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Reviews

Management of Advanced Hepatocellular Carcinoma: A
Review and Practical Guide
Vishnu Nagalapuram, MBBS1 ; Niveditha Popuri, MBBS2
Kelsey S
...
Nipp, MD, MPH1

; Susanna V
...
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There is an
ongoing epidemiologic shift in risk factors for HCC from hepatotropic virus–related liver
disease to alcohol and metabolic dysfunction–associated steatotic liver disease
...
Despite advances in targeted therapies, the role
of molecular testing in HCC remains unclear
...
With the approval of immune checkpoint inhibitors and
tyrosine kinase inhibitors targeting tumor angiogenesis, the treatment landscape of advanced
HCC has evolved considerably in the past decade, leading to improvements in patient outcomes
...
There are several
ongoing trials evaluating systemic therapies with novel mechanisms of action including
adoptive cell therapy
...


INTRODUCTION
Hepatocellular carcinoma (HCC) constitutes approximately
80% of primary liver malignancies, posing a global health
challenge requiring complex, individualized treatment decisions
...
1-3 Treatment modalities for HCC
include multiple curative options, such as liver transplantation
(LT), surgical resection, and ablation for earlier-stage disease,
and palliative modalities such as transarterial embolization
approaches, external-beam radiation therapy, and systemic
therapy for more advanced stages
...
4 In recent years, ASCO and the American Association for the Study of Liver Diseases (AASLD) have issued
detailed guidelines on the management of HCC
...


SCREENING AND DIAGNOSIS
Primary liver cancer, which includes HCC (75%-85%),
cholangiocarcinoma (10%-15%), and other rare tumor
types, ranks sixth in global cancer incidence and is the third

JCO Oncol Pract 00:1-10
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Clinical Oncology

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Article

leading cause of cancer-related mortality worldwide
...
Frequently associated risk factors
include chronic infection with hepatitis B (HBV) and hepatitis C, environmental factors such as aflatoxin B1, and
lifestyle factors such as alcohol and other substance use
...
1
Because about 90% of HCC occurs in patients with cirrhosis,
screening programs have been developed with the goal of
diagnosing HCC at an early stage and hence reducing
disease-specific mortality
...
5 However, early diagnosis of HCC is challenging because of low HCC screening rates and diagnostic delays in
patients with abnormal screening tests
...
5
Noninvasive imaging has traditionally played an important
role in the diagnosis of HCC, in contrast to other solid tumors

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Characteristic enhancement patterns on dynamic multiphasic computed tomography (CT) or magnetic resonance
imaging can detect HCC with a high degree of sensitivity and
specificity when stringent criteria are applied
...
11 In addition, the Liver Imaging Reporting and Data
System (LI-RADS) is a comprehensive system now endorsed
by the AASLD, which provides standardization across all
aspects of HCC imaging and provides imaging algorithms for
different clinical contexts
...
12
The inclination toward noninvasive diagnosis has largely
been due to the risk of tumor bleeding, inability to access
certain lesions safely, and theoretical possibility of neoplastic seeding of the biopsy tract
...
However, for
uncertain lesions and in patients without underlying liver
disease who have a low-pretest probability of HCC, all
guidelines are concordant in their recommendations for a
histologic diagnosis
...
13,14 Hence, clinicians should consider
obtaining a confirmatory tissue diagnosis in the appropriate
clinical setting
...
15 Best practice
guidelines do not currently recommend the routine use of
tissue or blood-based molecular testing in HCC outside of
clinical trials
...
16

STAGING
Before starting systemic therapy, cross-sectional imaging
of the chest, abdomen, and pelvis should be obtained to
assess disease burden and to serve as a baseline to monitor
future response to therapy
...
Among these, the Barcelona
Clinic Liver Cancer (BCLC) staging classification represents
the most widely adopted for treatment planning and
prognostic assessment
...
It emphasizes the importance of personalizing HCC treatment decisions on the basis of an expert
multidisciplinary evaluation that considers factors such as
patient comorbidities, baseline and projected posttreatment liver function, and the availability of local expertise
...
Also, in this update, patients with BCLC-B HCC
are stratified into three groups: (1) patients with welldefined HCC nodules who may be candidates for LT on
the basis of extended institutional criteria; (2) LT-ineligible
patients who may still qualify for locoregional therapies
(LRTs) on the basis of preserved portal flow and defined
tumor burden; and (3) patients with diffuse, infiltrative,
extensive HCC who are best served with systemic therapy
...

