
==== Front
BMC Cancer
BMC Cancer
BMC Cancer
1471-2407
BioMed Central London

39300392
12940
10.1186/s12885-024-12940-0
Research
Sequential vs. concurrent systemic therapies in combination with FOLFOX-HAIC for locally advanced hepatocellular carcinoma: a single-center, real-world cohort study
Sun Liyang 123
Hu Zhiwen 123
Xie Wa 123
Yang Zhenyun 123
Zeng Huilan 123
Zhang Yaojun 123
Chen Minshan 123
Hu Dandan hudd@sysucc.org.cn

123
Zhou Zhongguo zhouzhg@sysucc.org.cn

123
Pan Yangxun panyx@sysucc.org.cn

123
1 https://ror.org/0400g8r85 grid.488530.2 0000 0004 1803 6191 Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong 510060 People’s Republic of China
2 grid.488530.2 0000 0004 1803 6191 Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 510060 People’s Republic of China
3 https://ror.org/0400g8r85 grid.488530.2 0000 0004 1803 6191 Guangdong Provnvial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060 People’s Republic of China
19 9 2024
19 9 2024
2024
24 116822 12 2023
11 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Tri-combination therapy based on hepatic arterial infusion chemotherapy (HAIC) of infusion fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the locally advanced hepatocellular carcinoma (HCC) patients have been proven effective. However, whether it was best for these HCC patients to start with the most potent therapeutic pattern was still under debate. This retrospective study evaluated the efficacy and safety of FOLFOX-HAIC combined with systemic therapies in the patterns of sequential and concurrent schedules.

Methods

This real-world study included 117 unresectable HCC patients who initially received either FOLFOX-HAIC monotherapy (HAIC group, n = 44) or concurrent ICIs and TKIs (ConHAIC group, n = 73) from March 2020 and June 2022, during the period of FOLFOX-HAIC monotherapy in HAIC group, patients in the HAIC group (n = 30) experienced progressive disease (PD) would have their treatment pattern converted from the FOLFOX-HAIC monotherapy to the combination of FOLFOX-HAIC plus ICIs and TKIs sequentially (SeqHAIC group). The progression-free survival (PFS) and overall survival (OS), as primary outcomes, were compared between patients in the SeqHAIC and ConHAIC groups.

Results

The median follow-up time of the SeqHAIC group was 24.92 months (95% CI, 12.74–37.09 months) and of the ConHAIC group was 17.87 months (95% CI, 16.85–18.89 months) and no significant difference was observed in both PFS (HR, 1.572; 95% CI, 0.848–2.916; p = 0.151) and OS (HR, 1.212; 95% CI, 0.574–2.561; p = 0.614) between the SeqHAIC and the ConHAIC groups. As for the tumor responses, there was no significant difference between the two groups regarding tumor responses, overall response rates (p = 0.658) and disease control rates (p = 0.641) were 50.0%, 45.2%, and 83.3%, 89.0% for the SeqHAIC and the ConHAIC groups, respectively.

Conclusion

Our study revealed that sequential systemic ICIs and TKIs in combination with FOLFOX-HAIC provides similar long-term prognosis and better tolerability compared to concurrent therapy for locally advanced HCC patients. Prospective studies with a larger sample size and longer follow-up are required to validate these findings.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12885-024-12940-0.

Keywords

Hepatocellular carcinoma
Real-world cohort study
Immune checkpoint inhibitors
Tyrosine kinase inhibitors
Hepatic artery infusion chemotherapy
National Natural Science Foundation of China82103566 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcIntroduction

Primary liver cancer (PLC) is the third leading cause of cancer mortality worldwide in 2020, of which hepatocellular carcinoma (HCC) accounting for over 70% of PLC cases [1, 2]. Given the insidious onset of HCC, almost 50% of HCC patients in China were diagnosed as locally advanced HCC with macrovascular invasion (MVI) and suffered from a poor median survival of less than 5 months if only received supportive care [3, 4].

Recently, several studies revealed that combination therapies based on the hepatic arterial infusion chemotherapy (HAIC) for borderline resectable or locally advanced HCC had potent effects on the tumor control and conversion rates in the Asia-Pacific region [5–10]. The HAIC of infusion fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) was able to achieve a 35.4% overall response rate (ORR) for advanced HCC whose ORR was 5.3% if received recommended therapy of sorafenib according to guidelines [8–10]. Moreover, based on HAIC, the ORR could dramatically increase to 54.3-65.9% if concurrently applied chemoradiotherapy or systemic therapies for the locally advanced HCC patients [11–13]. These results raised the interest of clinical practitioners to further explore the efficacy and safety of HAIC-based combination therapies.

Interestingly, our previous study found that FOLFOX-HAIC possessed the ability to enhance the efficacy of following lenvatinib plus programmed death receptor-1 (PD-1) inhibitors in treating HCC patients with portal vein tumor thrombosis (PVTT) [14], which indirectly indicated the timing of combination therapy could play a role in the treatment of HCC patient to some extent. However, whether the sequential combination therapy sacrificed the chance of tumor response for patients who received FOLFOX-HAIC monotherapy initially was still unknown yet. Moreover, due to the sequential and concurrent therapeutic patterns that have been discussed in other malignant tumors [15–17], it also inspired us to investigate these two therapeutic patterns in the treatment of borderline resectable or locally advanced HCC patients which was yet to be discussed in HCC. This retrospective study evaluated FOLFOX-HAIC combined with systemic therapies in the patterns of sequential and concurrent schedules and thus discussed this topic from the perspective of efficacy and safety.

