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Background The aim of this study was to explore the relationship between follow-up imaging characteristics and overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients under sorafenib treatment. Methods Associations between OS and objective response (OR) by mRECIST or early tumor shrinkage (ETS; ≥20% reduction in enhancing tumor diameter at the first follow-up imaging) were analyzed in HCC patients treated with sorafenib within a multicenter phase II trial (SORAMIC). 115 patients were included in this substudy. The relationship between survival and OR or ETS were explored. Landmark analyses were performed according to OR at fixed time points. Cox proportional hazards models with OR and ETS as a time-dependent covariate were used to compare survival with factors known to influence OS. Results The OR rate was 29.5%. Responders had significantly better OS than non-responders (median 30.3 vs. 11.4 months; HR, 0.38 [95% CI, 0.22–0.63], p < 0.001), and longer progression-free survival (PFS; median 10.1 vs. 4.3 months, p = 0.015). Patients with ETS ≥ 20% had longer OS (median 22.1 vs. 11.4 months, p = 0.002) and PFS (median 8.0 vs. 4.3 months, p = 0.034) than patients with ETS < 20%. Besides OR and ETS, male gender, lower bilirubin and ALBI grade were associated with improved OS in univariate analysis. Separate models of multivariable analysis confirmed OR and ETS as independent predictors of OS. Conclusion OR according to mRECIST and ETS in patients receiving sorafenib treatment are independent prognostic factors for OS. These parameters can be used for assessment of treatment benefit and optimal treatment sequencing in patients with advanced HCC.
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R E S E A R C H A R T I C L E Open Access
Early tumor shrinkage and response
assessment according to mRECIST predict
overall survival in hepatocellular carcinoma
patients under sorafenib
Osman Öcal
1
, Regina Schinner
1
, Kerstin Schütte
2
, Enrico N. de Toni
3
, Christian Loewe
4
, Otto van Delden
5
,
Vincent Vandecaveye
6
, Bernhard Gebauer
7
, Christoph J. Zech
8
, Christian Sengel
9
, Irene Bargellini
10
,
Antonio Gasbarrini
11
, Bruno Sangro
12
, Maciej Pech
13
, Peter Malfertheiner
3
, Jens Ricke
1
, Max Seidensticker
1*
and for
the SORAMIC study group
Abstract
Background: The aim of this study was to explore the relationship between follow-up imaging characteristics and
overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients under sorafenib treatment.
Methods: Associations between OS and objective response (OR) by mRECIST or early tumor shrinkage (ETS; 20%
reduction in enhancing tumor diameter at the first follow-up imaging) were analyzed in HCC patients treated with
sorafenib within a multicenter phase II trial (SORAMIC). 115 patients were included in this substudy. The relationship
between survival and OR or ETS were explored. Landmark analyses were performed according to OR at fixed time
points. Cox proportional hazards models with OR and ETS as a time-dependent covariate were used to compare
survival with factors known to influence OS.
Results: The OR rate was 29.5%. Responders had significantly better OS than non-responders (median 30.3 vs. 11.4
months; HR, 0.38 [95% CI, 0.220.63], p< 0.001), and longer progression-free survival (PFS; median 10.1 vs. 4.3
months, p= 0.015). Patients with ETS 20% had longer OS (median 22.1 vs. 11.4 months, p= 0.002) and PFS
(median 8.0 vs. 4.3 months, p= 0.034) than patients with ETS < 20%. Besides OR and ETS, male gender, lower
bilirubin and ALBI grade were associated with improved OS in univariate analysis. Separate models of multivariable
analysis confirmed OR and ETS as independent predictors of OS.
Conclusion: OR according to mRECIST and ETS in patients receiving sorafenib treatment are independent
prognostic factors for OS. These parameters can be used for assessment of treatment benefit and optimal
treatment sequencing in patients with advanced HCC.
Keywords: Hepatocellular carcinoma, Sorafenib, mRECIST, Early tumor shrinkage, Objective response
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* Correspondence: max.seidensticker@med.lmu.de
1
Department of Radiology, University Hospital, LMU Munich,
Marchioninistrasse 15, 81377 Munich, Germany
Full list of author information is available at the end of the article
Öcal et al. Cancer Imaging (2022) 22:1
https://doi.org/10.1186/s40644-021-00439-x
Introduction
Hepatocellular carcinoma (HCC) is the most frequent
primary liver cancer and the third leading cause of
cancer-related death [1]. Approximately 6080% of
patients with newly diagnosed HCC have an under-
lying liver disease, including chronic hepatitis B or C
infections, alcoholic liver cirrhosis, and non-alcoholic
steatohepatitis. Despite screening populations at risk,
only about 30% of patients are diagnosed at early
stages that might benefit from potentially curative
treatments.
Sorafenib is a multitarget tyrosine kinase inhibitor
that interrupts tumor proliferation and angiogenesis,
and was shown in the phase III SHARP trial and the
Asia-Pacific trial to improve overall survival (OS) in
HCC [2,3]. Although OS and time to progression
were improved in the sorafenib arm in both studies,
the objective response (OR) rate according to RECIST
was 23% and this failed to capture patients with sur-
vival benefit. To overcome this problem, mRECIST
has been proposed for response assessment in pa-
tients with HCC, which, in contrast to RECIST, em-
ploys the arterially enhancing portion of the target
lesions only [4]. Whereas some retrospective studies
showed better OS in patients with OR according to
mRECIST in patients receiving sorafenib, others failed
to demonstrate improved outcomes [59]. One study
which combined analysis of two prospective phase II
studies showed patients with an OR had significantly
longer survival; however, this significance was lost in
multivariate analysis including macrovascular invasion
and extrahepatic disease [10]. However, most of these
studies were single-center and retrospectively con-
ducted, and in none of them, statistical methods to
exclude biased estimates of survival were applied [11].
Recently a subanalysis of the phase III SILIUS trial
comparing sorafenib alone vs. sorafenib and hepatic
arterial infusion chemotherapy in Japan demonstrated
that OR was an independent prognostic factor for OS
using appropriate statistical methods [12].
Although patients continue to receive their assigned
treatment unless disease progression is encountered at
follow-up imaging, not all patients with disease con-
trol benefit equally from treatment. A retrospective
analysis of HCC patients receiving sorafenib revealed
that patients who had stable disease (SD) for more
than three months had similar OS to patients who
had an OR, while patients with SD for a shorter dur-
ation had worse outcomes, similar to patients with
progressive disease (PD) [6].
In clinical practice, early identification of patients
benefitting from sorafenib treatment is crucial to avoid
overtreatment, which may lead to toxicities or subopti-
mal treatment sequencing, especially in light of
alternative treatments [1315]. Early tumor shrinkage
(ETS) is defined as a reduction in tumor size at the first
radiological follow-up evaluation and it has been shown
to predict treatment outcome in patients with metastatic
colorectal carcinoma, pancreatic cancer, renal cell car-
cinoma, and also in patients with HCC receiving lenvati-
nib treatment [1619].
This study aimed to evaluate the prognostic role of
OR and ETS in patients receiving sorafenib therapy for
the treatment of advanced HCC in a Western cohort.
Material and methods
Study population
SORAMIC was a prospective, randomized, controlled,
phase II trial comparing the effects of sorafenib mono-
therapy and a combination of selective internal radiation
therapy (Yttrium-90 radioembolization) and sorafenib,
performed in 38 centers in 12 countries in Europe and
Turkey. The inclusion criteria for SORAMIC have been
described previously [20]. The main criteria were a diag-
nosis of HCC with Barcelona Clinic Liver Cancer
(BCLC) B (not eligible for transarterial chemoemboliza-
tion) or C, preserved liver function (Child-Pugh scores A
to B7), and an Eastern Cooperative Oncology Group
performance status 2. Extrahepatic metastases were
permitted if the disease was liver-dominant and did not
involve the lungs.
