Abstract
Background: Patients with advanced hepatocellular carcinoma (HCC) arising in nonalcoholic fatty liver disease (NAFLD) may not be suitable for systemic therapy due to metabolic syndrome-related diseases. Recent trials did not show a survival benefit of radioembolization (RE) compared to sorafenib in advanced stage HCC but RE may represent an adequate alternative in patients with contraindications to systemic therapy due to its favorable safety profile. Aim: To investigate the impact of NAFLD-related comorbidities on safety and efficacy of RE for HCC treatment in a retrospective monocentric cohort study. Patients and Methods: Safety and efficacy of RE were evaluated in patients with NAFLD-associated HCC. Hepatitis B virus (HBV)-related HCC patients served as controls, exhibiting matching Barcelona Liver Cancer Clinic (BCLC) stages while showing significantly fewer metabolic comorbidities. Results: Overall, 87 HCC patients with NAFLD (mean age 71.3 ± 6.9 years) and 62 HCC patients with HBV (mean age 58.8 ± 10.9 years) not amenable to surgical or conventional locoregional treatments were included. Patients with HBV-related HCC had a comparable liver function to HCC patients with NAFLD. RE treatment-related toxicity did not differ between the two groups (increase in bilirubin Common Terminology Criteria for Adverse Events grade in 29 [38.7%] NAFLD and 20 [39.2%] HBV patients, p = 0.91). Overall survival was similar in HCC patients with NAFLD and HBV (11.1 [interquartile range, IQR, 18.27] vs. 9.3 months [IQR 14.73], p = 0.38), also in the subgroup analyses of BCLC B and C stages. Conclusion: RE showed similar survival outcomes at a comparable toxicity profile in HCC patients with NAFLD and HBV. NAFLD-associated metabolic comorbidities did not exhibit limitations for RE while offering comparable therapeutic efficacy as compared to HBV patients.
References
1.
2.
White
DL
, Kanwal
F
, El-Serag
HB
: Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review.
Clin Gastroenterol Hepatol 2012
;10:1342-1359 e1342. 3.
Ertle
J
, Dechêne
A
, Sowa
JP
, Penndorf
V
, Herzer
K
, Kaiser
G
, et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis
. Int J Cancer
. 2011
May
;128
(10
):2436
–43
.
[PubMed]
0020-71364.
Bechmann
LP
, Hannivoort
RA
, Gerken
G
, Hotamisligil
GS
, Trauner
M
, Canbay
A
. The interaction of hepatic lipid and glucose metabolism in liver diseases
. J Hepatol
. 2012
Apr
;56
(4
):952
–64
.
[PubMed]
0168-82785.
El-Serag
HB
, Richardson
PA
, Everhart
JE
. The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans
. Am J Gastroenterol
. 2001
Aug
;96
(8
):2462
–7
.
[PubMed]
0002-92706.
Marrero
JA
, Fontana
RJ
, Fu
S
, Conjeevaram
HS
, Su
GL
, Lok
AS
. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma
. J Hepatol
. 2005
Feb
;42
(2
):218
–24
.
[PubMed]
0168-82787.
Jemal
A
, Bray
F
, Center
MM
, Ferlay
J
, Ward
E
, Forman
D
. Global cancer statistics
. CA Cancer J Clin
. 2011
Mar-Apr
;61
(2
):69
–90
.
[PubMed]
0007-92358.
Bruix
J
, Sherman
M
; American Association for the Study of Liver Diseases
. Management of hepatocellular carcinoma: an update
. Hepatology
. 2011
Mar
;53
(3
):1020
–2
.
[PubMed]
0270-91399.
Llovet
JM
, Fuster
J
, Bruix
J
. Prognosis of hepatocellular carcinoma
. Hepatogastroenterology
. 2002
Jan-Feb
;49
(43
):7
–11
.
[PubMed]
0172-639010.
Groupe d’Etude et de Traitement du Carcinome Hépatocellulaire
. A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma
. N Engl J Med
. 1995
May
;332
(19
):1256
–61
.
[PubMed]
0028-479311.
Galle
PR
, Forner
A
, Llovet
JM
, Mazzaferro
V
, Piscaglia
F
, Raoul
JL
, et al.; European Association for the Study of the Liver
. Electronic address eee, European Association for the Study of the L: EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma
. J Hepatol
. 2018
;69
(1
):182
–236
. 0168-827812.
Llovet
JM
, Ricci
S
, Mazzaferro
V
, Hilgard
P
, Gane
E
, Blanc
JF
, et al.; SHARP Investigators Study Group
. Sorafenib in advanced hepatocellular carcinoma
. N Engl J Med
. 2008
Jul
;359
(4
):378
–90
.