Methods

Patients

The medical records of borderline resectable or locally advanced HCC patients from the Department of Liver Surgery in Sun Yat-sen University Cancer Center (SYSUCC) who initially received FOLFOX-HAIC monotherapy or combination of FOLFOX-HAIC plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) at the same course between March 2020 and June 2022 were retrospectively retrieved in this study. The inclusion criteria were: [1] patients were diagnosed with HCC according to clinical or pathological characteristics based on the American Association for the Study of Liver Diseases (AASLD) practice guidelines [18]; [2] borderline resectable or locally advanced HCC and unable to achieve R0 resection initially [19] defined as: (a) a solitary tumor with excessive volume; (b) tumor close contacted with the main vessel; (c) unilobar multifocal disease (either with > 3 tumors or one tumor > 3 cm) or bilobar disease; (d) high-risk of post-hepatectomy liver failure [3]. at least one measurable intra-hepatic lesion per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria; [4] initially received either FOLFOX-HAIC monotherapy (HAIC group) or FOLFOX-HAIC plus ICIs and TKIs at the same course (ConHAIC group); and [5] at least received 1–2 courses of FOLFOX-HAIC. Exclusion criteria were [1] extrahepatic metastasis [2] coexistence of other malignancies or immune-related diseases; and [3] incomplete follow-up data. The protocol complied with the ethical guidelines of the Declaration of Helsinki of the World Medical Association and was approved by the ethics committee of the Sun Yat-sen University Cancer Center (SYSUCC) (approval No. B2022-301-01). All patients provided written informed consent for HCC treatment and the use of their medical records for research purposes.

Treatments

For patients in the HAIC group, FOLFOX-HAIC was performed every 3–4 weeks, chemotherapy agents were infused through a percutaneous microcatheter inserted and placed in the tumor feeding artery identified by repeat arteriography at each course. The following regimen was administered via hepatic artery, oxaliplatin 130 mg/m2 infusion for 2 h, D1; leucovorin 200 mg/m2 infusion for 1 h, D1; 5-fluorouracil 400 mg/m2 infusion bolus followed by 2400 mg/m2 over 24 h [10]. During the period of FOLFOX-HAIC treatment, part of patients (n = 30) detected progressive disease (PD) would have their treatment pattern converted from the FOLFOX-HAIC monotherapy to the combination of FOLFOX-HAIC plus ICIs and TKIs (SeqHAIC group) until convert to surgery, developed PD or intolerable toxicity. For patients in the ConHAIC group, FOLFOX-HAIC procedure was the same as that of the HAIC group. Meanwhile, patients received combined therapy of ICIs and TKIs on the first course of FOLFOX-HAIC until convert to surgery, developed PD or intolerable toxicity. TKIs were administrated on the first day of FOLFOX-HAIC and ICIs were intravenously injected on the second day after the FOLFOX-HAIC was completed. Due to the lack of solid evidence to prove the superiority among various ICIs, the choices of ICIs were mainly based on the patients’ medical insurance and economic condition. The TKIs were administrated according to the guidelines (20–21). The exact types and statistical analysis of ICIs and TKIs were listed in the Tables S1 and there was no difference between the SeqHAIC group and the ConHAIC group (p > 0.050).

Clinical endpoints

The primary clinical endpoints were progression-free survival (PFS) and overall survival (OS). For patients in ConHAIC group, the PFS was defined as the date of treatment initiation to the verified radiological progression during treatment course. For patients in SeqHAIC group, the PFS was defined as date of treatment initiation of FOLFOX-HAIC monotherapy to the verified radiological progression after sequential ICIs and TKIs systemic therapies during treatment course. The OS for both groups was defined as the date of the initiation of FOLFOX-HAIC to the date of death due to any cause. Tumor response to treatment was defined as complete response (CR), partial response (PR), stable disease (SD), or PD based on the RECIST v1.1 criteria [22]. The secondary outcomes included conversion rate, overall response rate (ORR), disease control rate (DCR), and safety. Treatment-related adverse events (TRAEs) were documented during each phase of treatment and assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0) [23].

Evaluation

All baseline data were retrieved from medical records and imaging examinations. All patients generally underwent scheduled blood test, enhanced computed tomography (CT) or magnetic resonance imaging (MRI) every 2–3 months to evaluate the efficacy and safety during the treatment. During the first 2 years of follow-up, complete blood counts, blood chemistry, tumor biomarkers and CT or MRI were repeated every 3 months. Thereafter, patients were examined every 6 months until discovered disease progression or died.

Statistical analysis

Continuous variables were analyzed by using an unpaired student’s t-test or Mann-Whitney test. Categorical variables were compared using the χ2 or Fisher’s exact test. Survival analysis was performed and compared using the Kaplan-Meier method and log-rank tests. COX regression was applied to identify the independent risk factors for PFS and OS. Univariate regression was first performed, and all variables were included in the multivariate analysis using the forward conditional method. Moreover, subgroup analysis was conducted based on the different tumor characteristics which might impact on tumor progression or survival on the basis of clinical experience of enrolled patients. All statistical analyses were performed using SPSS (version 25.0; SPSS, Inc., Chicago, United States) or R (version 4.2.1; R Foundation, Vienna, Austria). A two-sided p value < 0.050 was considered statistically significant.