The present study represents a post hoc analysis of
patients in the sorafenib-only arm of the palliative
trial cohort. The study cohort comprised 208 patients
randomized to receive sorafenib monotherapy. The
study protocol was approved by the institutional re-
view board of participating centers. Written, informed
consent was obtained from all patients. The primary
aim of the analysis was to explore the radiological re-
sponse rate to sorafenib treatment and its correlation
with OS. Criteria were OR, ETS, and depth of
response (DpR).
Follow-up imaging every three months was recom-
mended, but was not a mandatory part of the SORAMIC
trial. The imaging modality computed tomography
(CT) or magnetic resonance imaging (MRI) was
chosen by the local investigator. Centralized image as-
sessment was not included in the main study. Imaging
follow-up of a total of 136 patients was available for re-
view. The following inclusion criteria were applied for
this study: (1) at least one follow-up before 6 months or
6 months follow-up other than PD, (2) follow-up im-
aging until death or PD (last imaging within 6 months)
or disease control (SD, partial response [PR], complete
response [CR]) at 12 months after randomization, (3)
minimum follow-up duration of 6 months unless PD was
encountered before. A total of 115 patients were in-
cluded in this study (Supplementary Fig. 1).
Öcal et al. Cancer Imaging (2022) 22:1 Page 2 of 13
Table 1 Patient characteristics of responders and non-responders
Variable Total n= 115 Responders n= 34 Non-responders n=81 p-value
Sex
Female 15 (13.0%) 7 (20.6%) 8 (9.9%) 0.1196
Male 100 (87.0%) 27 (79.4%) 73 (90.1%)
Age, years
Mean (SD) 65.3 (8.7) 66.1 (7.8) 65.0 (9.1) 0.5156
Median (IQR) 65.0 (12.0) 67.0 (13.0) 65.0 (12.0)
Age category, years
65 55 (47.8%) 15 (44.1%) 40 (49.4%) 0.606
>65 60 (52.2%) 19 (55.9%) 41 (50.6%)
Ethnicity
Missing 10 (8.7%) 4 (11.8%) 6 (7.4%) 0.6638
Hispanic or Latin 5 (4.8%) 1 (3.3%) 4 (5.3%)
Other 100 (95.2%) 29 (96.7%) 71 (94.7%)
Race
Missing 11 (9.6%) 4 (11.8%) 7 (8.6%) 0.2326
Black 2 (1.9%) 0 2 (2.7%)
Other 3 (2.9%) 2 (6.7%) 1 (1.4%)
White 99 (95.2%) 28 (93.3%) 71 (95.9%)
ECOG status
090 (78.3%) 27 (79.4%) 63 (77.8%) 0.8463
125 (21.7%) 7 (20.6%) 18 (22.2%)
HCC diagnosis by:
Missing 2 (1.7%) 1 (2.9%) 1 (1.2%) 0.7518
EASL criteria 50 (43.5%) 13 (38.2%) 37 (45.7%)
Histology 50 (43.5%) 15 (44.1%) 35 (43.2%)
Other 13 (11.3%) 5 (14.7%) 8 (9.9%)
Hepatitis B
No 104 (90.4%) 31 (91.2%) 73 (90.1%) 0.8609
Yes 11 (9.6%) 3 (8.8%) 8 (9.9%)
Hepatitis C
No 81 (70.4%) 26 (76.5%) 55 (67.9%) 0.3581
Yes 34 (29.6%) 8 (23.5%) 26 (32.1%)
Alcohol etiology
No 63 (54.8%) 16 (47.1%) 47 (58.0%) 0.2809
Yes 52 (45.2%) 18 (52.9%) 34 (42.0%)
Previous therapies
TACE 28 (24.3%) 9 (26.5%) 19 (23.5%) 0.7311
TAE 2 (1.7%) 0 2 (2.5%) 0.3553
Resection 21 (18.3%) 9 (26.5%) 12 (14.8%) 0.1398
RFA 12 (10.4%) 6 (17.6%) 6 (7.4%) 0.1012
Brachytherapy 5 (4.3%) 1 (2.9%) 4 (4.9%) 0.6318
Max. diameter of largest lesion
Mean (SD) 68.0 (59.6) 69.8 (85.5) 67.3 (44.6) 0.2678
Median (IQR) 57.0 (45.0) 50.0 (40.0) 59.5 (52.0)
Öcal et al. Cancer Imaging (2022) 22:1 Page 3 of 13
Sorafenib treatment
Patients were administered sorafenib with a starting
dose of 200 mg b.i.d. for 1 week. After the first week,
the dose was increased to the target dose of 400 mg
b.i.d., and, in case of toxicity, the sorafenib dose was
modified according to pre-defined dosing guidelines.
The lowest accepted dose was 200 mg b.i.d. on alter-
nate days. Following the resolution of toxicities, main-
taining the highest tolerable dose level was attempted
with a stepwise dose re-escalation. Treatment-related
adverse events and routine laboratory tests were re-
corded every two months, and sorafenib treatment
was continued until disease progression (evaluated by
the local investigator) or toxicity which required
discontinuation.
Image analysis
All patients underwent CT and MRI at baseline for
study inclusion according to previously published pro-
tocols [21].Follow-upCTin60patients,MRIin45
patients, and both MRI and CT in 10 patients were
available. Review was performed by a fully blinded,
board-certified radiologist specialized in gastrointes-
tinal imaging. mRECIST was used for all assessments
(Supplementary Fig. 2). Two liver lesions were se-
lected as target lesions, according to published criteria
[22]; in the case of extrahepatic disease at baseline,
up to three extrahepatic lesions were selected as tar-
get lesions. As described in mRECIST, overall tumor
diameter measurements were used in intrahepatic
lesions with atypical enhancement patterns and all
extrahepatic lesions.
In addition to routine response analysis according
to mRECIST, progression-free survival (PFS; from
randomization to disease progression or death, cen-
sored at last imaging in patients without progres-
sion), time to response (from randomization to first
objective response), DpR (relation of smallest target
lesion diameter to baseline diameter), ETS (20% re-
duction in enhancing tumor diameter at the first
follow-up imaging), and time to DpR (from
randomization to DpR) was evaluated. For DpR and
ETS assessments, only hepatic target lesions were
evaluated and diameter measurements were taken
Table 1 Patient characteristics of responders and non-responders (Continued)
Variable Total n= 115 Responders n= 34 Non-responders n=81 p-value
Portal vein infiltration
Yes 60 (52.2%) 21 (61.8%) 39 (48.1%) 0.1822
Baseline metastasis
Yes 6 (5.2%) 0 6 (7.4%) 0.1031
BCLC
B34 (29.6%) 9 (26.5%) 25 (30.9%) 0.6375
C81 (70.4%) 25 (73.5%) 56 (69.1%)
Up-to-7 criterion
Inside 17 (14.8%) 7 (20.6%) 10 (12.3%) 0.2558
Outside 98 (85.2%) 27 (79.4%) 71 (87.7%)
Total bilirubin (μmol/L)
Mean (SD) 16.1 (7.1) 15.4 (7.3) 16.3 (7.1) 0.4752
Median (IQR) 14.9 (10.0) 14.4 (9) 15.0 (9.5)
Albumin g/L
Mean (SD) 37.8 (8.3) 38.9 (8.5) 37.4 (8.2) 0.3823
Median (IQR) 39.0 (7.7) 39.9 (6.5) 39.0 (8.0)
ALBI score
Mean (SD) 2.5 (0.7) 2.6 (0.8) 2.4 (0.7) 0.2331
Median (IQR) 2.5 (0.8) 2.7 (0.7) 2.5 (0.7)
Child-Pugh score
A105 (91.3%) 33 (97.1%) 72 (88.9%) 0.1559
B10 (8.7%) 1 (2.9%) 9 (11.1%
ALBI albumin-bilirubin, BCLC Barcelona Clinic Liver Cancer, EASL European Association for the Study of the Liver, ECOG Eastern Cooperative Oncology Group, HCC
hepatocellular carcinoma, IQR interquartile range, RFA radiofrequency ablation, SD standard deviation, TACE transarterial chemoembolization, TAE
transarterial embolization
Öcal et al. Cancer Imaging (2022) 22:1 Page 4 of 13
according to mRECIST. In patients with disease pro-
gression, the first progression site was noted (hep-
atic, extrahepatic, or both). In order to evaluate
whether further subgrouping of patients translated to
better survival prediction, patients with the best re-
sponse of PR were dichotomized according to me-
dian DpR.
