GASTROINTESTINAL CANCER—GASTROESOPHAGEAL, PANCREATIC, AND HEPATOBILIARY

The Treatment of Hepatocellular Carcinoma With

Portal Vein Tumor Thrombosis
Motaz Qadan, MD, PhD1; Nishita Kothary, MD2; Bruno Sangro, MD, PhD3; and Manisha Palta, MD4
overview

Hepatocellular carcinoma (HCC) is the sixth most common cancer and third leading cause of cancer-related
death worldwide. HCC is also is a tumor with a distinct ability to invade and grow within the hepatic vas-
culature. Approximately 20% of patients with HCC have macrovascular invasion (MVI) at the time of diagnosis.
MVI is associated with dismal prognosis, with median survival ranging from 2 to 5 months. Current staging
systems designate MVI as advanced disease. Recent advances in multimodal approaches, including systemic
therapies, radiation therapy, liver-directed therapies, and surgical approaches, in the treatment of HCC with
MVI have rendered this disease process more treatable with improved outcomes and are discussed here.

INTRODUCTION decompensation, with resultant ascites, jaundice, vari-

Hepatocellular carcinoma (HCC) is the sixth most com-
mon cancer and third leading cause of cancer-related
death worldwide.1 HCC is also is a tumor with a distinct
ability to invade and grow within the hepatic vasculature.
Although macrovascular invasion (MVI) may involve
hepatic veins or portal veins, invasion of portal venous
branches is more common. Approximately 20% of pa-
tients have MVI at the time of diagnosis. Among patients
with unresectable tumors, the probability of developing
portal vein tumor thrombosis (PVTT) at 1 and 3 years is
21% and 46%, respectively.
The Barcelona Clinic Liver Cancer (BCLC) staging
system designates PVTT as advanced disease (BCLC
class C) for which only systemic therapy is currently
recommended.2,3 MVI, PVTT, and/or hepatic vein
invasion is associated with dismal prognosis, with
median survival ranging from 2 to 5 months with best
supportive care.4,5 On one hand, MVI impairs liver
function through reduced liver perfusion as a result
of impaired blood flow, either directly via reduced
inflow in PVTT or via elevated sinusoidal pressure in
hepatic vein invasion. On the other hand, extension
Author affiliations of tumor within the vasculature promotes tumor
and support spread beyond the liver via direct seeding and ex-
information (if tension. The impact on prognosis is thus profound
applicable) appear
and predictable. In fact, the relative impact of MVI
at the end of this
article. on mortality in untreated patients (odds ratio [OR]
1.9) is stronger than that of extrahepatic spread
Accepted on
February 20, 2020 (OR 1.6) or performance status (OR 1.2). The lo-
and published at cation and extent of MVI may further affect prog-
ascopubs.org on nosis through the limitations exerted on the use
March 26, 2020:
DOI https://doi.org/
of treatment modalities such as transplantation,
10.1200/EDBK_ resection, and transarterial therapies. Finally, MVI
280811 can result in portal hypertension and associated liver
ces, or encephalopathy.
Recent advances in multimodal approaches in the
treatment of HCC with MVI have rendered this disease
process more treatable with improved outcomes and
are discussed here.
SYSTEMIC THERAPIES
HCC is highly resistant to traditional cytotoxic che-
motherapy.6 Oral multi-targeted tyrosine kinase in-
hibitors (TKIs) are the mainstay systemic agents of
choice in the treatment of HCC. There are four drugs
approved worldwide. Ten years ago, sorafenib proved
superior to placebo in prolonging overall survival (OS)
of patients with advanced HCC, with preserved liver
function in the pivotal SHARP trial.7 More recently,
lenvatinib was found to be noninferior to sorafenib as
a first-line agent, with a comparable toxicity profile and
a similar impact in health-related quality of life.8 Im-
portantly, patients with PVTT involving the main trunk
were excluded from the REFLECT trial; as a result, only
21% had PVTT compared with 38% in SHARP.
Cabozantinib resulted in prolonged survival compared
with placebo in patients progressing to one or two lines
of therapy (including sorafenib) in the CELESTIAL trial.9
Importantly, patients with hepatic vein invasion were
excluded from this trial. In the RESORCE trial, patients
who stably tolerated sorafenib (at least 400 mg daily for
at least 20 of the 28 days before discontinuation) but
experienced radiologic progression had an improved
survival with regorafenib compared with those who re-
ceived placebo.10
Antiangiogenic monoclonal antibodies, including
bevacizumab11 and ramucirumab,12 failed to prove
activity as single agents. However, a post hoc analysis

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 Treatment of Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis

(13.9 months vs. 10.6 months; p = .023), although the

PRACTICAL APPLICATIONS
• The treatment of hepatocellular carcinoma with
macrovascular invasion, including portal vein
tumor thrombus, remains challenging to treat
and has poor outcomes.
• Approximately 20% of patients with hepato-
cellular carcinoma have macrovascular in-
vasion at the time of diagnosis.
• Recent advances in the management of this
challenging condition have emerged.
• Multimodal approaches in the treatment of
hepatocellular carcinoma with macrovascular
invasion have improved outcomes associated
with this advanced entity.
of the negative trial with ramucirumab suggested a potential
efficacy among patients with high serum levels of alpha-
fetoprotein greater than 400 ng/mL. The signal was later
confirmed in the REACH-2 trial and demonstrated a favor-
able safety profile.13
Immunotherapy with immune checkpoint inhibitors as an
entity is transforming systemic therapy in HCC. The PD-1
inhibitors nivolumab and pembrolizumab first demonstrated
activity in single-arm trials in the second-line setting.14,15
This led to accelerated approval by the U.S. Food and Drug
Administration and other regulatory agencies. The most
important finding in these trials was the 15% to 20% rate of
objective remissions that were durable and associated with
prolonged survival. In the CheckMate 040 trial, the median
duration of response to nivolumab was 17 months, and the
2-year survival rate among responders was greater than
80%.14 The KEYNOTE 240 trial compared pembrolizumab
with placebo after progression to sorafenib and showed
a statistically significant prolongation of median survival
difference did not meet the prespecified statistical thresh-
old.16 The median duration of response to pembrolizumab
at 13.8 months was comparable to that of nivolumab, in-
dicating a drug class effect. Recently, the CheckMate 459
trial compared nivolumab with sorafenib in the first-line
setting.17 Improved median survival was observed in
nivolumab-treated patients (16.4 months vs. 14.7 months;
p = .07), although the predefined threshold of statistical
significance was not met. In the postprogression setting,
31% of patients in the sorafenib arm received an immu-
notherapeutic or investigational agent that was often a check-
point blockade inhibitor, and a TKI was received by a similar
proportion of patients in both arms (36% after nivolumab
and 23% after sorafenib). Nivolumab induced objective
responses more frequently than sorafenib (15% vs. 7%),
including 4% of patients exhibiting complete responses and
with responses in patients with PVTT (Fig. 1). Complete
responses to sorafenib have also been reported among pa-
tients with MVI.18
The presence of MVI and that of extrahepatic disease were
incorporated as stratification factors in the pivotal SHARP
trial and subsequent phase III trials, thereby allowing
comparison of outcomes in patients with MVI in subgroup
post hoc analyses. As shown in Table 1, the treatment
benefit with all of these agents in the overall population is
replicated in the subgroup of patients with MVI, with the
exception of ramucirumab. The median survival was sig-
nificantly higher in the ramucirumab group than in the
placebo group (8.5 months vs. 7.3 months; p = .0199).
However, in the post hoc subgroup analysis, the benefit
persisted among patients without MVI (HR, 0.60; 95% CI,
0.42–0.87) but not in those with vascular invasion (HR,
0.97; 95% CI, 0.61–1.53). It should be noted that, in the
REFLECT and CheckMate 459 trials, post hoc analyses were
available for combined MVI and extrahepatic disease but
not for MVI alone.

FIGURE 1. Hepatitis C Virus–

Related Cirrhosis and an Advanced
Hepatocellular Carcinoma Tumor
With Portal Venous Invasion
(A) The patient received nivolu-
mab as first-line therapy. A partial
response was observed after 8
weeks, followed by a complete
response, including disappear-
ance of the portal vein tumor
thrombus. Nivolumab was dis-
continued after 1 year of therapy.
(B) The patient remains free of
disease 1 year later.
Abbreviation: AFP, alpha-fetoprotein.

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Qadan et al

TABLE 1. Magnitude of Treatment Benefit of Systemic Therapies Among Patients With Hepatocellular Carcinoma and Macrovascular Invasion
CheckMate
Variable SHARP7 REFLECT8 RESORCE10 CELESTIAL9 REACH-213 45917 KEYNOTE 24016
Investigational Sorafenib Lenvatinib Regorafenib Cabozantinib Ramucirumab Nivolumab Pembrolizumab
agent
Control Placebo Sorafenib Placebo Placebo Placebo Sorafenib Placebo
Percentage of 38 21 28 30 35 73 13
patients with
MVI
HR (95% CI)
MVI 0.68 (0.49–0.93) 0.87a (0.73–1.04) 0.67 (0.46–0.98) 0.75 (0.54–1.03) 0.97 (0.61–1.53) 0.74a (0.61–0.90) 0.57 (0.29–1.13)
No MVI 0.74 (0.54–1.00) 1.05a (0.79–1.40) 0.67 (0.52–0.86) 0.80 (0.64–1.01) 0.60 (0.42–0.87) 1.14a (0.81–1.62) 0.82 (0.63–1.06)

Abbreviations: HR, hazard ratio; MVI, macrovascular invasion.

a
HR was calculated for the subgroup of patients with MVI and extrahepatic spread or neither.