This BCLC system also defines two concepts that are relevant to the management of patients with non–LRTeligible HCC: (1) treatment stage migration and (2)
untreatable progression
...

For example, a patient with BCLC stage B disease for whom
LRT is not an ideal option may be best treated with systemic
therapy
...
For example, a patient with BCLC stage B disease for
whom upfront LRT does not achieve an adequate response
may necessitate the use of systemic therapy
...


SYSTEMIC THERAPY FOR HCC: GENERAL
TREATMENT APPROACH
Patients with non–LRT-eligible HCC with adequate performance status and liver function are ideal candidates for
systemic therapy, as prognosis in the absence of cancerdirected therapy ranges between three and ten months
...
Occasionally, patients may have CPS-B/C
disease due to acute decompensation of their cirrhosis; these
patients may become eligible for systemic therapies pending
improvement in their hepatic function over time
...
Since then, the advent of newer multikinase inhibitors,
immune checkpoint inhibitors (ICIs), and antiangiogenic
agents have led to several FDA-approved single-agent and

Management of Advanced Hepatocellular Carcinoma
TABLE 1
...
5 g/dL

2
...
5 g/dL

<2
...
7

1
...
3

>2
...
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combination regimens (Table 2)
...


FIRST-LINE SYSTEMIC THERAPY
Sorafenib, an oral multikinase inhibitor, was approved by the
FDA in 2007 as the first systemic therapy for patients with
previously untreated non–LRT-eligible HCC
...
7 months versus 7
...
21 Lenvatinib, another oral
multikinase inhibitor, was shown to be noninferior to sorafenib in the REFLECT study, leading to FDA approval in
2018
...

In the IMBrave150 trial, the ICI atezolizumab in combination with the VEGF inhibitor bevacizumab was compared
with sorafenib with a median OS of 19
...
5
months
...
Because bevacizumab is associated with a high risk of hemorrhagic events in patients
with cancer (all-grade: 30%, grade ≥3: 4%),24 patients in
the IMBrave150 trial were mandated to have undergone
esophagogastroduodenoscopy within 6 months before
initiation of study treatment; those with untreated or incompletely treated esophageal or gastric varices were
excluded from the study
...
8%,
grade 3-4: 2
...
23 Atezolizumab/bevacizumab
has been associated with a higher incidence of irLI compared with patients with other solid tumors receiving ICI
(all grades: 2
...
25 Subsequent observational studies have confirmed the clinical
benefit of atezolizumab/bevacizumab, albeit less pronounced compared with the outcomes reported in
IMBrave150
...
30
The HIMALAYA trial evaluated the superiority of the Single
Tremelimumab Regular Interval Durvalumab (STRIDE)
regimen compared with sorafenib as well as the noninferiority of durvalumab compared with sorafenib
...
4 months, 16
...
8 months
in the STRIDE, durvalumab, and sorafenib arms, respectively
...
Patients randomly
assigned to the STRIDE regimen reported better global
health status/quality of life, functioning, and diseasespecific symptoms compared with those in the sorafenib
group
...

Single-agent durvalumab was also shown to be noninferior to sorafenib and can be considered for those who
are at high risk of toxicity from the STRIDE regimen
...
org/journal/op | Volume nnn, Issue nnn | 3

Study

SHARP

REFLECT

IMbrave150

HIMALAYA

RESOURCE

CELESTIAL

REACH-2

FDA approval

November 2007

August 2018

May 2020

October 2022

April 2017

January 2019

May 2019

Line of therapy

First

First

First

First

Second

Second/third

Second

Key inclusion and
exclusion criteria

Included: advanced
HCC, CPS-A

Included: advanced Included: advanced HCC pro- Included: advanced HCC
Included: advanced HCC,
Included: advanced HCC, Included: advanced HCC,
progressed on or intolgressed on sorafenib, up to
HCC progressed
CPS-A
CPS-A
CPS-A
erant to sorafenib, CPStwo previous systemic
on sorafenib only,
Excluded: clinically
Excluded: 50% or higher Excluded: autoimmune
A, AFP ≥400 ng/dL
therapies for HCC, CPS-A
CPS-A
meaningful ascites, main
disease, coinfection with
liver involvement by
portal vein thrombosis, or
HBV or HCV, untreated or
tumor, obvious
coinfection with HBV or
incompletely treated
invasion of bile duct,
HCV, history of
esophageal or gastric
main portal vein
autoimmune disease
varices
invasion

