European Journal of Radiology 142 (2021) 109890

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European Journal of Radiology

journal homepage: www.elsevier.com/locate/ejrad

Prognostic nomogram predicting survival of patients with unresectable

hepatocellular carcinoma after hepatic arterial infusion chemotherapy
Jie Mei a, b, 1, Wen-Ping Lin a, b, 1, Feng Shi c, 1, Wei Wei a, b, Jia-Bao Liang a, b, Ming Shi a, b,
Lie Zheng b, d, Shao-Hua Li a, b, *, 2, Rong-Ping Guo a, b, *, 2
a
Department of Liver Surgery of the Sun Yat-sen University Cancer Center, China
b
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
c
Department of Interventional Radiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
d
Department of Medical Imaging of the Sun Yat-sen University Cancer Center, China

A R T I C L E I N F O A B S T R A C T

Keywords: Background and aim: Hepatic arterial infusion chemotherapy (HAIC) has shown encouraging efficacy in the
Hepatocellular carcinoma treatment of hepatocellular carcinoma (HCC). This study aims to establish and validate a novel nomogram to
Hepatic arterial infusion chemotherapy predict individualized survival outcomes for patients with unresectable HCC after HAIC.
Nomogram
Methods: Between January 2016 and December 2018, 463 patients diagnosed with HCC who initially received
Unresectable
Survival
HAIC were included in this study (training cohort: n = 308; validation cohort: n = 153). The prognostic
nomogram was constructed based on the training cohort using the independent predictors assessed by the
multivariate Cox proportional hazards model. The predictive accuracy and discriminative ability of the model
were evaluated by the concordance index (C-index), calibration curve and area under the time-dependent
receiver operating characteristic (tdAUC) curve.
Results: After a median follow-up of 35.4 months, 358 patients had died. Six factors, including C-reactive protein,
albumin-bilirubin grade, alpha fetoprotein, extrahepatic metastasis, portal vein invasion and tumor size, were
selected to establish the nomogram. In the training cohort, the C-index of the nomogram was 0.710, which was
significantly better than that of six conventional staging systems (P < 0.001), and the nomogram had a higher
tdAUC over time. The calibration curve showed good agreement between the predicted probability and actual
outcome. According to specified values, the nomogram stratified patients into three or four risk groups (P <
0.001). Similar findings could be observed in the validation cohort.
Conclusion: The nomogram in this study accurately predicted the OS of patients with unresectable HCC after
HAIC.

1. Introduction as the optimal treatment option for intermediate unresectable HCC[4,5].

Hepatocellular carcinoma (HCC) is one of the most common types of
liver cancer and the fourth leading cause of cancer-related death
worldwide[1]. A recent comparative study of more than 8000 HCC cases
worldwide showed that less than 10% of patients met the criteria for
operative resection[2]. For patients who are not ideal surgical candi­
dates, percutaneous and catheter-directed locoregional approaches have
evolved as major treatment modalities for unresectable HCC[3].
Transarterial chemoembolization (TACE) has long been recommended
In recent years, hepatic arterial infusion chemotherapy (HAIC) has been
widely reported and has shown better efficacy and safety in the treat­
ment of unresectable HCC than TACE[6–9]. Unfortunately, due to the
tremendous variations in liver function and tumor extent, as well as
individual differences in sensitivity to chemotherapeutic agents, the
overall survival (OS) of HCC patients treated with HAIC is highly het­
erogeneous[10]. Therefore, a practical and reliable prognostic staging
system based on objective measures is needed for these patients.
To date, only a few studies have proposed that favorable liver

* Corresponding authors at: Department of Liver Surgery, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.
E-mail addresses: lishaoh@sysucc.org.cn (S.-H. Li), guorp@sysucc.org.cn (R.-P. Guo).
1
These authors equally contributed to this study.
2
These are co-corresponding authors.

https://doi.org/10.1016/j.ejrad.2021.109890
Received 22 April 2021; Received in revised form 19 July 2021; Accepted 30 July 2021
Available online 4 August 2021
0720-048X/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
J. Mei et al. European Journal of Radiology 142 (2021) 109890

Patients with HCCs treated with

HAIC from 1/2016 to 12/2018
(n = 701)

Excluded: (n = 238)
Received previous therapies (n = 83)
Heterogeneous anti-cancer therapy (n = 21)
Resectable HCC (n = 113)
Age < 18 or > 80 years old (n = 2)
Child –Pugh stage C (n = 2)
Performance status score > 1 (n = 2)
Diagnosed with other malignant tumors (n = 8)
Incomplete medical records (n = 7)

Assessed for eligibility

(n = 463)

Training cohort Validation cohort

(n = 308) (n = 155)

Fig. 1. Flow diagram summarizing the patient selection process. HCC, hepatocellular carcinoma; HAIC, hepatic arterial infusion chemotherapy; OS, overall survival;
ROC, receiver operating characteristic curve.