Substantial experience has been accumulated over the
years with sorafenib to increase median OS from 10.7 to
14.7 months since the last reported trial. When patients are
fit to receive a second agent upon progression, survival
figures greater than 2 years are seen.19 Recently, the
IMbrave 150 trial was reported to have met its coprimary
endpoints, demonstrating superior survival for the com-
bination of atezolizumab and bevacizumab (median 16.4
months) compared with sorafenib in the first-line setting.17
This finding is likely to establish the combination as
a global standard of care in the management of advanced
HCC, and it illustrates how the activity of current systemic
therapies provides clinically significant benefits for patients
with HCC.
In summary, available systemic agents, including TKIs,
immunotherapy agents with checkpoint blockade inhibitors,
and vascular endothelial growth factor inhibitors, have all
been shown to prolong survival in patients with advanced
HCC with strong (level 1) scientific evidence. In addition,
sequencing the available agents offers prolonged survival
for many patients. Indeed, response to systemic therapies
may open the door for locoregional therapies, including
surgery, to further improve prognosis.
RADIATION THERAPY
Clinical Outcomes of Radiotherapy for HCC
Stereotactic body radiotherapy (SBRT) involves treating
primary tumors or metastases with a few high doses of
ionizing radiation. The benefits of SBRT are that it is
a noninvasive outpatient procedure typically delivered in 3
to 10 fractions. In SBRT, tumor kill is maximized and dose to
surrounding tissue is minimized via precise and accurate
delivery of multiple radiation beams to the target. This is
particularly challenging with liver malignancies, because
these lesions move with respiration and are irregular in shape,
necessitating careful treatment planning and continual man-
agement of such motion and patient position during irradiation.20
Technological advances in radiation delivery in the past
several decades allow delivery of safe and effective ablative
doses to the liver. These advances include respiratory
motion assessment, respiratory motion management, and
treatment planning and delivery. Conformal techniques
allow both dose escalation to target volumes and normal
tissue sparing. These advances have allowed radiotherapy
to be an important modality in the management of HCC,
demonstrating promising local control and quality of life with
acceptable rates of toxicity. Given these advances, radio-
therapy has evolved from a purely palliative treatment to that
of a bridge to transplantation or even definitive curative
intent treatment.21
A number of prospective nonrandomized studies have
evaluated the use of hypofractionated image-guided radi-
ation therapy for treatment of HCC. Select studies are
presented in Table 2. These experiences suggest that SBRT
is well tolerated, with acceptable toxicities and excellent
local control rates. Follow-up is short, however, because
many have not reached a median survival endpoint. In
addition, few randomized studies comparing radiation
therapy with other locoregional modalities exist.
Bujold et al22 reported a sequential phase I and II trial of 102
patients with Child–Turcotte–Pugh (CTP) class A HCC.
Larger tumors were included (median diameter 7.2 cm),
and more than half of patients had previous liver-directed
treatment and tumor vascular thrombosis. The phase I dose
escalation tested 24 to 54 Gy in six fractions, with a median
dose for the pooled analysis of 36 Gy in six fractions. Despite
this poorer-prognosis patient population, SBRT was asso-
ciated with reasonable outcomes and modest toxicity.
Median survival was 17 months, with a 1-year OS of 55%.
Thirty-six percent of patients had grade 3+ toxicity, and 29%
had deterioration of CTP scores at 3 months, with most
patients recovering liver function at 12 months. All declines
in liver function, regardless of etiology from progressive
cirrhosis or sequelae of radiation toxicity, were scored as

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 TABLE 2. Select Prospective Clinical Trials of More Than 50 Patients Evaluating Role of Radiation in Hepatocellular Carcinoma
VI/ Median
No. of Patients Tumor Size TVT Survival Toxicity (collective ‡ grade
Study Design (No. of lesions) CP Class (%) Dose/Fx (cm) (%) ORR (%) LC (%) OS (%) (months) 3)a
Bujold et al, Phase I, II 102 A (100) 24–54 Gy/6 fx Median 55 54 87, 1 year 55, 1 year 17 36%
201322 (3  week) diameter
7.2
Median 36 Gy Range 29% progression of CP
in 6 fx (1.4–23.1) class at 3 months
6% progression of CP class
at 12 months
7 patients with grade 5
(including 2 with massive
TVT progression)
Lasley et al, Phase I, II 59 (65) A (64) CP-A: Max 20 CP-A: 89 CP-A: 91, 1 CP-A: 94, CP-A: 44.8 11% CP-A
201523 36–48 Gy/3 diameter 6 (includes year, 2 1 year
fx SD) years,
3 years
CP-A: Median,
48 Gy in 3 fx
B (36) CP-B: CP-A: 72, 38% CP-B
40–55 Gy/5 2 years
fx
CP-B: median CP-B: 95 CP-B: 17 14% RILD (CP-B only)
55 Gy in 5 fx (includes
CP-A: 61, CP-A: 42% progression to
SD)
3 years CP-B
CP-B: 82, 1 CP-A: 8% progression to
year, 2 CP-C
years,
CP-B: 14% transient
3 years
Treatment of Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis

progression to CP-C

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CP-B: 57, CP-B: 33% progression to
1 year CP-C