Statistical analysis
All statistical analyses were performed using SAS ver-
sion 9.4 for Windows (Copyright SAS Institute Inc.,
Cary, NC, USA) and R statistical and computing soft-
ware, version 3.5.0 (http://www.r-project.org). Numer-
ical data are presented as means with standard
deviations. For categorical data, results are given as
absolute numbers with percentages. For comparison
of categorical data between responders and non-
responders, chi-square tests were applied; for continu-
ous data, T-tests or Mann-Whitney U tests were used
for testing the homogeneity of independent samples.
OS in responders and non-responders was estimated
by the unweighted Kaplan-Meier method. The same
analysis was repeated for patients with and without
ETS. The Mantel-Byar test was used to assess statis-
tical significance. Landmark analysis of OS by the ob-
jective response was conducted at 6 and 12 months
after randomization. The log-rank test was used for
the inference associated to the landmark analysis. For
all variables, univariate Cox proportional hazard re-
gression was performed as time-fixed covariates, while
objective response and ETS were analyzed as a time-
dependent variable. Statistically significant variables in
the univariate analyses (including objective response
as a time-dependent covariate) were analyzed in a
multivariate Cox regression model to explore prog-
nostic factors for OS. A separate multivariate Cox re-
gression model was used to explore the prognostic
value of ETS.
Fig. 1 Overall survival of patients with, compared to patients without, objective response. CI, confidence interval; HR, hazard ratio; OR, objective
response; OS, overall survival
Öcal et al. Cancer Imaging (2022) 22:1 Page 5 of 13
Results
At the end of study, 93 (80.8%) patients had died, with a
median OS of 14.3 months. Out of 115 patients, 34
(29.5%) were responders and the remaining 81 (70.4%)
were non-responders according to mRECIST. Best re-
sponse during follow-up was CR in 6 (5.2%) patients, PR
in 28 (24.3%) patients, SD in 50 (43.4%) patients, and PD
in 31 (26.9%) patients. Median time to response was 3.8
(range 1.38.1) months. The baseline and clinical char-
acteristics of patients with and without OR are shown in
Table 1. No significant differences were observed in the
baseline characteristics of responders and non-
responders.
The median OS was 30.3 months (95% CI, 16.344.8)
in responders and 11.4 months (95% CI, 9.716.1) in
non-responders (HR, 0.38 [95% CI, 0.220.63, p< 0.001)
(Fig. 1). Landmark analyses at 6 and 12 months showed
longer OS in responders compared to non-responders
(Supplementary Figs. 3&4). According to best response
by mRECIST, the median OS in patients with CR was
49.1 (95% CI, 38.859.5), PR 17.6 (95% CI, 14.844.8),
SD 14.3 (95% CI, 12.920.4), and PD 8.0 (95% CI, 6.3
11.4) months (Supplementary Fig. 5). Patients with PR
had significantly longer OS than patients with SD (HR,
0.56 [0.320.97], p= 0.037). Median DpR of patients
with PR was 54.4% (range, 3388.2). There was no sig-
nificant OS difference between PR patients with a DpR
greater than or lower than the median (HR, 1.09 [0.44
2.67], p= 0.854; Supplementary Fig. 6). Median time to
DpR was 4.8 months in responders.
Responders also had longer PFS than non-responders
(10.1 vs. 4.3 months, p= 0.015; Fig. 2). Progression was
Fig. 2 Progression-free survival of patients with, compared to patients without, objective response. CI, confidence interval; PFS,
progression-free survival
Öcal et al. Cancer Imaging (2022) 22:1 Page 6 of 13
encountered in 24 (70.6%) responders and 63 (77.8%)
non-responders (p= 0.412). Although the difference is
not significant, in none of the responders was the first
progression extrahepatic (0/24 vs. 9/63, p= 0.058).
Besides OR, in univariate analysis, male gender (HR,
0.50 [95% CI, 0.270.91], p= 0.024) was associated with
better OS, while bilirubin 17 μmol/L (HR, 1.55 [95%
CI, 1.022.36], p= 0.039) and albumin-bilirubin (ALBI)
grade 23 (HR, 1.74 [95% CI, 1.142.66], p= 0.009) were
associated with poorer OS. Multivariate Cox regression
analysis revealed that OR assessed by mRECIST was an
independent prognostic factor (HR, 0.32 [95% CI, 0.18
0.55], p< 0.001). Male gender (HR, 0.41 [95% CI, 0.22
0.75], p= 0.004) and ALBI grade (HR, 1.88 [95% CI,
1.212.92], p= 0.005) were also independent prognostic
factors for OS (Table 2).
Among the 115 patients, ETS 20% was achieved in
32 (27.8%) patients. The baseline clinical characteristics
of patients with ETS 20% compared with ETS < 20%
are shown in Table 3. There were no significant differ-
ences between patients with ETS 20% and ETS < 20%,
except for more patients with a history of hepatitis C in
the ETS < 20% group (34.9% vs. 15.6%, p= 0.041).
Median time from randomization to the imaging used
for ETS evaluation was 2.2 (range, 0.85.2) months. In
patients with OR, the median time to ETS was
significantlyshorterthanthetimetoresponse(2.2vs.
3.8 months, p= 0.004). Patients with ETS 20% had a
longer OS (median 22.1 vs. 11.4 months, p< 0.001) and
PFS (median 8.0 vs. 4.3 months, p= 0.034) than patients
with ETS < 20% (Fig. 3and Supplementary Fig. 7). Only
6 (7.2%) of 83 patients with ETS < 20% had an OR
during follow-up and an ETS 20% was significantly
associated with OR (p< 0.001). The multivariate
analysis with a second model (using ETS instead of OR,
Table 4)confirmedETS(p< 0.001) as an independent
prognostic factor, besides gender (p= 0.004) and ALBI
grade (p= 0.022).
Discussion
This analysis of data from the SORAMIC trial showed
that OR by mRECIST is an independent predictor of
OS and PFS in patients receiving sorafenib treatment.
The OR rate was 29.5%, and responders had signifi-
cantly longer median OS than non-responders (30.3
vs. 11.4 months). Besides OR assessment, ETS was an
independent predictive factor in our study, identifying
responders to treatment earlier than assessment by
mRECIST.
