Lu JL, Cheng Y, Xu ZL, Qian GX, Wei MT, Jia WD. Immune checkpoint inhibitors plus anti-angiogenesis in patients with resected high-risk hepatitis B virus-associated hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17(4): 101371 [DOI: 10.4251/wjgo.v17.i4.101371]
Corresponding Author of This Article
Wei-Dong Jia, MD, PhD, Professor, Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, No. 17 Lujiang Road, Hefei 230001, Anhui Province, China. jwd1968@ustc.edu.cn
Research Domain of This Article
Immunology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Jian-Lin Lu, Zi-Ling Xu, Ming-Tong Wei, Wei-Dong Jia, Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, Anhui Province, China
Yuan Cheng, Gui-Xiang Qian, Department of Hepatic Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
Author contributions: Lu JL, Cheng Y, and Jia WD contributed to conception and design, and wrote and revised the manuscript; Lu JL and Cheng Y analyzed and interpreted the data, and contributed equally as co-first authors; Lu JL, Xu ZL, Qian GX, and Wei MT contributed to data acquisition; and all authors have approved the final version to be published.
Supported by the Key Research and Development Projects of Anhui Province, No. 202104j07020048; and National Key Research and Development Program of China, No. 2022YFA1304500.
Institutional review board statement: This study was approved by the Ethics Committee of the Anhui Provincial Hospital Affiliated to Anhui Medical University (No. 2023-RE-392).
Informed consent statement: The need for informed consent was waived owing to the retrospective nature of the study.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets generated and/or analyzed in the current study are not publicly available because of privacy concerns; however, masked information is available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wei-Dong Jia, MD, PhD, Professor, Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, No. 17 Lujiang Road, Hefei 230001, Anhui Province, China. jwd1968@ustc.edu.cn
Received: September 12, 2024 Revised: January 25, 2025 Accepted: February 13, 2025 Published online: April 15, 2025 Processing time: 194 Days and 4.8 Hours
Abstract
BACKGROUND
Currently, there is a lack of effective adjuvant therapies for patients at high-risk of recurrent hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) after radical resection. Given the efficacy of anti-programmed death 1/anti-programmed death ligand 1 plus anti-vascular endothelial growth factor receptor agents in advanced HCC, we conducted this study to investigate the efficacy of this combination regimen in the postoperative adjuvant treatment of patients with HBV-HCC.
AIM
To evaluate the value of postoperative combined therapy (PCT) with anti-programmed death 1/anti-programmed death ligand 1 and anti-vascular endothelial growth factor receptor agents in patients with HBV-HCC.
METHODS
Patients with HBV-HCC who underwent radical resection surgery at Anhui Provincial Hospital Affiliated to Anhui Medical University between July 2020 and April 2023 were included. Recurrence-free survival (RFS) and overall survival were assessed using propensity score matching and inverse probability of treatment weighting. Cox regression analysis was used to identify factors affecting recurrence, and subgroup analysis was conducted to investigate the impact of medications on different populations. Treatment-related adverse events and liver function measurements were evaluated.
RESULTS
A total of 150 patients were recruited, of whom 30 underwent PCT and 120 did not. After adjusting for confounders, patients who underwent PCT had better RFS at 6 and 12 months than those who did not (P > 0.05). Similar results were observed in the Kaplan-Meier curves after propensity score matching or inverse probability of treatment weighting, although the difference was not statistically significant (P > 0.05). A maximum diameter of > 5 cm, vascular invasion, satellite nodules, and high gamma-glutamyl transferase levels were independent risk factors for recurrence (P < 0.05). No significant interaction effects were observed in subgroup analyses. The most prevalent adverse event was hypertension (66.7%). PCT was associated with an increased risk of hepatic impairment which may predict RFS rates (P = 0.041).
CONCLUSION
The recurrence rate was not significantly reduced in patients who underwent PCT. Hepatic impairment during treatment may indicate recurrence, and close monitoring of liver function and HBV infection is recommended.
Core Tip: The postoperative combined therapy with anti-programmed death 1/anti-programmed death ligand 1 and anti-vascular endothelial growth factor receptor agents has not been shown to be effective but not significant in reducing early recurrence in patients with hepatitis B virus-associated hepatocellular carcinoma. And thorough evaluation and close monitoring of liver function and hepatitis B-related markers in patients with hepatitis B virus-associated hepatocellular carcinoma are critical when implementing this combined treatment approach.
Citation: Lu JL, Cheng Y, Xu ZL, Qian GX, Wei MT, Jia WD. Immune checkpoint inhibitors plus anti-angiogenesis in patients with resected high-risk hepatitis B virus-associated hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17(4): 101371
Hepatocellular carcinoma (HCC) is a prevalent cancer and the third leading cause of cancer-related deaths worldwide, based on data from the 2020 GLOBOCAN Survey[1]. Although the incidence of non-viral HCC is on the rise, hepatitis B virus (HBV) remains an important risk factor, particularly in China. Furthermore, patients with HCC associated with viral hepatitis have a relatively poor prognosis[2]. Radical hepatic resection plays a crucial role in the management of HCC. Nonetheless, the recurrence rate can be as high as 70% within 5 years after surgery, and efforts to reduce recurrence are needed to improve overall outcomes[3-5]. In recent decades, numerous efforts have been made to develop effective methods for reducing postoperative recurrence. However, a standard global postoperative adjuvant regimen remains lacking[3-5]. Therefore, there is an urgent need to develop a rational adjuvant regimen specifically for viral hepatitis-associated HCC. Currently, continuous antiviral therapy continues to have a positive impact on postoperative adjuvant treatment[4,5]. Additionally, transcatheter arterial chemoembolization (TACE) can serve as both a monitoring tool and a therapeutic intervention for early recurrence in HBV-associated HCC (HBV-HCC) patients who are at an intermediate-to-high risk of recurrence after radical hepatectomy[6,7].