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CP-B: 33,
2 year
CP-B: 26,
3 year
(Continued on following page)

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177
 TABLE 2. Select Prospective Clinical Trials of More Than 50 Patients Evaluating Role of Radiation in Hepatocellular Carcinoma (Continued)

178
VI/ Median
No. of Patients Tumor Size TVT Survival Toxicity (collective ‡ grade
Study Design (No. of lesions) CP Class (%) Dose/Fx (cm) (%) ORR (%) LC (%) OS (%) (months) 3)a
Takeda Phase II 90 A (91) 35–40 Gy/5 fx Median NR NR 96, 3 years 67, 3 year 54.7 8%
et al, diameter
B (8) Median 40 Gy 9% progression of CP score
201624 4
in 5 fx by 2 points
Feng et al, Phase II 90 A (77) 23–60 Gy in Median 3 18 99, 1 year 67, 1 year NR NR
201825 3–5 fx
B (23) Range 95, 2 years 36,
(0–13) 2 years
Hong et al, Phase II, 83b A (73) 15.1–67.5 GyE/ Median 30 NR 94, 2 years 77, 1 year 50 6%
201626 proton 15 fx diameter
therapy 5.0
44 HCC (58) B (21); no Median 58 GyE Range 63, 4% progression of CP class
cirrhosis in 15 fx (1.9–12.0) 2 years (A to B)
(7)

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Kasuya Phase I and 124 (133) A (77) 15.1–67.5 GyE/ Median 17 NR 95, 1 year 90, 1 year 35.4 20%
et al, II, carbon 12–14 fx diameter
201727 ion 4.0
B (23) Median 52.8 Range 91, 3 years 50, 33% progression of CP
GyE in 4 fx (1.0–12.0) 3 years score at 3 months
90, 5 years 25, 25% progression of CP
5 years score at 6 months
Qadan et al

Abbreviations: CP, Child–Pugh; fx, fractions; GyE, Gy equivalent; LC, local control; NR, not reported; ORR, objective response rate (including complete and partial response); OS, overall survival;
RILD, radiation-induced liver disease; SD, stable disease; TVT, tumor vascular thrombus; VI, vascular invasion.
a
Toxicity was calculated as total grade 3 or higher toxicities as stated or all cumulative grade 3 or higher toxicities as reported, divided by patients in trial; therefore, it may represent multiple grade 3
toxicities within the same patient.
b
Hong et al26 included 39 patients with intrahepatic cholangiocarcinoma. Toxicities are calculated from all patients in the trial (83 patients); other reported values are from patients with HCC only.