function and reduced alpha fetoprotein (AFP) levels in HCC patients
might be associated with good prognosis after HAIC treatment[10,11]. A
retrospective study with limited cases indicated that the neutrophil-to-
lymphocyte ratio (NLR) might be a useful prognostic factor for the
suitability of HAIC[12]. No studies have reported prognostic models for
predicting the outcomes of HCC patients undergoing HAIC. Currently,
nomograms are well developed and can provide personalized, evidence-
based, and accurate risk estimations[13]. The purpose of this study was
to build and validate a novel nomogram using baseline independent
variables to predict individualized survival outcomes for patients with
unresectable HCC after HAIC.
2. Materials and methods
This study was conducted according to the ethical guidelines of the
1975 Declaration of Helsinki. The analysis of patient data was reviewed
and approved by the Institutional Review Board and Human Ethics
Committee (B2020-318-01) at the Sun Yat-sen University Cancer Center
(SYSUCC; Guangzhou, China).
(MRI) examination within a week before the start of HAIC. Femoral
artery puncture and catheterization were performed in every cycle of
treatment. The FOLFOX regimen was administered via the hepatic ar­
tery: oxaliplatin 85 or 135 mg/m2, leucovorin 400 mg/m2, and fluoro­
uracil 400 mg/m2 on the first day, and fluorouracil 2400 mg/m2 for 46
h. Repeated HAIC was performed every 3–4 weeks. Routinely, efficacy
was evaluated by imaging examination after every 2 cycles of HAIC. The
discontinuation of treatment depended on disease progression, unac­
ceptable toxicity, patient withdrawal of consent, or changes in treatment
plan.
2.3. Follow up
Contrast enhanced CT or MRI was performed every 2 cycles of HAIC
approximately every 1–2 months. Blood tests of liver function and tumor
markers were also performed. Chest X-rays were performed every 6
months for the diagnosis of extrahepatic metastases. Chest-enhanced CT
and bone radiography were conducted if necessary. The final follow-up
ended on September 30, 2020.

2.1. Patients 2.4. Staging and definitions

Between January 2016 and December 2018, patients diagnosed with
HCC who received HAIC at our center were screened for eligibility.
Patients were included based on the following criteria: (a) diagnosed
with HCC through imaging or pathology according to the American
Association for the Study of Liver Diseases (AASLD) practice guidelines
[14] and confirmed to have unresectable carcinoma by a multidisci­
plinary team; (b) received no cancer-related therapies before HAIC; (c)
aged from 18 to 80 years; (d) had a performance status (PS) score less
than 2 and a Child-Pugh (CP) stage of A or B; (e) had no other malignant
tumors; and (f) had complete medical and follow-up data.
Patients were staged according to the commonly recognized staging,
including American Joint Committee on Cancer (AJCC) guidelines
eighth edition[15]. Barcelona Clinic Liver Cancer (BCLC) staging system
[16]. Hong Kong Liver Cancer (HKLC) staging system[17]. Japan Inte­
grated Staging (JIS) score [18]. China integrated score (CIS)[19]. and
Okuda classification[20]. The endpoint of this study was overall survival
(OS). OS was defined as the time interval from date of the first procedure
of HAIC to date of either cancer-related death or last follow-up.
2.5. Statistical analysis

2.2. Treatment procedure
All laboratory serum test data were collected within 3 days before
the initial treatment. The imaging evaluation included a contrast
enhanced computed tomography (CT) or magnetic resonance imaging
The results are described using the mean ± standard error (S.E.) for
normally distributed values and the median and range for nonnormally
distributed values. The Mann–Whitney U test was performed to compare
continuous variables, and either Pearson’s χ2 test or Fisher’s exact test
was performed to compare categorical data. Univariate and multivariate

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J. Mei et al. European Journal of Radiology 142 (2021) 109890

Table 1
Baseline clinical characteristics of patients.
Characteristic Total Training cohort Validation cohort P value*
(n ¼ 463) (n ¼ 308) (n ¼ 155)

