Vol.:(0123456789)
1 3
Cancer Immunology, Immunotherapy
https://doi.org/10.1007/s00262-023-03390-x
REVIEW
Efficacy andsafety ofimmune checkpoint inhibitors forhepatocellular
carcinoma patients withmacrovascular invasion orextrahepatic
spread: asystematic review andmeta‑analysis of54 studies with6187
hepatocellular carcinoma patients
Cheng‑LongHan1· Bao‑WenTian1· Lun‑JieYan1· Zi‑NiuDing1· HuiLiu1· Xin‑ChengMao1· Jin‑ChengTian1·
Jun‑ShuaiXue1· Si‑YuTan1· Zhao‑RuDong1· Yu‑ChuanYan1· Jian‑GuoHong1· Zhi‑QiangChen1· Dong‑XuWang1·
TaoLi2
Received: 7 December 2022 / Accepted: 27 January 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023
Abstract
Background and aims The impacts of macrovascular invasion (MVI) or extrahepatic spread (EHS) on the efficacy and safety
of immune checkpoint inhibitors (ICIs) among hepatocellular carcinoma (HCC) patients remain unclear. Thus, we conducted
a systematic review and meta-analysis to clarify whether ICI therapy is a feasible treatment option for HCC with MVI or EHS.
Methods Eligible studies published before September 14, 2022, were retrieved. In this meta-analysis, the objective response
rate (ORR), progression-free survival (PFS), overall survival (OS), and occurrence of adverse events (AEs) were outcomes
of interest.
Results Fifty-four studies involving 6187 individuals were included. The findings indicated that the presence of EHS in
ICI-treated HCC patients may indicate an inferior ORR (OR 0.77, 95% CI 0.63–0.96), but may not significantly affect the
PFS (multivariate analyses: HR 1.27, 95% CI 0.70–2.31) and OS (multivariate analyses: HR 1.23, 95% CI 0.70–2.16). Addi-
tionally, the presence of MVI in ICI-treated HCC patients may not have significant prognostic impact on ORR (OR 0.84,
95% CI 0.64–1.10), but may indicate inferior PFS (multivariate analyses: HR 1.75, 95% CI 1.07–2.84) and OS (multivariate
analyses: HR 2.03, 95% CI 1.31–3.14). The presence of EHS or MVI in ICI-treated HCC patients may not significantly
impact the occurrence of any serious immune-related adverse events (irAEs) (grades ≥ 3) (EHS: OR 0.44, 95% CI 0.12–1.56;
MVI: OR 0.68, 95% CI 0.24–1.88).
Conclusion The presence of MVI or EHS in ICI-treated HCC patients may not significantly impact the occurrence of serious
irAEs. However, the presence of MVI (but not EHS) in ICI-treated HCC patients may be a significant negative prognostic
factor. Therefore, ICI-treated HCC patients with MVI warrant more attention.
Keywords Objective response rate· Progression-free survival· Overall survival· Immune-related adverse events· Adverse
events· Immune therapy· Vascular invasion· Extrahepatic metastasis· Primary liver cancer· Meta-analyses
Abbreviations
AEs Adverse events
CI Confidence intervals
CTLA-4 Cytotoxic T lymphocyte-associated protein 4
EHS Extrahepatic spread
HCC Hepatocellular carcinoma
HR Hazard ratios
ICIs Immune checkpoint inhibitors
irAEs Immune-related adverse events
MVI Macrovascular invasion
NOS Newcastle–Ottawa Scale
OR Odds ratio
ChengLong Han and Bao Wen Tian have contributed equally as first
author.
* Tao Li
litao7706@163.com
1 Department ofGeneral Surgery, Qilu Hospital, Shandong
University, Jinan250012, People’sRepublicofChina
2 Present Address: Department ofGeneral Surgery,
Qilu Hospital, The Second Hospital ofShandong
University, 107 West Wen Hua Road, Jinan250012,
People’sRepublicofChina
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ORR Objective response rate
OS Overall survival
PD-1 Programmed cell death 1
PD-L1 Programmed cell death ligand-1
PFS Progression-free survival
PRISMA Preferred Reporting Items for Systematic
Reviews and Meta-Analysis
PVTT Portal vein tumor thrombus
RoB2 Risk of bias tool 2.0
Introduction
Primary liver cancer, which is predominantly composed
of hepatocellular carcinoma (HCC), caused approximately
830,000 new deaths in 2020 and is the third leading cause
of cancer-related deaths globally [1]. Although there are
numerous existing therapies for HCC patients, many inter-
ventions, such as surgery, are more applicable for patients
with early HCC [2], while restricted efficient therapies
are suitable for advanced HCC patients. Fortunately, with
the advancement of immune checkpoint inhibitors (ICIs),
which involve monoclonal antibodies against programmed
cell death 1 (PD-1), its major ligand (PD-L1), and cytotoxic
T lymphocyte-associated protein 4 (CTLA-4) [3, 4], there
is hope for a new intervention that is suitable for advanced
HCC patients, although intrinsic resistance exists in the
majority of these patients [5].
