Abstract
Introduction: Patients with advanced-stage or intermediate-stage hepatocellular carcinoma (HCC) unsuitable for transarterial chemoembolization (TACE) had poor prognoses. Recent advancements in hepatic arterial infusion chemotherapy (HAIC) and immune checkpoint inhibitors (ICIs) have demonstrated higher tumor response rates, which improved overall survival (OS). HAIC achieves an OS rate of approximately 14.5–15.3 months with a 39.1–42.5% tumor response rate. In comparison, ICIs have a 12–14 month OS rate with a 26–33% tumor response rate. Given these promising responses, this study evaluates the efficacy of conversion therapy with curative intent following HAIC or ICIs, focusing on survival outcomes. Methods: We retrospectively analyzed 80 patients with advanced or TACE-unsuitable intermediate HCC. Patients completed two HAIC or four ICI cycles, followed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria imaging. Based on demographics, cirrhosis status, Barcelona Clinic Liver Cancer classification (BCLC) stage, treatment responses, and treatment modality, survival impacts were analyzed. OS was compared between HAIC and immunotherapy groups. The effect of conversion therapy with curative intent on survival outcomes was analyzed using a Cox regression model. Results: Among the 80 patients, 26 achieved positive response (CR/PR) with HAIC or ICIs, and 9 of them subsequently underwent conversion therapy with curative intent. Key prognostic factors included Child-Pugh stage B versus A (HR = 2.21, p = 0.041), BCLC stage C versus B (HR = 4.38, p = 0.011), and elevated alpha-fetoprotein levels (HR = 5.02, p < 0.001). Positive responders saw substantial survival benefits (HR = 0.26, p = 0.001). Patients undergoing conversion therapy exhibited significantly enhanced survival. Median OS was 13.58 months with standard therapy, while the curative intent surgery group did not reach the median OS (p = 0.002). For CR/PR patients, 48-month survival was 75.0% for the curative surgery group versus 38.0% for standard treatment. Conclusion: Conversion therapy with curative intent following HAIC or ICIs might enhance survival in patients with advanced or TACE-unsuitable intermediate-stage HCC.
References
1.
Bray
F
, Ferlay
J
, Soerjomataram
I
, Siegel
RL
, Torre
LA
, Jemal
A
. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
. CA Cancer J Clin
. 2018
;68
(6
):394
–424
. 2.
Wu
J
. The changing epidemiology of hepatocellular carcinoma in Asia versus United States and Europe
. Adv Mod Oncol Res
. 2017
;3
(s1
):51
–8
. 3.
Bruix
J
, Sherman
M
; American Association for the Study of Liver Diseases
. Management of hepatocellular carcinoma: an update
. Hepatology
. 2011
;53
(3
):1020
–2
. 4.
Su
CW
, Chau
GY
, Hung
HH
, Yeh
YC
, Lei
HJ
, Hsia
CY
, et al. Impact of steatosis on prognosis of patients with early-stage hepatocellular carcinoma after hepatic resection
. Ann Surg Oncol
. 2015
;22
(7
):2253
–61
. 5.
Vogel
A
, Martinelli
E
; ESMO Guidelines Committee Electronic address clinicalguidelines@esmoorg
, ESMO Guidelines Committee
. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines
. Ann Oncol
. 2021
;32
(6
):801
–5
. 6.
Vogel
A
, Meyer
T
, Sapisochin
G
, Salem
R
, Saborowski
A
. Hepatocellular carcinoma
. Lancet
. 2022
;400
(10360
):1345
–62
. 7.
Hatanaka
T
, Yata
Y
, Naganuma
A
, Kakizaki
S
. Treatment strategy for intermediate-stage hepatocellular carcinoma: transarterial chemoembolization, systemic therapy, and conversion therapy
. Cancers
. 2023
;15
(6
):1798
. 8.
Benson
AB
, D’Angelica
MI
, Abbott
DE
, Anaya
DA
, Anders
R
, Are
C
, et al. Hepatobiliary cancers, version 2.2021, NCCN clinical practice guidelines in Oncology
. J Natl Compr Canc Netw
. 2021
;19
(5
):541
–65
. 9.
Su
GL
, Altayar
O
, O’Shea
R
, Shah
R
, Estfan
B
, Wenzell
C
, et al. AGA clinical practice guideline on systemic therapy for hepatocellular carcinoma
. Gastroenterology
. 2022
;162
(3
):920
–34
. 10.
Jeong
SW
, Jang
JY
, Shim
KY
, Lee
SH
, Kim
SG
, Cha
SW
, et al. Practical effect of sorafenib monotherapy on advanced hepatocellular carcinoma and portal vein tumor thrombosis
. Gut Liver
. 2013
;7
(6
):696
–703
. 11.
Kuo
YH
, Wu
IP
, Wang
JH
, Hung
CH
, Rau
KM
, Chen
CH
, et al. The outcome of sorafenib monotherapy on hepatocellular carcinoma with portal vein tumor thrombosis
. Invest New Drugs
. 2018
;36
(2
):307
–14
. 12.