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 Treatment of Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis
radiation-induced liver disease (RILD). Seven patients had
grade 5 toxicity, with liver failure in five patients (including
“massive” tumor thrombus progression in two patients,
which probably contributed to the decline in liver function).
A phase II study by Takeda et al24 of 90 patients treated in
Japan with tumors smaller than 4 cm was reported. Ninety-
one percent were in CTP class A, and patients received
a median dose of 40 Gy in five fractions. The median survival
was 54.7 months, with a 3-year OS of 67%. Eight percent
had grade 3+ toxicity (laboratory only), and 9% had pro-
gression of CTP scores by more than two points.
Given concern for liver complications and RILD with SBRT,
investigators at the University of Michigan evaluated a risk-
adapted model such that the radiation dose selected would
result in predicted risk of RILD of less than 15%. All patients
underwent indocyanine green testing before beginning
radiation and again after completing three treatments.
Based on the authors’ findings, a determination was made
regarding whether the final two fractions would be delivered
as planned, delivered with a reduced dose, or not delivered.
Ninety patients with 116 tumors were enrolled in this pro-
spective phase II study. Local control was 99% and 95% at
1 and 2 years, respectively, and OS was 67% and 36% at 1
and 2 years, respectively. The five patients whose disease
recurred all had tumor vascular thrombosis.25 Using bio-
markers such as indocyanine green to adapt liver radio-
therapy is a promising area for future research and may
mitigate some of the toxicities associated with radiotherapy.
Another technique for potentially reducing the risk of liver
toxicity is the use of particle-based radiotherapy. Both protons
and carbon ions have been prospectively evaluated in the
treatment of patients with HCC. A multi-institutional phase II
trial by Hong et al26 evaluated 83 patients with HCC or
intrahepatic cholangiocarcinoma (44 patients with HCC).
Thirty percent had tumor vascular thrombosis, and 20% were
in CTP class B. All patients were treated with a median dose of
58 Gy equivalents (GyE) in 15 fractions. Two-year local control
was 95%, with no nonhematologic toxicities seen in the HCC
cohort. Kasuya et al27 reported outcomes from a phase I and II
study demonstrating safety and efficacy of carbon ions in
a cohort of 127 patients with HCC. The phase I portion of the
study established 52.8 GyE in four fractions, which was used
in the phase II portion of the trial. Local control was 95%, 91%,
and 90% at 1, 3, and 5 years, respectively.
Radiotherapy Compared With Other Modalities
For patients with advanced HCC, no prospective trials have
compared radiotherapy with other liver-directed modalities,
and much of the available comparative data stems from
systematic reviews, database analyses, and retrospective
single-institution experiences. A meta-analysis and sys-
tematic review by Rim et al28 evaluated the efficacy and
toxicity of three-dimensional conformal radiation therapy,
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SBRT, and selective internal radiation therapy (SIRT).
Thirty-seven studies with a total of 2,513 patients were
included in the analysis. Although no differences in 1-
year OS were seen, the response rates to treatment were
best in the cohort that received SBRT, at 70%, compared
with SIRT at 30%. A single-institution retrospective study
evaluated outcomes of patients receiving transarterial
chemoembolization (TACE) or SBRT between 2006 and
2014. Propensity score analysis was performed to compare
outcomes and adjust for imbalances in a cohort of 209
patients with one or two tumors (TACE, 84 patients; SBRT,
125 patients). Patients were similarly matched in terms of
underlying liver disease and baseline liver function. However,
patients undergoing SBRT were slightly older and had smaller
tumors. The 1-year and 2-year local control favored SBRT
(97% vs. 47% at 1 year and 91% vs. 23% at 2 years). Grade
3+ toxicity was seen in 13% of patients after TACE and 8% of
patients after SBRT. Given the retrospective nature of these
studies, further prospective studies and comparative evalu-
ation of liver-directed therapies are warranted.
REGIONAL LIVER-DIRECTED THERAPIES
Recent data, reflected in the Hong Kong Liver Cancer
staging system, underscore the growing role of liver-directed
therapies for carefully selected patients with liver-dominant
disease, limited PVTT, and preserved liver synthetic func-
tion.29 Liver-directed therapies for PVTT include percuta-
neous thermal ablation and transarterial therapies. Data on
percutaneous thermal ablation for PVTT are limited,30 and
the procedure is technically challenging for central PVTT
because of the proximity to the bile ducts and hepatic
vasculature. Transarterial therapies include transarterial
embolization with microspheres, TACE, and transarterial
administration of 90Y-labeled microspheres, often called
transarterial radioembolization (TARE) or SIRT. Because
TACE and TARE are the most commonly offered liver-
directed therapies in clinical practice, the rationale and
data for both therapies are discussed below.
Transarterial Chemoembolization for PVTT
Two randomized controlled trials, several meta-analyses,
and smaller studies have demonstrated increased OS after
TACE for patients with intermediate-stage HCC without
PVTT (BCLC class B).3 TACE is the current liver-directed
therapy of choice to bridge patients to transplantation3 and
can be used for tumor downstaging.31 HCC tumors are fed
primarily by hepatic arteries, and the remaining liver pa-
renchyma derives blood supply from the portal circulation.
The unique dual supply allows transarterial delivery of high-
dose chemotherapeutic agents, usually cisplatin or doxo-
rubicin emulsified in ethiodized oil or eluted by drug-loaded
microspheres, to the tumor, thereby maximizing drug delivery
while minimizing collateral damage. Because of its embolic
nature, both BCLC and the National Comprehensive Cancer
2020 ASCO EDUCATIONAL BOOK | asco.org/edbook 179

