Introduction: Pharmacological treatment of unresectable hepatocellular carcinoma (uHCC) includes sorafenib and lenvatinib, a tyrosine kinase inhibitor, which are linked to low serum levels of carnitine and reduced skeletal muscle volume. Nowadays, atezolizumab plus bevacizumab (Atezo/Bev) combination therapy is recommended as the first-line treatment for patients with uHCC. However, the association with decreased muscle mass or cardiac function is unknown. Therefore, this study aimed to evaluate the effects of Atezo/Bev on skeletal muscle volume and cardiac function in patients with uHCC. Methods: This retrospective study included 55 adult Japanese patients with chronic liver diseases and uHCC treated with Atezo/Bev. Patients were divided into three groups according to age: middle, preold, and old. Serum levels of carnitine and cardiac function were measured before and after 3 weeks of treatment. The psoas muscle index (PMI) was measured before and after 6 weeks of treatment. Results: After treatment, the global longitudinal strain was significantly lower in the old group, whereas the PMI and ejection fraction were significantly lower in the preold and old groups. However, no significant difference in serum levels of total carnitine and those fractions with treatment in each group was found. Cardiac function decreased in the preold and old groups. Conclusion: When treating patients with uHCC by Atezo/Bev, caution should be taken in preold and old patients because they are vulnerable to decreased skeletal muscle mass and deterioration of cardiac function. Strength training and regular monitoring of cardiac function are encouraged in these groups.

1.
Abou-Alfa
GK
,
Lau
G
,
Kudo
M
,
Chan
SL
,
Kelley
RK
,
Furuse
J
, et al
.
Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma
.
NEJM Evid
.
2022
;
1
(
8
):
EVIDoa2100070
.
2.
Reck
M
,
Mok
TSK
,
Nishio
M
,
Jotte
RM
,
Cappuzzo
F
,
Orlandi
F
, et al
.
Atezolizumab plus bevacizumab and chemotherapy in nonsmall-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial
.
Lancet Respir Med
.
2019
;
7
(
5
):
387
401
.
3.
Montano-Loza
AJ
,
Meza-Junco
J
,
Prado
CMM
,
Lieffers
JR
,
Baracos
VE
,
Bain
VG
, et al
.
Muscle wasting is associated with mortality in patients with cirrhosis
.
Clin Gastroenterol Hepatol
.
2012
;
10
(
2
):
166
73.e1
.
4.
Kaido
T
,
Ogawa
K
,
Fujimoto
Y
,
Ogura
Y
,
Hata
K
,
Ito
T
, et al
.
Impact of sarcopenia on survival in patients undergoing living donor liver transplantation
.
Am J Transplant
.
2013
;
13
(
6
):
1549
56
.
5.
Hanai
T
,
Shiraki
M
,
Nishimura
K
,
Ohnishi
S
,
Imai
K
,
Suetsugu
A
, et al
.
Sarcopenia impairs prognosis of patients with liver cirrhosis
.
Nutrition
.
2015
;
31
(
1
):
193
9
.
6.
Liu
Y
,
Kobayashi
S
,
Karako
K
,
Song
P
,
Tang
W
.
The latest policies, practices, and hotspots in research in conjunction with the aging of Japan’s population
.
Biosci Trends
.
2024
;
18
(
3
):
219
23
.
7.
Dayhoff
NE
,
Suhrheinrich
J
,
Wigglesworth
J
,
Topp
R
,
Moore
S
.
Balance and muscle strength as predictors of frailty among older adults
.
Gerontol Nurs
.
1998
;
24
(
7
):
18
55
.
8.
Kinugasa
Y
,
Yamamoto
K
.
The challenge of frailty and sarcopenia in heart failure with preserved ejection fraction
.
Heart
.
2017
;
103
(
3
):
184
9
.
9.
Kendler
BS
.
Carnitine: an overview of its role in preventive medicine
.
Prev Med
.
1986
;
15
(
4
):
373
90
.
10.
Flanagan
JL
,
Simmons
PA
,
Vehige
J
,
Willcox
MD
,
Garrett
Q
.
Role of carnitine in disease
.
