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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
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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
© 2025 by American Society of
Clinical Oncology

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Article

leading cause of cancer-related mortality worldwide
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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
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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
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15 Best practice
guidelines do not currently recommend the routine use of
tissue or blood-based molecular testing in HCC outside of
clinical trials
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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
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For example, a patient with BCLC stage B disease for whom
LRT is not an ideal option may be best treated with systemic
therapy
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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
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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
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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
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5 g/dL

2
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5 g/dL

<2
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7

1
...
3

>2
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combination regimens (Table 2)
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6) v
119 (30
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5) v
104 (26
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9) v
166 (42
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6 v 12
...
2 v 13
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4
Durvalumab: 16
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8

10
...
8

10
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5 v 7
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3 v 3
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9 v 4
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8
Durvalumab: 3
...
1

3
...
5

5
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9

2
...
6

2v1

41 v 12

30 v 11

7v3
STRIDE: 20
Durvalumab: 17 v sorafenib:
5

4v<1

5v1

Complete response 0 v 0
rate (%)

<1 v <1

8 v <1

STRIDE: 3
Durvalumab: 2 v sorafenib:
0

0v0

0v0

74 v 55

1v0
STRIDE: 60
Durvalumab: 55 v sorafenib:
61

64 v 33

60 v 39

Hand-foot skin reAST/ALT increase: 7
...
8% v 5
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4%, 1
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3% Hypertension: 13% v
3%
Fatigue: 6% v 2%

Palmar-plantar erythrodysesthesia: 17% v 0%
Hypertension: 16% v 2%
Fatigue: 10% v 4%
Diarrhea: 10% v 2%

Hypertension: 8% v 2%

HBV: 56 (19) v 55
Etiologic factors
(18)
between experimental and con- HCV: 87 (29) v 82
(27)
trol group, No
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7 v 7
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5 v 2
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Pivotal Phase III Trials Evaluating Systemic Therapies in HCC That Led to FDA Approval

Study
Patient-reported
outcome data
(measure)

SHARP

REFLECT

Fatigue, pain, diarrhea,
Median time to
diet, and body image
symptomatic probetter (EORTC QLQgression: 4
...
9
C30 and HCC18)
months (FHSI8)

IMbrave150
Appetite, diarrhea, fatigue,
and pain better (EORTC
QLQ-C30 and HCC18)

HIMALAYA
Appetite, diarrhea, fatigue,
and pain better (EORTC
QLQ-C30 and HCC18)

RESOURCE
No difference in
HRQoL (FACTHep, EQ-5D, EQVAS)

CELESTIAL

REACH-2

HRQoL and QALY better (EQ5D-5L)

Median time to symptomatic progression:
3
...
9 months
(FHSI8); no difference
in HRQoL (EQ-5D-5L)

Abbreviations: AFP, alpha-fetoprotein; Alc, alcohol; CPS, Child-Pugh score; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EQ-5D,
EuroQoL 5 Dimension; EQ-5D-5L, EuroQoL 5 Dimension 5 Level; EQ-VAS, EuroQoL Visual Analog Scale; FACT-Hep, Functional Assessment of Cancer Therapy-Hepatobiliary; FDA, Food and Drug
Administration; FHSI8, Functional Assessment of Cancer Therapy-Hepatobiliary Symptom Index 8; HBV, hepatitis B; HCC, hepatocellular carcinoma; HCC18, European Organisation for Research and
Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18-question module; HCV, hepatitis C; HRQoL, health-related quality of life; QALY, quality-adjusted life-year; STRIDE,
Single Tremelimumab Regular Interval Durvalumab; TRAE, treatment-related adverse event
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JCO Oncology Practice

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Approach to systemic therapy in advanced HCC
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bRisk of variceal
bleeding high if untreated or incompletely treated varices on esophagogastroduodenoscopy within 6 months of treatment initiation
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dThe role of atezolizumab/bevacizumab, durvalumab/tremelimumab,
and nivolumab/ipilimumab in the second-line setting is unclear and decisions should be individualized in eligible patients
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association with mortality than extrahepatic spread or
performance status in untreated patients with HCC
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34 At a
median follow-up of 35
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7 months and 20
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This combination
is not currently FDA-approved
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However, sorafenib, atezolizumab/bevacizumab,
and single-agent nivolumab have been shown in observational
studies to have similar tolerability in patients with CPS-B7 to
B9 cirrhosis but inferior OS when compared with patients with
CPS-A cirrhosis
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35-38
6 | © 2025 by American Society of Clinical Oncology

Other key trials evaluating first-line systemic therapy include LEAP 002,39 ORIENT-32,40 CARES-310,41 RATIONALE-301,42 and COSMIC-312
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39 ORIENT-32 evaluated sintilimab (anti–PD-1 antibody) and a bevacizumab biosimilar (IBI305); this combination showed a significant OS benefit when compared
with sorafenib, but results have yet to be confirmed outside
of China
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43 CARES-310 studied the combination
of camrelizumab (anti–PD-1 antibody) and rivoceranib
(VEGFR2 TKI) versus sorafenib in the first-line setting and
median OS was 22
...
2 months, respectively
...
The RATIONALE-301 trial demonstrated noninferiority of tislelizumab versus sorafenib in the first-line
setting
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Management of Advanced Hepatocellular Carcinoma

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SECOND-LINE SYSTEMIC THERAPY
Among patients who participated in the pivotal trials
evaluating first-line systemic therapy for non–LRTeligible HCC, only 40%-50% received second-line treatment,44 and observational studies have shown that fewer
than 20% of patients in the United States receive secondline therapy in real-world practice, likely because of factors
such as worsening liver function and declining performance
status
...
With recent approvals of atezolizumab/
bevacizumab and the STRIDE regimen in the first-line setting, there are no randomized controlled trials to guide
systemic therapy for patients who have progressed on these
regimens and the role of using an alternate first-line option
among these patients in the second-line setting is unclear
...
Although quality of evidence is
low, AASLD and ASCO guidelines recommend sorafenib or
lenvatinib as second-line therapy after first-line treatment
with atezolizumab/bevacizumab or the STRIDE regimen
...
For those who are ineligible for ICI and who have
progressed on first-line sorafenib or lenvatinib, ramucirumab
(if AFP ≥400 ng/mL) can be considered, given its different
mechanism of action

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