Hepatic Arterial Infusion Chemotherapy as a Timing Strategy for Conversion Surgery to Treat Hepatocellular Carcinoma: A Single-Center Real-World Study

Abstract

Objective
To evaluate whether surgery-related complications are increased after hepatic arterial infusion chemotherapy (HAIC) using oxaliplatin plus fluorouracil/leucovorin for conversion compared with primary hepatocellular carcinoma (HCC) resection and the optimal timing of conversion surgery (CS).

Background
HAIC has been widely used for advanced HCC, especially initially unresectable HCC, to facilitate conversion to curative-intent resection in approximately 23.8% of cases. However, the optimal timing of surgery to reduce surgical complications must be clarified.

Methods
Data from 320 HCC patients, including 107 initially unresectable patients in the HAIC-Surgery group and 213 patients in the Surgery group, were retrospectively collected and analyzed. Survival outcomes and the incidence of surgery-related complications were compared.

Results
There was no significant difference in recurrence-free survival (RFS) between the HAIC-Surgery group and the Surgery group (HR: 1.140, 95% CI: 0.8027–1.618, p=0.444). The HAIC-Surgery group had a higher incidence of surgery-related complications than the Surgery group [biliary leakage (10.3% vs 4.2%, p=0.035), abdominal bleeding (10.3% vs 3.8%, p=0.020), pleural effusion (56.1% vs 23.0%, p<0.0001) and ascites effusion (17.8% vs 5.2%, p<0.0001)]. In the HAIC-Surgery group, postoperative liver function decreased and abdominal bleeding increased with more preoperative HAIC cycles (Spearman=0.229, p=0.042, Spearman=0.198, p=0.041, respectively). The pathological complete remission (pCR) rate after 3–5 HAIC cycles was significantly higher than that after 1–2 cycles (29.4% vs 13.2%, p=0.043).

Conclusion
The prognosis of advanced HCC after conversion surgery is comparable to that after direct surgery. Rather than increasing pCR, more HAIC cycles can exacerbate liver dysfunction and surgery-related complications.

Full text

ORIGINAL RESEARCH
Hepatic Arterial Infusion Chemotherapy as a Timing
Strategy for Conversion Surgery to Treat
Hepatocellular Carcinoma: A Single-Center
Real-World Study
Jiongliang Wang
1,2,
*, Zhikai Zheng
1,2,
*, Tianqing Wu
1,2,
*, Wenxuan Li
1,2,
*, Juncheng Wang
1,2
,
Yangxun Pan
1,2
, Wei Peng
1,2
, Dandan Hu
1,2
, Jiajie Hou
1,2
, Li Xu
1,2
, Yaojun Zhang
1,2
,
Minshan Chen
1,2
, Rongxin Zhang
2,3
, Zhongguo Zhou
1,2
1
Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China;
2
Sun Yat-sen University Cancer Center;
State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China;
3
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Zhongguo Zhou, Department of Liver Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South
China, Collaborative Innovation Center for Cancer Medicine, Dongfeng Road East 651, Guangzhou, Guangdong, 510060, People’s Republic of China,
Tel +86-20-87343117, Email zhouzhg@sysucc.org.cn; Rongxin Zhang, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State
Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Dongfeng Road East 651, Guangzhou,
Guangdong, 510060, People’s Republic of China, Tel +86-411-84672130, Email zhangrx@sysucc.org.cn
Objective: To evaluate whether surgery-related complications are increased after hepatic arterial infusion chemotherapy (HAIC)
using oxaliplatin plus uorouracil/leucovorin for conversion compared with primary hepatocellular carcinoma (HCC) resection and the
optimal timing of conversion surgery (CS).
Background: HAIC has been widely used for advanced HCC, especially initially unresectable HCC, to facilitate conversion to
curative-intent resection in approximately 23.8% of cases. However, the optimal timing of surgery to reduce surgical complications
must be claried.
Methods: Data from 320 HCC patients, including 107 initially unresectable patients in the HAIC-Surgery group and 213 patients in
the Surgery group, were retrospectively collected and analyzed. Survival outcomes and the incidence of surgery-related complications
were compared.
Results: There was no signicant difference in recurrence-free survival (RFS) between the HAIC-Surgery group and the Surgery
group (HR: 1.140, 95% CI: 0.8027–1.618, p=0.444). The HAIC-Surgery group had a higher incidence of surgery-related complications
than the Surgery group [biliary leakage (10.3% vs 4.2%, p=0.035), abdominal bleeding (10.3% vs 3.8%, p=0.020), pleural effusion
(56.1% vs 23.0%, p<0.0001) and ascites effusion (17.8% vs 5.2%, p<0.0001)]. In the HAIC-Surgery group, postoperative liver
function decreased and abdominal bleeding increased with more preoperative HAIC cycles (Spearman=0.229, p=0.042,
Spearman=0.198, p=0.041, respectively). The pathological complete remission (pCR) rate after 3–5 HAIC cycles was signicantly
higher than that after 1–2 cycles (29.4% vs 13.2%, p=0.043).
Conclusion: The prognosis of advanced HCC after conversion surgery is comparable to that after direct surgery. Rather than
increasing pCR, more HAIC cycles can exacerbate liver dysfunction and surgery-related complications.
Keywords: hepatocellular carcinoma, conversion therapy, hepatic artery chemotherapy infusion
Introduction
HCC is the sixth leading cause of cancer and the third most lethal malignancy worldwide.
1,2
Although hepatic resection
has been considered a standard radical treatment for resectable HCCs,
3,4
approximately 60% of patients with HCC lose
Journal of Hepatocellular Carcinoma 2022:9 999–1010 999
© 2022 Wang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.
php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the
work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For
permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
Journal of Hepatocellular Carcinoma Dovepress
open access to scientific and medical research
Open Access Full Text Article
Received: 28 June 2022
Accepted: 9 September 2022
Published: 14 September 2022