Results

Demographic characteristics of the study population

The patient inclusion flowchart was presented in Fig. 1. From March 2020 and June 2022, 117 borderline resectable or locally advanced HCC patients who initially received either FOLFOX-HAIC monotherapy (n = 44), or concurrent of ICIs and TKIs (n = 73) were included, during the treatment procession 30 HCC patients converted to SeqHAIC group because of detected disease progression. The baseline characteristics of the HAIC group and the ConHAIC group were presented in the Table S2. The median cycles of FOLFOX-HAIC from initial treatment were 4 [4, 6] in HAIC group and there was no statistic difference in terms of tumor burden between the two groups (p > 0.050). In general, the cohort included 107 (91.5%) males and 10 (8.5%) females, with an average age of 55.7 years old, most of enrolled patients were hepatitis B virus (HBV) related HCC (100 cases, 85.5%) with preserved liver function. The mean measurable tumor diameter of the enrolled patients was 10.1 cm, and more than half of them suffered from PVTT (71 cases, 60.7%). In addition, as presented in the Table 1, the median cycles of FOLFOX-HAIC from initial treatment were 5 [4, 6] in SeqHAIC group and 4 [3, 4] in ConHAIC group (p > 0.050), and no significant difference was observed in the other baseline variables of the SeqHAIC group and the ConHAIC group.

Fig. 1 Patient disposition. HCC, hepatocellular carcinoma; FOLFOX-HAIC, HAIC of infusion fluorouracil, leucovorin, and oxaliplatin; ICIs, immune checkpoint inhibitors; TKIs, tyrosine kinase inhibitors; PD, progressive disease

Table 1 Clinicopathological characteristics of patients by different treatment groups

Characteristics	Total
(n = 103)	SeqHAIC group
(n = 30)	ConHAIC group
(n = 73)	p value	
Age, years, Mean ± SD	55.6 ± 11.7	52.8 ± 13.3	56.8 ± 10.8	0.110	
Male, n (%)	95 (92.2)	28 (93.3)	67 (91.8)	1.000	
ECOG status, n (%)				0.976	
PS = 0	38 (36.9)	11 (36.7)	27 (37.0)		
PS = 1–2	65 (63.1)	19 (63.3)	46 (63.0)		
Child-Pugh score, n (%)				0.789	
5	89 (86.4)	25 (83.3)	64 (87.7)		
6	14 (13.6)	5 (16.7)	9 (12.3)		
Tumor size, cm, Mean ± SD	10.0 ± 3.1	10.5 ± 3.2	9.9 ± 3.0	0.542	
≥ 10 cm	57 (55.3)	18 (60.0)	39 (53.4)		
< 10 cm	46 (44.7)	12 (40.0)	34 (46.6)		
Tumor number, n (%)				0.324	
Single	42 (40.8)	10 (33.3)	32 (43.8)		
Multiple	61 (59.2)	20 (66.7)	41 (56.2)		
PVTT, n (%)				0.053	
Yes	63 (61.2)	14 (46.7)	49 (67.1)		
No	40 (38.8)	16 (53.3)	24 (32.9)		
AFP, n (%)				0.764	
≥ 400ng/ml	56 (54.4)	17 (56.7)	39 (53.4)		
< 400ng/ml	47 (45.6)	13 (43.3)	34 (46.6)		
PIVKA-II, n (%)				0.316	
≥ 1000mAU/ml	85 (82.5)	23 (76.7)	62 (84.9)		
< 1000mAU/ml	18 (17.5)	7 (23.3)	11 (15.1)		
BCLC Stage, n (%)				0.069	
A	14 (13.6)	5 (16.7)	9 (12.3)		
B	24 (23.3)	11 (36.7)	13 (17.8)		
C	65 (63.1)	14 (46.7)	51 (69.9)		
ALBI grade, n (%)				0.726	
I	66 (64.1)	20 (66.7)	46 (63.0)		
II	37 (35.9)	10 (33.3)	27 (37.0)		
ALT, IU/L, (Median, IQR)	39.4 (29.5, 55.9)	33.7 (25.3, 59.8)	41.7 (30.3, 56.1)	0.537	
AST, IU/L, (Median, IQR)	55.0 (39.0, 95.5)	56.9 (39.4, 114.1)	53.6 (38.5, 87.4)	0.195	
CRP, mg/L, (Median, IQR)	14.1 (2.9, 28.9)	17.8 (4.8, 30.6)	12.8 (2.7, 28.7)	0.569	
HBV infection, n(%)				1.000	
Yes	88 (85.4)	26 (86.7)	62 (84.9)		
No	15 (14.6)	4 (13.3)	11 (15.1)		
Cycles of FOLFOX-HAIC from initial treatment, (Median, IQR)	4 (3, 5)	5 (4, 6)	4 (3, 4)	< 0.050	
ECOG, eastern cooperative oncology group; PS, performance status; SD, standard deviation; PVTT, portal vein tumor thrombosis; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II; BCLC, Barcelona Clinic Liver Cancer; ALBI grade, Albumin-Bilirubin grade; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reaction protein; IQR, interquartile range; HBV, Hepatitis B virus