Network recommend against TACE for patients with PVTT,32
lest the concurrent interruption of the hepatic arterial flow
and portal thrombosis incite severe hepatic ischemia.
However, a more nuanced approach that differentiates
between intrahepatic, branch vessel, and main PVTT and
stratifies patients based on their CTP score is needed. The
safety of superselective TACE for patients with PVTT has
been reported in several studies and is associated with
increased OS.33-36 In a large prospective, nonrandomized
study, Luo et al36 reported higher 1-year and 2-year survival
rates with TACE compared with best supportive care (30.9%
and 9.2% vs. 3.8% and 0%, respectively; p , .001), with
a median OS of 7.1 months in the TACE arm and 4.1 months
in the best supportive care arm (p , .001) and a 30-day
mortality of 1.2%. Of note, although all patients in the TACE
arm did better than those in the conservative arm, TACE
patients with only branch vessel PVTT did significantly
better than those with main PVTT, including greater tumor
response (77% vs. 51%, respectively) and increased OS
(median OS, 10.2 months vs. 5.3 months). Chung et al34
demonstrated the importance of preserved baseline liver
function to ensure improved outcomes, with patients in CTP
class B doing poorly irrespective of treatment delivered
(2.8 months vs. 1.9 months). Other studies, including
a meta-analysis, reported a median OS of 7.1 to 14.9
months, with increased survival for patients with branch
vessel PVTT.33,37 The reported incidence of grade 3 and
higher complications was uncommon, predominantly re-
stricted to postembolization syndrome (pain, fever, and
nausea).33,36
Transarterial Radioembolization for PVTT
TARE is a new technique for transarterial delivery of ther-
apeutic radiation doses to the tumor. A pure beta-emitting
isotope, 90Y decays to 90Zr, with a half-life of 64 hours.
Although it is colloquially described as radioembolization or
TARE, the radiolabeled microspheres are less than 60 mm in
diameter and thus do not alter vascular dynamics for pa-
tients with PVTT. In fact, preservation of hepatic arterial flow
is critical for radiation-induced free radical cell death. Be-
cause HCC tumors are hypervascular tumors, 90Y particles
preferentially flow to the tumor, delivering 100 to 3,000 Gy in
the process. However, because the median depth of pen-
etration for the 90Y particles is only 2.5 mm, the surrounding
liver parenchyma is spared despite the lethal dose delivered
to the tumor. Furthermore, the lack of a true embolic effect
provides a clear advantage over TACE, and TARE is well
tolerated with limited grade 1 or 2 toxicities, including
predominantly fatigue and elevated liver enzymes.38,39 Se-
rious complications, such as radiation pneumonitis, gastric
ulceration, and radiation-induced liver toxicity, are rare in
experienced hands (, 2%) and with careful preprocedure
planning.39
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Qadan et al
Although there are no large randomized controlled trials
that compare TACE with TARE for patients with PVTT,
nonrandomized, prospective, and retrospective data have
reported a slightly superior OS and progression-free survival
with TARE, with notably fewer side effects.40,41 In the largest
prospective, nonrandomized study, Salem et al42 reported
a median OS of 10.4 months (95% CI, 7.2–16.6) for patients
in CTP class A. As expected, patients in CTP class A with
branch vessel PVTT did remarkably better than those with
main PVTT (16.6 month vs. 7.7 months, respectively).42
Unfortunately, patients in CTP class B fared poorly, irre-
spective of the extent of PVTT (6.5 months vs. 4.5 months,
respectively), underscoring the prognostic role of intact
baseline liver function.42 Other studies performed in Europe
and North America have reported comparable median OS of
10 to 13 months for patients with PVTT.43,44 Interventional
radiologists continue to refine the technique and dosimetry,
and recent studies report a median OS of 45 months after
selective delivery of radiation doses greater than 200 Gy
(ablative TARE).45 Reported objective tumor responses
ranging from 20% to 77%, with successful downstaging to
allow resection with curative intent, have been reported in
well-selected patients.42-44,46 Although larger studies are
needed, it appears that, for patients in CTP class A with
branch vessel PVTT, TARE probably confers a superior OS of
16.6 months compared with 10.2 months for TACE, with
fewer side effects and adverse events, thereby making it the
preferred liver-directed therapy option for patients with HCC
and associated PVTT and preserved synthetic function.
Rationale for Using Liver-Directed Therapies for Patients
With HCC and PVTT
As therapeutic options evolve and new data emerge, the
limitations of the BCLC system for patients with PVTT have
become evident. A more nuanced approach that takes into
account the extent of the PVTT, underlying liver function as
measured by the CTP score, and the presence or absence of
extrahepatic metastases as critical factors is used to provide
a more tailored approach for patients within this large
spectrum of BCLC class C disease. Emerging data on im-
proved outcomes in the treatment of this heterogenous
group of patients will probably be included in future staging
systems as granularity improves.3
The synergistic and individual roles of TARE and sorafenib
have been a topic of active research. Two recently com-
pleted randomized control trials, SARAH and SIRveNIB,
compared TARE with sorafenib.47,48 SIRveNIB accrued
patients from the Asia-Pacific region, whereas SARAH
accrued patients across France. Both trials were designed
to be superiority trials. However, the reported median OS
results for TARE and sorafenib were statistically similar, and
neither trial met its primary endpoint. Tumor response rates