Age, y, Mean ± SD 48.6 ± 11.82 48.94 ± 11.86 47.95 ± 11.75 0.397

Gender (male/female)* 399/64 (86/14) 260/48 (84/16) 139/16 (90/10) 0.160
Hepatitis B (no/yes) 62/401 (13/87) 41/267 (13/87) 21/134 (14/86) 1.000
HBV-DNA copies, Median (range) 6310 (201–116500) 6130 (303–116500) 6130 (145–114250) 0.612
Hepatitis C (no/yes) 456/7 (98/2) 303/5 (98/2) 153/2 (99/1) 1.000
Liver cirrhosis (no/yes) 282/181 (61/39) 195/113 (63/37) 87/68 (56/44) 0.163
Ascite (no/yes) 421/42 (91/9) 287/21 (93/7) 135/21 (86/14) 0.027
WBC, 10E9/L, Median (range) 6.4 (2.0–26.1) 6.4 (2.0–20.3) 6.4 (2.1–26.1) 0.819
NEU, 10E9/L, Median (range) 4.2 (0.7–22.4) 4.2 (1.2–14.6) 4.1 (0.7–22.4) 0.647
LYM, 10E9/L, Median (range) 1.4 (0.2–4.9) 1.4 (0.3–4.9) 1.4 (0.2–3.2) 0.604
HB, g/L, Median (range) 144.0 (71.0–209.0) 144.0 (71.0–209.0) 143.0 (87.0–196.0) 0.604
PLT, 10E9/L, Median (range) 231.0 (61.0–698.0) 236.5 (72.0–664.0) 220.0 (61.0–698.0) 0.272
ALT, U/L, Median (range) 45.8 (7.2–309.0) 47.6 (7.2–309.0) 44.2 (13.6–243.7) 0.389
AST, U/L, Median (range) 65.5 (13.7–644.4) 66.5 (13.7–644.4) 60.9 (20.9–366.5) 0.550
ALB, ng/ml, Median (range) 40.7 (24.1–51.8) 40.7 (26.8–51.8) 40.9 (24.1–49.2) 0.538
TBIL, umol/L, Median (range) 15.2 (4.8–65.7) 15.3 (4.8–65.7) 15.1 (4.9–43.2) 0.964
CRE, umol/L, Mean ± SD 70.1 ± 16.7 69.6 ± 16.9 71.1 ± 16.4 0.383
PT, sec, Median (range) 12.2 (9.1–17.9) 12.3 (9.1–17.9) 12.1 (5.6–16.3) 0.763
CRP, mg/L, Median (range) 12.8 (0.2–221.7) 12.8 (0.2–200.3) 12.9 (0.2–221.7) 0.308
AFP, ng/ml, Median (range) 4829 (1–121000) 5513 (1–121000) 4087 (1–121000) 0.969
PIVKA-II, mAU/ml, 2432 1917 3642 0.110
Median (range) (2–75000) (2–75000) (2–75000)
NLR, Median (range) 3.0 (0.6–24.3) 3.0 (0.8–24.3) 2.9 (0.6–23.6) 0.661
PLR, Median (range) 154.7 (12.6–842.4)) 159.3 (12.6–645.0) 147.3 (44.3–842.4) 0.244
LCR, Median (range) 1134.2 (27.1–116666.7) 1104.2 (31.7–72222.2) 1222.9 (27.1–116666.7) 0.349
ALBI score, Median (range) − 2.7 (-3.7- − 1.2) − 2.7 (-3.7 - − 1.2) − 2.7 (-3.5 - − 1.2) 0.542
Child-Pugh (A/B) 449/14 (97/3) 302/6 (98/2) 147/8 (95/5) 0.081
Largest tumor size, cm 10.3 (1.7–27.8) 10.5 (1.7–27.8) 9.6 (1.9–19.5) 0.051
Tumor number (1/>1) 104/359 (22/78) 65/243 (21/79) 39/116 (25/75) 0.385
Bi-lobar distribution(no/yes) 191/272 (41/59) 117/191 (38/62) 74/81(48/52) 0.056
Portal vein invasion 185/161/117 127/106/75 58/55/42 0.699
(none/branch/main portal vein) (40/35/25) (41/35/24) (37/36/27)
Extrahepatic metastasis (no/yes) 355/77 (77/23) 238/70 (77/23) 117/38 (75/25) 0.754
HAIC cycles, Median (range) 4 (1–8) 4 (1–8) 4 (1–8) 0.897

Staging System
AJCC 8th 38/128/201/96 25/86/133/64 13/42/68/32 1.000
(II/IIIA/IIIB/IV) (8/28/43/21) (8/28/43/21) (8/27/44/21)
BCLC (A/B/C) 28/138/297 (6/30/64) 18/93/197 (6/30/64) 13/67/71 (8/27/65) 0.980
HKLC 34/321/108 23/215/70 11/106/38 0.909
(IIb/III/IV) (7/69/24) (7/70/23) (7/69/24)
JIS Score 34/216/213 21/149/138 13/67/75 0.543
(1/2/3–4) (7/47/46) (7/48/45) (8/43/49)
CIS 127/233/43/60 94/147/29/38 33/86/14/22 0.193
(0/1/2/3–4) (27/50/9/13) (31/48/9/12) (21/55/9/15)
Okuda 106/329/28 66/225/17 40/104/11 0.406
(I/II/III) (23/71/6) (21/73/6) (26/67/7)

*P was calculated according to the difference between the training cohort and the validation cohort.
HBV: hepatitis B virus; WBC: white blood cell; NEU: neutrophil; LYM: lymphocyte; HB: haemoglobin; PLT: blood platelet; ALT: alanine aminotransferase; AST:
aspartate aminotransferase; ALB: albumin; TBIL: total bilirubin; CRE: creatinine; PT: prothrombin time; CRP: C-reactive protein; AFP: alpha fetoprotein; PIVKA-II,
protein induced by vitamin K absence or antagonist-I; NLR: neutrophil lymphocyte rate; PLR: blood platelet lymphocyte rate; LCR: lymphocyte C-reactive protein
rate; ALBI: albumin-bilirubin; HAIC: hepatic arterial infusion chemotherapy; AJCC: American Joint Committee on Cancer; BCLC: Barcelona Clinic Liver Cancer; HKLC:
Hong Kong Liver Cancer; JIS: Japan Integrated Staging; CIS: China integrated score.