Following the demonstration of clinical efficacy in
the SHARP trial and Asia-Pacific trial, sorafenib has
been the primary treatment of advanced HCC in
Table 2 Univariable and multivariable analysis of factors associated with overall survival
Parameter Univariate analysis Multivariate analysis
HR (95% CI) pvalue HR (95% CI) pvalue
Best response (CR + PR vs. SD + PD) 0.38 (0.220.63) < 0.0001 0.32 (0.180.55) < 0.001
Sex (male vs. female) 0.50 (0.270.91) 0.0241 0.41 (0.220.75) 0.004
Age (65 vs. < 65 years) 1.01 (0.671.54) 0.9310
ECOG (1 vs. 0) 0.80 (0.481.35) 0.4184
Cirrhosis (yes vs. no) 1.22 (0.632.37) 0.5457
Hepatitis B etiology (yes vs. no) 1.22 (0.612.44) 0.5677
Hepatitis C etiology (yes vs. no) 1.17 (0.741.85) 0.4847
Alcohol etiology (yes vs. no) 0.78 (0.511.21) 0.2798
TACE history (yes vs. no) 0.86 (0.541.37) 0.5434
PVI (yes vs. no) 1.10 (0.731.67) 0.6260
Child-Pugh (B vs. A) 1.59 (0.783.20) 0.1950
BCLC (C vs. B) 1.06 (0.671.67) 0.7845
Beyond up-to-7 (yes vs. no) 1.28 (0.662.47) 0.4636
Bilirubin (17 vs. < 17 μmol/L) 1.55 (1.022.36) 0.0391
Albumin (36 vs. < 36 g/L) 0.66 (0.421.04) 0.0759
ALBI (grade 2/3 vs. grade 1) 1.74 (1.142.66) 0.0091 1.88 (1.212.92) 0.005
AFP (400 vs. < 400 ng/mL) 1.06 (0.671.66) 0.8012
All covariates were time-fixed except for best response, which was time dependent
AFP alfa-fetoprotein, ALBI albumin-bilirubin, BCLC Barcelona Clinic Liver Cancer, CR complete response, ECOG Eastern Cooperative Oncology Group, HR hazard
ratio, PD progressive disease, PR partial response, PVI portal vein invasion, SD stable disease, TACE transarterial chemoembolization
Öcal et al. Cancer Imaging (2022) 22:1 Page 7 of 13
Table 3 Baseline characteristics of patients with ETS 20% compared to ETS < 20% (no ETS)
Variable Total n= 115 ETS 20% n= 32 ETS < 20% n=83 p-value
Sex
Female 15 (13.0%) 7 (21.8%) 8 (9.6%) 0.0808
Male 100 (87.0%) 25 (78.1%) 75 (90.4%)
Age, years
Mean (SD) 65.3 (8.7) 67.4 (7.4) 64.5 (9.1) 0.1106
Median (IQR) 65.0 (12.0) 67.5 (12.0) 64.0 (13.0)
Age category, years
65 55 (47.8%) 13 (40.6%) 42 (50.6%) 0.3371
>65 60 (52.2%) 19 (59.4%) 41 (49.4%)
Ethnicity
Missing 10 (8.7%) 4 (12.5%) 6 (7.2%) 0.6299
Hispanic or Latin 5 (4.8%) 1 (3.1%) 4 (4.8%)
Other 100 (95.2%) 27 (84.3%) 73 (87.9%)
Race
Missing 11 (9.6%) 4 (12.5%) 7 (8.4%) 0.2052
Black 2 (1.9%) 0 2 (2.6%)
Other 3 (2.9%) 2 (7.1%) 1 (1.3%)
White 99 (95.2%) 26 (92.9%) 73 (96.1%)
ECOG status
090 (78.3%) 24 (75.0%) 66 (79.5%) 0.5986
125 (21.7%) 8 (25.0%) 17 (20.5%)
HCC diagnosis by
Missing 2 (1.7%) 0 2 (2.4%) 0.6537
EASL criteria 50 (43.5%) 12 (37.5%) 38 (45.8%)
Histology 50 (43.5%) 16 (50.0%) 34 (41.0%)
Other 13 (11.3%) 4 (12.5%) 9 (10.8%)
Hepatitis B
No 104 (90.4%) 29 (90.6%) 75 (90.4%) 0.9657
Yes 11 (9.6%) 3 (9.4%) 8 (9.6%)
Hepatitis C
No 81 (70.4%) 27 (84.4%) 54 (65.1%) 0.0419
Yes 34 (29.6%) 5 (15.6%) 29 (34.9%)
Alcohol etiology
No 63 (54.8%) 17 (53.1%) 46 (55.4%) 0.8245
Yes 52 (45.2%) 15 (46.9%) 37 (44.6%)
Previous therapies
TACE 28 (24.3%) 6 (18.8%) 22 (26.5%) 0.3851
TAE 2 (1.7%) 0 2 (2.4%) 0.3757
Resection 21 (18.3%) 8 (25.0%) 13 (15.7%) 0.2454
RFA 12 (10.4%) 4 (12.5%) 8 (9.6%) 0.6528
Brachytherapy 5 (4.3%) 1 (3.1%) 4 (4.8%) 0.6897
Max. diameter of largest lesion
Mean (SD) 68.0 (59.6) 59.1 (41.3) 71.6 (65.3) 0.2127
Median (IQR) 57.0 (45.0) 50.0 (38.0) 59.5 (55.0)
Öcal et al. Cancer Imaging (2022) 22:1 Page 8 of 13
recent years [2,3]. Response assessment used RECIST
in both these studies, where the OR rate was 2 and
3.3% and failed to capture patients who benefited
more from treatment. Failure to differentiate patients
who do not benefit from sorafenib may delay a switch
in treatment and patients may present with progres-
sion that precludes further treatment. In 2010, mRE-
CIST was proposed to address the drawbacks of
RECIST caused by the unique complexities of both
HCC and its treatment. A meta-analysis confirmed
that OR by mRECIST can predict outcome after loco-
regional therapies [23]. However, additional data are
needed to establish the role of mRECIST in follow-up
of systemic therapies [1].
Five retrospective studies used mRECIST for re-
sponse assessment in patients receiving sorafenib.