Progression-free and overall survival

As of September 1st, 2023, for the overall population, the median follow-up was 18.9 months (95% confidence interval [95% CI], 17.54–20.26 months). As shown in the Fig.S1, the median PFS for all patients was 5.8 months (95% CI, 3.21–8.39 months), and a total of 43 (36.8%) deaths were observed, the median OS was 27.33 months (95% CI, 21.64–33.02 months). The HAIC group demonstrated obvious disadvantage in both PFS (hazard ratio [HR], 10.821; 95% CI, 5.914–19.800; p < 0.001) and OS (HR, 2.119; 95% CI, 1.137–3.950; p = 0.018) compared to the ConHAIC group (Fig.S2A-B). For the 44 patients who initiated with the FOLFOX-HAIC monotherapy (HAIC group), only 4 patients did not develop PD, 10 patients combined with TKIs only sequentially when developed PD during the follow-up period. After excluded 14 patients who did not meet eligibility criteria, the rest 30 patients were finally included into the SeqHAIC group for further analysis. Notably, no significant difference was observed in both PFS (HR, 1.572; 95% CI, 0.848–2.916; p = 0.151) and OS (HR, 1.212; 95% CI, 0.574–2.561; p = 0.614) between the SeqHAIC and the ConHAIC groups (Fig. 2A-B). In detail, the median follow-up time of the SeqHAIC group was 24.92 months (95% CI, 12.74–37.09 months) and of the ConHAIC group was 17.87 months (95% CI, 16.85–18.89 months). At the data cut-off, 13 (43.3%) and 18 (24.7%) patients died in the SeqHAIC and ConHAIC groups, respectively. The median PFS was 11.6 months (95% CI, 9.34–13.87 months) in the SeqHAIC group and 19.37 months (95% CI, 12.90–25.84 months) in the ConHAIC group, respectively (Fig. 2A). Additionally, the 6-, 12-, 18- and 24-month PFS rates were 83.3%, 40.0%, 16.7% and 3.3%, respectively, in the SeqHAIC group and 53.4%, 37.0%, 13.7% and 2.7% in the ConHAIC group, respectively (Fig. 2A). A total of 25 patients in the ConHAIC group who developed PD or unacceptable toxicity during the follow-up period, appropriate second-line treatments were recommended according to the multi-discipline team (MDT). In detail, 6 patients switched to second-line TKIs monotherapy, 15 patients received combined therapy of ICIs and TKIs, and 4 patients lost follow-up. The median OS of the SeqHAIC group was 27.33 months (95% CI, 18.60-36.06 months), and the median OS of the ConHAIC group was not reached at the data cut-off (Fig. 2B). The 6-, 12-, 18- and 24-month OS rates were comparable between the two groups, 100%, 73.3%, 53.3% and 36.7%, and 87.7%, 74.0%, 38.4% and 13.7% in the SeqHAIC and ConHAIC groups, respectively (Fig. 2B).

Fig. 2 Kaplan–Meier curves for progression-free survival (A) and overall survival (B) of patients in the SeqHAIC group (n = 30) and the ConHAIC group (n = 73). HR, hazard ratio; CI, confidence interval

Response and conversion to resection

The tumor responses were presented in the Fig. 3A and the Table S3. There was no significant difference between the two groups regarding tumor responses, the ORRs and DCRs were 50.0%, 45.2%, and 83.3%, 89.0% for the SeqHAIC and the ConHAIC groups, respectively (Fig. 3A; p > 0.050). However, for the 44 patients who received the FOLFOX-HAIC monotherapy, the ORR and DCR were 25% and 43.2% before enrolled in the SeqHAIC group, respectively (11 patients achieved PR and no patients achieved CR). The best response for intra-hepatic target lesions according to the RECIST v1.1 criteria was also shown in the Fig. 3B. 2 patients in the SeqHAIC group and 6 patients in the ConHAIC group suffered from extrahepatic metastasis in the case of stable controlling of the intra-hepatic lesions, respectively (6.7% vs. 8.2%, p = 1.000 Fig. 3B). In addition, 3 (10.0%) and 9 (12.3%) patients in the SeqHAIC and the ConHAIC groups had received surgical resection, respectively (Fig. 3B). At the data cut-off, 3 and 5 patients in the SeqHAIC and the ConHAIC groups who converted to hepatectomy experienced an intra-hepatic recurrence but all of them remained alive after receiving subsequent therapies.

Fig. 3 Barplot for tumor responses rates based on RECIST v1.1 in the SeqHAIC group (n = 30) and the ConHAIC group (n = 73) (A) and (B) Waterfall plot for tumor size changes of intrahepatic target lesions. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease

Subgroup and prognostic analysis

Given patients in the SeqHAIC group tended to suffer from larger tumor size (10.5 cm ± 3.2 vs. 9.9 cm ± 3.0, p = 0.542) while patients in the ConHAIC group had more PVTT (46.7% vs. 67.1%, p = 0.053; Table 1), hierarchical subgroup analysis in terms of PFS and OS was further conducted (Fig. 4A-B). After stratification, concurrent FOLFOX-HAIC plus ICIs and TKIs was able to postpone tumor progression for unresectable HCC patients with tumor size smaller than 10 cm (HR, 0.25; 95% CI, 0.08–0.78; p = 0.017). No significant difference was observed in both PFS and OS across different tumor numbers, PVTT status and alpha-fetoprotein (AFP) levels in either the SeqHAIC or the ConHAIC group (p > 0.050; Fig. 4A-B). Additionally, univariate and multivariate COX analysis was presented in Table 2. After the multivariate COX regression analysis, escalated C-reaction protein (CRP) levels (HR, 3.86; 95% CI, 1.71–8.73; p = 0.001) for borderline resectable or locally advanced HCC patients were identified as independently risk prognostic factors for PFS (Table 2).

Fig. 4 Forest plots of (A) progression-free survival and (B) overall survival in terms of interested subgroups for the SeqHAIC and the ConHAIC groups. HR, hazard ratio; CI, confidence interval; PVTT, portal vein tumor thrombosis; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II; ALBI, Grade Albumin-Bilirubin grade; HBV, Hepatitis B virus infection

Table 2 The COX regression analysis for progression free survival and overall survival