HBV can be sustained as covalently closed circular DNA in infected hepatocytes with prolonged antigenic stimulation. A tolerant environment in the liver often results in immune depletion and T cell reduction as well as the formation of HBV-specific CD8+ T cells, which are critical for viral clearance and are depleted in the presence of programmed death 1 (PD-1) positivity[8]. Use of PD-1/programmed death ligand 1 (PD-L1) inhibitors promotes HBV-specific humoral and cellular immune response maturation and reduces serum levels of HBV-DNA and hepatitis B surface antigen (HBsAg)[9,10]. A meta-analysis by Haber et al[11] suggests that immune checkpoint inhibitors (ICIs) were more effective in patients with HBV-HCC than in those who were not infected with HBV. In addition, PD-1/PD-L1 pathway-mediated suppression of immune function promotes HCC recurrence after surgery[12].
Vascular endothelial growth factor-mediated angiogenesis plays a crucial role in hepatocarcinogenesis, as HCC is a hyper-vascularized tumor, and HBV infection upregulates the expression of this factor and promotes HCC development[13]. The combination of PD-1/PD-L1 blockade with anti-angiogenesis has shown promise in treating HCC, as it reprograms the immune microenvironment and promotes vascular normalization[14,15]. Although anti-vascular endothelial growth factor receptor (VEGFR) drugs alone do not differ in effectiveness according to etiology[11], combination therapy has shown better efficacy than anti-VEGFR drugs alone in HBV-HCC[16]. Atezolizumab and bevacizumab have demonstrated the most prolonged median overall survival (OS) in advanced HCC patients thus far, and the American Association for the Study of Liver Diseases now recommends ICI-based systemic therapy for patients with HCC who are at high-risk of recurrence after undergoing hepatectomy or local ablation, based on the findings of the recent IMbrave 050 study[3,17]. Currently, the effectiveness of postoperative combined therapy (PCT) with anti-PD-1/PD-L1 and anti- VEGFR drugs for recurrence after liver resection in high-risk HBV-HCC patients remains unknown. Therefore, in this retrospective study, we sought to evaluate the efficacy and safety of this therapy in this group of patients.
MATERIALS AND METHODS
Study design and participants
This study was conducted retrospectively in patients with HCC who were initially treated at the Anhui Provincial Hospital Affiliated to Anhui Medical University between July 2020 and April 2023. The patients in the study were chosen based on specific criteria and were followed up until November 2023. A total of 150 patients were included in the final analysis. The surgical procedures were performed by an experienced surgical team. This study was approved by the hospital’s ethics committee (No. 2023-RE-392) and met the requirements of the Declaration of Helsinki. Given the retrospective nature of this study, the requirement for informed consent was waived.
The inclusion criteria for the study were as follows: (1) Age ≥ 18 years; (2) Diagnosed with HBV-HCC for the first time and underwent curative resection without any prior antitumor therapy[4]; (3) Negative margins confirmed by postoperative pathology and a confirmed diagnosis of HCC; (4) One or more high-risk factors for recurrence, including a maximum tumor diameter > 5 cm, vascular invasion (including microvascular invasion and invasion of secondary branches or distal portals by portal vein thrombi), low differentiation (Edmondson-Steiner grades III-IV), satellite nodules, or multiple lesions; (5) Child-Pugh A or B; and (6) Eastern Cooperative Oncology Group Performance Status 0-1.
The exclusion criteria were as follows: (1) Spontaneous tumor rupture and bleeding before surgery; (2) Monotherapy, such as anti-PD-1/PD-L1 or anti-VEGFR, or unknown adjuvant therapies; (3) Without HBV infection, with a hepatitis virus other than HBV, or co-infected of HBV with other hepatitis viruses; (4) Previous or current history of other cancers; (5) Alpha-fetoprotein (AFP) levels that did not return to the normal range within 2 months after surgery; and (6) Loss of follow-up.
Treatment
The patients were categorized into two groups after screening. One group received regular outpatient follow-ups for disease surveillance without PCT. The other group received PCT involving the administration of single anti-PD-1/PD-L1 antibody [atezolizumab, 1200 mg, every 3 weeks (Q3W); or camrelizumab, 200 mg, Q3W; or sintilimab, 200 mg, Q3W; or tislelizumab, 200 mg, Q3W] alongside anti-VEGFR drugs [bevacizumab, 15 mg/kg, Q3W; or apatinib, 250 mg, per day (QD); or sitravatinib, 100 mg, QD; or lenvatinib, 8 mg (weight < 60 kg) or 12 mg (weight ≥ 60 kg), QD]. This treatment was typically administered 4 weeks after surgery when all other test results were normal. One course of treatment typically lasted 3 weeks, and 17 cycles were performed in total, with the possibility of interruptions or dosage adjustments if the patient experienced adverse events (AEs) or for other reasons. Medication interruption was defined as an interruption in the use of both medications occurring in their entirety. Medication duration was the time from the first initiation of use to the last use of one of the two drugs. The physician suggested a postoperative treatment plan based on the condition of the patient, which the patient voluntarily chose. In the event of recurrence, the treatment plan was adjusted promptly.