While four of these studies showed that OR success-
fully predicts OS [58], the other failed to show OS
benefit [9]. A combined analysis of two phase II stud-
ies showed that OR by mRECIST predicted OS bene-
fit, but, in multivariate analysis, significance was
marginally lost [10]. As this was a combined analysis
of patients receiving sorafenib and nintedanib, the
total number of patients receiving sorafenib was only
63. Another limitation of these studies was the
utilization of a simple comparison of responders with
non-responders, leading to guarantee-time bias or im-
mortal time bias. Recently, subgroup analysis of a
phase III study conducted in Japan showed superior
OS (27.2 vs. 8.9 months, p< 0.001) in patients with
OR after sorafenib treatment [12]. In this analysis,
landmark analyses, Mantel-Byar test were used to
eliminate guarantee-time bias, and OR was incorpo-
rated into multivariable analysis as a time-dependent
variable, as in our study. Our study confirms these
findings in a Western population. Univariate analysis
revealed gender, total bilirubin, and ALBI grade as
predictive factors, besides OR, and multivariate ana-
lysis confirmed these findings (bilirubin was excluded
because of interactions with ALBI). Patients with
ALBI grade 2 and 3 had worse OS than those with
grade 1 in our study (HR, 1.88 [95% CI, 1.212.92],
Table 3 Baseline characteristics of patients with ETS 20% compared to ETS < 20% (no ETS) (Continued)
Variable Total n= 115 ETS 20% n= 32 ETS < 20% n=83 p-value
Portal vein infiltration
Yes 60 (52.2%) 19 (59.4%) 41 (49.4%) 0.3371
Baseline metastasis
Yes 6 (5.2%) 0 6 (7.2%) 0.1182
BCLC
B34 (29.6%) 8 (25.0%) 26 (31.3%) 0.5053
C81 (70.4%) 24 (75.0%) 57 (68.7%)
Up-to-7 criterion
Inside 17 (14.8%) 5 (15.6%) 12 (14.5%) 0.8744
Outside 98 (85.2%) 27 (84.4%) 71 (85.5%)
Total bilirubin (μmol/L)
Mean (SD) 16.1 (7.1) 15.3 (7.3) 16.3 (7.1) 0.3959
Median (IQR) 14.9 (10.0) 14.0 (9.3) 15.1 (9.9)
Albumin g/L
Mean (SD) 37.8 (8.3) 40.0 (6.1) 37.0 (8.9) 0.2368
Median (IQR) 39.0 (7.7) 40.0 (6.0) 38.9 (8.0)
ALBI score
Mean (SD) 2.5 (0.7) 2.7 (0.7) 2.4 (0.8) 0.1644
Median (IQR) 2.5 (0.8) 2.7 (0.7) 2.5 (0.8)
Child-Pugh score
A105 (91.3%) 31 (96.8%) 74 (89.1%) 0.2792
B10 (8.7%) 1 (3.1%) 9 (10.8%)
ALBI albumin-bilirubin, BCLC Barcelona Clinic Liver Cancer, EASL European Association for the Study of the Liver, ECOG Eastern Cooperative Oncology Group, HCC
hepatocellular carcinoma, IQR interquartile range, RFA radiofrequency ablation, SD standard deviation, TACE transarterial chemoembolization, TAE
transarterial embolization
Öcal et al. Cancer Imaging (2022) 22:1 Page 9 of 13
p= 0.005), and this finding is in agreement with pre-
vious reports [24,25]. A surprising result was the
better OS in male patients in our study, unlike most
previous reports [6,12]. However, this may be the re-
sult of the small number of female patients (15, 13%).
ETS has been shown to predict treatment outcome
in various tumor types, but, to date, only one study
has evaluated ETS in patients with HCC. Takahashi
et al. showed that patients with ETS 10% had better
OS and PFS than patients with ETS < 10% after len-
vatinib treatment [19]. In that study, ETS was defined
based on RECIST criteria, and a cut-off of 10% was
chosen. However, in our study, measurement of en-
hancing tumor instead of overall diameter was used
to overcome problems related to the unique features
of HCC described above, and a cut-off of 20% was
chosen, as most previous authors have done [1618].
ETS can detect patients who do not benefit from
treatment earlier than response assessment with mRE-
CIST, and makes possible necessary therapeutic ad-
justments before progression is encountered. Early
detection of patients who do not benefit from sorafe-
nib treatment gains greater importance in the light of
other emerging, effective second-line drugs [13,15].
With early sequencing of treatment, progression pre-
cluding further treatment or associated with shorter
post-progression survival (i.e. new macrovascular inva-
sion) can be avoided.
This study has some limitations. First, follow-up im-
aging was not conducted according to a standardized
protocol, since follow-up imaging was at the discretion
of the local investigator. However, baseline imaging of
all patients was done in a standardized fashion within
the diagnostic arm of the SORAMIC trial, and the im-
ages used for follow-up assessment were high-quality
state-of-the-art triphasic images. Second, follow-up
Fig. 3 Overall survival of patients with ETS 20% vs. ETS < 20%. CI, confidence interval; ETS, early tumor shrinkage; HR, hazard ratio; OS,
overall survival
Öcal et al. Cancer Imaging (2022) 22:1 Page 10 of 13
imaging was not available in 30.9% of the patients who
received sorafenib treatment in the SORAMIC trial.
There is an inherent risk of selection of responders and
patients with longer survival. Patients with poorer per-
formance status or liver function might not have under-
gone cross-sectional follow-up imaging due to earlier
deterioration in their clinical situation. The OS of the
patients included in this study was a little longer than
the OS of the sorafenib arm in the SORAMIC study
(14.3 vs. 11.4 months). Nevertheless, this study was con-
ducted on patients using prospectively collected data
from the phase II SORAMIC trial, and it showed, for the
first time in a Western population, a correlation between
OR by mRECIST and OS in HCC patients receiving so-
rafenib, and also, for the first time, a correlation between
ETS and OS in the same cohort.
Conclusion
OR assessments by mRECIST and ETS in HCC patients
receiving sorafenib monotherapy are associated with
treatment outcome and survival. Both assessments can
be used to identify patients who do not benefit from so-
rafenib and to guide the decision-making process in the
era of effective second-line therapies. However, the use
of ETS needs further validation.
Abbreviations
ALBI: Albumin-Bilirubin; BCLC: Barcelona Clinic Liver Cancer; CI: Confidence
interval; CR: Complete response; CT: Computed tomography; DpR: Depth of
response; ETS: Early tumor shrinkage; HCC: Hepatocellular carcinoma;
HR: Hazard ratio; mRECIST: modified Response Evaluation Criteria in Solid
Tumors; MRI: Magnetic resonance imaging; OR: Objective response;
OS: Overall survival; PD: Progressive disease; PFS: Progression-free survival;
PR: Partial response; SD: Stable disease
Supplementary Information
The online version contains supplementary material available at https://doi.
org/10.1186/s40644-021-00439-x.
Additional file 1: Supplementary Fig. 1. Consort diagram.
Additional file 2: Supplementary Fig. 2. Examples for image analysis.
Additional file 3: Supplementary Fig. 3. Overall survival of patients
with partial response according to depth of response (DpR) more or less
than the median DpR. CI, confidence interval; HR, hazard ratio.
Additional file 4: Supplementary Fig. 4. Progression-free survival of
patients with ETS 20% vs. ETS < 20%. CI, confidence interval; ETS, early
tumor shrinkage; HR, hazard ratio; PFS, progression-free survival.
Additional file 5: Supplementary Fig. 5. Overall survival of patients
according to best response. BR, best response; CI, confidence interval; CR,
complete response; HR, hazard ratio; PR, partial response; PD, progressive
disease; SD, stable disease.
Additional file 6: Supplementary Fig. 6. Landmark Kaplan-Meier
curve as function of tumor response at 6 months. OR, objective response.
Additional file 7: Supplementary Fig. 7. Landmark Kaplan-Meier
curve as function of tumor response at 12 months. OR, objective
response.