Nutr Metab
.
2010
;
7
:
30
.
11.
Koizumi
T
,
Nikaido
H
,
Hayakawa
J
,
Nonomura
A
,
Yoneda
T
.
Infantile disease with microvesicular fatty infiltration of viscera spontaneously occurring in the C3H-H-2(0) strain of mouse with similarities to Reye’s syndrome
.
Lab Anim
.
1988
;
22
(
1
):
83
7
.
12.
Magoulas
PL
,
El-Hattab
AW
.
Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management
.
Orphanet J Rare Dis
.
2012
;
7
:
68
.
13.
Rudman
D
,
Sewell
CW
,
Ansley
JD
.
Deficiency of carnitine in cachectic cirrhotic patients
.
J Clin Invest
.
1977
;
60
(
3
):
716
23
.
14.
Ohtani
Y
,
Nishiyama
S
,
Matsuda
I
.
Renal handling of free and acylcarnitine in secondary carnitine deficiency
.
Neurology
.
1984
;
34
(
7
):
977
9
.
15.
Hu
C
,
Lancaster
CS
,
Zuo
Z
,
Hu
S
,
Chen
Z
,
Rubnitz
JE
, et al
.
Inhibition of OCTN2-mediated transport of carnitine by etoposide
.
Mol Cancer Ther
.
2012
;
11
(
4
):
921
9
.
16.
Amanuma
M
,
Nagai
H
,
Igarashi
Y
.
Sorafenib might induce sarcopenia in patients with hepatocellular carcinoma by inhibiting carnitine absorption
.
Anticancer Res
.
2020
;
40
(
7
):
4173
82
.
17.
Nagai
H
,
Amanuma
M
,
Mukozu
T
,
Kobayashi
K
,
Nagumo
H
,
Mohri
K
, et al
.
Effects of lenvatinib on skeletal muscle volume and cardiac function in patients with hepatocellular carcinoma
.
Oncology
.
2023
;
101
(
10
):
634
44
.
18.
Finn
RS
,
Ikeda
M
,
Zhu
AX
,
Sung
MW
,
Baron
AD
,
Kudo
M
, et al
.
Phase Ib study of lenvatinib plus Pembrolizumab in patients with unresectable hepatocellular carcinoma
.
J Clin Oncol
.
2020
;
38
(
26
):
2960
70
.
19.
Llovet
JM
,
Di Bisceglie
AM
,
Bruix
J
,
Kramer
BS
,
Lencioni
R
,
Zhu
AX
, et al
.
Design and endpoints of clinical trials in hepatocellular carcinoma
.
J Natl Cancer Inst
.
2008
;
100
(
10
):
698
711
.
20.
Lencioni
R
,
Llovet
JM
.
Modified RECIST (mRECIST) assessment for hepatocellular carcinoma
.
Semin Liver Dis
.
2010
;
30
(
1
):
52
60
.
21.
Harimoto
N
,
Shirabe
K
,
Yamashita
YI
,
Ikegami
T
,
Yoshizumi
T
,
Soejima
Y
, et al
.
Sarcopenia as a predictor of prognosis in patients following hepatectomy for hepatocellular carcinoma
.
Br J Surg
.
2013
;
100
(
11
):
1523
30
.
22.
Takahashi
M
,
Ueda
S
,
Misaki
H
,
Sugiyama
N
,
Matsumoto
K
,
Matsuo
N
, et al
.
Carnitine determination by an enzymatic cycling method with carnitine dehydrogenase
.
Clin Chem
.
1994
;
40
(
5
):
817
21
.
23.
Mollema
SA
,
Delgado
V
,
Bertini
M
,
Antoni
ML
,
Boersma
E
,
Holman
ER
, et al
.
Viability assessment with global left ventricular longitudinal strain predicts recovery of left ventricular function after acute myocardial infarction
.
Circ Cardiovasc Imaging
.
2010
;
3
(
1
):
15
23
.
24.
Bertini
M
,
Mollema
SA
,
Delgado
V
,
Antoni
ML
,
Ng
ACT
,
Holman
ER
, et al
.
Impact of time to reperfusion after acute myocardial infarction on myocardial damage assessed by left ventricular longitudinal strain
.