The intrinsic resistance to ICIs among advanced HCC
patients has gravely restricted the development of ICIs,
which may be partly solved by precision medicine [6] that
applies the optimal ICI type and dose to a given patient after
gauging the effectiveness according to known prognostic
factors before the complete breakthrough of the intrinsic
resistance mechanism. Moreover, in line with the concept of
precision medicine, we can also recommend that unsuitable
HCC patients receive other effective interventions in time,
thereby providing survival benefits to these individuals. The
identification of prognostic factors to ICIs is of paramount
importance to the application of precision medicine, but only
a limited number of these factors have been determined [7].
Therefore, it is necessary to identify prognostic factors that
would specifically anticipate the exact benefits of ICIs for
a given HCC patient to adjust the application of ICIs. This
process may also facilitate the subsequent resolution of the
resistance mechanism, as some prognostic factors may be
closely associated with intrinsic resistance mechanisms [7].
Macrovascular invasion (MVI) (tumor thrombosis in
the portal vein or hepatic vein) [8] and extrahepatic spread
(EHS) (metastasis outside the liver) [9] are two key charac-
teristics of advanced HCC patients [10]. HCC patients with
MVI and/or EHS are not amenable to curative therapies and
exhibit a very poor prognosis. ICIs therapy has shown its
promising antitumor efficacy for such patients, but concrete
data in clinical settings are still rare. Some literature has sug-
gested that the presence of MVI or EHS may significantly
impair the efficacy of ICIs among HCC patients; however,
contradictory results also exist. Therefore, a meta-analysis
is warranted to clarify whether the presence of MVI or EHS
decreases the efficacy of ICIs among HCC patients. The
current meta-analysis also aimed to identify the potential
relationship between MVI or EHS and the safety of ICIs
among HCC patients.
Methods
This meta-analysis was designed and conducted in accord-
ance with the Preferred Reporting Items for Systematic
Reviews and Meta-Analysis (PRISMA) guidelines [11]. The
meta-analysis protocol, which included the inclusion crite-
ria and every necessary analytical method, was developed
before the onset of the study.
Search strategy andselection criteria
The PubMed, Embase, and Cochrane Library databases
were searched from their inception until September 14,
2022, to identify relevant publications. Only articles pub-
lished in English were included. The detailed search strategy
was developed based on the PICOS model and is shown in
Supplementary Table1. We previously decided to use MVI
and EHS-associated words as the keywords in the search
strategy, but some relevant articles only had suitable out-
comes in the tables or even in the supplementary materials,
thus making them difficult to identify when using MVI and
EHS-associated words as the keywords in the search strat-
egy. Therefore, to acquire the most complete dataset, we did
not use MVI and EHS-associated words as the keywords in
the search strategy.
The inclusion criteria for this meta-analysis were as fol-
lows: (1) HCC patients with a confirmed pathological or
clinical diagnosis; (2) ICIs were employed for all individuals
alone or as part of combination therapy; (3) the impact of
MVI or EHS on the efficacy or safety of ICI interventions
among HCC patients was indicated by hazard ratios (HRs) or
odds ratios (ORs) and their 95% confidence intervals (CIs);
and (4) published in English. The exclusion criteria were as
follows: (1) a high risk of bias (such as Newcastle‒Ottawa
Scale (NOS) scores of less than five); (2) abstracts, which
did not hold adequate information for us to evaluate the risk
of bias; and (3) duplicate studies; only the newest studies
or studies with the most complete data were included; (4)
studies with a risk of involving overlapping patients; only
the most suitable study was included in each meta-analysis.
Studies with a risk of involving overlapping patients were
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those that involved individuals from the same hospital, and
at least part of the enrollment period and the type of ICIs
overlapped. In these cases, the most suitable study was deter-
mined by assessing the number of involved individuals, the
duration of the enrollment period, and the publication year.
Data extraction andquality assessment
The availability of each article was assessed independently
by two reviewers (C-LH and B-WT), and all disputes were
addressed by discussion with other investigators. A struc-
tured data extraction form was employed to extract the fol-
lowing information from each trial: first author, publication
year, study region, enrollment period, number of patients,
type of ICIs, combination intervention, previous therapy,
age, viral status (HBV and HCV), index involved in this
article, and study type. All supplementary materials in these
papers were also extracted to obtain the most complete data.
Cohort studies were classified as either high, medium or
low-quality studies if they had NOS scores of 8–9, 5–7, or
less than 5, respectively [12]. The study qualities of nonran-
domized and randomized trials were assessed using ROB-
INS-I [13] and the risk of bias tool 2.0 (RoB2) tools [14].
Statistical analysis
For this study, outcome measures of interest were objec-
tive response rate (ORR), progression-free survival (PFS),
overall survival (OS), or occurrence of adverse events (AEs).
