1.26
mg/d, and the Child-Pugh score was decreased to 6 (class A). At 13 months post-SBRT, the patient visited the emergency department because of fever, hyperventilation, and drowsiness.
A liver abscess at the left lateral lobe (8.1 cm) and mild
ascites were noted on CT. Sono-guided percutaneous abscess
drainage was performed and enterococcus faecalis was grown
in culture. Antibiotic therapy was initiated; the patient’s condition
fluctuated but ultimately deteriorated further. AFP and
PIVKA-II levels were 2.7 ng/mL and 48 mAU/mL, respectively.
The Child-Pugh score was 7 (class B). At 15 months postSBRT,
the patient was re-admitted due to exacerbation of fever and of the abscess on imaging. AFP and PIVKA-II levels
at this point were 2.8 ng/mL and 62 mAU/mL, respectively;
the Child-Pugh score was 11 (class C), and severe ascites with
multiple liver abscesses were observed on CT. The patient
died 5 days after admission owing to uncontrolled fever, leukocytosis,
and progression to sepsis. The liver images obtained
over time are shown in Fig. 1.

Figure 2. Stereotactic body radiotherapy planning to treat the tumor at
the porta hepatis. (A) Schematic delineation of radiation dose distribution.
(B) Dose-volume histogram showing the doses received by organs and
the relevant volumes.
DISCUSSION
Portal vein invasion is found in 10–40% of HCC patients at
diagnosis12; curative treatment is challenging, and such patients
only survive 2–4 months with best supportive care.12,13 EBRT has been commonly applied to HCC with portal vein
invasion with its availability to treat encompassing major vessels.2 Median survival times in previous studies ranged from 7 to 12 months, and the response rate was 35–62%.13 Unlike
the past, TACE is safely performed for the cases of HCC with
portal invasion, and the survival benefit was shown in recent prospective studies.14,15 HAIC is less commonly administered
than TACE, but has the advantage of delivering high doses of
chemotherapeutic drugs to tumors directly via tumor-feeding
arteries without developing post-embolization complications.
In clinical practice, chemotherapeutic local treatment including
TACE and HAIC are used in combination with EBRT to
maximize the therapeutic efficacy.5,6 EBRT with conventional fractions, usually performed for
5–7 weeks using 1.8–2.5 Gy per fraction, is a good palliation
method conferring a modest extension of survival, but is not
regarded as curative even when combined with local chemotherapeutic
modalities. On the other hand, SBRT can be performed
with curative intent. Prospective studies have shown
local control rates of about 90%.16,17 A recent meta-analysis
showed that SBRT had better response rate than conventional
EBRT in treatment of HCC with PVT (70.7% [95%CI
63.7–76.8] vs. 51.3% [95% CI: 45.7–57.0]).18 In the same meta-analysis,
most common grade >3 side effects of conventional
EBRT were lymphocytopenia, gastric/duodenal ulcer, and
liver function deterioration. Grade >3 biliary toxicities were
reported in 3 of 21 studies. Although SBRT was associated with
fewer side effects than conventional EBRT in general, but two
of three studies reported grade >3 biliary toxicities. Two studies attributed biliary toxicity caused by SBRT to its
effect on the central hepatobiliary tract. Osmundson et al.19 reported
that 24% of grade >2 and 18% of grade >3 biliary toxicities,
and suggested VBED1072 < 21 cm3
(5-fractionated SBRT:
V40 < 21 cm3; 3-fractionated SBRT: V33.8 < 21 cm3), VBED1066
< 24 cm3 (5-fractionated SBRT: V37.7 < 24 cm3; 3-fractionated
SBRT: V32 < 24 cm3
) as constraints to reduce biliary toxicity.
Eriguchi et al.20 performed SBRT with 35–50 Gy in 5 fractions
and reported radiation-induced biliary stenosis in only
1 of 50 patients; they concluded that 40 Gy SBRT to the central
biliary system in 5 fractions is safe. Our patient maintained complete response until his last follow-up
visit. The patient experienced a grade 3 biliary stricture
during follow-up and died of liver abscess-related complications.
The cause of this abscess was unknown and may have
been multifactorial; various treatments and procedures such
as chemoport insertion, SBRT, HAIC, and stent insertion might
have contributed to the complications. To date, no studies have been conducted exclusively on SBRT and HAIC combined
treatment for HCC that involves the portal vein, or the
related side effects. Our case suggests that combining SBRT
and HAIC may have potent therapeutic efficacy, and that careful
consideration should be given to possible complications
including biliary toxicity.
AUTHOR CONTRIBUTIONS
Chai Hong Rim mainly wrote the manuscript. Won Sup
Yoon designed the study. All the authors supervised the
manuscript and approved the final version for publication.
Conflicts of Interest
The authors have no conflicts of interests to disclose.
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