the chance of surgery.
4,5
Targeted therapy combined with immunotherapy as the standard pharmacological treatment
effectively prolong the survival of patients with advanced liver cancer.
6–9
Therefore, The scheme of targeted therapy
combined with immunotherapy was recommended to be the preferred option in rst-line setting for advanced primary
liver cancer in both the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN
Guidelines) for hepatocellular carcinoma and the Guidelines for diagnosis and treatment of primary liver cancer in China.
Recently, several studies have reported favorable results either in response rate or survival when HAIC is based on
oxaliplatin plus uorouracil/leucovorin (FOLFOX) alone or accompanied with sorafenib used for advanced HCC.
10–12
Additionally, FOLFOX-based HAIC, either as a single agent or in combination with other treatment modalities, is an
attractive conversion therapy approach for unresectable patients.
13–16
It is widely believed that successful conversion treatment can provide patients an opportunity for prolonged survival in
cases of initially unresectable disease.
17,18
This approach directly delivers chemotherapeutic agents into tumor-associated
hepatic arterial branches locally at high concentrations,
19
achieving strong antitumor efcacy and lower systemic toxicity
through a greater rst-pass effect in the liver.
20
However, a series of complications can occur due to the liver damage caused by
chemotherapy drugs. A pattern of hepatic vascular injury has been reported in patients receiving neoadjuvant therapy with
5-FU and leucovorin in combination with oxaliplatin or irinotecan before the resection of liver metastases from colorectal
cancer.
21
Histologically, oxaliplatin-induced liver injury is associated with damage related to sinusoidal obstruction syndrome
(SOS).
22
Accordingly, HAIC with the FOLFOX regimen has resulted in some chemotherapy-related complications during
treatment, such as leucopenia, vomiting, hyperbilirubinemia, AST elevation, and ascites.
23,24
Furthermore, among colorectal
cancer patients with liver metastases, those who have been successfully converted with chemotherapy regimens based on
oxaliplatin and uorouracil are more likely to suffer from perioperative complications.
25–28
In fact, in addition to the possible liver damage caused by HAIC, the duration of HAIC treatment and the use of
concomitant medication remain controversial. In addition, reports on the post-transformation-related complications of HAIC
with the FOLFOX regimen have mainly focused on colorectal cancer with liver metastases, and there is still a lack of
research reports on primary liver tumors. Thus, in this retrospective study, we aimed to evaluate whether the incidence of
complications will increase after HAIC conversion therapy compared with HCC resection and the optimal timing of surgery.
Methods
Patients
Data from patients who were diagnosed with HCC according to the American Association for the Study of Liver Diseases
practice guidelines and treated by hepatic resection or HAIC-Surgery between January 2015 and June 2021 were retrieved.
The inclusion criteria were as follows: Surgery group: (a) pathological diagnosis of hepatocellular carcinoma; (b) Barcelona
clinic liver cancer (BCLC) stage A or B; (c) Child–Pugh Grade A and (d) residual liver volume >40% after resection.
HAIC-Surgery group: (a) pathological diagnosis of hepatocellular carcinoma; (b) Child–Pugh Grade A; (c) before HAIC,
tumors not amenable to radical surgical resection due to insufcient surgical margins after assessment by multi-disciplinary
treatment (MDT) group, or an estimated <40% residual liver volume (FLV) remaining after resection and (d) after HAIC,
residual liver volume >40% after resection. Cases were excluded if they met any of the following criteria: (a) a previous
history of HCC treatment; (b) signs of vascular invasion or distant metastasis on imaging; (c) severe underlying cardiac,
pulmonary, or renal diseases; or (d) a second primary malignancy. This study was approved by the Institutional Review
Board of Sun Yat-sen University Cancer Center (SYSUCC, Guangzhou, China) and was performed following the
Declaration of Helsinki of 1975 as revised in 1983.
Propensity Score Analysis
Propensity score matching (PSM) was applied to reduce selection bias by equating the 2 groups. All possible
clinicopathological covariates, including age, sex, degree of tumor differentiation, China liver cancer staging
(CNLC), tumor size, tumor number, alpha-fetoprotein (AFP), alanine transaminase (ALT), albumin (ALB), total
bilirubin (TBIL), and hepatitis B surface antigen (HBsAg), which might have increased the incidence of complications,
were included when performing PSM. Using NCSS 10 Statistical Software (LLC, Kaysville, UT, USA), the greedy
https://doi.org/10.2147/JHC.S379326
DovePress
Journal of Hepatocellular Carcinoma 2022:9
1000
Wang et al Dovepress
Powered by TCPDF (www.tcpdf.org)