Postoperative follow-up and data collection
The initial postoperative follow-up usually occurred approximately 4 weeks after surgery, followed by subsequent evaluations every 2-3 months within the first 2 years and then at six-month intervals. These evaluations primarily involved liver function tests, AFP measurements, and imaging techniques such as contrast-enhanced computed tomography and magnetic resonance imaging. The diagnosis of tumor recurrence was based on imaging results (contrast-enhanced computed tomography, magnetic resonance imaging, or hepatic artery angiography during TACE) for the identification of neoplastic lesions combined with persistently elevated tumor markers. We collected repeated measurements of liver function indices at 1-, 3-, 6-, 9-, and 12-months post-surgery, including albumin (ALB), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), and total bilirubin (TBIL).
Outcomes and safety
Recurrence-free survival (RFS) was defined as the time from radical resection to the detection of tumor recurrence or patient death, whichever occurred first. OS was defined as the time from radical surgery to death from any cause. In this study, the Common Terminology Criteria for Adverse Events v5.0 was used to assess the severity of AEs. Hepatic impairment was defined as any elevation in ALT, AST, or TBIL levels, with or without elevated GGT or ALP levels.
Statistical analysis
All statistical analyses and associated chart plots were performed using R language (version 4.3.1, R Foundation for Statistical Computing, Vienna, Austria), and a two-sided P < 0.05 indicated statistical significance. For continuous quantitative data, the mean ± SD was used to describe data when the distribution was normal, and comparisons between groups were made using the t-test. The median [interquartile range (IQR)] was used for data description when the distribution was not normal, and the Mann-Whitney U test was used to compare groups. Count data are described as the number of cases (%), and comparisons between groups were performed using the χ2-test or Fisher’s exact probability method. Rank data are described as the number of cases (%), and comparisons between groups were performed using the Mann-Whitney U test. Kaplan-Meier (KM) survival curve analysis and the log-rank test were used to assess disparities in RFS and OS among distinct treatment cohorts. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors for RFS and OS, and variables with P < 0.05 in univariate Cox regression were included in multivariate Cox regression for further analysis. In addition, subgroup analyses were performed to evaluate potential variations in the prognostic impact of different population attributes after treatment. Owing to the limited sample size of this study, these subgroup analyses were performed without considering relevant covariates, and the interaction effects were assessed using likelihood ratio tests.
After controlling for confounding variables, we analyzed the data using 1:1 propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Propensity scores were calculated using binary logistic modeling, and the caliper value was set to 0.1. Confounding variables included antiviral therapy, adjuvant TACE, vascular invasion, maximum diameter, satellite nodule, Edmondson-Steiner grade, HBsAg, hepatitis B e antigen, and HBV DNA. Subsequently, after PSM and IPTW, KM curves were plotted and (weighted) log-rank tests were performed to verify the association between grouping and RFS and OS. Univariate (weighted) Cox regression modeling was employed to estimate hazard ratios (HRs) and determine 95% confidence intervals (CIs).
After dichotomization based on the presence or absence of hepatic impairment, medication interruption, and the median duration of medication, odds ratios and 95%CIs were calculated using binary logistic regression. Due to missing follow-up data, patients who did not have any of the measurements at follow-up were removed, and the remaining baseline missing values were filled in using the median. Logarithmic transformations were performed for severely skewed data, and the generalized estimating equation model was employed to estimate between-group differences for repeated measures data. Additionally, the model was corrected for baseline biochemical levels. The line plots visually represented the estimated means at various time points and within different subgroups.
RESULTS
Patient characteristics
A total of 288 individuals underwent screening for the study, and 150 patients were ultimately included after application of the exclusion criteria owing to tumor rupture, bleeding, monotherapy, unknown adjuvant therapies, and loss to follow-up (Figure 1). There were 30 PCT recipients and the remaining 120 patients did not undergo PCT. Patients were categorized based on baseline factors such as median, risk of recurrence, and medical history. Except for ALP and TACE, the patients were well-matched at baseline. The median age of the patients with HBV-HCC was 57 years (IQR: 52-66), 86.7% were Barcelona Clinical Liver Cancer stage A, 96.7% were Child-Pugh stage A, 40.7% had received postoperative adjuvant TACE, and 76.7% were on long-term antiviral therapy (Table 1).
Figure 1 Research flowchart.
HCC: Hepatocellular carcinoma; PCT: Postoperative combined therapy; PSM: Propensity score matching; IPTW: Inverse probability of treatment weighting; TACE: Transcatheter arterial chemoembolization; PD-1: Programmed death 1; PD-L1: Programmed death ligand 1; VEGFR: Vascular endothelial growth factor receptor.
Table 1 Baseline characteristics of patients before and after propensity score matching or inverse probability of treatment weighting, n (%).