Pooled ORs or HRs with their 95% CIs were used to clarify
the impact of the presence of MVI or EHS on the efficacy
and safety of ICIs among HCC patients. ORs or HRs with
their 95% CIs were obtained by comparing the outcomes
of interest in ICI (alone or as part of combination therapy)-
treated HCC patients with MVI or EHS and those patients
without MVI or EHS. Data analysis was performed using a
random-effects model through Stata 12.0 (Stata Corp LP,
College Station, TX) with p < 0.05 considered statistically
significant. Heterogeneity was assessed by the I2 value. I2
values greater than 0%, 50% to 75% were considered to indi-
cate minor heterogeneity, moderate heterogeneity to large
heterogeneity, respectively. For OS and PFS, pooled HRs
and 95% CIs acquired by multivariate analyses were first
applied as references.
Sensitivity analysis was conducted using the leave-one-
out method, and an outcome will be excluded if the removal
of this outcome resulted in a significant difference in the
pooled outcomes. Publication bias was detected using fun-
nel plots in which the figure should resemble a symmetri-
cal inverted funnel if there was no significant publication
bias [15]; on the other hand, asymmetrical plots indicated
potential publication bias. Egger’s and Begg’s test were also
used to detect the potential publication bias, with p < 0.05
indicated risk of publication bias. The trim-and-fill method
was applied to obtain the corrected outcomes by filling in
the potential missed outcomes if potential publication bias
existed. Subgroup analyses were performed by region, sam-
ple size, ICI type, age, and study design to assess the poten-
tial sources of heterogeneity.
Results
Study selection andcharacteristics
The flowchart of the systematic literature search process is
illustrated in Fig.1. A total of 4551 records were initially
identified. After screening the titles and abstracts, 1250
duplicates and 3061 nonrelevant studies were excluded, and
240 articles remained. After reviewing the full texts of the
remaining studies, 186 articles were excluded due to shar-
ing the same participants or the risk of involving overlapped
patients, not including relevant participants, not providing
sufficient data to calculate effect sizes, or having low qual-
ity. The reference lists of the relevant articles were also
manually searched to acquire additional eligible studies.
Ultimately, 54 articles that involved 6187 HCC patients and
were published between 2019 and 2022 were included in
this meta-analysis [16–69]. The main characteristics of the
relevant studies that fit our selection criteria are summarized
in Table1. None of the studies were considered to have a
high risk of bias based on the NOS scores, ROBINS-I, and
RoB2 tools (Table1; Supplementary Table2–4).
The prognostic impact ofMVI orEHS ontheefficacy
andsafety ofICIs inHCC patients
According to the pooled ORs and 95% CIs, ICI-treated HCC
patients with EHS may have a lower ORR than HCC patients
without EHS. (OR 0.77, 95% CI 0.63–0.96; Fig.2A). In
contrast, the presence of MVI in ICI-treated HCC patients
may not have a significant impact on the ORR (OR 0.84,
95% CI 0.64–1.10; Fig.2B).
According to the pooled HRs and 95% CIs, the presence
of EHS in ICI-treated HCC patients may not have a signifi-
cant prognostic impact on the PFS (univariate analyses: HR
1.13, 95% CI 0.95–1.34; multivariate analyses: HR 1.27,
95% CI 0.70–2.31; Supplementary Fig.1), but HCC patients
with MVI may experience fewer benefits from ICI interven-
tion for PFS than HCC patients without MVI (univariate
analyses: HR 1.32, 95% CI 1.05–1.66; multivariate analyses:
HR 1.75, 95% CI 1.07–2.84; Fig.3 in Supplementary file 2).
Based on the pooled HRs and 95% CIs, the presence of
EHS in ICI-treated HCC patients may not have a significant
prognostic impact on the OS (univariate analyses: HR 1.08,
95% CI 0.95–1.24; multivariate analyses: HR 1.23, 95% CI
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0.70–2.16; Supplementary Fig.2), but HCC patients with
MVI may experience fewer benefits from ICI intervention
for OS than HCC patients without MVI (univariate analyses:
HR 1.76, 95% CI 1.29–2.41; multivariate analyses: HR 2.03,
95% CI 1.31–3.14; Fig.4 in Supplementary file 2).
The pooled ORs and 95% CIs indicated that the presence
of EHS or MVI in ICI-treated HCC patients may not have a
significant prognostic impact on the occurrence of serious
irAEs (grades ≥ 3) (EHS: OR 0.44, 95% CI 0.12–1.56; MVI:
OR 0.68, 95% CI 0.24–1.88; Supplementary Fig.3).
Sensitivity analyses andpublication bias test
The robustness of every outcome was satisfactory according
to sensitivity analyses (Supplementary Fig.4A–13A). For
the meta-analyses about the prognostic impact of MVI on
the OS of ICIs in HCC patients, the pooled outcome that
was obtained using univariate analysis data was less confi-
dent because although the P value of Egger’s test was 0.05,
the P value of Begg’s test was 0.04 and the funnel plot was
asymmetrical (Supplementary Fig.12B), which implied that
there may be a lack of some negative outcomes. Therefore,
the trim-and-fill method was applied to correct this pooled
outcome, and the corrected pooled outcome was HR 1.27,
95% CI 1.12–1.44 (Supplementary Fig.14), which was still
statistically significant. All other funnel plots were approxi-
mately symmetrical (Supplementary Fig.4B–11B and Sup-
plementary Fig.13B) and had no p values < 0.05 for Begg’s
and Egger’s tests (Supplementary Table5; Supplementary
Fig.4C–13C; Supplementary Fig.4D–11D and Supplemen-
tary Fig.13D). Thus, significant publication bias was not
observed for other outcomes (Table2).