Table 4 Univariable and multivariable analysis of factors associated with overall survival (model with ETS)
Parameter Univariate analysis Multivariate analysis
HR (95% CI) pvalue HR (95% CI) pvalue
ETS 20% vs. < 20% 0.44 (0.260.74) 0.002 0.44 (0.240.69) < 0.001
Sex (male vs. female) 0.50 (0.270.91) 0.0241 0.41 (0.220.75) 0.004
Age (65 vs. < 65 years) 1.01 (0.671.54) 0.9310
ECOG (1 vs. 0) 0.80 (0.481.35) 0.4184
Cirrhosis (yes vs. no) 1.22 (0.632.37) 0.5457
Hepatitis B etiology (yes vs. no) 1.22 (0.612.44) 0.5677
Hepatitis C etiology (yes vs. no) 1.17 (0.741.85) 0.4847
Alcohol etiology (yes vs. no) 0.78 (0.511.21) 0.2798
TACE history (yes vs. no) 0.86 (0.541.37) 0.5434
PVI (yes vs. no) 1.10 (0.731.67) 0.6260
Child-Pugh (B vs. A) 1.59 (0.783.20) 0.1950
BCLC (C vs. B) 1.06 (0.671.67) 0.7845
Beyond up-to-7 (Yes vs. No) 1.28 (0.662.47) 0.4636
Bilirubin (17 vs. < 17 μmol/L) 1.55 (1.022.36) 0.0391
Albumin (36 vs. < 36 g/L) 0.66 (0.421.04) 0.0759
ALBI (grade 2/3 vs. grade 1) 1.74 (1.142.66) 0.0091 1.65 (1.082.53) 0.022
AFP (400 vs. < 400 ng/mL) 1.06 (0.671.66) 0.8012
All covariates were time-fixed except for ETS, which was time dependent
AFP alfa-fetoprotein, ALBI albumin-bilirubin, BCLC Barcelona Clinic Liver Cancer, CR complete response, ECOG Eastern Cooperative Oncology Group, ETS early tumor
shrinkage, HR hazard ratio, PD progressive disease, PR partial response, PVI portal vein invasion, SD stable disease, TACE transarterial chemoembolization
Öcal et al. Cancer Imaging (2022) 22:1 Page 11 of 13
Acknowledgments
SORAMIC is an investigator-initiated trial sponsored by the University of
Magdeburg.
Authorscontributions
Osman Öcal: Conception and design of the study; Generation, collection,
assembly, analysis and/or interpretation of data; Drafting or revision of the
manuscript; Approval of the final version of the manuscript. Regina Schinner:
Generation, collection, assembly, analysis and/or interpretation of data;
Drafting or revision of the manuscript; Approval of the final version of the
manuscript. Kerstin Schuette: Generation, collection, assembly, analysis and/
or interpretation of data; Drafting or revision of the manuscript; Approval of
the final version of the manuscript. Enrico de Toni: Generation, collection,
assembly, analysis and/or interpretation of data; Drafting or revision of the
manuscript; Approval of the final version of the manuscript. Christian Loewe:
Generation, collection, assembly, analysis and/or interpretation of data;
Drafting or revision of the manuscript; Approval of the final version of the
manuscript. Otto van Delden: Generation, collection, assembly, analysis and/
or interpretation of data; Drafting or revision of the manuscript; Approval of
the final version of the manuscript. Vincent Vandecaveye: Generation,
collection, assembly, analysis and/or interpretation of data; Drafting or
revision of the manuscript; Approval of the final version of the manuscript.
Bernhard Gebauer: Generation, collection, assembly, analysis and/or
interpretation of data; Drafting or revision of the manuscript; Approval of the
final version of the manuscript. Christoph J Zech: Generation, collection,
assembly, analysis and/or interpretation of data; Drafting or revision of the
manuscript; Approval of the final version of the manuscript. Christian Sengel:
Generation, collection, assembly, analysis and/or interpretation of data;
Drafting or revision of the manuscript; Approval of the final version of the
manuscript. Irene Bargellini: Generation, collection, assembly, analysis and/or
interpretation of data; Drafting or revision of the manuscript; Approval of the
final version of the manuscript. Antonio Gasbarrini: Generation, collection,
assembly, analysis and/or interpretation of data; Drafting or revision of the
manuscript; Approval of the final version of the manuscript. Bruno Sangro:
Generation, collection, assembly, analysis and/or interpretation of data;
Drafting or revision of the manuscript; Approval of the final version of the
manuscript. Maciej Pech: Generation, collection, assembly, analysis and/or
interpretation of data; Drafting or revision of the manuscript; Approval of the
final version of the manuscript. Peter Malfertheiner: Conception and design
of the study; Generation, collection, assembly, analysis and/or interpretation
of data; Drafting or revision of the manuscript; Approval of the final version
of the manuscript. Jens Ricke: Conception and design of the study;
Generation, collection, assembly, analysis and/or interpretation of data;
Drafting or revision of the manuscript; Approval of the final version of the
manuscript. Max Seidensticker: Conception and design of the study;
Generation, collection, assembly, analysis and/or interpretation of data;
Drafting or revision of the manuscript; Approval of the final version of the
manuscript.
Funding
Financial support was granted by Sirtex Medical and Bayer Healthcare. Open
Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
Data are available through corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
The study was approved by the local ethics committees. Study procedures
were performed in accordance with the protocol and ethical principles that
have their origin in the Declaration of Helsinki and the International Council
for Harmonization-Good Clinical Practice. All patients provided written, in-
formed consent to participate in the study. ClinicalTrials.gov number,
NCT01126645; EudraCT 2009012576-27.
Consent for publication
Not applicable.
Competing interests
Kerstin Schuette: Personal fees: Bayer. Enrico de Toni: Personal fees: Bayer,
during the conduct of the study. Personal fees: Ipsen, Eli Lilly & Co, Eisai,
outside the submitted work. Bernhard Gebauer: Personal fees: Bayer, Sirtex.
Christoph J Zech: Personal fees: Bayer. Irene Bargellini: Grants: Sirtex, during
the conduct of the study. Personal fees: Bayer, Sirtex, Biocompatibles,
Terumo, outside the submitted work. Bruno Sangro: Personal fees: Sirtex,
BTG, Bayer, BMS, Astra Zeneca, Eli Lilly, Merck, Novartis, Terumo,
Adaptimmune; Non-financial support: Sirtex, BMS, outside the submitted
work. Maciej Pech: Grants: Sirtex, Bayer; Personal fees: Sirtex. Peter Malferthei-
ner: Grants: Bayer, Sirtex. Jens Ricke: Grants: Sirtex, Bayer; Personal fees: Sirtex,
Bayer. Max Seidensticker: Personal fees: Bayer, Sirtex.
Author details
1
Department of Radiology, University Hospital, LMU Munich,
Marchioninistrasse 15, 81377 Munich, Germany.
2
Department of Internal
Medicine and Gastroenterology, Niels-Stensen-Kliniken Marienhospital,
Osnabrück, Germany.
3
Department of Internal Medicine II, University Hospital,
LMU Munich, Munich, Germany.
4
Section of Cardiovascular and
Interventional Radiology, Department of Bioimaging and Image-Guided
Therapy, Medical University of Vienna, Vienna, Austria.
5
Department of
Radiology and Nuclear Medicine, Academic Medical Center, University of
Amsterdam, Amsterdam, The Netherlands.
6
Department of Radiology,
University Hospitals Leuven, Leuven, Belgium.
7
Department of Radiology,
Charité University Medicine Berlin, Berlin, Germany.
8
Radiology and Nuclear
Medicine, University Hospital Basel, University of Basel, Basel, Switzerland.
9
Radiology Department, Grenoble University Hospital, La Tronche, France.
10
Department of Vascular and Interventional Radiology, University Hospital of
Pisa, Pisa, Italy.
11
Gastroenterology, Gemelli Foundation, Catholic University,
Rome, Italy.
12
Liver Unit, Clínica Universidad de Navarra, Pamplona, Spain.
13
Departments of Radiology and Nuclear Medicine, University of Magdeburg,
Magdeburg, Germany.