Variables	PFS		OS	
	Univariate COX regression		Multivariate COX regression		Univariate COX regression		Multivariate COX regression	
	HR (95% CI)	p value		HR (95% CI)	p value		HR (95% CI)	p value		HR (95% CI)	P value	
Age (50 years)	0.57 (0.32–1.04)	0.067					1.36 (0.62–2.98)	0.439				
Sex (Male)	0.74 (0.26–2.08)	0.566					1.91 (0.26–14.09)	0.527				
Tumor size (≥ 10 cm)	1.43 (0.78–2.59)	0.245					0.90 (0.44–1.86)	0.782				
Tumor number (Multiple)	1.47 (0.78–2.78)	0.234					1.83 (0.81–4.13)	0.146				
PVTT (Yes)	0.71 (0.39–1.29)	0.259					1.02 (0.50–2.12)	0.949				
AFP (≥ 400 ng/ml)	1.65 (0.89–3.07)	0.110					1.22 (0.60–2.48)	0.592				
PIVKA-II (≥ 1000mAU/ml)	1.12 (0.52–2.41)	0.778					1.43 (0.50–4.10)	0.504				
ALT (≥ 50 IU/L)	0.72 (0.37–1.39)	0.328					0.65 (0.28–1.51)	0.312				
AST (≥ 40 IU/L)	0.92 (0.48–1.76)	0.797					1.45 (0.62–3.36)	0.391				
ALBI grade (II)	1.21 (0.67–2.20)	0.534					1.32 (0.65–2.68)	0.443				
HBV infection (Yes)	0.81 (0.34–1.94)	0.634					1.35 (0.47–3.86)	0.579				
CRP (≥ 3 mg/L)	2.44 (1.13–5.26)	0.023		2.60 (1.05–6.45)	0.040		1.02 (0.45–2.29)	0.963				
Underwent SeqHAIC (Yes)	1.54 (0.85–2.77)	0.154					1.21 (0.58–2.51)	0.615				
HR, hazard ratio; CI, confidence interval; PVTT, portal vein tumor thrombosis; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALBI grade, Albumin-Bilirubin grade; HBV, hepatitis B virus; CRP, C-reaction protein

Toxicity events

Overall, no patient died because of TRAEs during the follow-up period and there was no significant difference between the SeqHAIC and ConHAIC groups in the types of severe (i.e., grade 3/4) TRAEs (46.7% vs. 61.6%, p = 0.163; Table 3). The most common TRAEs were albumin decrease (100.0%) and the elevation of total bilirubin (80.6%), while patients in the ConHAIC group underwent significantly more frequent hand-foot-skin reaction (10.0% vs. 28.8%, p = 0.041) and hypertension (3.3% vs. 21.9%, p = 0.044) than those of the SeqHAIC group (Table 3).

Table 3 Treatment-related adverse events for the study population

Adverse events	Any grades		Grades 3/4	
Total (n = 103)	SeqHAIC (n = 30)	ConHAIC (n = 73)	p value		Total (n = 103)	SeqHAIC (n = 30)	ConHAIC (n = 73)	p value	
Treatment-related AEs, n(%)										
Hemoglobin decreased	81 (78.6)	21 (70.0)	60 (82.2)	0.170		3 (2.9)	1 (3.3)	2 (2.7)	0.872	
Leukopenia	53 (51.5)	15 (50.0)	38 (52.1)	0.850		3 (2.9)	1 (3.3)	2 (2.7)	0.872	
Platelet count decreased	60 (58.3)	16 (53.3)	44 (60.3)	0.516		20 (19.4)	5 (16.7)	15 (20.5)	0.651	
ALT increased	52 (50.5)	13 (43.3)	39 (53.4)	0.352		5 (4.9)	1 (3.3)	4 (5.5)	1.000	
AST increased	81 (78.6)	23 (76.7)	58 (79.5)	0.754		19 (18.4)	5 (16.7)	14 (19.2)	0.765	
Total bilirubin increased	83 (80.6)	25 (83.3)	58 (79.5)	0.651		8 (7.8)	1 (3.3)	7 (9.6)	0.501	
Albumin decreased	103 (100.0)	30 (100.0)	73 (100.0)	-		1 (1.0)	0 (0.0)	1 (1.4)	0.405	
Creatinine increased	22 (21.4)	4 (13.3)	18 (24.7)	0.203		0 (0.0)	0 (0.0)	0 (0.0)	-	
Hypothyroidism	4 (3.9)	1 (3.3)	3 (4.1)	1.000		0 (0.0)	0 (0.0)	0 (0.0)	-	
Hand-foot-skin reaction	24 (23.3)	3 (10.0)	21 (28.8)	0.041		0 (0.0)	0 (0.0)	0 (0.0)	-	
Pain	15 (14.6)	3 (10.0)	12 (16.4)	0.593		0 (0.0)	0 (0.0)	0 (0.0)	-	
Fever	7 (6.8)	1 (3.3)	6 (8.2)	0.642		0 (0.0)	0 (0.0)	0 (0.0)	-	
Diarrhea	8 (7.8)	1 (3.3)	7 (9.6)	0.501		0 (0.0)	0 (0.0)	0 (0.0)	-	
Fatigue	4 (3.9)	0 (0.0)	4 (5.5)	0.455		0 (0.0)	0 (0.0)	0 (0.0)	-	
Nausea	3 (2.9)	0 (0.0)	3 (4.1)	0.147		0 (0.0)	0 (0.0)	0 (0.0)	-	
Vomit	5 (4.9)	0 (0.0)	5 (6.8)	0.335		0 (0.0)	0 (0.0)	0 (0.0)	-	
Decreased appetite	7 (6.8)	1 (3.3)	6 (8.2)	0.642		0 (0.0)	0 (0.0)	0 (0.0)	-	
Edema peripheral	1 (1.0)	0 (0.0)	1 (1.4)	0.405		0 (0.0)	0 (0.0)	0 (0.0)	-	
Hypertension	17 (16.5)	1 (3.3)	16 (21.9)	0.044		0 (0.0)	0 (0.0)	0 (0.0)	-	
AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase

Discussion

It has been controversial for a long time, whether subject to the most potent therapeutic options directly or gradually for locally advanced HCC patients who were expected to have a chance to receive curative resection theoretically. The present study preliminarily explored the efficacy and safety of these two treatment patterns in treating borderline resectable or locally advanced HCC patients. The results revealed that FOLFOX-HAIC-based sequential or concurrent systemic ICIs and TKIs possessed comparable long-term prognosis and tolerability for locally advanced HCC patients, which first provided evidence regarding the timing and sequencing of locoregional and systemic therapies in the treatment of locally advanced HCC patients.