Subgroup analysis
The outcomes of every subgroup analyses are presented in
Tables3 and 4 (Supplementary file 2) and Supplementary
Tables6–8, and the reduced heterogeneity in some subgroup
analyses indicated that these factors may be potential sources
of heterogeneity. According to subgroup analyses, region,
sample size, ICI type, age, and study design may have been
potential sources of moderate or high heterogeneity herein.
Discussion
In this systematic review and meta-analysis, 54 studies that
involved 6187 individuals and that were published between
2019 and 2022 were included to elucidate the prognostic
impact of EHS or MVI on the efficacy and safety of ICI
treatment in HCC patients. Overall, there was no high risk of
bias observed in these studies. Based on Egger’s test, Begg’s
test, and funnel plots, there was no evidence of significant
publication bias for the outcomes except for one outcome
that was obtained using univariate analysis data about
the prognostic impact of MVI on the OS of ICIs in HCC
patients. Therefore, we mainly apply the outcome that was
obtained using multivariate analysis data about this impact
as reference; the finding also indicated that the presence of
MVI in ICI-treated HCC patients may lead to an inferior
OS. According to sensitivity analyses, the robustness of all
pooled outcomes was satisfactory. The sources of involved
individuals were sufficient. There were nine global studies
in this meta-analysis that were conducted with individuals
from more than one continent. It should be noted that differ-
ent regions, sample sizes, ICI types, ages, and study designs
Fig. 1 Flow diagram of the
articles included in the meta-
analysis
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Table 1 Study characteristics
First author Year Region Enrollment
period
Patient no.aIntervention AgebData collection Study type Study qualityc
P. Fessas 2020 Global 2017–2019 233 Nivolumab 64 (median) OS,PFS Retro NOS(9)
J. I. Yu 2019 Asia 2017.03–
2018.05
76 Nivolumab 62 (median-
RT), 64
(median-no
RT)
OS Retro NOS(8)
K. Y. Y. Ng 2021 Asia 2015.05–
2018.06
114 ICIs 66 (median) OS Retro NOS(6)
K. Toshida 2022 Asia 2018.04–
2022.03
35 Atezolizumab 71, 72 (median) OS,PFS Retro NOS(8)
M. S. Lee 2020 Global 2016.07–
2018.07
104 Atezolizumab 62 (median) ORR Clinic Moderate risk
S. Xu 2021 Asia 2019.01–
2020.04
65 PD-1 inhibitors < 65 (51) OS Retro NOS(8)
H. Y. Kuo 2020 Asia 2016.11–
2019.01
42 PD-1 inhibitors 58 (median) OS,PFS Retro NOS(8)
P. C. Lee 2020 Asia 2017.05–
2019.08
95 PD-1 inhibitors 65.5 (median) ORR,OS Retro NOS(8)
A. L. Cheng 2022 Global 2018.03–
2019.01
336 Atezolizumab < 65 (175) ORR Clinic Low risk
M. Kudo 2021 Asia 2017.09–
2018.01
22 Avelumab 68.5 (median) ORR Clinic Low risk
J. Xu 2021 Asia 2018.03–
2019.01
190 Camrelizumab 53 (median-
First line),
51 (median-
Second line)
ORR Clinic Moderate risk
W. F. Hsu 2020 Asia 2017.05–
2019.12
87 Nivolumab 63.4 (median) ORR.OS,AE Retro NOS(8)
W. M. Choi 2020 Asia 2017.07–
2019.02
150 Nivolumab 58.5 (mean-R),
56.9 (mean-
N)
ORR Retro NOS(8)
M. Vithayathil 2022 Global 2020.01–
2021.12
191 Atezolizumab 68.4 (median) OS,PFS Retro NOS(8)
T. Jun 2021 Global 2017–2019 314 PD-1 inhibitors 66 (median) ORR,OS Retro NOS(9)
W. F. Hsu 2021 Asia 2017.05–
2021.06
95 PD-1 inhibitors 63.8 (median) OS,PFS Retro NOS(8)
S. Chen 2021 Asia 2018.03–
2021.03
170 Pembrolizumab 52 (median-
PLH), 53
(median-PL)
OS,PFS Retro NOS(9)
W. M. Choi 2021 Asia 2017.07–
2020.06