Total (n =150)
Before PSM and IPTW, PCT (n = 30)
Before PSM and IPTW, non-PCT (n = 120)
Before PSM and IPTW, P value
After PSM, PCT (n = 29)
After PSM, non-PCT (n = 29)
After PSM, P value
After IPTW, PCT (134.1)
After IPTW, non-PCT (150.8)
After IPTW, P value
Sex, male
124 (82.7)
24 (80)
100 (83.3)
0.666
23 (79.3)
25 (86.2)
0.487
107.9 (80.4)
125.1 (83.0)
0.752
Age, ≤ 57 years
76 (50.7)
18 (60)
58 (48.3)
0.253
17 (58.6)
14 (48.3)
0.43
85.3 (63.6)
74.7 (49.5)
0.195
BMI, ≤ 23.9 kg/m²
87 (58)
16 (53.3)
71 (59.2)
0.563
16 (55.2)
19 (65.5)
0.421
70.6 (52.6)
90.5 (60.0)
0.501
TACE
61 (40.7)
7 (23.3)
54 (45)
0.031
7 (24.1)
7 (24.1)
1
46.5 (34.6)
60.8 (40.3)
0.622
Extent of resection, major
29 (19.3)
6 (20)
23 (19.2)
0.918
6 (20.7)
5 (17.2)
0.738
28.0 (20.9)
28.5 (18.9)
0.819
Cirrhosis
126 (84)
27 (90)
99 (82.5)
0.412
27 (93.1)
27 (93.1)
1
124.6 (92.9)
124.3 (82.4)
0.153
Number, solitary
142 (94.7)
29 (96.7)
113 (94.2)
1
28 (96.6)
27 (93.1)
1
131.2 (97.8)
141.1 (93.6)
0.276
Maximum diameter, > 5 cm
73 (48.7)
16 (53.3)
57 (47.5)
0.567
15 (51.7)
12 (41.4)
0.43
59.8 (44.6)
73.2 (48.5)
0.717
Vascular invasion
100 (66.7)
23 (76.7)
77 (64.2)
0.194
22 (75.9)
21 (72.4)
0.764
96.8 (72.2)
100.9 (66.9)
0.615
Edmondson-Steiner, III-IV
79 (52.7)
16 (53.3)
63 (52.5)
0.935
15 (51.7)
18 (62.1)
0.426
79.3 (59.1)
80.7 (53.5)
0.608
Satellite nodules
30 (20)
7 (23.3)
23 (19.2)
0.61
6 (20.7)
6 (20.7)
1
25.9 (19.3)
30.1 (20.0)
0.939
Margin, narrow
92 (61.3)
21 (70)
71 (59.2)
0.276
20 (69)
15 (51.7)
0.18
100 (74.6)
89.9 (59.6)
0.149
Necrosis
48 (32)
9 (30)
39 (32.5)
0.793
8 (27.6)
6 (20.7)
0.539
42.3 (31.6)
49.5 (32.8)
0.906
BCLC stage, A
130 (86.7)
24 (80)
106 (88.3)
0.272
23 (79.3)
27 (93.1)
0.194
99.8 (74.4)
133.0 (88.2)
0.05
Child-Pugh, A
145 (96.7)
28 (93.3)
117 (97.5)
0.261
27 (93.1)
27 (93.1)
1
6.6 (4.9)
3.9 (2.6)
0.474
Antiviral treatment
115 (76.7)
26 (86.7)
89 (74.2)
0.148
25 (86.2)
27 (93.1)
0.67
115.3 (86.0)
116.1 (77.0)
0.306
HBV-DNA, ≥ 2000 IU/mL
50 (33.3)
10 (33.3)
40 (33.3)
1
10 (34.5)
10 (34.5)
1
39.4 (29.4)
49.8 (33.0)
0.715
HBsAg, ≥ 250 IU/mL
96 (64)
20 (66.7)
76 (63.3)
0.734
19 (65.5)
20 (69)
0.78
85.1 (63.5)
96.1 (63.7)
0.979
HBeAg, positive
18 (12)
4 (13.3)
14 (11.7)
0.759
4 (13.8)
4 (13.8)
1
17.7 (13.2)
18.4 (12.2)
0.889
AFP, ≥ 400 ng/mL
52 (34.7)
7 (23.3)
45 (37.5)
0.145
7 (24.1)
11 (37.9)
0.256
33.8 (25.2)
58.3 (38.7)
0.214
ALT, IU/L
32.00 (21.00, 52.75)
32.00 (25.25, 77.25)
31.50 (19.52, 48.00)
0.174
32.00 (25.00, 81.00)
32.00 (16.00, 54.00)
0.199
55.99 (44.63)
47.10 (61.55)
0.415
AST, IU/L
34.00 (24.18, 52.75)
34.10 (28.00, 58.50)
34.00 (24.00, 52.00)
0.431
34.00 (28.00, 60.00)
34.00 (24.00, 46.00)
0.597
47.23 (28.58)
47.87 (47.64)
0.926
GGT, IU/L
38.00 (25.00, 98.50)
47.15 (31.15, 105.25)
36.00 (23.00, 96.75)
0.185
46.00 (31.00, 97.00)
26.00 (19.00, 133.00)
0.305
73.69 (73.31)
88.28 (128.05)
0.404
ALP, IU/L
85.50 (72.00, 113.75)
101.50 (83.25, 136.25)
83.50 (70.00, 109.50)
0.014
100.00 (83.00, 128.00)
87.00 (66.00, 113.00)
0.159
105.55 (34.27)
96.81 (44.53)
0.26
ALB, g/L
41.53 (4.31)
40.69 (5.13)
41.74 (4.08)
0.302
40.87 (5.12)
39.90 (3.92)
0.424
41.35 (5.22)
41.83 (4.10)
0.661
TBIL, µmol/L
15.90 (11.62, 20.10)
13.95 (11.53, 17.95)
16.45 (11.67, 20.30)
0.169
13.80 (11.40, 16.90)
17.80 (11.10, 25.20)
0.084
14.91 (7.10)
17.27 (7.38)
0.132
Survival analysis
The median follow-up time was 17.40 months (IQR: 12.60-26.70). Prior to adjusting for confounding factors, the endpoint event, RFS, occurred in 12 (40.0%) patients in the PCT group compared to 53 (44.2%) patients in the non-PCT group. The median RFS in the PCT was 29.20 months [95%CI: 13.03-not available (NA)] with 6-, 12-, 18-, and 24-month RFS rates of 93.3%, 79.3%, 59.8%, and 53.2%, respectively. In comparison, the median RFS in the non-PCT group was 22.77 months (95%CI: 19.03-NA) with 6-, 12-, 18-, and 24-month RFS rates of 81.7%, 67.9%, 59.8%, and 49.7%, respectively. The two groups did not show a statistically significant difference (HR: 0.89, 95%CI: 0.47-1.67, P = 0.713) (Figure 2A, Table 2). However, after adjusting for confounding variables as previously defined, there was a notable difference in RFS rates at 6 and 12 months (RFS6mo HR: 0.17, 95%CI: 0.04-0.78, P = 0.022; RFS12mo HR: 0.32, 95%CI: 0.12-0.80, P = 0.015) (Table 2).