Experimental and
control arms
(number of
patients)

Sorafenib (299) v
placebo (302)

Lenvatinib (478) v sorafenib (476)

Study design

Randomized,
double-blind,
placebocontrolled, phase
III

Randomized (2:1),
Randomized, open-label, Randomized (2:1), openRandomized, open-label,
double-blind,
noninferiority, phase III
label, superiority, phase III
sponsor-blind, superiority
placebo(STRIDE v sorafenib),
controlled, phase
phase III
III

Randomized (2:1), doubleblind, placebo-controlled,
phase III

Randomized (2:1),
double-blind, placebocontrolled, phase III

HBV: 251 (53) v 228 (48) HBV: 164 (49) v 76 (46)
HCV: 91 (19) v 126 (26) HCV: 72 (21) v 36 (22)
Alc: 36 (8) v 21 (4)
Other: 100 (30) v 53 (32)
Other: 100 (21) v 105 (21)

HBV: 122 (31), 119 (30
...
6)
HCV: 110 (28), 107 (27
...
7)
Other: 161 (41), 163 (41
...
7)

HBV: 143 (38) v
73 (38)
HCV: 78 (21) v
41 (21)
Alc: 90 (24) v 55 (28)
Other: 119 (31) v 55
(28)

HBV: 178 (38) v 89 (38)
HCV: 113 (24) v 55 (23)
Alc: 112 (24) v 39 (16)
Other: 150 (32) v 90 (39)

HBV: 71 (36) v 36 (38)
HCV: 48 (24) v 28 (29)
Alc: 48 (24) v 21 (22)
Other: 48 (25) v 90 (39)

13
...
3

19
...
4

STRIDE: 16
...
6 v
sorafenib: 13
...
6 v 7
...
2 v 8

8
...
3

7
...
6

6
...
3

STRIDE: 3
...
7 v
sorafenib: 4
...
1 v 1
...
2 v 1
...
8 v 1
...
8%,
action: 13% v 1%
9
...
1%
Diarrhea: 4
...
5% v 4
...
(%)
Alc: 79 (26) v 80 (26)
Other: 77 (25) v 85
(29)
Median overall survival (months)

10
...
9

5
...
8
Median
progression-free
survival (months)
Objective response
rate (%)

Atezolizumab/bevacizumab (336) v sorafenib
(165)

Disease control
rate (%)

43 v 32

73 v 59

Most common
grade ≥3 TRAEs

Diarrhea: 8% v 2%
Hand-foot skin
reaction: 8% v
<1%

Hypertension: 23% v 14% Hypertension: 12% v 9%
AST increase: 5% v 3%
Bilirubin increase: 7% v
Proteinuria: 4% v <1%
5%
Decreased weight: 8% v
3%

STRIDE (393), durvalumab
(389) v sorafenib (389)

(continued on following page)

Regorafenib (379) v Cabozantinib (470) v placebo
placebo (194)
(237)

11 v 4

Ramucirumab (197) v
placebo (95)

Nagalapuram et al

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3 v 1
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Management of Advanced Hepatocellular Carcinoma

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Pivotal Phase III Trials Evaluating Systemic Therapies in HCC That Led to FDA Approval (continued)

Nagalapuram et al

Very earlyintermediate stage
HCC (BCLC 0, A, B)

Multidisciplinary discussion
evaluation for
Liver transplantation
Resection
Ablation
TACE, TARE
SBRT

No (autoimmune
disorder, post solid
organ transplant)

Advanced-stage HCC (BCLC
C) or Intermediate-stage HCC
(multifocal or infiltrative
BCLC B)a

HCC (any stage)
CPS C, ECOG 3-4

Candidate for
immunotherapy?