With decades of development across the world, HAIC became a promising locoregional therapy with 27.6-31.5% responsive rates for locally advanced HCC [9, 24, 25]. By placing the catheter to the tumor feeding arterial under digital subtraction angiography (DSA), high concentrations of chemotherapy antigens were able to pump into tumor tissue directly and attenuated the damages towards liver parenchyma [26, 27]. Since Qin et al.. proved the safety and efficacy of FOLFOX4 regimen as systemic therapy for advanced HCC patients [28, 29], the locoregional control rate of HAIC was further improved via applying FOLFOX regimen on HAIC [9]. Li et al.. reported that response rate of FOLFOX-HAIC peaked to 45.9% for large HCC patients who not suitable for resection [7]. Therefore, FOLFOX-HAIC was supposed to be a promising therapy in controlling locally advanced HCC, which has been recommended in some guidelines [6, 21].

Given the potent response rate of FOLFOX-HAIC for locally advanced HCC patients, a series of FOLFOX-HAIC-based combination therapies were carried out by clinical practicians and validated for efficacy. When combined with TKIs, FOLFOX-HAIC plus sorafenib increased 13.7% of DCR compared to FOLFOX-HAIC alone for patients with advanced HCC [30], which preliminarily proved the feasibility of FOLFOX-HAIC-based combinations patterns. Furthermore, as evaluated the HAIC plus ICIs, Wu et al.. revealed that HAIC combined with ICIs had a superior response of PVTT compared to HAIC alone and was correlated to reduced risk of progression or death [31]. Based on the above practice, the FOLFOX-HAIC combined with ICIs and TKIs which was supposed to be the strongest therapeutic patterns for locally advanced HCC patients was reasonable to explore from a multi-center level [32, 33]. The ORRs were able to reach 37–42.5% for FOLFOX-HAIC plus ICIs and TKIs in treatment of intermediate and advanced HCC patients, which was similar to the current study [32, 33]. Therefore, it was believed that FOLFOX-HAIC combined with ICIs and TKIs could be further developed in the future. However, in order to deeply understand the mechanisms behind triple therapy, the roles of locoregional and systemic therapies should be further depicted from different perspectives.

Inspired by Fu et al.. who described the inductive role of FOLFOX-HAIC in treating HCC patients with PVTT with triple therapy [14], the sequence of locoregional and systemic therapies for locally advanced HCC has attracted attention in the clinical practice. The induction therapy of FOLFOX-HAIC and ICIs plus TKIs in the initial period of treatment and then dual maintenance therapy of ICIs and TKIs demonstrated significantly superior disease control rates and long-term prognosis to the systemic therapy alone for HCC patients with PVTT [14]. Oxaliplatin-induced multidrug regimen was reported to induce high levels of necrosis and apoptosis in tumor tissue and release antigens which enhanced the effectiveness of following immune therapy [34, 35]. In the current study, the FOLFOX-HAIC-based combination therapy achieved extremely high ORRs of almost 50%, which obviously higher than systemic combination therapies from other studies for locally advanced HCC patients [36, 37]. Meanwhile, in our clinical practice, as the triplet treatment has a potent efficacy on tumor control, on the other hand, patients also suffer from significantly higher adverse effects. In this study, we compared sequential and concurrent FOLFOX-HAIC plus systemic therapies, and the results indicated that FOLFOX-HAIC sequential ICIs and TKIs did not compromise the efficacy for locally advanced HCC patients, nevertheless, the occurrence of TRAEs was able to significantly decrease which have patients had better compliance and quality of life. In addition, the SeqHAIC group consisted mostly of patients who were resistant to FOLFOX-HAIC monotherapy, but the patients in ConHAIC group were not necessarily refractory to it, which might be the reason of the ConHAIC group seemed to have longer PFS in Kaplan-Meier curve.

Subgroup analysis in the current study revealed that locally advanced HCC patients with tumors less than 10 cm might benefit from FOLFOX-HAIC plus ICIs and TKIs in terms of PFS, while patients with huge tumors failed to demonstrate benefits regardless of sequential or concurrent systemic therapies combined with FOLFOX-HAIC, suggesting that smaller tumors were more likely to be controlled by concurrent FOLFOX-HAIC plus ICIs and TKIs in the short term, but this advantage was not demonstrated in larger tumors. In the multivariate analysis, higher CRP were found to be predictive variables for long-term prognosis, which was similar to other studies [38–40].

With comparable tumor control rate and long-term prognosis, concurrent FOLFOX-HAIC plus ICIs and TKIs significantly increased the incidence of TRAEs. A higher incidence of hand-foot-skin reaction and hypertension was observed in the ConHAIC group, which might be due to direct cytotoxicity to hepatocytes and hematopoietic cells by concurrent FOLFOX-HAIC plus ICIs and TKIs. And the FOLFOX-HAIC sequenced by ICIs and TKIs were able to screen patients who sensitive to FOLFOX-HAIC monotherapy and cloud save money and energies for the subsequent systemic therapies in the future. Moreover, in the ConHAIC group, patients received an average of 3.6 times of FOLFOX-HAIC, while patients in the SeqHAIC group underwent 4.9 times on average, which suggested that the sequential strategy enabled the patients to tolerate the side effects of FOLFOX-HAIC better and thus received more treatment courses which were expected to have more durable tumor control. Majority of the TRAEs were generally controllable and did not aggravate the disease, and the abnormal liver function indicators could be recovered between two cycles of HAIC treatment with corresponding supporting medications.