analyses were performed using Cox proportional hazards models, and
hazard ratios (HRs) and confidence intervals (CIs) were simultaneously
calculated. All variables with a P value < 0.05 in the univariate analyses
were further included in the multivariate analyses to identify indepen­
dent risk factors of OS. The abovementioned statistical analyses were
performed using SPSS 25.0 software (SPSS Inc., Chicago, IL).
The grouping randomization for training and validation cohort was
performed by computer-generated random numbers. A prognostic
nomogram was formulated based on the independent predictors in the
multivariate Cox proportional hazards model and by the package “rms”
in R version 4.0.2. The concordance index (C-index) was calculated, and
the area under the time-dependent receiver operating characteristic
(tdAUC) curve was determined to evaluate the predictive ability of the
model compared with that of other staging systems. Bootstrapping with
1000 resamples was used for the validation of the nomogram and cali­
bration curve construction to quantify overfitting of the modeling.
Survival analysis was performed using the Kaplan-Meier method, and
differences between the survival curves were analyzed with a log-rank
test. A two-tailed P < 0.05 was considered statistically significant. The
abovementioned statistical analyses were performed using R version
4.0.2.
3. Results
3.1. Identification and characteristics of the study patients
From January 2016 to December 2018, 701 patients with HCC
treated with HAIC were screened. Among them, 83 received previous
anticancer therapies before the initiation of HAIC, 21 were treated with
heterogeneous anticancer therapies during HAIC treatment, 113 were
evaluated as having resectable HCC, 6 failed to meet the inclusion
criteria of age, CP stage or PS score, 8 were diagnosed with other

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Table 2
Univariate and multivariate analysis of risk factors for overall survival in training cohort.
Characteristic* Overall Survival

Univariate analysis Multivariate analysis

HR 95% CI P HR 95% CI P

Age, y (≤/>50) 0.860 0.666–1.109 0.245

Gender (male/female) 0.704 0.484–1.018 0.062
Hepatitis (no/yes) 0.762 0.531–1.093 0.140
HBV-DNA copies (≤/>10E3) 1.176 0.898–1.541 0.239
Liver cirrhosis (no/yes) 0.776 0.592–1.017 0.067
Ascite (no/yes) 1.493 0.934–2.386 0.094
WBC, 10E9/L, (≤/>3.5) 0.913 0.430–1.939 0.813
NEU, 10E9/L, (≤/>2.0) 1.722 0.551–5.382 0.350
LYM, 10E9/L, (≤/>0.8) 0.574 0.304–1.084 0.087
HB, g/L, (≤/>130) 0.907 0.686–1.201 0.497
PLT, 10E9/L, (≤/>100) 0.846 0.376–1.907 0.687
ALT, U/L, (≤/>50) 1.285 0.996–1.658 0.054
AST, U/L, (≤/>50) 1.625 1.113–2.373 0.012
ALB, ng/ml, (≤/>40) 0.636 0.492–0.822 0.001
TBIL, umol/L, (≤/>20.5) 1.090 0.810–1.466 0.571
CRE, umol/L, (≤/>100) 1.044 0.637–1.710 0.866
PT, sec, (≤/>13.5) 1.777 1.239–2.547 0.002
CRP, mg/dL, (≤/>1) 1.679 1.287–2.190 <0.001 1.411 1.058–1.882 0.019

AFP, ng/ml
> 20–400 1.217 0.795–1.863 0.367 1.181 0.762–1.830 0.458
> 400 1.529 1.104–2.119 0.011 1.470 1.050–2.056 0.025
PIVKA-II, mAU/ml, (≤/>400) 1.029 0.748–1.417 0.860
NLR (≤/>4) 1.325 1.000–1.757 0.050
PLR (≤/>150) 1.307 1.010–1.690 0.042
LCR (≤/>6000) 0.602 0.418–0.867 0.006
ALBI grade (1/2–3) 1.575 1.220–2.034 <0.001 1.337 1.024–1.746 0.033
Child-Pugh score (5/>5) 1.249 0.918–1.699 0.157

Largest tumor size, cm

>7–15 1.385 0.943–2.034 0.096 1.094 0.731–1.638 0.662
>15 2.077 1.304–3.310 0.002 1.651 1.014–2.689 0.044
Tumor number (1/>1) 1.141 0.834–1.561 0.410
Bi-lobar distribution(no/yes) 1.064 0.819–1.382 0.644

Portal vein invasion

Branch portal vein 1.389 1.028–1.877 0.033 1.108 0.810–1.517 0.520
Main portal vein 2.058 1.492–2.837 <0.001 1.704 1.215–2.388 0.002
Extrahepatic metastasis (no/yes) 1.775 1.322–2.384 <0.001 1.441 1.060–1.960 0.020

HBV: hepatitis B virus; WBC: white blood cell; NEU: neutrophil; LYM: lymphocyte; HB: haemoglobin; PLT: blood platelet; ALT: alanine aminotransferase; AST:
aspartate aminotransferase; ALB: albumin; TBIL: total bilirubin; CRE: creatinine; PT: prothrombin time; CRP: C-reactive protein; AFP: alpha fetoprotein; PIVKA-II,
protein induced by vitamin K absence or antagonist-I; NLR: neutrophil lymphocyte rate; PLR: blood platelet lymphocyte rate; LCR: lymphocyte C-reactive protein
rate; ALBI: albumin-bilirubin; HR: hazard rate; CI: confidence interval.