Received: 6 August 2021 Accepted: 5 December 2021
References
1. EASL Clinical Practice Guidelines. Management of hepatocellular carcinoma.
J Hepatol. 2018;69(1):182236. https://doi.org/10.1016/j.jhep.2018.03.019.
2. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib
in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):37890.
https://doi.org/10.1056/NEJMoa0708857.
3. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety
of sorafenib in patients in the Asia-Pacific region with advanced
hepatocellular carcinoma: a phase III randomised, double-blind, placebo-
controlled trial. Lancet Oncol. 2009;10(1):2534. https://doi.org/10.1016/S14
70-2045(08)70285-7.
4. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for
hepatocellular carcinoma. Semin Liver Dis. 2010;30(1):5260. https://doi.
org/10.1055/s-0030-1247132.
5. Edeline J, Boucher E, Rolland Y, Vauléon E, Pracht M, Perrin C, et al.
Comparison of tumor response by response evaluation criteria in solid
tumors (RECIST) and modified RECIST in patients treated with sorafenib for
hepatocellular carcinoma. Cancer. 2012;118(1):14756. https://doi.org/10.1
002/cncr.26255.
6. Arizumi T, Ueshima K, Chishina H, Kono M, Takita M, Kitai S, et al. Duration
of stable disease is associated with overall survival in patients with
advanced hepatocellular carcinoma treated with sorafenib. Dig Dis. 2014;
32(6):70510. https://doi.org/10.1159/000368006.
7. Ronot M, Bouattour M, Wassermann J, Bruno O, Dreyer C, Larroque B, et al.
Alternative response criteria (Choi, European association for the study of the
liver, and modified response evaluation criteria in solid tumors [RECIST])
versus RECIST 1.1 in patients with advanced hepatocellular carcinoma
treated with sorafenib. Oncologist. 2014;19(4):394402. https://doi.org/10.1
634/theoncologist.2013-0114.
8. Takada J, Hidaka H, Nakazawa T, Kondo M, Numata K, Tanaka K, et al.
Modified response evaluation criteria in solid tumors is superior to response
evaluation criteria in solid tumors for assessment of responses to sorafenib
in patients with advanced hepatocellular carcinoma. BMC Res Notes. 2015;
8(1):609. https://doi.org/10.1186/s13104-015-1565-2.
Öcal et al. Cancer Imaging (2022) 22:1 Page 12 of 13
9. Arizumi T, Ueshima K, Takeda H, Osaki Y, Takita M, Inoue T, et al.
Comparison of systems for assessment of post-therapeutic response to
sorafenib for hepatocellular carcinoma. J Gastroenterol. 2014;49(12):157887.
https://doi.org/10.1007/s00535-014-0936-0.
10. Meyer T, Palmer DH, Cheng AL, Hocke J, Loembé AB, Yen CJ. mRECIST to
predict survival in advanced hepatocellular carcinoma: analysis of two
randomised phase II trials comparing nintedanib vs sorafenib. Liver Int.
2017;37(7):104755. https://doi.org/10.1111/liv.13359.
11. Giobbie-Hurder A, Gelber RD, Regan MM. Challenges of guarantee-time bias. J
Clin Oncol. 2013;31(23):29639. https://doi.org/10.1200/JCO.2013.49.5283.
12. Kudo M, Ueshima K, Chiba Y, Ogasawara S, Obi S, Izumi N, et al. Objective
response by mRECIST is an independent prognostic factor for overall
survival in hepatocellular carcinoma treated with Sorafenib in the SILIUS
trial. Liver Cancer. 2019;8(6):50519. https://doi.org/10.1159/000503032.
13. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib
for patients with hepatocellular carcinoma who progressed on sorafenib
treatment (RESORCE): a randomised, double-blind, placebo-controlled,
phase 3 trial. Lancet. 2017;389(10064):5666. https://doi.org/10.1016/S0140-
6736(16)32453-9.
14. 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):1894905. https://doi.org/10.1056/NEJMoa1915745.
15. Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, et al. Efficacy
and safety of Nivolumab plus Ipilimumab in patients with advanced
hepatocellular carcinoma previously treated with Sorafenib: the CheckMate
040 randomized Clinical trial. JAMA Oncol. 2020;6(11):e204564. https://doi.
org/10.1001/jamaoncol.2020.4564.
16. Primavesi F, Fadinger N, Biggel S, Braunwarth E, Gasser E, Sprung S, et al.
Early response evaluation during preoperative chemotherapy for colorectal
liver metastases: combined size and morphology-based criteria predict
pathological response and survival after resection. J Surg Oncol. 2019;121(2):
38291. https://doi.org/10.1002/jso.25796.
17. Shirotake S, Kondo H, Okabe T, Makino S, Araki R, Komatsuda A, et al. Early
tumor shrinkage as a predictive factor of metastatic renal cell carcinoma in
molecular targeted therapy: a single institutional study. Mol Clin Oncol.
2019;10(1):12531. https://doi.org/10.3892/mco.2018.1762.
18. Vivaldi C, Fornaro L, Cappelli C, Pecora I, Catanese S, Salani F, et al. Early
tumor shrinkage and depth of response evaluation in metastatic pancreatic
cancer treated with first line chemotherapy: an observational retrospective
cohort study. Cancers (Basel). 2019;11(7):939. https://doi.org/10.3390/ca
ncers11070939.
19. Takahashi A, Moriguchi M, Seko Y, Shima T, Mitsumoto Y, Takashima H, et al.
Early tumor shrinkage as a predictive factor for outcomes in hepatocellular
carcinoma patients treated with lenvatinib: a multicenter analysis. Cancers
(Basel). 2020;12(3):754. https://doi.org/10.3390/cancers12030754.
20. Ricke J, Klümpen HJ, Amthauer H, Bargellini I, Bartenstein P, de Toni EN,
et al. Impact of combined selective internal radiation therapy and sorafenib
on survival in advanced hepatocellular carcinoma. J Hepatol. 2019;71(6):
116474. https://doi.org/10.1016/j.jhep.2019.08.006.
21. Ricke J, Steffen IG, Bargellini I, Berg T, Jaureguizar JIB, Gebauer B, et al.
Gadoxetic acid-based hepatobiliary MRI in hepatocellular carcinoma. JHEP
Reports. 2020;2(6):100173. https://doi.org/10.1016/j.jhepr.2020.100173.
22. Llovet JM, Lencioni R. mRECIST for HCC: performance and novel refinements. J
Hepatol. 2020;72(2):288306. https://doi.org/10.1016/j.jhep.2019.09.026.
23. Vincenzi B, Di Maio M, Silletta M, D'Onofrio L, Spoto C, Piccirillo MC, et al.
Prognostic relevance of objective response according to EASL criteria and
mRECIST criteria in hepatocellular carcinoma patients treated with loco-
regional therapies: a literature-based meta-analysis. PLoS One. 2015;10(7):
e0133488. https://doi.org/10.1371/journal.pone.0133488.
24. Kaneko S, Tsuchiya K, Yasui Y, Inada K, Kirino S, Yamashita K, et al. Strategy
for advanced hepatocellular carcinoma based on liver function and portal
vein tumor thrombosis. Hepatol Res. 2020;50(12):137585. https://doi.org/1
0.1111/hepr.13567.
25. Rovesti G, Orsi G, Kalliopi A, Vivaldi C, Marisi G, Faloppi L, et al. Impact of
baseline characteristics on the overall survival of HCC patients treated with
Sorafenib: ten years of experience. Gastrointest Tumors. 2019;6(34):92107.
https://doi.org/10.1159/000502714.