There are potential limitations in the current study. First of all, given the retrospective nature of present study, the selection bias was inevitable. To further discuss this topic, a large-volume and prospective design is needed in the future. Second, in most of population in current study, HBV was the major reason that developed HCC. Whether the survival benefit of different treatment sequencing patterns apply in the absence of HBV has yet to be determined. Finally, in the present study, the types of TKIs and ICIs were comparable between two groups. However, due to the retrospective nature of current study, it was hard to identify the associations between dose of TKIs and the toxicities which we also curious. We hope this question could be answered in prospective in the future.

Conclusion

In conclusion, our study revealed that sequential systemic ICIs and TKIs in combination with FOLFOX-HAIC provides similar long-term prognosis and better tolerability compared to concurrent therapy for locally advanced HCC patients. Prospective studies with a larger sample size and longer follow-up are required to validate these findings.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1: Figure S1 Kaplan–Meier curves for progression-free survival (A) and overall survival (B) of patients in the HAIC and the ConHAIC groups (n = 117). Kaplan–Meier curves for progression-free survival (C) and overall survival (D) of patients in the SeqHAIC and the ConHAIC groups (n = 103). HR, hazard ratio; CI, confidence interval.

Supplementary Material 2

Supplementary Material 3

Supplementary Material 4

Supplementary Material 5: Figure S2 Kaplan–Meier curves for progression-free survival (A) and overall survival (B) of patients in the HAIC group (n = 44) and the ConHAIC group (n = 73). HR, hazard ratio; CI, confidence interval

Acknowledgements

We would like to thank the patients and their families, as well as the investigators and personnel for their significant contribution.

Author contributions

LS: conceptualization, methodology, software, formal analysis, writing—original draft; ZH: methodology, software, formal analysis; WX: software, data curation, revise; ZY: conceptualization, software, resources, data curation; HZ: resources, investigation; YZ: supervision, data curation; MC: conceptualization, project administration, supervision; DH: resources, funding acquisition, investigation; ZZ: conceptualization, project administration, supervision; YP: conceptualization, methodology, project administration, supervision, writing—review & editing.

Funding

This work is funded by the National Natural Science Foundation of China (No. 82103566).