method was used for matching the study groups at a 2:1 ratio with a caliper width of 0.2-fold the standard deviation of
the propensity score between the two groups. The standardized mean difference (SMD) was used to evaluate the
covariate balance after PSM.
HAIC Treatment and Hepatic Resection After Conversion
A catheter was placed and xed in the tumor feeding artery for the FOLFOX-based chemotherapy infusion at the
following dosage: 130 mg/m
2
oxaliplatin infusion for 3 hours; 200 mg/m
2
leucovorin infusion for 2 hours; and
1200 mg/ m
2
5-FU continuous infusion for 23 hours. HAIC treatment was repeated every 3 weeks. Hepatectomy was
performed after careful evaluation by 2 experienced surgeons when the estimated residual liver volume was >30–40%
after resection.
29
Hepatectomy was performed using cutting ultrasonic aspiration (CUSA) and an ultrasonic scalpel via
open or laparoscopic surgery.
Follow-Up and Major Complication Evaluation
Blood cell counts, liver function tests, and serum AFP levels were determined before each cycle. Adverse events/
complications were graded according to the Clavien–Dindo version before each cycle. Biliary leakage: According to the
denition of biliary stula by the International Liver Surgery Study Group (ISGLS), biliary leakage was dened as
leakage occurring ≥3 days after surgery and a bilirubin concentration at least 3 times the normal plasma bilirubin
concentration in the drainage uid or bile accumulation or bilirubin in the drainage uid. Cases of biliary peritonitis
required interventional or surgical treatment.
30
Abdominal bleeding: Abdominal bleeding was dened as a decrease in
hemoglobin of more than 3 g/dl compared to preoperative values and at least two doses of postoperative hemostatic
drugs.
31
Pleural effusion: Pleural effusion was dened as perioperative or rst postoperative follow-up imaging depicting
pleural effusion compared with preoperative chest imaging. Ascites effusion: Ascites effusion was dened as periopera-
tive or rst postoperative follow-up imaging revealing ascites compared with preoperative abdominal imaging.
Evaluation of changes in liver function: Deterioration in liver function was dened as a difference between the
postoperative albumin-bilirubin scoring model (ALBI) grade and preoperative ALBI grade greater than 1; otherwise,
a difference between the postoperative ALBI grade and preoperative ALBI grade less than or equal to 1 was dened as
no deterioration in liver function.
Statistical Analyses
RFS was measured from the date of liver resection until disease progression or recurrence or the last follow-up visit.
Survival curves were analyzed using the Kaplan–Meier method and the Log rank test. Categorical variables were
analyzed using the chi-square test, and continuous variables were analyzed using Student’s t test. The correlation
coefcient and p value were calculated using Spearman’s rank correlation analysis. A p<0.05 was considered statistically
signicant. All data were processed with the Statistics for Social Sciences package version 24.0 (IBM Corp).
Result
Characteristics of the Total Study Cohort
Among a total of 320 patients included in our original study, 213 (66.6%) and 107 (33.4%) patients were included in the
HAIC-Surgery and Surgery groups, respectively (Figure 1). The baseline data of these patients are shown in Table 1.
Before the PSM analysis, most characteristics were not signicantly different between HAIC-Surgery and Surgery
groups, except a higher proportion of patients in the HAIC-surgery group had a signicantly more advanced CNLC stage
after HAIC (Ia 26.0% vs 47.9%; Ib 38.9% vs 36.4%; IIa 9.2% vs 6.0%; IIb 15.3% vs 3.7%; III 10.7% vs 6.0%,
p<0.0001) and a higher tumor number (18.3% vs 2.3%, p<0.0001) (Table 1). After 2:1 PSM of the 320 patients (213 in
the Surgery group and 107 in the HAIC-Surgery group), most of the characteristics analyzed in this work were balanced
between the two groups (Figure 2). Finally, no signicant differences were observed between the patients in the two
groups in terms of confounding factors in subsequent analyses.
Journal of Hepatocellular Carcinoma 2022:9 https://doi.org/10.2147/JHC.S379326
DovePress
1001
Dovepress Wang et al
Powered by TCPDF (www.tcpdf.org)

Survival Outcomes
Downstaging occurred in 58 of 107 patients, accounting for 54.2% of the population who underwent HAIC before liver
resection. In addition, Similar rates of partial hepatectomy (75.6% vs 77.6%) and hepatolobectomy(24.4% vs 22.4%)
were performed in the two groups. The median follow-up period was 39.8 months. The median RFS was 38.7 months for
the Surgery group and 22.9 months for the HAIC-Surgery group. The Surgery group did not show superiority over the
HAIC-Surgery group in terms of RFS (HR: 1.140, 95% CI: 0.8027–1.618, p=0.444, Figure 3).
Figure 1 Flow diagram of patients with hepatocellular carcinoma who underwent either hepatectomy or HAIC-hepatectomy.
Table 1 Baseline Characteristics of Patients with Hepatocellular Carcinoma
Variables Before PSM After PSM
Surgery
(n=217)
HAIC-Surgery
(n=131)
p value Surgery
(n=213)
HAIC-Surgery
(n=107)
SMD p value
Gender 0.621 0.012 0.921
Male 188(86.6%) 111(84.7%) 184(86.4%) 92(86.0%)
Female 29(13.4%) 20(15.3%) 29(13.6%) 15(14.0%)
Age(years) 0.946 0.003 0.978
≥60 72(33.2%) 43(32.8%) 70(32.9%) 35(32.7%)
<60 145(66.8%) 88(67.2%) 143(67.1%) 72(67.3%)
Degree of tumor
differentiation
0.256 0.163 0.431
High 13(6.0%) 3(2.3%) 13(6.1%) 3(2.8%)
Moderate 177(81.6%) 109(83.2%) 173(81.2%) 89(83.2%)
Low 27(12.4%) 19(14.5%) 27(12.7%) 15(14.0%)
(Continued)
https://doi.org/10.2147/JHC.S379326
DovePress
Journal of Hepatocellular Carcinoma 2022:9
1002
Wang et al Dovepress
Powered by TCPDF (www.tcpdf.org)