were significantly higher with TARE, but this too did not
 Treatment of Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis
translate to increased progression-free survival. Of note, the
inclusion criteria in these trials were overly broad and in-
cluded patients with BCLC class B and C and patients with
extrahepatic metastases, which may have negated the
beneficial impact of TARE for patients with PVTT specifi-
cally. In addition, only a minority of patients had PVTT, and
subset analysis was not performed. Therefore, the potential
clinical benefit in patients with PVTT, especially those with
segmental PVTT only, was not evaluated. Most importantly,
both trials reported fewer grade 3 or higher adverse events
with TARE than with sorafenib (20.8% vs. 35.2% in SIR-
veNIB and 27.7% vs. 50.6% in SARAH) in addition to the
distinct possibility of tumor downstaging to allow potentially
curative resection. Given that most patients in BCLC class C
survive less than a year from diagnosis, the importance of
quality of life in avoidance of side effects and complications
cannot be overstated.
SURGICAL APPROACHES
Surgical approaches for the treatment of HCC with PVTT
have been described since the early 1980s and 1990s,
albeit with dramatically worse survival outcomes compared
with HCC without PVTT.49,50 Numerous retrospective series
have evaluated multiple aspects related to surgical resection
of HCC with PVTT.
The tumor biologic determinants for resection of HCC and
PVTT in highly selected patients arguably are the most
important determinants of oncologic outcomes. However,
the technical criteria for surgical treatment of HCC with
PVTT depend largely on the degree of tumor extension
within the vasculature. Surgical resection of HCC with PVTT
is considered technically challenging51 and is increasingly
performed in Asian centers in particular. The objectives of
surgery have broadly included complete tumor extirpation
and prevention of downstream sequelae of portal hyper-
tension secondary to obstructive tumor thrombus. Broadly,
the options depend on the extent of PVTT (ipsilateral vs.
extension to, or beyond, the main portal vein bifurcation).
Varying extents of tumor thrombus, the need for in-
dividualized surgical approaches, and variable manage-
ment modalities have thus limited prospective evaluation of
outcomes. Surgical options include the following:
• Hepatectomy with en bloc resection of ipsilateral tumor
thrombus
• Resection of tumor and PVTT extending to or beyond the
main portal vein bifurcation, treated with en bloc vascular
resection, repair, and reconstruction
• Tumor thrombectomy in PVTT extending to or beyond the
main portal vein bifurcation.
In a report by Chok et al,52 the authors compared these three
modalities and noted median OS times of 10.1 months, 9.4
months, and 8.6 months, respectively. In addition, median
disease-free survivals were 4.2 months, 3.8 months, and
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
1.5 months, respectively. Interestingly, complication rates
mirrored technical complexity and were 31.9%, 50.0%, and
71.4%, respectively, representing the technical challenges
associated with PVTT resection in healthy and highly se-
lected patients. Although there were no statistically signif-
icant differences in any of the authors’ reported figures,
these data reflected the low survival figures seen in patients
with PVTT despite complete surgical extirpation of disease,
highlighting the aggressive nature of PVTT and need for
complementary therapies.
Currently, there are no prospective data comparing surgical
resection against other treatment modalities. However, the
criteria for safe resection and improved survival compared
with no treatment (best supportive care) continue to ex-
pand.53 Overall, the median survival time among the studies
was 25.4 months for highly selected patients.54 In a Japa-
nese nationwide analysis between 2000 and 2007, 6,474
patients with HCC and PVTT were included, of whom 2,093
underwent surgical resection.55 In a propensity-matched
analysis performed by the authors comparing surgical re-
section with nonsurgical therapy, surgical resection was
associated with a median survival of 2.9 years, compared
with 1.1 years among patients in the nonsurgical group.
Importantly, however, the authors were unable to demon-
strate an association with improved survival in patients with
PVTT extending into or beyond the main venous bifurcation,
representing the aggressive nature of extensive PVTT at
diagnosis.
These data potentially support surgical resection for highly
selected patients, although application to Western cohorts
remains largely unknown. The retrospective nature of all
these studies does not preclude confounders that represent
exceptional tumor biology, which reflects the broad mes-
sage in this context. In addition, complication rates in the
50% range merit pause before embarking on management
of this technically challenging entity.
Combination Strategies With Surgical Resection
Combinations of complementary modalities and surgical
resection have been reported and are potentially associated
with increased benefit.56
For example, TACE after resection has been associated with
an increase in median OS and decline in overall disease
recurrence, especially for patients with large tumors asso-
ciated with vascular invasion in a study by Peng et al57
(13 months vs. 9 months).
Sorafenib as an adjuvant systemic therapy initially showed
promising results in orthotopic animal models. However,
whether these results will eventually materialize to show
benefit after resection of HCC with PVTT remains to be
determined.58 In a report by Tang et al,59 the authors ret-
rospectively compared best supportive care, chemotherapy,
2020 ASCO EDUCATIONAL BOOK | asco.org/edbook 181