Yau
T
, Hsu
C
, Kim
TY
, Choo
SP
, Kang
YK
, Hou
MM
, et al. Nivolumab in advanced hepatocellular carcinoma: sorafenib-experienced Asian cohort analysis
. J Hepatol
. 2019
;71
(3
):543
–52
. 13.
Finn
RS
, Qin
S
, Ikeda
M
, Galle
PR
, Ducreux
M
, Kim
TY
, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma
. N Engl J Med
. 2020
;382
(20
):1894
–905
. 14.
Finn
RS
, Ryoo
BY
, Merle
P
, Kudo
M
, Bouattour
M
, Lim
HY
, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial
. J Clin Oncol
. 2020
;38
(3
):193
–202
. 15.
Zayac
A
, Almhanna
K
. Hepatobiliary cancers and immunotherapy: where are we now and where are we heading
. Transl Gastroenterol Hepatol
. 2020
;5
:8
. 16.
Ding
X
, He
M
, Chan
AWH
, Song
QX
, Sze
SC
, Chen
H
, et al. Genomic and epigenomic features of primary and recurrent hepatocellular carcinomas
. Gastroenterology
. 2019
;157
(6
):1630
–45.e6
. 17.
Ren
Z
, Xu
J
, Bai
Y
, Xu
A
, Cang
S
, Du
C
, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study
. Lancet Oncol
. 2021
;22
(7
):977
–90
. 18.
Kudo
M
. Durvalumab plus tremelimumab in unresectable hepatocellular carcinoma
. Hepatobiliary Surg Nutr
. 2022
;11
(4
):592
–6
. 19.
Korean Liver Cancer Association KLCA and National Cancer Center NCC Korea
. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma
. Clin Mol Hepatol
. 2022
;28
(4
):583
–705
. 20.
Choi
JH
, Chung
WJ
, Bae
SH
, Song
DS
, Song
MJ
, Kim
YS
, et al. Randomized, prospective, comparative study on the effects and safety of sorafenib vs. hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis
. Cancer Chemother Pharmacol
. 2018
;82
(3
):469
–78
. 21.
Lu
J
, Zhang
XP
, Zhong
BY
, Lau
WY
, Madoff
DC
, Davidson
JC
, et al. Management of patients with hepatocellular carcinoma and portal vein tumour thrombosis: comparing East and West
. Lancet Gastroenterol Hepatol
. 2019
;4
(9
):721
–30
. 22.
Moriya
K
, Namisaki
T
, Sato
S
, Furukawa
M
, Douhara
A
, Kawaratani
H
, et al. Bi-monthly hepatic arterial infusion chemotherapy as a novel strategy for advanced hepatocellular carcinoma in decompensated cirrhotic patients
. Clin Mol Hepatol
. 2019
;25
(4
):381
–9
. 23.
Ueshima
K
, Ogasawara
S
, Ikeda
M
, Yasui
Y
, Terashima
T
, Yamashita
T
, et al. Hepatic arterial infusion chemotherapy versus sorafenib in patients with advanced hepatocellular carcinoma
. Liver Cancer
. 2020
;9
(5
):583
–95
. 24.
Miyaki
D
, Aikata
H
, Honda
Y
, Naeshiro
N
, Nakahara
T
, Tanaka
M
, et al. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma according to Child-Pugh classification
. J Gastroenterol Hepatol
. 2012
;27
(12
):1850
–7
. 25.
Zhuang
BW
, Li
W
, Xie
XH
, Hu
HT
, Lu
MD
, Xie
XY
. Sorafenib versus hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: a systematic review and meta-analysis
. Jpn J Clin Oncol
. 2019
;49
(9
):845
–55
. 26.
Liang
HL
, Huang
JS
, Lin
YH
, Lai
KH
, Yang
CF
, Pan
HB
. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma by placing a temporary catheter via the subclavian route
. Acta Radiol
. 2007
;48
(7
):734
–40
. 27.
Tsai
WL
, Lai
KH
, Liang
HL
, Hsu
PI
, Chan
HH
, Chen
WC
, et al. Hepatic arterial infusion chemotherapy for patients with huge unresectable hepatocellular carcinoma
. PLoS One
. 2014
;9
(5
):e92784
. 28.
Chen
KT
, Tsai
KF
, Leung
HWC
, Chan
ALF
, Wang
SY
, Liang
HL
, et al. Hepatic arterial infusion chemotherapy followed by lipiodol infusion for advanced hepatocellular carcinoma with portal vein tumor thrombus: a single-center experience
. Medicina
. 2021
;57
(8
):779
. 29.
Li
QJ
, He
MK
, Chen
HW
, Fang
WQ
, Zhou
YM
, Xu
L
, et al. Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin versus transarterial chemoembolization for large hepatocellular carcinoma: a randomized phase III trial
. J Clin Oncol
. 2022
;40
(2
):150
–60
. 30.
Sun
HC
, Zhu
XD
. Downstaging conversion therapy in patients with initially unresectable advanced hepatocellular carcinoma: an overview
. Front Oncol
. 2021
;11
:772195
. 31.