194 Nivolumab 57.4 (mean) OS,PFS Retro NOS(7)
T. de Castro 2022 Global 2019.11–
2021.11
147 Atezolizumab 68.7 (mean) OS Retro NOS(9)
D. Dong 2022 Asia 2018.07–
2021.02
38 ICIs 57 (median) OS,PFS Retro NOS(8)
X. Hu 2022 Asia 2019.07–
2021.10
70 PD-1 inhibitors 52.5 (mean) PFS Retro NOS(8)
H. Matsumoto 2022 Asia 2020.10–
2022.02
32 Atezolizumab 77 (median) PFS Retro NOS(7)
A. Muhammed 2022 Global 2015–2018 362 ICIs 65 (median) OS,PFS Retro NOS(8)
B. Scheiner 2022 Global 2015.07–
2020.12
190 ICIs 66.2 (mean) OS Retro NOS(8)
Y. Y. Shao 2019 Asia 2013–2018 43 ICIs 55 (mean), 54
(median)
OS,PFS Retro NOS(7)
X. Sun 2021 Asia 2018.01–
2019.12
235 PD-1 inhibitors > 50 (126) ORR,OS,PFS Retro NOS(8)
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Table 1 (continued)
First author Year Region Enrollment
period
Patient no.aIntervention AgebData collection Study type Study qualityc
R. Mahn 2020 Europe 2016.05–
2019.01
14 PD-1 inhibitors 64.6 (mean) ORR,AE Retro NOS(6)
C. J. Wu 2022 Asia 2019.07–
2021.02
71 Pembrolizumab 63 (median) OS Pro NOS(8)
H. M. Tsai 2021 Asia 2016.11–
2019.12
68 PD-1 inhibitors 61.0, 61.5
(median)
OS Retro NOS(5)
K. Maesaka 2022 Asia 2020.10–
2021.05
88 Atezolizumab 75 (median) OS Pro NOS(8)
M. Kudo 2022 Global 2017–2020.07 104 Pembrolizumab 68 (median) ORR Clinic Moderate risk
M. Zhao 2022 Asia 2018.01–
2020.12
160 ICIs 58 (median) OS,PFS Retro NOS(8)
W. Zhang 2022 Asia 2018.10–
2020.01
50 Sintilimab 56 (median) PFS Clinic Moderate risk
R. You 2022 Asia 2019.08–
2021.05
101 Camrelizumab 56.8 (mean) ORR,OS,PFS Pro NOS(8)
J. Yao 2022 Asia 2018.04–
2021.07
136 PD-1 inhibitors 58 (median) ORR,OS,PFS Retro NOS(9)
Y. Xin 2022 Asia 2020.10–
2021.09
52 Atezolizumab 55.9 (mean) PFS Retro NOS(9)
W. Teng 2022 Asia 2020.09–
2022.01
89 Atezolizumab 61.3 (median) ORR,OS,PFS Retro NOS(8)
W. Teng 2021 Asia 2015–2019 90 Nivolumab 61.4 (median) OS,PFS Retro NOS(8)
K. Su 2022 Asia 2019.06–
2021.10
47 PD-1 inhibitors < 60 (34) OS,PFS Retro NOS(7)
M. An 2022 Asia 2018.06–
2020.12
217 PD-1 inhibitors 54 (median) OS,PFS Retro NOS(8)
Y. C. Shen 2021 Asia 2015.08–
2019.03
48 ICIs 63 (median) OS Pro NOS(7)
Y. Shen 2021 Asia 2020.01–
2020.12
57 PD-1 inhibitors 58 (median) OS,PFS Retro NOS(8)
H. Ochi 2022 Asia 2020.09–
2021.10
242 Atezolizumab 75, 74 (median) PFS Retro NOS(9)
M. Morita 2021 Asia 2015.08–
2017.09
34 PD-1 inhibitors 67.1 (median) ORR Retro NOS(7)
T. Matsumae 2022 Asia 2020.11–
2021.05
85 Atezolizumab 74 (median) OS,PFS Pro NOS(9)
J. Liu 2021 Asia 2019.04–
2019.12
22 Camrelizumab 57.7 (mean) OS,PFS Retro NOS(8)
X. Li 2022 Asia 2019.06–
2021.05
114 PD-1 inhibitors 53 (median) OS,PFS Retro NOS(7)
S. W. Lee 2022 Asia 2019.04–
2021.07
33 ICIs 66 (median) ORR Retro NOS(8)
N. Kim 2021 Asia 2017.03–
2018.12
102 Nivolumab 61.3 (median) OS,PFS Retro NOS(8)
H. S. Kim 2022 Asia 2012.06–
2018.03
261 Nivolumab 59 (median) ORR.OS,PFS Retro NOS(7)
S. Ju 2022 Asia 2017.03–
2021.09
80 Camrelizumab 52 (median) OS,PFS Retro NOS(8)
S. H. Jeon 2022 Asia Unknown 45 Nivolumab 59 (median-
DCB), 60
(median-
NDB)
OS,PFS Pro NOS(8)
J. Cheon 2022 Asia 2020.05–
2020.11
121 Atezolizumab 61 (median) OS,PFS Retro NOS(9)
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may cause potential moderate or high heterogeneity for some
meta-analyses.
The presence of EHS in ICI-treated HCC patients may
indicate a worse ORR, but may not have impact on the PFS
and OS. Therefore, the presence of EHS in HCC patients
may not be a significant prognostic factor for ICI efficacy.