Am J Cardiol
.
2009
;
104
(
4
):
480
5
.
25.
Leitman
M
,
Lysyansky
P
,
Sidenko
S
,
Shir
V
,
Peleg
E
,
Binenbaum
M
, et al
.
Two-dimensional strain-a novel software for real-time quantitative echocardiographic assessment of myocardial function
.
J Am Soc Echocardiogr
.
2004
;
17
(
10
):
1021
9
.
26.
Reisner
SA
,
Lysyansky
P
,
Agmon
Y
,
Mutlak
D
,
Lessick
J
,
Friedman
Z
.
Global longitudinal strain: a novel index of left ventricular systolic function
.
J Am Soc Echocardiogr
.
2004
;
17
(
6
):
630
3
.
27.
Kitajima
Y
,
Takahashi
H
,
Akiyama
T
,
Murayama
K
,
Iwane
S
,
Kuwashiro
T
, et al
.
Supplementation with branched-chain amino acids ameliorates hypoalbuminemia, prevents sarcopenia, and reduces fat accumulation in the skeletal muscles of patients with liver cirrhosis
.
J Gastroenterol
.
2018
;
53
(
3
):
427
37
.
28.
Malaguarnera
M
,
Vacante
M
,
Giordano
M
,
Pennisi
G
,
Bella
R
,
Rampello
L
, et al
.
Oral acetyl-L-carnitine therapy reduces fatigue in overt hepatic encephalopathy: a randomized, double-blind, placebo-controlled study
.
Am J Clin Nutr
.
2011
;
93
(
4
):
799
808
.
29.
Takahashi
S
.
Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy
.
Biol Pharm Bull
.
2011
;
34
(
12
):
1785
8
.
30.
Hicklin
DJ
,
Ellis
LM
.
Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis
.
J Clin Oncol
.
2005
;
23
(
5
):
1011
27
.
31.
Stanton
T
,
Leano
R
,
Marwick
TH
.
Prediction of all-cause mortality from global longitudinal speckle strain: comparison with ejection fraction and wall motion scoring
.
Circ Cardiovasc Imaging
.
2009
;
2
(
5
):
356
64
.
32.
Li
W
,
Croce
K
,
Steensma
DP
,
McDermott
DF
,
Ben-Yehuda
O
,
Moslehi
J
.
Vascular and metabolic implications of novel targeted cancer therapies: focus on kinase inhibitors
.
J Am Coll Cardiol
.
2015
;
66
(
10
):
1160
78
.
33.
Lankhorst
S
,
Saleh
L
,
Danser
AJ
,
van den Meiracker
AH
.
Etiology of angiogenesis inhibition-related hypertension
.
Curr Opin Pharmacol
.
2015
;
21
:
7
13
.
34.
Li
Y
,
Tian
W
,
Yue
D
,
Chen
C
,
Li
C
,
Zhang
Z
, et al
.
Bevacizumab-induced mitochondrial dysfunction, endoplasmic reticulum stress, and ERK inactivation contribute to cardiotoxicity
.
Oxid Med Cell Longev
.
2021
;
2021
(
1
):
5548130
.
35.
Horiguchi
H
,
Kadomatsu
T
,
Yamashita
T
,
Yumoto
S
,
Terada
K
,
Sato
M
, et al
.
ANGPTL2 promotes immune checkpoint inhibitor-related murine autoimmune myocarditis
.
Commun Biol
.
2023
;
6
(
1
):
965
.
36.
Gergely
TG
,
Drobni
ZD
,
Sayour
NV
,
Ferdinandy
P
,
Varga
ZV
.
Molecular fingerprints of cardiovascular toxicities of immune checkpoint inhibitors
.
Basic Res Cardiol
.
2024
.
37.
Tandon
P
,
Ney
M
,
Irwin
I
,
Ma
MM
,
Gramlich
L
,
Bain
VG
, et al
.
Severe muscle depletion in patients on the liver transplant wait list: its prevalence and independent prognostic value
.
Liver Transpl
.
2012
;
18
(
10
):
1209
16
.
You do not currently have access to this content.