Complications
The complications observed in this study are shown in Table 2. We found higher cumulative incidences of biliary
leakage (10.3% vs 4.2%, p=0.035), abdominal bleeding (10.3% vs 3.8%, p=0.020), pleural effusion (56.1% vs 23.0%,
p<0.0001) and ascites effusion (17.8% vs 5.2%, p<0.0001) in the HAIC-Surgery group than in the surgery group.
However, there were no signicant differences in the rate of complications between the two groups, including pulmonary
infection (5.6% vs 5.2%, p=0.868), bowel obstruction (0 vs 2.3%, p=0.263), fever (≥38.1°C) (7.5% vs 12.7%, p=0.160),
and nausea and vomiting (15.9% vs 17.4%, p=0.738). Although the HAIC-Surgery group had a higher rate of
complications, it was comparable to the Surgery group in terms of the number of patients experiencing grade ≥ 3
adverse effects. (Table 2)
It should be noted that both HAIC and liver resection have an impact on liver function to some extent. Here, we used
the ALBI grade to comprehensively evaluate the liver function of the two groups before and after surgery. Moreover, to
reect the changes in liver function and to better describe the possible impact of HAIC on postoperative liver function,
we compared the ALBI grade between the two groups of patients before and after surgery. Supplementary Table 1 and
Figure 4 show that most patients in both the HAIC-Surgery group and the Surgery group had decreased postoperative
liver function, especially the latter group (70.1% vs 55.4%, p=0.011).
Table 1 (Continued).
Variables Before PSM After PSM
Surgery
(n=217)
HAIC-Surgery
(n=131)
p value Surgery
(n=213)
HAIC-Surgery
(n=107)
SMD p value
CNLC <0.0001 0.367 0.051
Ia 104(47.9%) 34(26.0%) 100(46.9%) 34(31.8%)
Ib 79(36.4%) 51(38.9%) 79(37.1%) 51(47.7%)
IIa 13(6.0%) 12(9.2%) 13(6.1%) 12(11.2%)
IIb 8(3.7%) 20(15.3%) 8(3.8%) 2(1.9%)
III 13(6.0%) 14(10.7%) 13(6.1%) 8(7.5%)
ALT(U/L) 0.623 0.007 0.954
>40 69((31.8%) 45(34.4%) 67(31.5%) 34(31.8%)
≤40 148(68.2%) 86(65.6%) 146(68.5%) 73(68.2%)
ALB(g/L) 0.128 0.234 0.066
≥35 212(97.7%) 123(93.9%) 209(98.1%) 100(93.5%)
<35 5(2.3%) 8(6.1%) 4(1.9%) 7(6.5%)
TBIL(μmol/L) 0.951 0.024 0.839
>17.1 32(14.7%) 19(14.5%) 32(15.0%) 17(15.9%)
≤17.1 185(85.3%) 112(85.5%) 181(85.0%) 90(84.1%)
AFP(ng/mL) 0.291 0.217 0.073
≤400 137(63.1%) 90(68.7%) 136(63.8%) 79(73.8%)
>400 80(36.9%) 41(31.3%) 77(36.2%) 28(26.2%)
HBsAg 0.783 0.092
Positive 190(87.6%) 116(88.5%) 187(87.8%) 97(90.7%) 0.445
Negative 27(12.4%) 15(11.5%) 26(12.2%) 10(9.3%)
Main tumor size(cm) 0.882 0.031 0.796
≥10 26(12.0%) 15(11.5%) 26(12.2%) 12(11.2%)
<10 191(88.0%) 116(88.5%) 187(87.8%) 95(88.8%)
Tumor number <0.0001 0.029 1
≤3 212(97.7%) 107(81.7%) 208(97.7%) 104(97.2%)
>3 5(2.3%) 24(18.3%) 5(2.3%) 3(2.8%)
Journal of Hepatocellular Carcinoma 2022:9 https://doi.org/10.2147/JHC.S379326
DovePress
1003
Dovepress Wang et al
Powered by TCPDF (www.tcpdf.org)

Analysis of Complications Related to the HAIC Cycle
Among the 107 patients in the HAIC-Surgery group in our study, the patients underwent 1 to more than 5 HAIC cycles
before reaching the standard of conversion surgery for resection. Here, we performed a correlation analysis of the HAIC
cycle with pre-HAIC tumor size and clinical stage (CNLC). As shown in Table 3, the number of HAIC cycles had
Figure 2 A visualization of the Propensity Score Matching.
Figure 3 Kaplan-Meier curves for RFS in the Surgery and HAIC-Surgery groups. Vertical bars indicate censoring of patients alive at their last follow-up.
https://doi.org/10.2147/JHC.S379326
DovePress
Journal of Hepatocellular Carcinoma 2022:9
1004
Wang et al Dovepress
Powered by TCPDF (www.tcpdf.org)

a signicant positive correlation with tumor size (Spearman=0.311, p=0.001) and clinical stage (Spearman=0.301,
p=0.002), indicating that when the tumor burden is greater, more HAIC cycles are needed to achieve conversion.
Biliary leakage (10.3%), abdominal bleeding (10.3%), pleural effusion (56.1%), and ascites effusion (17.8%) were the
4 most common complications after HAIC conversion surgery. As shown in Table 4, among these 4 complications, only
abdominal bleeding (Spearman=0.198, p=0.041) had a positive correlation with the number of HAIC cycles, which
means that as the number of HAIC cycles increases, the incidence of abdominal bleeding gradually increases.
Furthermore, Table 4 shows that receiving 3–8 cycles of HAIC treatment was more likely to cause abdominal bleeding
(16.7% vs 3.8%, p=0.028) than receiving 1–2 cycles of HAIC. However, there was no signicant correlation between
biliary leakage (p=0.323), pleural effusion (p=0.201), or ascites effusion (p=0.575) and the number of HAIC cycles
(Table 4).
Table 2 Study Surgery-Related Complications for Patients Who Underwent Either Hepatectomy or Hepatectomy After HAIC
Any Grade (Cases) Grade 3–4 (Cases)
Surgery (n=213) HAIC-Surgery (n=107) p value Surgery (n=213) HAIC-Surgery (n=107) p value
Biliary leak 9(4.2%) 11(10.3%) 0.035 3(1.4%) 4(3.7%) 0.348
Abdominal bleeding 8(3.8%) 11(10.3%) 0.020 1(0.5%) 4(3.7%) 0.081
Pleural effusion 49(23.0%) 60(56.1%) <0.0001 4(1.9%) 5(4.7%) 0.285
Ascites effusion 11(5.2%) 19(17.8%) <0.0001 4(1.9%) 2(1.9%) 1.000
Pulmonary infection 11(5.2%) 6(5.6%) 0.868 0 0 1.000
Bowel obstruction 5(2.3%) 0 0.263 2(0.9%) 0 0.800
Fever 27(12.7%) 8(7.5%) 0.160 0 0 1.000
Nausea and vomiting 37(17.4%) 17(15.9%) 0.738 0 0 1.000
Figure 4 Waterfall plots depicting the change of ALBI grade before and after hepatectomy (A and B); Comparison of ALBI score of patients after HAIC conversion therapy
and before surgery. ALBI, albumin-bilirubin (C). Yellow triangle: ALBI score before HAIC; blue marks: ALBI score before surgery; red squares: ALBI score after surgery; grey
lines: changes of ALBI score before HAIC and before surgery in the same patient; green lines: changes of ALBI score before and after surgery in the same patient.
Journal of Hepatocellular Carcinoma 2022:9 https://doi.org/10.2147/JHC.S379326
DovePress
1005
Dovepress Wang et al
Powered by TCPDF (www.tcpdf.org)