Figure 2 Kaplan-Meier analysis of recurrence-free survival and overall survival before and after propensity score matching or inverse probability of treatment weighting.
A: Recurrence-free survival (RFS) before propensity score matching and inverse probability of treatment weighting; B: RFS after propensity score matching; C: RFS after inverse probability of treatment weighting; D: Overall survival (OS) before propensity score matching and inverse probability of treatment weighting; E: OS after propensity score matching; F: OS after inverse probability of treatment weighting. PCT: Postoperative combined therapy; PSM: Propensity score matching; IPTW: Inverse probability of treatment weighting; RFS: Recurrence-free survival; OS: Overall survival; IQR: Interquartile range; FU: Follow up; HR: Hazard ratio; CI: Confidence interval; NA: Not available.
Table 2 Comparison of survival outcomes with or without postoperative combined therapy.
Duration (months)
Non-PCT, %
PCT, %
P of log-rank
HR (95%CI), P value
Adjusted HR (95%CI), P value
RFS before PSM and IPTW
6
81.7 (75.0, 88.9)
93.3 (84.8, 100.0)
0.119
0.33 (0.08-1.42), 0.138
0.17 (0.04-0.78), 0.022
12
67.9 (60.0, 76.9)
79.3 (65.8, 95.6)
0.183
0.56 (0.24-1.33), 0.188
0.32 (0.12-0.80), 0.015
18
59.8 (51.1, 69.9)
59.8 (42.8, 83.7)
0.590
0.83 (0.42-1.64), 0.590
0.48 (0.22-1.02), 0.055
24
49.7 (40.1, 61.7)
53.2 (35.4, 79.9)
0.567
0.83 (0.43-1.59), 0.567
0.50 (0.24-1.03), 0.061
RFS after PSM
6
79.3 (65.9, 95.5)
96.6 (90.1, 100.0)
0.041
0.15 (0.02-1.24), 0.078
12
72.1 (57.3, 90.6)
82.0 (68.9, 97.7)
0.322
0.57 (0.19-1.75), 0.328
18
62.7 (46.5, 84.6)
61.9 (44.6, 86.0)
0.855
0.92 (0.37-2.27), 0.855
24
55.8 (38.2, 81.4)
55.0 (36.8, 82.2)
0.908
0.95 (0.40-2.25), 0.908
RFS after IPTW
6
81.4 (74.5, 88.8)
92.1 (80.5, 100.0)
0.095
0.38 (0.07-1.96), 0.249
12
67.3 (59.2, 76.6)
78.6 (63.6, 97.3)
0.161
0.57 (0.23-1.44), 0.236
18
59.6 (50.8, 69.9)
65.0 (47.7, 88.5)
0.375
0.73 (0.34-1.55), 0.411
24
49.3 (39.5, 61.5)
56.9 (38.0, 85.3)
0.386
0.75 (0.37-1.51), 0.418
OS before PSM and IPTW
6
95.0 (91.2, 99.0)
100.0 (100.0, 100.0)
0.216
0.00 (0.00-Inf), 0.998
0.00 (0.00-Inf), 0.999
12
88.8 (83.2, 94.7)
96.7 (90.5, 100.0)
0.224
0.30 (0.04-2.33), 0.252
0.21 (0.03-1.71), 0.143
18
85.7 (79.4, 92.5)
96.7 (90.5, 100.0)
0.149
0.25 (0.03-1.90), 0.182
0.19 (0.02-1.49), 0.113
24
82.5 (75.2, 90.5)
89.2 (75.2, 100.0)
0.280
0.46 (0.11-1.97), 0.292
0.30 (0.06-1.41), 0.127
OS after PSM
6
93.1 (84.3, 100.0)
100.0 (100.0, 100.0)
0.154
0.00 (0.00-Inf), 0.999
12
89.7 (79.2, 100.0)
96.6 (90.1, 100.0)
0.300
0.32 (0.03-3.09), 0.326
18
89.7 (79.2, 100.0)
96.6 (90.1, 100.0)
0.300
0.32 (0.03-3.09), 0.326
24
83.3 (68.8, 100.0)
89.1 (75.1, 100.0)
0.463
0.53 (0.10-2.93), 0.470
OS after IPTW
6
95.1 (91.3, 99.0)
100.0 (100.0, 100.0)
0.016
0.00 (0.00-0.00), P < 0.001
12
88.3 (82.4, 94.6)
96.7 (90.5, 100.0)
0.083
0.29 (0.04-2.22), 0.233
18
85.4 (78.9, 92.5)
96.7 (90.5, 100.0)
0.036
0.25 (0.03-1.85), 0.174
24
82.4 (75.0, 90.5)
90.0 (76.8, 100.0)
0.133
0.41 (0.09-1.81), 0.242
After PSM, RFS in the PCT and non-PCT groups was 29.20 months (95%CI: 15.47-NA) and not reached (95%CI: 17.27-NA). A statistically significant difference between the two groups was not observed (HR: 1.04, 95%CI: 0.45-2.42, P = 0.919) (Figure 2B). After IPTW, the median RFS for the PCT and non-PCT groups was 29.20 months (95%CI: 15.47-NA) and 22.77 months (95%CI: 19.03-NA), respectively, without statistical significance (HR: 0.78, 95%CI: 0.39-1.55, P = 0.457) (Figure 2C). Although none of the RFS rates at different time points showed any significant differences regardless of whether PSM or IPTW was used (Table 2), first-year rates in the PCT was superior to that in the non-PCT.