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Öcal et al. Cancer Imaging (2022) 22:1 Page 13 of 13
... Due to unique challenges in imaging assessment of HCC, criteria for evaluation of these imaging-based secondary outcome parameters have been developed, and response analysis by mRECIST has been shown to correlate with survival in HCC patients who underwent locoregional therapies, including RE [17,18]. Furthermore, the correlation between survival and objective response according to mRECIST after sorafenib treatment has been confirmed in the SILIUS trial and in the post-hoc analysis of sorafenib arm of the SORAMIC trial [19,20]. ...
... The study protocol was approved by the institutional review board and competent authorities, and all patients gave written informed consent. Response assessment and its correlation with survival of the sorafenib arm were previously published [20]. ...
... Many previous studies have confirmed the better association between treatment outcome and response analysis according to mRECIST in HCC patients who received RE [17,26,27]. Recently, two studies, one in the Asian population and another in a Western population (a subanalysis of the sorafenib arm in SORAMIC), have shown that objective response assessment by mRECIST is able to predict survival after sorafenib treatment [19,20]. Besides these, some additional imaging-based markers have been described for earlier detection of treatment response. ...
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We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of target lesions’ longest diameters from baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 5.0 months. The receiver operating characteristic curve analysis in differentiating long-term responders (PFS ≥ 5.0 months) from short-term responders (PFS < 5.0 months) revealed an ETS cut-off value of 10%. ETS ≥ 10% was significantly correlated with better PFS and OS compared with ETS < 10%. Additionally, ETS ≥ 10% showed a better discrimination ability on prognosis compared with modified RECIST-based objective response at the first evaluation. Multivariate analysis confirmed ETS ≥ 10% as an independent predictor of better OS, as well as a Child–Pugh score of 5 and macrovascular invasion. In conclusion, ETS ≥ 10% was strongly associated with outcome in patients treated with LEN. This biomarker could allow earlier assessment of the treatment response and guide treatment decision-making for HCC.
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Background: Sorafenib has been established as the standard of care for patients with advanced hepatocellular carcinoma (HCC) since 2007 on the basis of two landmark trials (SHARP and Asia-Pacific). Ten years have passed since then and, despite much research in the field, still no validated real-life prognostic markers are available for HCC patients treated with this drug. Therefore, going through 10 years of research into sorafenib of several Italian Cancer Centers, we conducted a field-practice study aimed at identifying baseline clinical factors that could be significantly associated with overall survival (OS). Method: Univariate/multivariate analyses were conducted to retrospectively identify the impact of baseline characteristics on the OS of 398 advanced HCC patients treated with sorafenib. Results: Based on univariate analysis, α-fetoprotein (AFP), albumin, AST, bilirubin, Child-Pugh, ECOG, systemic immune-inflammation index (SII), albumin-bilirubin (ALBI) grade, and portal vein thrombosis were significantly associated with shorter OS. Following adjustment for clinical covariates positive in univariate analysis, the multivariate analysis including AFP, age, etiology, albumin, aspartate transaminase (AST), bilirubin, Child-Pugh, LDH, platelet-to-lymphocyte ratio, ECOG, ALBI grade, portal vein thrombosis, SII, and BCLC stage identified increase in LDH, age >70 years, no viral etiologies, ECOG >0, albumin <35, ALBI grade 2, and AST >40 as prognostic factors for poorer OS based on the 5% significance level. Conclusion: Our study highlights that baseline hepatic function, patient-centered variables, and etiology have prognostic value. These findings might have implications in terms of therapeutic decision-making and patient counseling.
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Background: The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma. Methods: In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Results: The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent. Conclusions: In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT03434379.).
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In 2010, modified RECIST (mRECIST) criteria were proposed as a way of adapting the RECIST criteria to the particularities of hepatocellular carcinoma (HCC). We intended to overcome some limitations of RECIST in measuring tumour shrinkage with local and systemic therapies, and also to refine the assessment of progression that could be misinterpreted with conventional RECIST 1.1, due to clinical events related to the natural progression of chronic liver disease (development of ascites, enlargement of lymph nodes, etc.). mRECIST has served its purpose since being adopted or included in clinical practice guidelines (European, American and Asian) for the management of HCC; it has also been instrumental for assessing response and time-to-event endpoints in several phase II and III investigations. Nowadays, mRECIST has become the standard tool for measurement of radiological endpoints at early/intermediate stages of HCC. At advanced stages, guidelines recommend both methods. mRECIST has been proven to capture higher objective response rates in tumours treated with molecular therapies and those responses have shown to be independently associated with better survival. With the advent of novel treatment approaches (i.e. immunotherapy) and combination therapies there is a need to further refine and clarify some concepts around the performance of mRECIST. Similarly, changes in the landscape of standard of care at advanced stages of the disease are pointing towards progression-free survival as a potential primary endpoint in some phase III investigations, as effective therapies applied beyond progression might mask overall survival results. Strict recommendations for adopting this endpoint have been reported. Overall, we review the performance of mRECIST during the last decade, incorporating novel clarifications and refinements in light of emerging challenges in the study and management of HCC.
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Background & aims: Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the efficacy and safety of a combination of sorafenib and selective internal radiation therapy (SIRT) - with yttrium-90 (90Y) resin microspheres - to sorafenib alone in patients with advanced HCC. Methods: SORAMIC is a randomised controlled trial comprising diagnostic, local ablation and palliative cohorts. Based on diagnostic study results, patients were assigned to local ablation or palliative cohorts. In the palliative cohort, patients not eligible for TACE were randomised 11:10 to SIRT plus sorafenib (SIRT + sorafenib) or sorafenib alone. The primary endpoint was overall survival (OS; Kaplan-Meier analysis) in the intention-to-treat (ITT) population. Results: In the ITT cohort, 216 patients were randomised to SIRT + sorafenib and 208 to sorafenib alone. Median OS was 12.1 months in the SIRT + sorafenib arm, and 11.4 months in the sorafenib arm (hazard ratio [HR] 1.01; 95% CI 0.81-1.25; p = 0.9529). Median OS in the per protocol population was 14.0 months in the SIRT + sorafenib arm (n = 114), and 11.1 months in the sorafenib arm (n = 174; HR 0.86; p = 0.2515). Subgroup analyses of the per protocol population indicated a survival benefit of SIRT + sorafenib for patients without cirrhosis (HR 0.46; 0.25-0.86; p = 0.02); cirrhosis of non-alcoholic aetiology (HR 0.63; p = 0.012); or patients ≤65 years old (HR 0.65; p = 0.05). Adverse events (AEs) of Common Terminology Criteria for AE Grades 3-4 were reported in 103/159 (64.8%) patients who received SIRT + sorafenib, 106/197 (53.8%) patients who received sorafenib alone (p = 0.04), and 8/24 (33.3%) patients who only received SIRT. Conclusion: Addition of SIRT to sorafenib did not result in a significant improvement in OS compared with sorafenib alone. Subgroup analyses led to hypothesis-generating results that will support the design of future studies. Lay summary: Sorafenib given orally is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). In selective internal radiation therapy (SIRT), also known as radioembolisation, microscopic, radioactive resin or glass spheres are introduced into the blood vessels that feed the tumours in the liver. This study found that the addition of SIRT with 90yttrium-loaded resin microspheres to sorafenib treatment in people with advanced HCC did not significantly improve overall survival compared with sorafenib treatment alone. However, the results give an indication of how future studies using this combination therapy in people with advanced HCC could be designed. Study registration: EudraCT 2009-012576-27, NCT0112 6645.