malignant tumors, and 7 had incomplete medical records. Ultimately,
the remaining 463 patients who met the criteria were included in the
study and were randomly divided into a training cohort (n = 308,
66.5%) and a validation cohort (n = 155, 33.4%). The patient selection
process is shown in Fig. 1.
The baseline characteristics of all patients, the training cohort and
the validation cohort are listed in Table 1. The number of HAIC cycles
ranged from 1 to 8, with a median of 4. All patient characteristics were
comparable between the training cohort and the validation cohort. 21
(7%) patients in the training group and 21 (14%) in the validation
cohort were found to have ascites (p = 0.027). There were almost no
significant differences between the two groups, indicating that the data
of the two groups had relatively strong homogeneity.
cohort, and 76.7%, 53.0% and 24.5 %for the validation cohort,
respectively. The survival curve showed no difference between the
training cohort and the validation cohort (Fig. S1).
3.3. Independent prognostic factors for overall survival
In univariate analysis, 30 factors related to survival were included
for the 308 patients in the training cohort. Of these, 11 factors were
considered to be significant survival-related variables and further
included in multivariate analysis. Ultimately, C-reactive protein (CRP),
AFP, albumin-bilirubin (ALBI) grade, tumor size, portal vein invasion
and extrahepatic metastasis were identified as six independent risk
factors for OS (Table 2).

3.2. Overall survival in the primary, training and validation cohorts 3.4. Construction and validation of the nomogram

Of the 463 patients, 358 patients had died by the end of the follow-
up. The median follow-up period was 35.4 months for the primary
cohort, 36.1 months for the training cohort, and 31.3 months for the
validation cohort. The median OS for the primary, training and valida­
tion cohorts was 12.6 months, 12.7 months and 12.6 months, respec­
tively. The 6-month, 1-year and 2-year OS rates were 77.4%, 52.5% and
25.2%, for the primary cohort, 77.7%, 52.2% and 25.5% for the training
The prognostic nomogram was built by integrating six significant
independent risk factors for OS in the training cohort. The projections
from the total points ranged from 0 to 500 on the accompanying scales,
indicating the predicted probabilities of 6-month, 1-year and 2-year
survival (Fig. 2). The calibration curve plot for the probability of sur­
vival at 6 months, 1 year, and 2 years after HAIC showed fair agreement
between the prediction by the nomogram and actual observation in both

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0 10 20 30 40 50 60 70 80 90 100
Points
1
CRP (mg/dL)
≤1
2-3
ALBI grade
1
>20 - 400
AFP (ng/ml)
≤ 20 > 400
Yes
Exrtahepatic metastasis
No
Branch of portal vein
Portal vein invasion
No Main portal vein
>7 - 15
Tumor size (cm)
≤7 > 15

Total Points
0 50 100 150 200 250 300 350 400 450 500

6−month survival
0.9 0.85 0.8 0.75 0.7 0.65 0.6 0.55 0.5 0.45 0.4 0.35

1-year survival
0.7 0.6 0.5 0.4 0.3 0.2 0.1

2-year survival
0.55 0.5 0.45 0.4 0.35 0.3 0.25 0.2 0.15 0.1 0.05

Fig. 2. Survival nomogram for patients with unresectable hepatocellular carcinoma after hepatic arterial infusion chemotherapy. To use the nomogram, an in­
dividual’s value is located on each variable axis. A line is drawn upward to determine the number of points assigned for each variable value. The sum of these
numbers is located on the total points axis, and a line is drawn downward to the survival axes to determine the likelihood of survival at 6 months, 1 year and 2 years.
CRP, C-reactive protein; ALBI, albumin-bilirubin; AFP, alpha fetoprotein.

Fig. 3. The calibration curve of the nomogram for 6-month, 1-year and 2-year survival of patients after hepatic arterial infusion chemotherapy in the training cohort
(A, B, C) and validation cohort (D, E, F).

the training cohort and the validation cohort (Fig. 3). Based on the
scores of the patients in the training cohort, the patients were classified
into low-, middle- and high-risk stages according to a trisection point,
and I, II, III and IV stages according to a quartile point. Kaplan-Meier
curves showed clearly different prognostic strata among patients in
the training cohort and the validation cohort (Fig. 4).
3.5. Comparison of the nomogram with conventional staging systems
The C-index of the nomogram for predicting OS was 0.710 (95% CI,

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A B
100% 100% I
Low
II
Middle
III
High
IV
75% 75%
Overall Survival

Overall Survival
50% 50%

25% 25%
p < 0.0001 p < 0.0001

0% 0%
0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36
Time after treatment (months) Time after treatment (months)
Number at risk Number at risk
Low 102 99 91 86 71 62 51 43 37 30 24 22 13 I 77 74 69 66 54 48 43 37 31 24 21 20 11
Middle 103 97 83 70 49 41 35 29 22 20 16 13 13 II 77 75 62 54 40 35 27 24 21 19 13 10 10
III 77 70 62 52 39 28 22 16 9 9 8 7 7
High 103 93 63 43 33 23 18 12 8 7 5 5 4 IV 77 70 44 27 20 15 12 7 6 5 3 3 2
0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36
Time after treatment (months) Time after treatment (months)