Owing to the short follow-up period, neither group reached the median OS. Regardless of whether PSM or IPTW was performed, no statistically significant difference in OS between the groups was observed (before PSM and IPTW, HR: 0.66, 95%CI: 0.19-2.22, P = 0.497; after PSM, HR: 0.82, 95%CI: 0.18-3.68, P = 0.797; after IPTW, HR: 0.63, 95%CI: 0.18-2.16, P = 0.406) (Figure 2D-F). However, after IPTW, a significant difference in OS at 6 months was observed between the groups (HR: 0.00, 95%CI: 0.00-0.00, P < 0.001) (Table 2). The interaction effect did not reach statistical significance in any of the subgroup analyses, which is probably because of the limited number of cases (Supplementary Figure 1).
Prognostic factors analysis
Univariate Cox regression analysis indicated that several factors, including maximum diameter, vascular invasion, satellite nodules, margin, necrosis, antiviral treatment, AFP, GGT, and ALP levels, significantly contributed to RFS in HBV-HCC after hepatectomy. Additionally, our multivariate Cox regression analysis reveals that maximum diameter > 5 cm (HR: 2.546, 95%CI: 1.464-4.428, P = 0.001), vascular invasion (HR: 2.510, 95%CI: 1.327-4.750, P = 0.005), satellite nodule (HR: 2.147, 95%CI: 1.189-3.879, P = 0.011), and high GGT (HR: 1.003, 95%CI: 1.000-1.006, P = 0.019) are independent risk factors for recurrence (Supplementary Table 1). Furthermore, maximum tumor diameter, necrosis, antiviral treatment, GGT, and ALP significantly affected OS in the univariate analysis. When considering these factors collectively in multivariate analysis, no antiviral treatment emerged as an independent risk factor for survival (HR: 0.286, 95%CI: 0.122-0.671, P = 0.004) (Supplementary Table 2).
Safety
In the PCT group, the median duration of medication with anti-PD-1/PD-L1 drugs was 7.8 months (IQR: 4.5-10.6). Dosing interruptions occurred in 17 patients (56.7%). Among these, 12 (40.0%) experienced temporary interruptions due to AEs, and two (6.7%) had permanent treatment discontinuation owing to exacerbation of psoriasis and recurrent proteinuria. The median duration of use of anti-VEGFR antibodies was 6.8 months (IQR: 4.4-10.4). Among these patients, 22 (73.3%) experienced dosing interruptions. Fifteen (50.0%) patients discontinued treatment temporarily owing to AEs, and four (13.3%) had permanent discontinuation due to worsening of hepatic function, persistent proteinuria, exacerbation of psoriasis, and progressive reduction in blood count (Supplementary Table 3). All patients experienced AEs of different intensities, with 20 (66.7%) experiencing grade 3 or higher AEs, which were frequently observed to be hypertension (33.3%), elevated GGT (16.7%), increased AST (13.3%), decreased platelet count (10.0%), and increased TBIL levels (10.0%). No grade 5 events were reported (Table 3).
Table 3 Adverse events of any grade occurring in ≥ 15% of patients according to Common Terminology Criteria for Adverse Events 5.0, n (%).
Adverse events
All grades
1
2
3-4
Hypertension
20 (66.7)
3 (10.0)
7 (23.3)
10 (33.3)
Platelet count decreased
14 (46.7)
6 (20.0)
5 (16.7)
3 (10.0)
Aspartate aminotransaminase increased
12 (40.0)
4 (13.3)
4 (13.3)
4 (13.3)
Total bilirubin increased
11 (36.7)
4 (13.3)
4 (13.3)
3 (10.0)
Proteinuria
11 (36.7)
2 (6.7)
8 (26.7)
1 (3.3)
Pain
10 (33.3)
4 (13.3)
5 (16.7)
1 (3.3)
Neutrophil count decreased
9 (30.0)
0
7 (23.3)
2 (6.7)
Alanine aminotransferase increased
9 (30.0)
4 (13.3)
4 (13.3)
1 (3.3)
Gamma glutamyl transferase increased
8 (26.7)
1 (3.3)
2 (6.7)
5 (16.7)
Diarrhea
7 (23.3)
3 (10.0)
3 (10.0)
1 (3.3)
Hypothyroidism
7 (23.3)
3 (10.0)
4 (13.3)
0
Hand-foot syndrome
7 (23.3)
1 (3.3)
4 (13.3)
2 (6.7)
Alkaline phosphatase increased
5 (16.7)
4 (13.3)
1 (3.3)
0
Hyperthyroidism
5 (16.7)
2 (6.7)
3 (10.0)
0
Rash
5 (16.7)
3 (10.0)
1 (3.3)
1 (3.3)
Weight loss
5 (16.7)
2 (6.7)
2 (6.7)
1 (3.3)
When considering the relationship between post-drug hepatic impairment and recurrence alone, patients who exhibited any level of this factor were found to have a 5.2 times greater likelihood of experiencing recurrence than those without such abnormalities (95%CI: 1.068-25.309, P = 0.041), and no significant disparity in long-term survival rates was observed between the two groups (odds ratio: 2.909, 95%CI: 0.234-36.164, P = 0.406). The duration and interruption of medication did not affect RFS or OS (Table 4).