[PubMed]
0028-479313.
Cho
YY
, Lee
M
, Kim
HC
, Chung
JW
, Kim
YH
, Gwak
GY
, et al. Radioembolization Is a Safe and Effective Treatment for Hepatocellular Carcinoma with Portal Vein Thrombosis: A Propensity Score Analysis
. PLoS One
. 2016
May
;11
(5
):e0154986
.
[PubMed]
1932-620314.
de la Torre
MA
, Buades-Mateu
J
, de la Rosa
PA
, Lué
A
, Bustamante
FJ
, Serrano
MT
, et al. A comparison of survival in patients with hepatocellular carcinoma and portal vein invasion treated by radioembolization or sorafenib
. Liver Int
. 2016
Aug
;36
(8
):1206
–12
.
[PubMed]
1478-322315.
Gramenzi
A
, Golfieri
R
, Mosconi
C
, Cappelli
A
, Granito
A
, Cucchetti
A
, et al.; BLOG (Bologna Liver Oncology Group)
. Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis
. Liver Int
. 2015
Mar
;35
(3
):1036
–47
.
[PubMed]
1478-322316.
Salem
R
, Gabr
A
, Riaz
A
, Mora
R
, Ali
R
, Abecassis
M
, et al. Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience
. Hepatology
. 2018
Oct
;68
(4
):1429
–40
.
[PubMed]
0270-913917.
Hilgard
P
, Hamami
M
, Fouly
AE
, Scherag
A
, Müller
S
, Ertle
J
, et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: european experience on safety and long-term survival
. Hepatology
. 2010
Nov
;52
(5
):1741
–9
.
[PubMed]
0270-913918.
Alberti
KG
, Eckel
RH
, Grundy
SM
, Zimmet
PZ
, Cleeman
JI
, Donato
KA
, et al.; International Diabetes Federation Task Force on Epidemiology and Prevention
; Hational Heart, Lung, and Blood Institute
; American Heart Association
; World Heart Federation
; International Atherosclerosis Society
; International Association for the Study of Obesity
. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity
. Circulation
. 2009
Oct
;120
(16
):1640
–5
.
[PubMed]
0009-732219.
Ascha
MS
, Hanouneh
IA
, Lopez
R
, Tamimi
TA
, Feldstein
AF
, Zein
NN
. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis
. Hepatology
. 2010
Jun
;51
(6
):1972
–8
.
[PubMed]
0270-913920.
Dawson
DA
, Grant
BF
, Harford
TC
. Variation in the association of alcohol consumption with five DSM-IV alcohol problem domains
. Alcohol Clin Exp Res
. 1995
Feb
;19
(1
):66
–74
.
[PubMed]
0145-600821.
Bruix
J
, Sherman
M
; Practice Guidelines Committee, American Association for the Study of Liver Diseases
. Management of hepatocellular carcinoma
. Hepatology
. 2005
Nov
;42
(5
):1208
–36
.
[PubMed]
0270-913922.
European Association For The Study Of The L
. European Organisation For R, Treatment Of C: EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma
. J Hepatol
. 2012
;56
(4
):908
–43
. 0168-827823.
Ganten
TM
, Stauber
RE
, Schott
E
, Malfertheiner
P
, Buder
R
, Galle
PR
, et al. Sorafenib in Patients with Hepatocellular Carcinoma-Results of the Observational INSIGHT Study
. Clin Cancer Res
. 2017
Oct
;23
(19
):5720
–8
.
[PubMed]
1078-043224.
Williet
N
, Clavel
L
, Bourmaud
A
, Verot
C
, Bouarioua
N
, Roblin
X
, et al. Tolerance and outcomes of sorafenib in elderly patients treated for advanced hepatocellular carcinoma
. Dig Liver Dis
. 2017
Sep
;49
(9
):1043
–9
.
[PubMed]
1590-865825.
Golfieri
R
, Bilbao
JI
, Carpanese
L
, Cianni
R
, Gasparini
D
, Ezziddin
S
, et al.; European Network on Radioembolization with Yttrium-90 Microspheres (ENRY) study collaborators
. Comparison of the survival and tolerability of radioembolization in elderly vs. younger patients with unresectable hepatocellular carcinoma
. J Hepatol
. 2013
Oct
;59
(4
):753
–61
.
[PubMed]
0168-827826.
Mazzaferro
V
, Sposito
C
, Bhoori
S
, Romito
R
, Chiesa
C
, Morosi
C
, et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study
. Hepatology
. 2013
May
;57
(5
):1826
–37
.