C D

100% 100% I
Low
II
Middle
III
High
IV
75% 75%
Overall Survival
Overall Survival

50% 50%

25% 25%
p < 0.0001 p < 0.0001

0% 0%
0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36
Time after treatment (months) Time after treatment (months)
Number at risk Number at risk
Low 39 38 37 33 29 23 22 20 16 13 11 8 8 I 30 30 29 25 22 17 17 16 13 10 9 7 7
Middle 66 62 52 39 32 24 22 13 11 7 5 3 3 II 51 48 42 34 29 22 20 12 10 7 5 4 4
III 39 37 28 21 17 13 7 5 4 3 2 0 0
High 50 43 29 22 17 14 6 3 1 1 1 0 0 IV 35 28 19 14 10 9 6 3 1 1 1 0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36
Time after treatment (months) Time after treatment (months)

Fig. 4. Kaplan–Meier curves of overall survival in patients stratified by points gained in the nomogram. Patients were staged by trisection cut-off points (A) and
quartile cut-off points (B) in the training cohort, trisection cut-off points (C) and quartile cut-off points (D) in the validation cohort.

Table 3
C-index of the nomogram and conventional staging system.
Staging system Training cohort Validation cohort
(n ¼ 308) (n ¼ 155)

C-index 95% CI P* C-index 95% CI P*

The nomogram 0.710 0.674–0.746 NA 0.716 0.664–0.768 NA

BCLC staging system 0.562 0.523–0.602 < 0.001 0.613 0.558–0.668 0.005
HKLC staging system 0.626 0.594–0.658 < 0.001 0.659 0.616–0.702 0.043
CIS 0.631 0.596–0.666 < 0.001 0.658 0.610–0.707 0.044
AJCC eighth edition 0.637 0.603–0.672 < 0.001 0.634 0.588–0.680 0.015
JIS score 0.619 0.582–0.655 < 0.001 0.638 0.587–0.689 0.017
Okuda classification 0.634 0.600–0.668 < 0.001 0.631 0.585–0.676 0.011

*P was calculated according to the difference between the nomogram and other staging system.
BCLC: Barcelona Clinic Liver Cancer; HKLC: Hong Kong Liver Cancer; CIS: China integrated score; AJCC: American Joint Committee on Cancer; JIS: Japan Integrated
Staging; HR: hazard rate; CI: confidence interval.