However, there are many types of EHS, and different sites
of metastasis may have different prognostic significance.
According to the current literature, the presence of peri-
toneum metastasis in ICI-treated HCC patients may indi-
cate significantly inferior OS and PFS but may not have
significant prognostic impact on the ORR [50]. This study
also provides data supporting that the presence of bile duct
involvement in ICI-treated HCC patients may indicate a
significantly inferior OS but may not have significant prog-
nostic impact on the ORR [50]. However, different results
were also revealed by another study [43]. Therefore, ques-
tions remain regarding the response and outcomes with ICIs
based on specific sites of metastasis and warrant further
investigation.
The management of HCC with vascular invasion is
challenging, and its therapeutic options are limited. The
therapeutic benefit of ICIs for HCC patients with vascular
tumor thrombosis remains unclear. In a recent real-world
analysis, the ORR was similar between patients with and
without tumor thrombi treated with ICIs, but the OS was
significantly better for patients without tumor thrombi
[44]. In accordance with this study, our analysis also found
that the presence of MVI in ICI-treated HCC patients may
not have significant prognostic impact on the ORR but may
indicate worse PFS and OS, which implies that the pres-
ence of MVI in HCC patients may be a vital prognostic
Table 1 (continued)
First author Year Region Enrollment
period
Patient no.aIntervention AgebData collection Study type Study qualityc
C. Zhan 2020 America 2015.04–
2018.05
26 ICIs 66 (median) ORR Retro NOS(6)
Patient no.—number of patients, clinic—clinical trials, retro—retrospective, pro—prospective, global—more than one continent
a The number of patients may not equal to the total number of included patients in some studies because some patients in these studies were
not relevant patients or lack of relevant outcomes for these patients. Therefore, we used the number of the remaining patients as the number of
patients for this study
b The presented form of age for all studies, including median age, mean age, and the number of patients greater or lower a certain age, was deter-
mined by the actual provided information in these studies. For some studies that not provided median or mean age of all patients which were
divided into different cohorts, we can only present the age of these studies as the age of all included cohorts, respectively. The cohorts’ names
were presented in the last
c The study quality of each study was evaluated based on the study’s type, and detailed information was presented in the methods section
Fig. 2 A Forest plot of the pooled OR and 95% CI. The pooled results
indicated that the presence of EHS in ICI-treated HCC patients may
have significant prognostic impact on the ORR. B Forest plot of the
pooled OR and 95% CI. The pooled results indicated that the pres-
ence of MVI in ICI-treated HCC patients may not have significant
prognostic impact on the on the ORR. Squares = individual study
point estimates. Horizontal lines = 95% CI. Rhombus = Pooled out-
comes
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Table 2 Cohorts characteristics
First author Year Region Patient no AgeaIntervention Virus-HBV
(+ / − /
unknown)
Virus-HCV
(+ / − /
unknown)
P. Fessas 2020 Global 233 64 (median) Nivolumab 83/150 95/138
J. I. Yu 2019 Asia 76 62 (median-RT), 64 (median-no RT) Nivolumab 56/20 6/70
K. Y. Y. Ng 2021 Asia 114 66 (median) ICIs 62/52 13/101
K. Toshida 2022 Asia 35 71, 72 (median) Atezolizumab 5/30 9/26
M. S. Lee 2020 Global 104 62 (median) Atezolizumab 51/53 31/73
S. Xu 2021 Asia 65 < 65 (51) PD-1 inhibitors 57/8 Unknown
H. Y. Kuo 2020 Asia 42 58 (median) PD-1 inhibitors 29/13 6/36
P. C. Lee 2020 Asia 95 65.5 (median) PD-1 inhibitors 62/33 21/74
A. L. Cheng 2022 Global 336 < 65 (175) Atezolizumab 164/172 72/264
M. Kudo 2021 Asia 22 68.5 (median) Avelumab 1/21 3/19
J. Xu (1) 2021 Asia 70 53 (median) Camrelizumab 62/8 0/70
J. Xu (2) 2021 Asia 120 51 (median) Camrelizumab 106/14 1/119
W. F. Hsu 2020 Asia 87 63.4 (median) Nivolumab 51/36 22/65
W. M. Choi 2020 Asia 150 56.9 (mean) Nivolumab 125/25 4/106
M. Vithayathil 2022 Global 191 68.4 (median) Atezolizumab 37/154 72/119
T. Jun 2021 Global 314 66 (median) PD-1 inhibitors 88/226 118/196
W. F. Hsu 2021 Asia 95 63.8 (median) PD-1 inhibitors 48/47 25/70
S. Chen 2021 Asia 170 52 (median-PLH), 53 (median-PL) Pembrolizumab 93/77 48/122
W. M. Choi 2021 Asia 194 57.4 (mean) Nivolumab 155/39 10/184
T. de Castro 2022 Europe 147 68.7 (mean) Atezolizumab 12/135 38/109
D. Dong 2022 Asia 38 57 (median) ICIs 34/4 2/36