surgery, and surgery with chemotherapy among 589 pa-
tients in a modern case series. The authors noted an as-
sociation with improved survival with any treatment
compared with no treatment and a greater effect with the
combination of surgery and chemotherapy. Zhou et al60
compared hepatectomy with thrombectomy versus hepa-
tectomy with thrombectomy plus chemotherapy in a retro-
spective analysis that included other treatment modalities
and showed that the addition of chemotherapy was asso-
ciated with substantially increased 1-year survival rates
(70% vs. 47%). However, there were minimal differences at
the 3-year mark for patients who received chemotherapy
compared with patients who did not (20% vs. 22%,
respectively).
In a rare prospective, randomized controlled trial in this
setting, Wei et al61 evaluated neoadjuvant radiation for re-
sectable HCC with PVTT in a multicenter controlled study
conducted in 2016 and 2017. Patients were randomly
assigned to receive neoadjuvant radiation followed by
hepatectomy versus hepatectomy alone for 164 patients
distributed equally between both study arms. The authors
reported OS rates at 6, 12, 18, and 24 months of 89.0%,
75.2%, 43.9%, and 27.4%, respectively, among patients
who received radiation compared with 81.7%, 43.1%,
16.7%, and 9.4%, respectively, in the surgery-alone group.
Corresponding disease-free survival rates were 56.9%,
33.0%, 20.3%, and 13.3% in the radiation group and
42.1%, 14.9%, 5.0%, and 3.3% in the surgery-alone group.
All findings were statistically significant and established
a novel role for radiation in a neoadjuvant setting for pa-
tients with PVTT followed by complete surgical resection.
To date, this remains the only prospectively validated
treatment algorithm and provides a potentially effective
treatment strategy for this patient population. Interestingly,
the authors were also able to establish that elevated
preradiation serum interleukin-6 levels were associated
with refractory responses to therapy, thus helping select
patients who may not benefit from aggressive treatment.
Liver Transplantation
Currently, liver transplantation for patients with PVTT re-
mains contraindicated, given the limited availability of or-
gans combined with the high recurrence rates noted earlier.
AFFILIATIONS
1
Department of Surgery, Massachusetts General Hospital and Harvard
Medical School, Boston, MA
2
Department of Radiology, Stanford University Medical Center, Palo Alto,
CA
3
Department of Medicine, Clinica Universidad de Navarra, Pamplona,
Spain
4
Department of Radiation Oncology, Duke University, Durham, NC
182 2020 ASCO EDUCATIONAL BOOK | asco.org/edbook
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
Qadan et al
Therefore, data are limited to living-donor liver transplantation
in conjunction with aggressive downstaging protocols.
In a report by Han et al,62 the authors evaluated use of
concurrent chemoradiation in conjunction with hepatic
arterial infusion chemotherapy before living-donor liver
transplantation. Eight patients underwent successful
transplantation after complete responses within their vas-
culature. One-year disease-free survival was an astounding
87.5%, and the median survival was 33 months. The
feasibility of liver transplantation for patients with down-
staged disease warrants evaluation in the modern era as
response rates to systemic therapies continue to improve.
However, this therapy is probably effective, once again, in
cases of exceptionally indolent tumor biology that is highly
responsive to neoadjuvant therapy.
Similarly impressive results were established with SIRT
before liver transplantation among four patients reported by
Levi Sandri et al.63 Tumor regression was noted among all
four patients, with disease-free survival of 39.1 months.
When external beam radiation was examined in a cohort
being evaluated for liver transplantation by Chino et al,21 the
authors noted a complete pathologic response of 27%
among 10 patients, with 100% survival after 5 years and
without recurrences observed.
CONCLUSION
Although diagnosis of HCC with PVTT or hepatic vein in-
vasion portends a poor prognosis, recent advances in the
treatment of patients with MVI has rendered this disease
entity a treatable one with improved oncologic outcomes.
Importantly, inclusion of highly selected patients with em-
phasis on tumor biology is necessary to achieve outstanding
long-term results. In addition, treatment of HCC with PVTT is
multimodal, with expansive combinations and sequences
that are becoming increasingly available to optimize out-
comes. However, it is important to note that there are con-
siderable variations in approach to the treatment of HCC with
PVTT between the Eastern and Western hemispheres, which
may also be related to variability in the underlying disease
process and management preferences. Finally, careful
emphasis should be placed on maintaining patient quality of
life, which cannot be underestimated in the aggressive
treatment of HCC and liver-associated complications.
CORRESPONDING AUTHOR
Motaz Qadan, MD, PhD, Division of Surgical Oncology, Department of
Surgery, Massachusetts General Hospital, 55 Fruit St., Yawkey 7B,
Boston, MA 02114; Twitter: @motazqadan; email: mqadan@mgh.
harvard.edu.
 Treatment of Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

AND DATA AVAILABILITY STATEMENT
Disclosures provided by the authors and data availability statement (if
applicable) are available with this article at DOI https://doi.org/10.1200/
EDBK_280811.

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