Table 4 Impact of hepatic impairment and medication use on recurrence-free survival and overall survival, n (%).
Yes
No
OR (95%CI)
P value
RFS events occurred
Any degree of hepatic impairment
5.200 (1.068-25.309)
0.041
Yes
8 (26.7)
5 (16.7)
No
4 (13.3)
13 (43.3)
Medication interruption events for any reason
2.000 (0.440-9.096)
0.370
Yes
8 (26.7)
9 (30)
No
4 (13.3)
9 (30)
Medication duration less than median
0.571 (0.130-2.503)
0.458
Yes
7 (23.3)
8 (26.7)
No
5 (16.7)
10 (33.3)
OS events occurred
Any degree of hepatic impairment
2.909 (0.234-36.164)
0.406
Yes
2 (6.7)
11 (36.7)
No
1 (3.3)
16 (53.3)
Medication interruption events for any reason
1.600 (0.129-19.838)
0.714
Yes
2 (6.7)
15 (50.0)
No
1 (3.3)
12 (40.0)
Medication duration less than median
0.464 (0.037-5.749)
0.550
Yes
2 (6.7)
13 (43.3)
No
1 (3.3)
14 (46.7)
Four individuals without any postoperative measurements were excluded, and the median was used to fill in three missing data points from baseline. Logarithmic conversion was performed because of the few extreme outliers in the GGT data. Subsequently, a generalized estimation equation analysis was performed. After adjusting for repeated measurements of liver function indicators, no statistically significant differences were found between the two groups at baseline. The group × time interaction effect for ALB, ALP, ALT, AST, and ln (GGT) was statistically significant (P < 0.05). However, neither the group effect (P = 0.808) nor the group × time effect (P = 0.540) for TBIL was statistically significant (Supplementary Tables 4 and 5). In the line plots, the levels of ALT and AST in the PCT group showed an initial increase followed by a decrease, whereas the levels of GGT and ALP showed a gradual increase and then remained at a certain level. In contrast, these four indicators showed slightly opposing trends in the non-PCT group. In addition, the overall ALB level was lower in the PCT group than that in the non-PCT group (Figure 3).
Figure 3 Line plots after generalized estimating equation for repeated measures of liver function.
A: Generalized estimating equation modelling results for alanine aminotransferase; B: Generalized estimating equation modelling results for aspartate aminotransaminase; C: Generalized estimating equation modelling results for ln (gamma glutamyl transferase); D: Generalized estimating equation modelling results for alkaline phosphatase; E: Generalized estimating equation modelling results for albumin; F: Generalized estimating equation modelling results for total bilirubin; Vertical coordinates represent mean SEs. aP < 0.05. PCT: Postoperative combined therapy; ALB: Albumin; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransaminase; GGT: Gamma glutamyl transferase; TBIL: Total bilirubin.
DISCUSSION
HBV remains the leading cause of liver cancer, and despite the timely vaccination strategy proposed by the World Health Organization in 2016, HBV will not be eliminated in many countries by 2030[18]. Recurrence of HCC is categorized as early or late recurrence. Early recurrence typically peaks approximately 1 year after surgery and is associated with a worse prognosis than late recurrence[19-21]. There is an urgent need for rational adjuvant therapeutic regimens to decrease the high postoperative recurrence rates and thus improve the overall outcomes in patients with HCC. Lenvatinib therapy enhances the prognosis of patients with HBV-HCC with microvascular invasion after radical resection[22]. Recently, a combination of ICIs and anti-angiogenic agents has demonstrated efficacy as a postoperative adjuvant therapy[17,20,23]. However, there is a lack of research on this regimen for high-risk postoperative recurrence in patients with HBV-HCC specifically. This observation prompted us to assess if targeting this population is a reasonable adjunctive regimen.
We focused on the statistically significant differences in RFS rates at 6 and 12 months after correcting for confounders before PSM and IPTW, which were equally reflected in the KM curves. In the IMbrave050 study, the KM curve separated early and gradually converged after the median follow-up period[17]. A similar trend was observed in the present study. Regardless of whether PSM or IPTW was performed, although there was no statistical difference in RFS at each period between the two groups, the KM curves were separated in the early stage. The non-PCT group showed a rapid decline before the 8-month postoperative mark, followed by a plateau period. However, the recurrence rate in patients who underwent PCT increased suddenly after 12 months, and fusion crossover occurred in the two sets of curves. The pathological features of high-risk tumors, such as tumor size and vascular invasion, influence tumor recurrence, as validated by multivariate analyses in our study patients with HBV[19,21,24-26]. This finding suggests intrahepatic micrometastases, which predominantly cause early postoperative recurrence[19]. PCT may play a vital role in delaying recurrence by blocking intrahepatic spread, and its effect on long-term prognosis needs to be observed over a longer follow-up period.