[PubMed]
0270-913927.
Wang
H
, Wang
H
, Yu
Z
, Liu
H
. Alternative treatment strategies to sorafenib in patients with advanced hepatocellular carcinoma: a meta-analysis of randomized Phase III trials
. OncoTargets Ther
. 2018
Aug
;11
:5195
–201
.
[PubMed]
1178-693028.
Vilgrain
V
, Pereira
H
, Assenat
E
, Guiu
B
, Ilonca
AD
, Pageaux
GP
, et al.; SARAH Trial Group
. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial
. Lancet Oncol
. 2017
Dec
;18
(12
):1624
–36
.
[PubMed]
1470-204529.
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
Mar
;391
(10126
):1163
–73
.
[PubMed]
0140-673630.
Chow
PK
, Gandhi
M
, Tan
SB
, Khin
MW
, Khasbazar
A
, Ong
J
, et al.; Asia-Pacific Hepatocellular Carcinoma Trials Group
. SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma
. J Clin Oncol
. 2018
Jul
;36
(19
):1913
–21
.
[PubMed]
0732-183X31.
Llovet
JM
, Bustamante
J
, Castells
A
, Vilana
R
, Ayuso
MC
, Sala
M
, et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials
. Hepatology
. 1999
Jan
;29
(1
):62
–7
.
[PubMed]
0270-913932.
Cabibbo
G
, Maida
M
, Genco
C
, Parisi
P
, Peralta
M
, Antonucci
M
, et al. Natural history of untreatable hepatocellular carcinoma: A retrospective cohort study
. World J Hepatol
. 2012
Sep
;4
(9
):256
–61
.
[PubMed]
1948-518233.
Spreafico
C
, Sposito
C
, Vaiani
M
, Cascella
T
, Bhoori
S
, Morosi
C
, et al. Development of a prognostic score to predict response to Yttrium-90 radioembolization for hepatocellular carcinoma with portal vein invasion
. J Hepatol
. 2018
Apr
;68
(4
):724
–32
.
[PubMed]
0168-827834.
Mohamad
B
, Shah
V
, Onyshchenko
M
, Elshamy
M
, Aucejo
F
, Lopez
R
, et al. Characterization of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis
. Hepatol Int
. 2016
Jul
;10
(4
):632
–9
.
[PubMed]
1936-053335.
Jun
TW
, Yeh
ML
, Yang
JD
, Chen
VL
, Nguyen
P
, Giama
NH
, et al. More advanced disease and worse survival in cryptogenic compared to viral hepatocellular carcinoma
. Liver Int
. 2018
May
;38
(5
):895
–902
.
[PubMed]
1478-322336.
Weinmann
A
, Alt
Y
, Koch
S
, Nelles
C
, Düber
C
, Lang
H
, et al. Treatment and survival of non-alcoholic steatohepatitis associated hepatocellular carcinoma
. BMC Cancer
. 2015
Apr
;15
(1
):210
.
[PubMed]
1471-240737.
Lee
CH
, Hsieh
SY
, Lin
JL
, Liu
MS
, Yen
TH
. Hepatocellular carcinoma in patients with chronic kidney disease
. World J Gastroenterol
. 2013
Apr
;19
(16
):2466
–72
.
[PubMed]
1007-932738.
Kennoki
T
, Kondo
T
, Kimata
N
, Murakami
J
, Ishimori
I
, Nakazawa
H
, et al. Clinical results and pharmacokinetics of sorafenib in chronic hemodialysis patients with metastatic renal cell carcinoma in a single center
. Jpn J Clin Oncol
. 2011
May
;41
(5
):647
–55
.
[PubMed]
0368-281139.
Garwood
ER
, Fidelman
N
, Hoch
SE
, Kerlan
RK
Jr, Yao
FY
. Morbidity and mortality following transarterial liver chemoembolization in patients with hepatocellular carcinoma and synthetic hepatic dysfunction
. Liver Transpl
. 2013
Feb
;19
(2
):164
–73
.
[PubMed]
1527-646540.
Op den Winkel
M
, Nagel
D
, Op den Winkel
P
, Trojan
J
, Paprottka
PM
, Steib
CJ
, et al. Transarterial chemoembolization for hepatocellular carcinoma: development and external validation of the Munich-TACE score
. Eur J Gastroenterol Hepatol
. 2018
Jan
;30
(1
):44
–53
.
[PubMed]
0954-691X© 2019 S. Karger AG, Basel
2019
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