Best supportive care

Yes

Risk of variceal
bleedingb

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Lenvatinib or sorafenib

Progression

Cabozantinib
Regorafenib
Ramucirumab (if AFP
t400 ng/mL)

High

Low

Tremilumumab + durvalumab
(STRIDE)
Durvalumab
Nivolumab + ipilimumabc

Atezolizumab + bevacizumab
Tremilumumab + durvalumab
(STRIDE)
Durvalumab
Nivolumab + ipilimumabc

Progressiond
Lenvatinib or sorafenib
Cabozantinib
Regorafenib
Ramucirumab (if AFP t400 ng/mL)

FIG 1
...
aPatients should be enrolled on clinical trials whenever feasible
...
cNot
currently approved for first-line use by the Food and Drug Administration
...
AFP, alphafetoprotein; BCLC, Barcelona Clinic Liver Cancer; CPS, Child-Pugh score; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular
carcinoma; SBRT, stereotactic body irradiation; STRIDE, Single Tremelimumab Regular Interval Durvalumab; TACE, transarterial chemoembolization; TARE, transarterial radioembolization
...
33
The more recent CheckMate 9DW trial evaluated ipilimumab/
nivolumab against lenvatinib or sorafenib as first-line systemic therapy for patients with unresectable HCC
...
2 months, the median OS was
23
...
6 months, and objective response rate
was 36% and 13% with the doublet ICI combination and
lenvatinib/sorafenib groups, respectively
...

Patients with CPS-B/C cirrhosis and/or Eastern Cooperative
Oncology Group score 2 have traditionally been excluded from
prospective clinical trials of systemic therapies for non–LRTeligible HCC
...
These benefits are modest, and treatment
decisions should be made on a case-by-case basis, taking into
account whether a patient’s liver dysfunction is related to their
tumor burden versus underlying cirrhosis
...
43 LEAP 002 evaluated the
superiority of pembrolizumab and lenvatinib against sorafenib in the first-line setting and did not meet its dual
primary end points of progression-free survival (PFS) and
OS
...
40 The COSMIC-312 trial evaluating first-line
cabozantinib and atezolizumab versus sorafenib failed to
show an OS benefit
...
1 months and 15
...
41
FDA approval for this combination is under review currently
...
42 However, tislelizumab is unlikely to add to the
established first-line combinations of atezolizumab/
bevacizumab and the STRIDE regimen, which have demonstrated superiority versus sorafenib
...
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29,45 Regorafenib, cabozantinib, and ramucirumab (if
AFP ≥400 ng/mL) have been FDA-approved for the secondline treatment of patients with non–LRT-eligible HCC who
have progressed on or are intolerant to sorafenib on the basis
of the RESOURCE,46 CELESTIAL,47 AND REACH-248 trials,
respectively (Table 2)
...
Enrolling these patients in clinical trials should be
prioritized whenever feasible
...
5,6,49
For patients who progress on sorafenib or lenvatinib as firstline treatment, atezolizumab/bevacizumab or the STRIDE
regimen should be offered if patients are candidates for these
therapies
...
Until further prospective data on
treatment sequencing are available, these decisions should be
individualized
...
If interested and able, these patients should be
encouraged to participate in early-phase clinical trials
...
The staging, diagnosis, and treatment of
HCC are complicated by nonspecific symptoms at presentation as well as underlying liver dysfunction in most patients
...
50 Because of the complex
pathophysiology of the disease and constantly evolving
treatment strategies, a multidisciplinary care (MDC) approach
is essential for promoting individualized treatment decisions
...
52 Similarly, support from ancillary
JCO Oncology Practice

services such as nutrition,53 physical and occupational
therapy,54 social work, psychology, psychiatry,55-58 and substance use counseling is crucial
...
59 A metaanalysis of 12 studies including 15,365 patients with HCC
found that MDC was associated with improved OS
...
61

FUTURE DIRECTIONS
With the advent of improved systemic therapies in HCC,
efforts are now being made to identify the role for combining systemic therapy with established LRT approaches
with the hope that LRT may induce hypoxia, tumor angiogenesis, and neoantigen presentation, thereby enhancing the efficacy of antiangiogenic agents and ICIs,
respectively (Table 3)
...
62
Additional immunomodulatory approaches are also under
investigation, including the inhibition of novel checkpoints
such as TIGIT (anti–T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory
motif domains)
...
64 Finally, earlierphase trials are investigating cellular therapy approaches
targeting glypican-3 (GPC-3), given the overexpression and
specificity of GPC-3 in HCC
...
67
In conclusion, several FDA approvals have changed the
treatment landscape of non–LRT-eligible HCC over the past
5 years
...