In addition to the above complications, postoperative liver function changes also showed a positive correlation with
the number of HAIC cycles. We used the difference between the postoperative ALBI score (that is, the day after the
operation, Spearman=0.229, p=0.042) and the preoperative ALBI score as the standard for liver function changes. Based
on the results shown in Supplementary Table 2 (the table summarizes only the changes in ALBI grade before and after
surgery) and Figure 4, it can be concluded that with an increase in the number of HAIC cycles, the postoperative liver
function decreases signicantly.
Analysis of pCR Related to the HAIC Cycle
Pathological complete response (pCR) was dened as no histological evidence of a malignant tumor in the primary tumor
site via multipoint sampling. Among the 107 patients who underwent surgery after HAIC treatment included in this
study, 22 patients met the criteria for pCR (Supplementary Table 3). Moreover, the rate of pCR in patients who received
3–5 cycles of HAIC was signicantly higher than that in patients who received 1–2 cycles (29.4% vs 13.2%, p=0.043).
Discussion
In this study, we tried to demonstrate that the optimal timing of CS after HAIC. Compared with the patients in the
surgery group, the number of advanced patients in the HAIC-Surgery group was signicantly higher. However, some
patients were downstaged and even reached the criteria for surgical resection after HAIC treatment. Nonetheless, patients
in the HAIC-Surgery group were staged later than those in the Surgery group. Therefore, we performed a PSM for the
tumor stage to enable two groups of patients comparable in preoperative stage, which reduces or avoids the inuence of
tumor stage on the results of subsequent analysis. According to our observations, postoperative complications such as
biliary leakage, abdominal bleeding, pleural effusion, and ascites effusion were signicantly higher in the HAIC-Surgery
group than in the Surgery group. At the meantime, we found the short-term survival benet (RFS) of patients who
underwent HAIC-Surgery is comparable to those direct surgery cohort on early stage.
Table 3 Correlation Analysis of Tumor Stage and Tumor Size with HAIC Cycles of Treatment
Cycles of
HAIC
Tumor Staging Tumor Size (mm)
I
(n=42)
II
(n=29)
III
(n=36)
Sperman p value 0–30
(n=4)
31–60
(n=27)
61–90
(n=32)
91-
(n=44)
Sperman p value
1 7 2 0 2 4 1 2
2 18 15 11 2 17 10 15
3 5 4 5 0.301 0.002 0 2 3 9 0.311 0.001
4 11 5 15 0 4 13 14
5- 1 3 5 0 0 5 4
Table 4 Correlation Analysis of 4 Major Postoperative Complications with HAIC Cycles of Treatment
Cycles of HAIC Abdominal Bleeding
(n=11)
Biliary Leak
(n=11)
Pleural Effusion
(n=60)
Ascites Effusion
(n=19)
1 (n=9) 0 3 (33.3%) 6 (66.7%) 1 (11.1%)
2 (n=44) 2 (4.5%) 4 (9.1%) 27 (61.4%) 9 (20.5%)
3 (n=14) 3 (21.4%) 2 (14.3%) 8 (57.1%) 1 (7.1%)
4 (n=31) 4 (12.9%) 1 (3.2%) 17 (54.8%) 7 (22.6%)
5- (n=9) 2 (22.2%) 1 (11.1%) 2 (22.2%) 1 (11.1%)
p value 0.041 0.115 0.088 0.952
Sperman 0.198
1–2 (n=53) 2 (3.8%) 7 (13.2%) 33 (62.3%) 10 (18.9%)
3–8 (n=54) 9 (16.7%) 4 (7.4%) 27 (50.0%) 8 (14.8%)
p value 0.028 0.323 0.201 0.575
https://doi.org/10.2147/JHC.S379326
DovePress
Journal of Hepatocellular Carcinoma 2022:9
1006
Wang et al Dovepress
Powered by TCPDF (www.tcpdf.org)