X. Hu 2022 Asia 70 52.5 (mean) PD-1 inhibitors 70/0 Unknown
H. Matsumoto 2022 Asia 32 77 (median) Atezolizumab 4/28 15/17
A. Muhammed 2022 Global 362 65 (median) ICIs 81/281 121/241
B. Scheiner 2022 Global 190 66.2 (mean) ICIs Unknown Unknown
Y. Y. Shao 2019 Asia 43 55 (mean), 54 (median) ICIs 29/14 8/35
X. Sun 2021 Asia 235 > 50 (126) PD-1 inhibitors 203/32 Unknown
R. Mahn 2020 Europe 14 64.6 (mean) PD-1 inhibitors 2/12 4/10
C. J. Wu 2022 Asia 71 63 (median) Pembrolizumab 45/26 11/60
H. M. Tsai 2021 Asia 68 61.0, 61.5 (median) PD-1 inhibitors 51/17 6/62
K. Maesaka 2022 Asia 88 75 (median) Atezolizumab Unknown Unknown
M. Kudo 2022 Global 104 68 (median) Pembrolizumab 22/81/1 26/78
M. Zhao 2022 Asia 160 58 (median) ICIs 143/17 Unknown
W. Zhang 2022 Asia 50 56 (median) Sintilimab 47/3 Unknown
R. You 2022 Asia 101 56.8 (mean) Camrelizumab 75/26 Unknown
J. Yao 2022 Asia 136 58 (median) PD-1 inhibitors 124/12 0/136
Y. Xin 2022 Asia 52 55.9 (mean) Atezolizumab 47/5 Unknown
W. Teng 2022 Asia 89 61.3 (median) Atezolizumab 69/20 10/79
W. Teng 2021 Asia 90 61.4 (median) Nivolumab 59/31 17/73
K. Su 2022 Asia 47 < 60 (34) PD-1 inhibitors 32/15 2/45
M. An 2022 Asia 217 54 (median) PD-1 inhibitors 217/0 Unknown
Y. C. Shen 2021 Asia 48 63 (median) ICIs 36/12 10/38
Y. Shen 2021 Asia 57 58 (median) PD-1 inhibitors 49/8 4/53
H. Ochi 2022 Asia 242 75, 74 (median) Atezolizumab 36/206 84/158
M. Morita 2021 Asia 34 67.1 (median) PD-1 inhibitors 9/25 13/21
T. Matsumae 2022 Asia 85 74 (median) Atezolizumab 22/63 29/56
J. Liu 2021 Asia 22 57.7 (mean) Camrelizumab 15/7 4/18
X. Li 2022 Asia 114 53 (median) PD-1 inhibitors 102/12 2/112
Cancer Immunology, Immunotherapy
1 3
factor for ICI efficacy. Therefore, ICIs in combination with
other suitable treatments may be applied to overcome the
impact of MVI on ICI efficacy. Portal vein tumor thrombus
(PVTT) is the most frequent form of MVI, and the pro-
portion of HCC patients with PVTT varies significantly
across different regions [70]. Current studies have mainly
focused on PVTT in ICI-treated HCC patients, while stud-
ies on hepatic vein tumor thrombus are rare. A small-scale
clinical study revealed a similar ORR between hepatic vein
tumor thrombus and PVTT for ICIs treatment [44], but
large-scale studies are needed in the future.
The number of relevant investigations that provided
information to clarify the potential prognostic impact
of EHS or MVI on the occurrence of AEs in ICI-treated
HCC patients was limited, which seriously restricted the
analyses of this relationship. One study found that EHS or
PVTT in ICI-treated HCC patients may not significantly
impact the occurrence of any treatment-related adverse
event [30]. Based on the ORs and 95% CIs, which can
be obtained manually, two relevant articles indicated that
EHS or MVI in ICI-treated HCC patients may not have
a significant prognostic impact on the occurrence of any
irAEs [21, 42]. According to the meta-analysis of data
from two articles [27, 42], the presence of EHS or MVI
in ICI-treated HCC patients may also not have a signifi-
cant prognostic impact on the occurrence of serious irAEs
(grades ≥ 3). The limited number of these relevant articles
significantly restricted the confidence in these outcomes.
A recent study has identified poor performance status, ele-
vated neutrophil/lymphocyte ratio and cancer type as sig-
nificant risk factors, which may help to develop risk scores
to identify patients at risk of developing severe irAEs [71].
ICIs have revolutionized the tumor therapy, and the pres-
ence of metastasis or vascular invasion may also hold a cer-
tain impact on the efficacy of ICIs in patients with other
cancer types. However, the clinical activity of ICIs is highly
variableand depends on histologic types, disease settings,
and concomitant treatment strategies [72]. Several studies
have implied the prognostic impact of metastasis on the effi-
cacy of ICIs in different cancers, such as gastric cancer, [73]
lung cancer [74], melanoma [75], and urothelial carcinoma
[76]. The different characteristics (“cold” or “hot”) of tumor
immune microenvironment in different metastatic sites may
be the underlying mechanism for the attenuated or enhanced
efficacy of ICIs. Metastasis or vascular responders to ICIs
have significantly longer survival than non-responders, and
it is urgently needed to predict good responders for personal-
ized therapy. ICIs in combination with treatment modalities
such as chemotherapy or targeted agents seem a promising
strategy, and translational research integrating molecular
profile, biological behavior and response to ICIs may help
to determine their role in the treatment of metastasis or vas-
cular invasion [72].