6
J. Mei et al.
A B
1.0
New model
BCLC
HKLC
CIS
0.9
AJCC8th
JIS Score
Okuda
0.8
AUC
0.7
0.6
0.5
10 15 20 25 30
Time after HAIC (months)
Fig. 5. Time-dependent AUC plot for survival prediction in the training cohort (A) and validation cohort (B). BCLC, Barcelona Clinic Liver Cancer; HKLC, Hong Kong
Liver Cancer; CIS, China integrated score; AJCC: American Joint Committee on Cancer; JIS, Japan Integrated Staging.
0.674–0.746) in the training cohort and 0.716 (95% CI, 0.664–0.768) in
the validation cohort. The C-index of the nomogram was significantly
higher than that of the AJCC guidelines eighth edition, BCLC staging
system, HKLC staging system, JIS score, CIS, and Okuda classification,
both in the training cohort and validation cohort (P < 0.05 for all)
(Table 3). Plots of the time-dependent AUCs are shown in Fig. 5. The
AUC of the nomogram fluctuated above 0.7 and was better than that of
other staging systems in both the training and validation cohorts,
proving the comparative stability and diagnostic capacity of the
nomogram for predicting OS in patients with unresectable HCC after
HAIC treatment.
4. Discussion
HAIC is an effective locoregional therapy for unresectable HCC and is
widely used, especially in the Asian-Pacific region[21]. In this study, we
established a prognostic nomogram integrating six independent prog­
nostic predictors, covering tumor burden and invasion, liver function,
and inflammatory activity, for patients with unresectable HCC who
initially underwent HAIC. The nomogram had a favorable discrimina­
tory ability with a C-index of 0.710 in the training cohort, and 0.716 in
the validation cohort, which were higher than that of several conven­
tional staging systems.
In this study, HAIC was performed for 463 unresectable HCC pa­
tients. Among them, 60% of patients had portal vein tumor thrombosis,
and 23% of patients had extrahepatic metastases. Therefore, the ma­
jority of patients were in an advanced stage, leading to a poor prognosis.
Several studies in Japan and Korea have reported that the median OS of
HCC patients with portal vein tumor thrombosis who underwent HAIC
ranged from 5.3 months to 14.9 months[22]. In the same center, Zhao M
reported 6- and 12-month OS rates of 71.4% and 55.1%, respectively, for
patients with advanced HCC treated with HAIC[23]. The survival out­
comes were consistent with those in the primary cohort in our study.
To date, no study has reported a model to predict the prognosis of
HAIC. Some Japanese studies proposed that lower AFP, NLR, and pro­
tein induced by vitamin K absence or antagonist-II (PIVKA-II) level and
good tumor response were associated with good efficacy for HAIC in
advanced HCC[11,12,24]. However, the chemotherapy regimen in this
study was based on oxaliplatin rather than cisplatin, which was
administered in a previous study, due to the relatively lower toxicity and
higher concentration ratios between the tumor and peripheral tissue
[25]. This difference might result in different prognostic factors for
7
European Journal of Radiology 142 (2021) 109890
1.0
New model
BCLC
HKLC
CIS
0.9
AJCC8th
JIS Score
Okuda
0.8
AUC
0.7
0.6
0.5
10 15 20 25 30
Time after HAIC (months)
HAIC. Tumor response can only be obtained by post-treatment assess­
ment and was therefore not suitable as an indicator to predict prognosis
prior to treatment. In this nomogram, tumor size, portal vein invasion
and extrahepatic metastasis reflected the tumor burden, which was a
large component of the assigned predictive score. Tumor stage is always
a major prognostic factor in determining patient outcome during anti­
cancer treatment. The ALBI gradeis a good indicator of liver function
and has been proven to be an important prognostic indicator for inter­
ventional therapy in HCC patients[26,27]. CRP was evaluated at the
optimal cutoff value of 1 mg/dL, which distinguished the degree of
inflammation and survival benefit[28]. The six predictors in this model
can be obtained by routine serum biochemical tests and imaging ex­
aminations. Accordingly, our nomogram has the potential to fill the gap
as an optimal tool for survival prediction among patients receiving HAIC
treatment.
The nomogram performed well compared with the staging systems
that are commonly used[15–20,29], and achieved a significantly higher
C-index in the training cohort (all P < 0.001) and validation cohort (all
P < 0.05). Given that the majority of the patients in this study had
hepatitis B-related HCC and liver cirrhosis, the HKLC staging system and
CIS were also evaluated to adapt to the specific conditions of Chinese
patients with HCC. From the data, the two systems failed to show a
strong predictive ability with a C-index less than 0.660. This nomogram
will be practical in selecting pre-treatment for patients who are appro­
priate candidates for HAIC. Individualized sensitivity to chemothera­
peutic agents varies widely, and this model might be useful for screening
drug-resistant patients using clinical data.
There were some limitations in this study. First, this study was
retrospective. Although the sustainability of HAIC treatment was not
controlled for, the medical data applied for analyzing prognosis were
accurate and well recorded by our reviewers. A total of 39 individuals
received only one cycle of HAIC because of disease progression or un­
acceptable toxicity, and might get a gloomy survival, which was
reasonable in clinical practice, but would inevitably lead to potential
prognostic bias. Second, the nomogram was established based on a
single-center cohort. The performance of this model in patients from
external institutions with different disease backgrounds remains to be
validated.
5. Conclusions
The nomogram in this study accurately predicted the overall survival
J. Mei et al.
of patients with unresectable HCC after HAIC. Compared to conven­
tional staging systems, this nomogram performed better in predicting
individualized survival information. This is an easy-to-use tool that
benefits physicians in the selection of therapeutic strategies during HAIC
treatment.
Funding
This study was supported by the National Natural Science Founda­
tion of China (No. 81871985); Natural Science Foundation of Guang­
dong Province (No. 2018A0303130098 and 2017A030310203); Science
and Technology Planning Project of Guangdong Province (No.
2017A020215112); Medical Scientific Research Foundation of Guang­