Zhou
H
, Song
T
. Conversion therapy and maintenance therapy for primary hepatocellular carcinoma
. Biosci Trends
. 2021
;15
(3
):155
–60
. 32.
Shi
XJ
, Jin
X
, Wang
MQ
, Wei
LX
, Ye
HY
, Liang
YR
, et al. Effect of resection following downstaging of unresectable hepatocelluar carcinoma by transcatheter arterial chemoembolization
. Chin Med J
. 2012
;125
(2
):197
–202
.33.
Zhang
Y
, Huang
G
, Wang
Y
, Liang
L
, Peng
B
, Fan
W
, et al. Is salvage liver resection necessary for initially unresectable hepatocellular carcinoma patients downstaged by transarterial chemoembolization? Ten years of experience
. Oncologist
. 2016
;21
(12
):1442
–9
. 34.
Huang
A
, Yang
XR
, Chung
WY
, Dennison
AR
, Zhou
J
. Targeted therapy for hepatocellular carcinoma
. Signal Transduct Target Ther
. 2020
;5
(1
):146
. 35.
Eisenhauer
EA
, Therasse
P
, Bogaerts
J
, Schwartz
LH
, Sargent
D
, Ford
R
, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
. Eur J Cancer
. 2009
;45
(2
):228
–47
. 36.
Lencioni
R
, Llovet
JM
. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma
. Semin Liver Dis
. 2010
;30
(1
):52
–60
. 37.
Nishikawa
H
, Osaki
Y
, Kita
R
, Kimura
T
. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma in Japan
. Cancers
. 2012
;4
(1
):165
–83
. 38.
Song
DS
, Song
MJ
, Bae
SH
, Chung
WJ
, Jang
JY
, Kim
YS
, et al. A comparative study between sorafenib and hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis
. J Gastroenterol
. 2015
;50
(4
):445
–54
. 39.
El-Khoueiry
AB
, Sangro
B
, Yau
T
, Crocenzi
TS
, Kudo
M
, Hsu
C
, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial
. Lancet
. 2017
;389
(10088
):2492
–502
. 40.
Sangro
B
, Gomez-Martin
C
, de la Mata
M
, Inarrairaegui
M
, Garralda
E
, Barrera
P
, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C
. J Hepatol
. 2013
;59
(1
):81
–8
. 41.
Zhang
W
, Ouyang
D
, Huang
Z
, Che
X
. Hepatic arterial infusion chemotherapy versus sorafenib for advanced hepatocellular carcinoma with portal vein tumor thrombus: an updated meta-analysis and systematic review
. Front Oncol
. 2023
;13
:1085166
. 42.
Lai
Z
, He
M
, Bu
X
, Xu
Y
, Huang
Y
, Wen
D
, et al. Lenvatinib, toripalimab plus hepatic arterial infusion chemotherapy in patients with high-risk advanced hepatocellular carcinoma: a biomolecular exploratory, phase II trial
. Eur J Cancer
. 2022
;174
:68
–77
. 43.
He
MK
, Liang
RB
, Zhao
Y
, Xu
YJ
, Chen
HW
, Zhou
YM
, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma
. Ther Adv Med Oncol
. 2021
;13
:17588359211002720
. 44.
Yu
B
, Zhang
N
, Feng
Y
, Zhang
Y
, Zhang
T
, Wang
L
. Hepatectomy after conversion therapy with hepatic arterial infusion chemotherapy, tyrosine kinase inhibitors and anti-PD-1 antibodies for initially unresectable hepatocellular carcinoma
. J Hepatocell Carcinoma
. 2023
;10
:1709
–21
. 45.
Kudo
M
. Adjuvant immunotherapy after curative treatment for hepatocellular carcinoma
. Liver Cancer
. 2021
;10
(5
):399
–403
. 46.
Lin
SY
, Pan
HW
, Liu
SH
, Jeng
YM
, Hu
FC
, Peng
SY
, et al. ASPM is a novel marker for vascular invasion, early recurrence, and poor prognosis of hepatocellular carcinoma
. Clin Cancer Res
. 2008
;14
(15
):4814
–20
. 47.
Lin
KY
, Chen
QJ
, Tang
SC
, Lin
ZW
, Zhang
JX
, Zheng
SM
, et al. Prognostic implications of alpha-fetoprotein and C-reactive protein elevation in hepatocellular carcinoma following resection (PACE): a large cohort study of 2770 patients
. BMC Cancer
. 2023
;23
(1
):1190
. 48.
Bruix
J
, Reig
M
, Sherman
M
. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma
. Gastroenterology
. 2016
;150
(4
):835
–53
. 49.
Kudo
M
, Finn
RS
, Qin
S
, Han
KH
, Ikeda
K
, Piscaglia
F
, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial
. Lancet
. 2018
;391
(10126
):1163
–73
. 50.
Zhu
AX
, Kang
YK
, Yen
CJ
, Finn
RS
, Galle
PR
, Llovet
JM
, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial
. Lancet Oncol
. 2019
;20
(2
):282
–96
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