The potential for HBV reactivation (HBVr) during treatment is noteworthy. Particularly in patients with advanced HCC who are HBsAg-positive, the application of TACE, anti-PD-1/PD-L1, tyrosine kinase inhibitors, or a combination of these regimens carries the risk of HBVr, regardless of whether or not the patient receives antiviral therapy[27-29]. Furthermore, patients who experience such events may demonstrate more rapid tumor progression and shorter survival times[28]. Liu et al[30] demonstrated the positive effects of postoperative adjuvant TACE on HBVr. In our study, three patients exhibited temporary measurable levels of HBV DNA during treatment. One patient did not receive continuous antiviral therapy, reached the highest level (142 IU/mL), and experienced recurrence 15.5 months after surgery. Another patient who was undergoing regular antiviral therapy had a transient measurable HBV DNA level of 657 IU/mL after half a month of complete discontinuation following recurrence, and experienced a relapse after 12.7 months. However, regular review of HBV DNA was not performed during the treatment period. Notably, all four patients did not receive TACE, tested positive for HBsAg, and had undetectable HBV DNA at the outset. Prevention of this risk is indispensable during PCT. We suggest that thorough evaluation and regular monitoring of the risk of HBVr are essential, along with antiviral therapy for susceptible patients and timely adjustment of antiviral regimens[31].
In this study, no AEs resulted in to death, and hypertension was the most prevalent AE. In addition, the rate of hepatic impairment was relatively high, and previous research has revealed that the presence of prior or existing HBV infection amplifies this risk[32]. PCT administration caused significant changes in the major liver function indicators, namely ALB, ALP, ALT, AST, and GGT, but not TBIL. Serum aminotransferases AST and ALT are sensitive indicators of hepatic impairment[33,34]. Patients with early-stage hepatic impairment exhibit abnormalities in these indicators, prompting most patients to discontinue the drug and seek treatment; moreover, liver damage does not progress further. This observation may explain the absence of difference in the TBIL levels between the two groups.
Remarkably, patients who experienced hepatic impairment were 5.2-fold more likely to also experience RFS events than those who did not when only this variable was considered. A comparison of long-term survival outcomes requires a longer follow-up period. Miah et al[35] reported extended survival in patients with cancer who developed ICI-related hepatitis. However, the study did not specify the number of patients with original liver involvement. In a recent study, Celsa et al[36] compared patients with HCC treated with atezolizumab plus bevacizumab with patients with other cancers treated with anti-PD-1/PD-L1 antibodies and found that mild to moderate immune-related hepatic impairment (grade 1-2) was significantly associated with better treatment outcomes, including longer OS and higher objective response rate. In our line graph of the estimated mean values after generalized estimating equations, the ALT elevations observed were mainly transient and resolved upon drug discontinuation, similar to the findings of the aforementioned studies[33,36]. During this period, the patients who underwent PCT had lower recurrence rates than those who did not.
However, after ALT levels decreased, the levels of GGT and ALP continued to increase steadily and remained relatively stable in the PCT group. Preoperative GGT and ALP levels may correlate with RFS, and GGT levels were particularly significant in our multivariate analysis. GGT promotes oxidative DNA damage and maintains intracellular glutathione levels, providing a growth advantage for tumor cells during the promotional phase of carcinogenesis[37]. High GGT levels during antiviral therapy may indicate the recurrence of HCC[38]. In patients with liver disease, an increase in GGT levels is typically accompanied by an increase in ALP levels, reflecting the state of cholestasis and hepatitis[34]. ALP may have a role in the occurrence and development of HCC through tumor proliferation or promotion mechanisms[39].
Given this, an increase in aminotransferases may indicate drug efficacy, and a relatively high increase in GGT and ALP levels may imply the possibility of recurrence. The relationship between changes in the levels of these enzymes and recurrence was similar in the non-PCT group. The association between hepatic impairment and patient outcomes emphasizes the need for further investigation, prompt identification, and intervention in this group of patients, before and during treatment, to achieve optimal outcomes. Our results suggest a role for PCT in the early postoperative period, although undeniable limitations exist. Owing to the retrospective nature of the study, despite efforts to minimize biases and confounders, they cannot be ruled out. Some patients do not return on schedule and, may not undergo monitoring for virus-related indicators. Therefore, we were unable to evaluate the liver function of these patients in detail or determine whether they developed HBV. Moreover, our assessment of patient adherence relied solely on the electronic medical record system, which may not accurately reflect medication usage, duration, AEs, or the specific use of antiviral therapy. Additionally, this study was limited to a single-center Chinese population, and the small sample size and short follow-up period further restricted the generalizability of our findings. We did not examine specific medications, necessitating studies with expanded sample sizes and extended follow-up periods are needed to assess the long-term prognosis of these patients.
CONCLUSION
In conclusion, this study showed that the use of PCT combined with anti-PD-1/PD-L1 and anti-VEGFR drugs demonstrated better RFS in patients with HBV-HCC although the effect was not significant; moreover, it may increase the risk of hepatic impairment. Therefore, it is crucial to thoroughly assess and monitor this population when implementing this combination treatment approach. Thus, large-scale multicenter randomized controlled trials are necessary to verify the findings of this study.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade C, Grade C
Novelty: Grade A, Grade B, Grade B
Creativity or Innovation: Grade B, Grade B, Grade B
Scientific Significance: Grade B, Grade B, Grade B
P-Reviewer: Janyakhantikul S; Wu HM S-Editor: Wei YF L-Editor: A P-Editor: Li X
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