dong Province (No. A2017477); Science and Technology Planning
Project of Guangzhou (No.201903010017 and No. 201904010479);
Clinical Trials Project (5010 Project) of Sun Yat-sen University (No.
5010-2017009).
CRediT authorship contribution statement
Jie Mei: Conceptualization, Writing – original draft, Writing – re­
view & editing. Wen-Ping Lin: Data curation, Software, Writing –
original draft. Feng Shi: Methodology. Wei Wei: Project administration,
Formal analysis. Jia-Bao Liang: Data curation. Ming Shi: Supervision,
Project administration. Lie Zheng: Formal analysis. Shao-Hua Li:
Project administration. Rong-Ping Guo: Investigation, Project admin­
istration, Supervision.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
The authors thank AJE (https://www.aje.cn) for English language
polishing.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ejrad.2021.109890.
References
[1] F. Bray, et al., Global cancer statistics 2018: GLOBOCAN estimates of incidence and
mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin. 68 (6)
(2018) 394–424.
[2] S. Roayaie, et al., The role of hepatic resection in the treatment of hepatocellular
cancer, Hepatology 62 (2) (2015) 440–451.
[3] M.S. Makary et al., Locoregional Therapy Approaches for Hepatocellular
Carcinoma: Recent Advances and Management Strategies, Cancers (Basel) 12(7)
(2020).
[4] European Association for the Study of the Liver. Electronic address, e.e.e. and L.
European Association for the Study of the, EASL Clinical Practice Guidelines:
Management of hepatocellular carcinoma. J. Hepatol. 69(1) (2018) 182-236.
European Journal of Radiology 142 (2021) 109890
[5] B. Yang, et al., Transarterial strategies for the treatment of unresectable
hepatocellular carcinoma: A systematic review, PLoS ONE 15 (2) (2020),
e0227475.
[6] M.K. He, et al., Hepatic artery infusion chemotherapy using mFOLFOX versus
transarterial chemoembolization for massive unresectable hepatocellular
carcinoma: a prospective non-randomized study, Chin. J. Cancer 36 (1) (2017) 83.
[7] W.L. Tsai, et al., Hepatic arterial infusion chemotherapy for patients with huge
unresectable hepatocellular carcinoma, PLoS ONE 9 (5) (2014), e92784.
[8] W.L. Tsai, et al., Hepatic arterial infusion chemotherapy vs transcatheter arterial
embolization for patients with huge unresectable hepatocellular carcinoma,
Medicine (Baltimore) 99 (32) (2020), e21489.
[9] M. Kudo, et al., JSH Consensus-Based Clinical Practice Guidelines for the
Management of Hepatocellular Carcinoma: 2014 Update by the Liver Cancer Study
Group of Japan, Liver Cancer 3 (3–4) (2014) 458–468.
[10] S. Obi, S. Sato, T. Kawai, Current Status of Hepatic Arterial Infusion Chemotherapy,
Liver Cancer 4 (3) (2015) 188–199.
[11] T. Yamasaki, et al., Prognostic factors in patients with advanced hepatocellular
carcinoma receiving hepatic arterial infusion chemotherapy, J. Gastroenterol. 40
(1) (2005) 70–78.
[12] K. Tajiri, et al., Neutrophil/lymphocyte ratio as a prognostic indicator of hepatic
arterial infusion chemotherapy with arterial cisplatin plus continuous 5-
fluorouracil, Hepatol. Res. 45 (7) (2015) 755–763.
[13] Z. Lei, et al., Nomogram for Preoperative Estimation of Microvascular Invasion
Risk in Hepatitis B Virus-Related Hepatocellular Carcinoma Within the Milan
Criteria, JAMA Surg. 151 (4) (2016) 356–363.
[14] J. Bruix, M. Reig, M. Sherman, Evidence-Based Diagnosis, Staging, and Treatment
of Patients With Hepatocellular Carcinoma, Gastroenterology 150 (4) (2016)
835–853.
[15] O. Abdel-Rahman, Assessment of the discriminating value of the 8th AJCC stage
grouping for hepatocellular carcinoma, HPB (Oxford) 20 (1) (2018) 41–48.
[16] J.M. Llovet, C. Bru, J. Bruix, Prognosis of hepatocellular carcinoma: the BCLC
staging classification, Semin. Liver Dis. 19 (3) (1999) 329–338.
[17] T. Yau, et al., Development of Hong Kong Liver Cancer staging system with
treatment stratification for patients with hepatocellular carcinoma,
Gastroenterology 146 (7) (2014) 1691–700 e3.
[18] M. Kudo, H. Chung, Y. Osaki, Prognostic staging system for hepatocellular
carcinoma (CLIP score): its value and limitations, and a proposal for a new staging
system, the Japan Integrated Staging Score (JIS score), J. Gastroenterol. 38 (3)
(2003) 207–215.
[19] B.H. Zhang, et al., A new staging system is more discriminant than conventional
staging systems for unresectable hepatocellular carcinoma, J. Cancer Res. Clin.
Oncol. 136 (6) (2010) 821–827.
[20] K. Okuda, et al., Natural history of hepatocellular carcinoma and prognosis in
relation to treatment. Study of 850 patients, Cancer 56 (4) (1985) 918–928.
[21] M. Omata, et al., Asia-Pacific clinical practice guidelines on the management of
hepatocellular carcinoma: a 2017 update, Hepatol. Int. 11 (4) (2017) 317–370.
[22] M. Liu, et al., Systematic review of hepatic arterial infusion chemotherapy versus
sorafenib in patients with hepatocellular carcinoma with portal vein tumor
thrombosis, J. Gastroenterol. Hepatol. 35 (8) (2020) 1277–1287.
[23] N. Lyu, et al., FOXAI: a phase II trial evaluating the efficacy and safety of hepatic
arterial infusion of oxaliplatin plus fluorouracil/leucovorin for advanced
hepatocellular carcinoma, Gut 67 (2) (2018) 395–396.
[24] I. Saeki, et al., A new therapeutic assessment score for advanced hepatocellular
carcinoma patients receiving hepatic arterial infusion chemotherapy, PLoS ONE 10
(5) (2015), e0126649.
[25] R. Dzodic, et al., Pharmacokinetic advantage of intra-arterial hepatic oxaliplatin
administration: comparative results with cisplatin using a rabbit VX2 tumor model,
Anticancer Drugs 15 (6) (2004) 647–650.
[26] I.C. Lee, et al., A new ALBI-based model to predict survival after transarterial
chemoembolization for BCLC stage B hepatocellular carcinoma, Liver Int. 39 (9)
(2019) 1704–1712.
[27] J.Y. Ni, et al., A nomogram to predict survival of patients with intermediate-stage
hepatocellular carcinoma after transarterial chemoembolization combined with
microwave ablation, Eur. Radiol. 30 (4) (2020) 2377–2390.
[28] W. Sieghart, et al., Single determination of C-reactive protein at the time of
diagnosis predicts long-term outcome of patients with hepatocellular carcinoma,
Hepatology 57 (6) (2013) 2224–2234.
[29] R. Tateishi, et al., Proposal of a new prognostic model for hepatocellular
carcinoma: an analysis of 403 patients, Gut 54 (3) (2005) 419–425.