Recently, there has been growing evidence that HAIC with infusional uorouracil, leucovorin, and oxaliplatin
(FOLFOX) can provide a signicant survival benet and is safe for patients with advanced HCC.
32–35
However, the
use of FOLFOX chemotherapy regimens, including oxaliplatin and uorouracil, has been associated with damage to the
liver parenchyma, described as SOS,
22
and vascular hepatic lesions (hemorrhagic centrilobular necrosis, HCN; nodular
regenerative hyperplasia, NRH), which may progress to brosis after long-term chemotherapy.
21
Furthermore, previous
studies have shown higher AST and ALT levels in patients with high-grade SOS, suggesting postoperative liver
failure.
36,37
Our study showed that patients in the HAIC- Surgery group had a more pronounced decrease in postoperative
liver function than those in the Surgery group, which appeared to be associated with the liver damage (SOS, HCN, RNH,
etc.) caused by oxaliplatin and uorouracil. Furthermore, hepatic sinusoidal injury and portal damage or increases in
spleen size related to hypertension caused by oxaliplatin-based chemotherapy could cause some sequelae, such as ascites,
hemorrhoidal and variceal bleeding, or persistent thrombocytopenia.
25–28
Considering the above study results, we also
investigated whether patients who underwent HAIC conversion therapy were more likely to develop biliary leakage,
abdominal bleeding, pleural effusion, and ascites effusion after surgery. In essence, we believe that these complications
are still related to the decrease in liver function caused by oxaliplatin-induced liver parenchymal injury. Coincidentally,
the review by Zhao et al claried that postoperative major morbidity and liver surgery-specic complications increased in
patients with severe SOS resulting from oxaliplatin-based chemotherapy and steatohepatitis after partial hepatectomy.
38
Although the liver injury caused by preoperative chemotherapy may cause postoperative complications, HAIC is still
an important approach to achieve tumor downstaging. What is more important is to explore the relationship between the
number of HAIC cycles and the incidence of complications so that a relative balance can be achieved between the
conversion effect and the occurrence of complications. In a study by Karoui et al, complication occurrence after liver
resection was associated with the number of preoperative chemotherapy cycles in colorectal cancer liver metastases.
Patients who received 6 cycles of chemotherapy showed increased morbidity compared to patients with less than 6 cycles
(54% vs 19%; n = 45; p=0.047).
39
Similarly, another study also showed that treatment with more than 12 cycles of
preoperative chemotherapy resulted in a higher reoperation rate and a longer hospital length of stay.
21
At the same time,
our study also revealed a signicant correlation (Spearmen=0.198, p=0.041) between postoperative abdominal bleeding
and preoperative HAIC treatment. The administration of 3 to 8 cycles of HAIC preoperatively are signicantly more
likely to lead to the development of abdominal bleeding than 1–2 cycles preoperatively. The frequency of chemotherapy
and obvious complications in this study is quite different from the results of previous studies, which may be related to the
method of preoperative chemotherapy administration. Relatedly, liver metastases from colorectal cancer are typically
treated with systemic chemotherapy, while HAIC increases the concentration of chemotherapy drugs in the liver, which
may cause more liver toxicity. On the other hand, in this study, the number of patients receiving more than 6 cycles HAIC
was small, which may also yield biased results. Although complications other than abdominal bleeding were not
signicantly correlated with the duration of HAIC, our results showed that the degree of postoperative liver function
deterioration gradually increased with an increase in the duration of HAIC (Spearmen=0.229, p=0.042). The only
chemotherapy-associated liver injury that negatively affected postoperative outcomes was NRH, which was associated
with a higher liver failure rate (7.8% vs 2.8%, p = 0.037).
40
Since HAIC with the FOLFOX regimen is generally
reviewed after every 2 cycles, we suggest that surgical resection be performed after 4 cycles to reach the standard for
conversion surgery and reduce the occurrence of postoperative complications. Of course, because postoperative compli-
cations increase with an increasing number of HAIC cycles, it is not necessary to continue treatment through the 4th
cycle of HAIC if patients can reach the standard for surgery after 2 cycles.
We also investigated whether the need for more preoperative HAIC cycles was associated with a advanced stage.
Obviously, we found that the advanced the preoperative tumor stage was (Spearmen=0.301, p=0.002), the larger the
tumor volume (Spearmen=0.311, p=0.001), and the more HAIC cycles were required for downstaging and conversion. In
addition, we conrmed that 3–5 cycles of HAIC achieved the highest pathological complete response (pCR) rate
(29.4%). In our study, pCR was more likely to be achieved after 3–5 cycles of HAIC than after fewer than 3 cycles
of HAIC (29.4% vs 13.2%, p=0.043). However, we did not nd that pCR increased with the number of HAIC cycles in
this study. This may be related to the small number of included patients who received more than 5 cycles of HAIC. For
pCR, some studies have shown that the tumor-free survival of patients after liver cancer conversion resection is related to
Journal of Hepatocellular Carcinoma 2022:9 https://doi.org/10.2147/JHC.S379326
DovePress
1007
Dovepress Wang et al
Powered by TCPDF (www.tcpdf.org)

the degree of pathological remission, with the postoperative tumor-free survival of patients with pathological remission
being longer.
41,42
However, Kishi et al showed that after more than 8 cycles of chemotherapy, the probability of major
pathological remission in colorectal cancer patients with liver metastases did not increase signicantly, but the proportion
of liver injury caused by chemotherapy did.
43
Importantly, SOS resulting from oxaliplatin has also been associated with
early tumor recurrence and decreased long-term survival.
44
Therefore, a higher number of HAIC cycles does not the pCR
rate and may negatively affect prognosis due to the liver damage caused by multiple cycles of HAIC.
Due to the high ORR rate of HAIC,
24,32
combined targeted therapy or immunotherapy is used to improve the survival
of patients with advanced HCC. Clinical trials in recent years have shown that the combination of HAIC with targeted
therapy, immunotherapy and a combination of treatment methods has further improved the transformation rate of liver
cancer.
13,45–47
However, as a single center retrospective study, we still need more prospective clinical studies to verify
these clinical ndings. In addition, in order to avoid confounding factors, patients with immune checkpoint inhibitors and
molecular targeted therapy were not involved in this study.
Conclusion
In conclusion, we found that the prognosis of advanced HCC after conversion surgery is comparable to that after direct
surgery. The optimal number of cycles for HAIC conversion therapy should not exceed 4; a higher number of cycles does
not increase pCR and can cause more severe liver dysfunction postoperatively and increase the incidence of complica-
tions, such as abdominal bleeding and pleural effusion.
Data Sharing Statement
All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the
corresponding author (Zhongguo Zhou).
Ethics Approval and Consent to Participate
This study was conducted according to the ethical guidelines of the 1975 Declaration of Helsinki. This research was
approved by the institutional review board of Sun Yat-sen University Cancer Center (Ethical review no. B2022-238-01).
The study used retrospective anonymous clinical data that were obtained after each patient agreed to treatment.
Author Contributions
All authors made a signicant contribution to the work reported, whether that is in the conception, study design,
execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically
reviewing the article; gave nal approval of the version to be published; have agreed on the journal to which the article
has been submitted; and agree to be accountable for all aspects of the work.
Funding
This work is funded by Sun Yat-sen University Cancer Center physician scientist funding (No. 16zxqk04), Wu Jieping
Medical Foundation - special fund for tumor immunity (320.6705.2021-02-76).
Disclosure
The authors declare no conicts of interest in this work.
References
1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185
countries. CA Cancer J Clin. 2021;71:209–249. doi:10.3322/caac.21660
2. IARC. Latest global cancer data Cancer burden rises to 19.3 million new cases and 10.0 million cancer deaths in 2020; 2020.
3. Qiu J, Peng B, Tang Y, et al. CpG methylation signature predicts recurrence in early-stage hepatocellular carcinoma: results from a multicenter study.
J Clin Oncol. 2017;35:734–742. doi:10.1200/JCO.2016.68.2153
4. Cucchetti A, Zhong J, Berhane S, et al. The chances of hepatic resection curing hepatocellular carcinoma. J Hepatol. 2020;72:711–717. doi:10.1016/
j.jhep.2019.11.016
https://doi.org/10.2147/JHC.S379326
DovePress
Journal of Hepatocellular Carcinoma 2022:9
1008
Wang et al Dovepress
Powered by TCPDF (www.tcpdf.org)