ICI combinations and antiangiogenic agents have established their role in the treatment of patients with non–LRTeligible HCC
...

ascopubs
...
gov identifier)

Status (as of October
1, 2024)

NCT01730937 (NRG/RTOG
1112)a

Active, not recruiting

BCLC stage B/C HCC, unsuitable for surgery, ablation, or TACE, CPS ≤7, ≤5 Phase III RCT, global
HCCs (total sum ≤20 cm), and distant metastasis ≤3 cm

SBRT 1 sorafenib
Sorafenib

OS

NCT03778957 (EMERALD-1)

Active, not recruiting

Embolization-eligible, unresectable HCC, CPS ≤7

Phase III RCT, doubleblinded, global

TACE 1 durvalumab 1 placebo
TACE 1 durvalumab 1
bevacizumab
TACE 1 placebo 1 placebo

PFS

NCT04246177 (LEAP-012)a

Active, not recruiting

HCC localized to the liver, without MVI and not amenable to curative
treatment, CPS ≤6

Phase III RCT, doubleblinded, global

TACE 1 pembrolizumab 1
lenvatinib
TACE 1 placebo 1 placebo

PFS, OS

NCT03905967 (LAUNCH)a

Unknown status

Advanced/unresectable HCC, systemic therapy–na¨ıve, CPS ≤6

Phase III RCT, openlabel, China only

TACE 1 lenvatinib
Lenvatinib

OS

NCT05301842 (EMERALD-3)

Recruiting

Embolization-eligible, unresectable HCC, single HCC lesion ≤10 cm or
multiple (≤10 foci) with tumor burden ≤50%, CPS ≤6

Phase III RCT, openlabel, global

TACE 1 durvalumab 1 tremelimumab 1 lenvatinib
TACE 1 durvalumab 1
tremelimumab
TACE

PFS

NCT04340193 (Checkmate
74W)

Terminated

Embolization-eligible, unresectable HCC, CPS ≤6

Phase III RCT, doubleblinded, global

TACE 1 nivolumab 1 ipilimumab
TACE 1 nivolumab
TACE 1 placebo

PFS, OS

IMBrave 152

Recruiting

Unresectable/advanced HCC, CPS ≤6, treatment-na¨ıve

Phase III RCT, doubleblinded, global

Atezolizumab 1 bevacizumab 1
tiragolumab
Atezolizumab 1 bevacizumab 1
placebo

PFS, OS

NCT04523493

Active, not recruiting

Unresectable/advanced HCC, CPS ≤6, treatment-na¨ıve

Phase III RCT, doubleblinded, global

Toripalimab 1 lenvatinib
Placebo 1 lenvatinib

OS

NCT05003895a

Recruiting

Unresectable/advanced HCC, CPS ≤6, progressed/intolerant to previous first Phase I
line of systemic therapy, GPC3 expression >25%

GPC3 targeted CAR-T cell therapy Safety and
feasibility

NCT05201404

Recruiting

Unresectable/advanced HCC, CPS ≤7, progressed on at least one previous Phase III RCT, doubleline of systemic therapy
blinded, global

Namodenoson
Placebo

NCT05337137

Recruiting

Unresectable/advanced HCC, CPS ≤6, treatment-na¨ıve

Study Population

Study Design

Interventions

Phase I/II RCT, double- Nivolumab 1 relatlimab 1
blinded, global
bevacizumab
Nivolumab 1 bevacizumab 1
placebo

Primary End
Point

OS
DLT, ORR

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; CAR-T cell therapy, chimeric antigen receptor T-cell therapy; CPS, Child-Pugh score; DLT, drug limiting toxicity; GPC3, glypican-3;
HCC, hepatocellular carcinoma; MVI, macrovascular invasion; NCT, national clinical trial; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RCT, randomized controlled
trial; SBRT, stereotactic body irradiation; TACE, transarterial chemoembolization
...


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TABLE 3
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V
...
and K
...
L
...
are co-senior authors
...
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AUTHOR CONTRIBUTIONS
Conception and design: Vishnu Nagalapuram, Ryan D
...

Ulahannan, Kelsey S
...
Ulahannan
Data analysis and interpretation: Vishnu Nagalapuram, Susanna V
...

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