There are still some limitations of this meta-analysis
that need to be considered. First, there were limited data
about AEs, which restricted the analysis of AEs. We
could only conduct simple meta-analyses of the effects
of MVI or EHS on the occurrence of AEs in ICI-treated
HCC patients, and no further subgroup analyses can be
performed. Second, EHS is a broad concept that can be
specially classified into numerous specified circumstances.
For instance, there are many different sites of metastasis
for EHS, including lung metastasis, bile duct involvement,
and lymph node metastasis. Some specific types of EHS
Table 2 (continued)
First author Year Region Patient no AgeaIntervention Virus-HBV
(+ / − /
unknown)
Virus-HCV
(+ / − /
unknown)
S. W. Lee 2022 Asia 33 66 (median) ICIs 19/14 8/25
N. Kim 2021 Asia 102 61.3 (median) Nivolumab 78/24 7/95
H. S. Kim 2022 Asia 261 59 (median) Nivolumab 198/63 17/244
S. Ju 2022 Asia 80 52 (median) Camrelizumab 65/15 Unknown
S. H. Jeon 2022 Asia 45 59 (median-DCB), 60 (median-NDB) Nivolumab 34/11 3/42
J. Cheon 2022 Asia 121 61 (median) Atezolizumab 93/28 6/115
C. Zhan 2020 America 26 66 (median) ICIs 8/18 10/16
Patient no.—number of patients, Global—more than one continent, ICIs—two or more types of inhibitors, including PD-1, PD-L1, and CTLA-4
inhibitors, were used
a The presented form of age for all cohorts, including median age, mean age, and the number of patients greater or lower a certain age, was
determined by the actual provided information in these cohorts. For the study that although divided patients into different cohorts but only pro-
vided data of all patients, we will consider this study as one cohort. For cohorts that not provided median or mean age of all patients which were
divided into different sub-cohorts, we can only present the age of these cohorts as the age of all included sub-cohorts, respectively. The sub-
cohorts’ names were presented in the last
Cancer Immunology, Immunotherapy
1 3
in HCC patients may be vital prognostic factors of ICI
efficacy. These conclusions cannot be acquired with the
limited data included herein. Moreover, we only assessed
MVI and EHS as dichotomous variables in this meta-
analysis, i.e., we classified ICI-treated HCC patients as
individuals with or without MVI or EHS. In fact, MVI
and EHS may also be regarded as continuous variables
based on the size or number of metastatic foci or tumor
thrombus. More or larger metastatic foci or tumor thrombi
in HCC patients may have differential effects on ICI effi-
cacy. Third, the number of outcomes in some subgroup
analyses was limited, which decreased the confidence in
these subgroup analyses’ outcomes and led us to use only
subgroup analyses to identify the potential sources of het-
erogeneity. At the same time, ICI-treated HCC patients in
the majority of included studies also received, or partly
received other combination therapies, which may cause
potential bias. Finally, except for the nine global studies,
the other studies from different countries, such as China,
Japan, Korea, were mainly conducted in Asia, which may
partly restrict the application of our results.
Interpretation
Overall, the prognostic impact of MVI or EHS in ICI-treated
HCC patients on the occurrence of serious irAEs may not
exist. However, the presence of MVI (but not EHS) in ICI-
treated HCC patients may be a significant negative prog-
nostic factor. These findings warrant verification by more
high-quality studies.
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s00262- 023- 03390-x.
Author contributions CL–H, BW-T, and T-L designed the meta-analy-
sis. CL–H, BW-T, and T-L conducted the systematic search of relevant
articles. CL–H, BW-T, LJ-Y, ZN-D, and T-L determined eligible stud-
ies and evaluated the study quality. CL–H, BW-T, H–L, XC-M, and
JC-T extracted eligible data from the manuscript and supplementary
materials of all original articles. CL–H, BW-T, JS-X, SY-T, ZR-D, and
YC-Y analyzed, interpreted the data. CL–H, BW-T, and JG-H drafted
this manuscript. CL–H, BW-T, ZQ-C, DX-W, and LT revised this
manuscript. All authors have assessed and approved the final version
of this manuscript.
Funding This work was supported by the grants from the Taishan
Scholars Program of Shandong Province(Grant No. tstp20221158),
National Natural Science Foundation of China (Grant Nos. 82073200
and 81874178), Major basic research of Shandong Provincial Natural
Science Foundation (Grant No. ZR2021ZD26) and funds for Independ-
ent Cultivation of Innovative Team from Universities in Jinan (Grant
No. 2020GXRC023).
Declarations
Conflict of interest There are no conflicts of interest to declare.
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