5. Shaya FT, Breunig IM, Seal B, et al. Comparative and cost effectiveness of treatment modalities for hepatocellular carcinoma in SEER-Medicare.
Pharmacoeconomics. 2014;32(1):63–74. doi:10.1007/s40273-013-0109-7
6. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–1905.
doi:10.1056/NEJMoa1915745
7. Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin
Oncol. 2020;38:2960–2970. doi:10.1200/JCO.20.00808
8. Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-
32): a randomised, open-label, Phase 2–3 study. Lancet Oncol. 2021;22:977–990. doi:10.1016/S1470-2045(21)00252-7
9. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022;1.
doi:10.1056/EVIDoa2100070
10. Kudo M. Treatment of advanced hepatocellular carcinoma with emphasis on hepatic arterial infusion chemotherapy and molecular targeted therapy.
Liver Cancer. 2012;1:62–70. doi:10.1159/000342402
11. Ikeda M, Shimizu S, Sato T, et al. Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular
carcinoma: randomized Phase II trial. Ann Oncol. 2016;27:2090–2096. doi:10.1093/annonc/mdw323
12. Ueshima K, Kudo M, Tanaka M, et al. Phase I/II study of sorafenib in combination with hepatic arterial infusion chemotherapy using low-dose
cisplatin and 5-uorouracil. Liver Cancer. 2015;4:263–273. doi:10.1159/000367751
13. Xu L, Zhang YJ, Wang XH, et al. Transarterial infusion chemotherapy (TAI) combined with Sintilimab in locally advanced, potentially resectable
hepatocellular carcinoma (HCC). J Clin Oncol. 2020;38:e16593–e16593. doi:10.1200/JCO.2020.38.15_suppl.e16593
14. He M, Li Q, Zou R, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, uorouracil, and leucovorin vs sorafenib alone for hepatocellular
carcinoma with portal vein invasion: a randomized clinical trial. JAMA Oncol. 2019;5:953–960. doi:10.1001/jamaoncol.2019.0250
15. Gourd K, Lai C, Reeves C. ESMO Virtual Congress 2020. Lancet Oncol. 2020;21:1403–1404. doi:10.1016/S1470-2045(20)30585-4
16. Li B, Qiu J, Zheng Y, et al. Conversion to resectability using transarterial chemoembolization combined with hepatic arterial infusion chemotherapy
for initially unresectable hepatocellular carcinoma. Ann Surg Open. 2021;2(2):e057. doi:10.1097/AS9.0000000000000057
17. Zhang ZF, Luo YJ, Lu Q, et al. Conversion therapy and suitable timing for subsequent salvage surgery for initially unresectable hepatocellular
carcinoma: what is new? World J Clin Cases. 2018;6:259–273. doi:10.12998/wjcc.v6.i9.259
18. Lau WY, Lai EC. Salvage surgery following downstaging of unresectable hepatocellular carcinoma--A strategy to increase resectability. Ann Surg
Oncol. 2007;14:3301–3309. doi:10.1245/s10434-007-9549-7
19. Bartkowski R, Berger MR, Aguiar JL, et al. Experiments on the efcacy and toxicity of locoregional chemotherapy of liver tumors with 5-uoro-
2’-deoxyuridine (FUDR) and 5-uorouracil (5-FU) in an animal model. J Cancer Res Clin Oncol. 1986;111:42–46. doi:10.1007/BF00402774
20. Kuan HY, Smith DE, Ensmiger WD, et al. Regional pharmacokinetics of 5-bromo-2’-deoxyuridine and 5-uorouracil in dogs: hepatic arterial
versus portal venous infusions. Cancer Res. 1996;56:4724–4727.
21. Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with uorouracil plus oxaliplatin in
colorectal cancer liver metastases. J Clin Oncol. 2006;24:4983–4990. doi:10.1200/JCO.2006.05.8156
22. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients
with metastatic colorectal cancer. Ann Oncol. 2004;15:460–466. doi:10.1093/annonc/mdh095
23. Choi JH, Chung WJ, Bae SH, et al. Randomized, prospective, comparative study on the effects and safety of sorafenib vs. hepatic arterial infusion
chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis. Cancer Chemother Pharmacol. 2018;82
(3):469–478. doi:10.1007/s00280-018-3638-0
24. Lyu N, Lin Y, Kong Y, et al. FOXAI: a phase II trial evaluating the efcacy and safety of hepatic arterial infusion of oxaliplatin plus uorouracil/
leucovorin for advanced hepatocellular carcinoma. Gut. 2018;67:395–396. doi:10.1136/gutjnl-2017-314138
25. Slade JH, Alattar ML, Fogelman DR, et al. Portal hypertension associated with oxaliplatin administration: clinical manifestations of hepatic
sinusoidal injury. Clin Colorectal Cancer. 2009;8:225–230. doi:10.3816/CCC.2009.n.038
26. Overman MJ, Maru DM, Charnsangavej C, et al. Oxaliplatin-mediated increase in spleen size as a biomarker for the development of hepatic
sinusoidal injury. J Clin Oncol. 2010;28:2549–2555. doi:10.1200/JCO.2009.27.5701
27. Arotçarena R, Calès V, Berthelémy P, et al. Severe sinusoidal lesions: a serious and overlooked complication of oxaliplatin-containing
chemotherapy? Gastroentérologie Clinique et Biologique. 2006;30:1313–1316. doi:10.1016/S0399-8320(06)73542-4
28. Agarwal V, Sgouros J, Smithson J, et al. Sinusoidal obstruction syndrome (veno-occlusive disease) in a patient receiving bevacizumab for
metastatic colorectal cancer: a case report. J Med Case Rep. 2008;2:227. doi:10.1186/1752-1947-2-227
29. Yang P, Qiu J, Li J, et al. Nomograms for pre- and postoperative prediction of long-term survival for patients who underwent hepatectomy for
multiple hepatocellular carcinomas. Ann Surg. 2016;263:778–786. doi:10.1097/SLA.0000000000001339
30. Schaible A, Schemmer P, Hackert T, et al. Location of a biliary leak after liver resection determines success of endoscopic treatment. Surg Endosc.
2017;31:1814–1820. doi:10.1007/s00464-016-5178-1
31. Rahbari NN, Garden OJ, Padbury R, et al. Post-hepatectomy haemorrhage: a denition and grading by the International Study Group of Liver
Surgery (ISGLS). HPB. 2011;13:528–535. doi:10.1111/j.1477-2574.2011.00319.x
32. Lyu N, Kong Y, Mu L, et al. Hepatic arterial infusion of oxaliplatin plus uorouracil/leucovorin vs. sorafenib for advanced hepatocellular
carcinoma. J Hepatol. 2018;69:60–69. doi:10.1016/j.jhep.2018.02.008
33. Li QJ, He MK, Chen HW, et al. Hepatic arterial infusion of oxaliplatin, uorouracil, and leucovorin versus transarterial chemoembolization for
large hepatocellular carcinoma: a randomized Phase III trial. J Clin Oncol. 2022;40:150–160. doi:10.1200/JCO.21.00608
34. He MK, Le Y, Li QJ, et al. Hepatic artery infusion chemotherapy using mFOLFOX versus transarterial chemoembolization for massive
unresectable hepatocellular carcinoma: a prospective non-randomized study. Chin J Cancer. 2017;36:83. doi:10.1186/s40880-017-0251-2
35. Qin S, Bai Y, Lim HY, et al. Randomized, multicenter, open-label study of oxaliplatin plus uorouracil/leucovorin versus doxorubicin as palliative
chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013;31:3501–3508. doi:10.1200/JCO.2012.44.5643
36. Soubrane O, Brouquet A, Zalinski S, et al. Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based
chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome. Ann Surg. 2010;251:454–460. doi:10.1097/
SLA.0b013e3181c79403
Journal of Hepatocellular Carcinoma 2022:9 https://doi.org/10.2147/JHC.S379326
DovePress
1009
Dovepress Wang et al
Powered by TCPDF (www.tcpdf.org)

37. Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver
metastases receiving preoperative chemotherapy. Ann Surg. 2008;247:118–124. doi:10.1097/SLA.0b013e31815774de
38. Zhao J, van Mierlo KMC, Gomez-Ramirez J, et al. Systematic review of the inuence of chemotherapy-associated liver injury on outcome after
partial hepatectomy for colorectal liver metastases. Br J Surg. 2017;104:990–1002. doi:10.1002/bjs.10572
39. Karoui M, Penna C, Amin-Hashem M, et al. Inuence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver
metastases. Ann Surg. 2006;243:1–7. doi:10.1097/01.sla.0000193603.26265.c3
40. Vigano L, De Rosa G, Toso C, et al. Reversibility of chemotherapy-related liver injury. J Hepatol. 2017;67:84–91. doi:10.1016/j.jhep.2017.02.031
41. Zhang W, Hu B, Han J, et al. 174P A real-world study of PD-1 inhibitors combined with TKIs for HCC with major vascular invasion as the
conversion therapy: a prospective, non-randomized, open-label cohort study. Ann Oncol. 2020;31:S1307. doi:10.1016/j.annonc.2020.10.195
42. Yarchoan M, Zhu QF, Durham JN, et al. Feasibility and efcacy of neoadjuvant cabozantinib and nivolumab in patients with borderline resectable
or locally advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2021;39:335. doi:10.1200/JCO.2021.39.3_suppl.335
43. Kishi Y, Zorzi D, Contreras CM, et al. Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver
insufciency after hepatic resection for colorectal liver metastases. Ann Surg Oncol. 2010;17:2870–2876. doi:10.1245/s10434-010-1166-1
44. Tamandl D, Klinger M, Eipeldauer S, et al. Sinusoidal obstruction syndrome impairs long-term outcome of colorectal liver metastases treated with
resection after neoadjuvant chemotherapy. Ann Surg Oncol. 2011;18:421–430. doi:10.1245/s10434-010-1317-4
45. He MK, Liang RB, Zhao Y, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced
hepatocellular carcinoma. Ther Adv Med Oncol. 2021;13:17588359211002720. doi:10.1177/17588359211002720
46. Yang X, Lin J, Zhao H. Potential areas of interest in a trial of sorafenib plus hepatic arterial infusion of oxaliplatin, uorouracil, and leucovorin for
Hepatocellular Carcinoma. JAMA Oncol. 2019. doi:10.1001/jamaoncol.2019.4049
47. Kudo M, Ueshima K, Yokosuka O, et al. Sorafenib plus low-dose cisplatin and uorouracil hepatic arterial infusion chemotherapy versus sorafenib
alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, Phase 3 trial. Lancet Gastroenterol Hepatol.
2018;3:424–432. doi:10.1016/S2468-1253(18)30078-5
Journal of Hepatocellular Carcinoma Dovepress
Publish your work in this journal
The Journal of Hepatocellular Carcinoma is an international, peer-reviewed, open access journal that offers a platform for the dissemination and
study of clinical, translational and basic research ndings in this rapidly developing eld. Development in areas including, but not limited to,
epidemiology, vaccination, hepatitis therapy, pathology and molecular tumor classication and prognostication are all considered for publication.
The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit
http://www.dovepress.com/testimonials.php to read real quotes from published authors.
Submit your manuscript here: https://www.dovepress.com/journal-of-hepatocellular-carcinoma-journal
DovePress Journal of Hepatocellular Carcinoma 2022:9
1010
Wang et al Dovepress
Powered by TCPDF (www.tcpdf.org)