Data availability

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The protocol complied with the ethical guidelines of the Declaration of Helsinki of the World Medical Association and was approved by the ethics committee of the Sun Yat-sen University Cancer Center (SYSUCC) (approval No. B2022-301-01). All patients provided written informed consent for HCC treatment and the use of their medical records for research purposes.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Sung H Ferlay J Siegel RL Laversanne M Soerjomataram I Jemal A Bray F Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2021 71 209 49 10.3322/caac.21660 33538338
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.33538338
2. Zhou M Wang H Zeng X Yin P Zhu J Chen W Li X Wang L Wang L Liu Y Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the global burden of disease study 2017 Lancet 2019 394 1145 58 10.1016/S0140-6736(19)30427-1 31248666
Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, Li X, Wang L, Wang L, Liu Y, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2019;394:1145–58.31248666
3. Llovet JM Kelley RK Villanueva A Singal AG Pikarsky E Roayaie S Lencioni R Koike K Zucman-Rossi J Finn RS Hepatocellular carcinoma Nat Rev Dis Primers 2021 7 6 10.1038/s41572-020-00240-3 33479224
Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.33479224
4. Reig M Forner A Rimola J Ferrer-Fàbrega J Burrel M Garcia-Criado Á Kelley RK Galle PR Mazzaferro V Salem R BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update J Hepatol 2022 76 681 93 10.1016/j.jhep.2021.11.018 34801630
Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, Kelley RK, Galle PR, Mazzaferro V, Salem R, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022;76:681–93.34801630
5. Kudo M Kawamura Y Hasegawa K Tateishi R Kariyama K Shiina S Toyoda H Imai Y Hiraoka A Ikeda M Management of hepatocellular carcinoma in Japan: JSH consensus statements and recommendations 2021 update Liver Cancer 2021 10 181 223 10.1159/000514174 34239808
Kudo M, Kawamura Y, Hasegawa K, Tateishi R, Kariyama K, Shiina S, Toyoda H, Imai Y, Hiraoka A, Ikeda M, et al. Management of hepatocellular carcinoma in Japan: JSH consensus statements and recommendations 2021 update. Liver Cancer. 2021;10:181–223.34239808
6. Sun J Guo R Bi X Wu M Tang Z Lau WY Zheng S Wang X Yu J Chen X Guidelines for diagnosis and Treatment of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus in China (2021 Edition) Liver Cancer 2022 11 4 315 28 10.1159/000523997 35978596
Sun J, Guo R, Bi X, Wu M, Tang Z, Lau WY, Zheng S, Wang X, Yu J, Chen X, et al. Guidelines for diagnosis and Treatment of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus in China (2021 Edition). Liver Cancer. 2022;11(4):315–28.35978596
7. Li Q-J He M-K Chen H-W Fang W-Q Zhou Y-M Xu L Wei W Zhang Y-J Guo Y Guo R-P Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin versus transarterial chemoembolization for large hepatocellular carcinoma: a randomized phase III trial J Clin Oncol 2022 40 150 60 10.1200/JCO.21.00608 34648352
Li Q-J, He M-K, Chen H-W, Fang W-Q, Zhou Y-M, Xu L, Wei W, Zhang Y-J, Guo Y, Guo R-P, et al. Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin versus transarterial chemoembolization for large hepatocellular carcinoma: a randomized phase III trial. J Clin Oncol. 2022;40:150–60.34648352
8. Lyu N Kong Y Mu L Lin Y Li J Liu Y Zhang Z Zheng L Deng H Li S Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma J Hepatol 2018 69 60 9 10.1016/j.jhep.2018.02.008 29471013
Lyu N, Kong Y, Mu L, Lin Y, Li J, Liu Y, Zhang Z, Zheng L, Deng H, Li S, et al. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2018;69:60–9.29471013
9. Ning Lyu X Wang J-B Li J-F Lai Q-F Chen S-L Li H-J Deng M He L-W Mu Zhao M Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: a biomolecular exploratory, randomized, phase III trial (FOHAIC-1) J Clin Oncol 2022 40 468 80 10.1200/JCO.21.01963 34905388
Ning Lyu X, Wang J-B, Li J-F, Lai Q-F, Chen S-L, Li H-J, Deng M, He L-W, Mu, Zhao M. Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: a biomolecular exploratory, randomized, phase III trial (FOHAIC-1). J Clin Oncol. 2022;40:468–80.34905388
10. He M Li Q Zou R Shen J Fang W Tan G Zhou Y Wu X Xu L Wei W Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial JAMA Oncol 2019 5 953 60 10.1001/jamaoncol.2019.0250 31070690
He M, Li Q, Zou R, Shen J, Fang W, Tan G, Zhou Y, Wu X, Xu L, Wei W, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial. JAMA Oncol. 2019;5:953–60.31070690
11. Ferlay J Colombet M Soerjomataram I Dyba T Randi G Bettio M Gavin A Visser O Bray F Lenvatinib, toripalimab plus hepatic arterial infusion chemotherapy in patients with high-risk advanced hepatocellular carcinoma: a biomolecular exploratory, phase II trial Eur J Cancer 2022 174 68 77 10.1016/j.ejca.2022.07.005 35981413
Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bettio M, Gavin A, Visser O, Bray F. Lenvatinib, toripalimab plus hepatic arterial infusion chemotherapy in patients with high-risk advanced hepatocellular carcinoma: a biomolecular exploratory, phase II trial. Eur J Cancer. 2022;174:68–77.35981413
12. Dongming Liu H Mu C Liu W Zhang Y Cui Q Wu X Zhu F Fang W Zhang W Xing Hepatic artery infusion chemotherapy (HAIC) combined with sintilimab and bevacizumab biosimilar (IBI305) for initial unresectable hepatocellular carcinoma (HCC): a prospective, single-arm phase II trial J Clin Oncol 2022 40 4073 10.1200/JCO.2022.40.16_suppl.4073
Dongming Liu H, Mu C, Liu W, Zhang Y, Cui Q, Wu X, Zhu F, Fang W, Zhang W, Xing, et al. Hepatic artery infusion chemotherapy (HAIC) combined with sintilimab and bevacizumab biosimilar (IBI305) for initial unresectable hepatocellular carcinoma (HCC): a prospective, single-arm phase II trial. J Clin Oncol. 2022;40:4073.
13. Zhang J Zhang X Mu H Yu G Xing W Wang L Zhang T Surgical conversion for initially unresectable locally advanced hepatocellular carcinoma using a triple combination of angiogenesis inhibitors, anti-PD-1 antibodies, and hepatic arterial infusion chemotherapy: a retrospective study Front Oncol 2021 11 729 64
Zhang J, Zhang X, Mu H, Yu G, Xing W, Wang L, Zhang T. Surgical conversion for initially unresectable locally advanced hepatocellular carcinoma using a triple combination of angiogenesis inhibitors, anti-PD-1 antibodies, and hepatic arterial infusion chemotherapy: a retrospective study. Front Oncol. 2021;11:729–64.
14. Fu Y Peng W Zhang W Yang Z Hu Z Pang Y Hu D Chen J Wang J Zhou Z Induction therapy with hepatic arterial infusion chemotherapy enhances the efficacy of lenvatinib and pd1 inhibitors in treating hepatocellular carcinoma patients with portal vein tumor thrombosis J Gastroenterol 2023 58 4 413 24 10.1007/s00535-023-01976-x 36894804
Fu Y, Peng W, Zhang W, Yang Z, Hu Z, Pang Y, Hu D, Chen J, Wang J, Zhou Z, et al. Induction therapy with hepatic arterial infusion chemotherapy enhances the efficacy of lenvatinib and pd1 inhibitors in treating hepatocellular carcinoma patients with portal vein tumor thrombosis. J Gastroenterol. 2023;58(4):413–24.36894804
15. Huang H Feng YL Wan T Zhang YN Cao XP Huang YW Xiong Y Huang X Zheng M Li YF Effectiveness of sequential chemoradiation vs concurrent chemoradiation or Radiation alone in Adjuvant Treatment after Hysterectomy for Cervical Cancer: the STARS phase 3 Randomized Clinical Trial JAMA Oncol 2021 7 3 361 9 10.1001/jamaoncol.2020.7168 33443541
Huang H, Feng YL, Wan T, Zhang YN, Cao XP, Huang YW, Xiong Y, Huang X, Zheng M, Li YF, et al. Effectiveness of sequential chemoradiation vs concurrent chemoradiation or Radiation alone in Adjuvant Treatment after Hysterectomy for Cervical Cancer: the STARS phase 3 Randomized Clinical Trial. JAMA Oncol. 2021;7(3):361–9.33443541
16. Verma V Moreno AC Haque W Fang P Lin SH Sequential Versus Concurrent Chemoradiation Therapy by Surgical Margin Status in Resected Non-small Cell Lung Cancer J Natl Compr Canc Netw 2018 16 5 508 16 10.6004/jnccn.2018.7007 29752325
Verma V, Moreno AC, Haque W, Fang P, Lin SH. Sequential Versus Concurrent Chemoradiation Therapy by Surgical Margin Status in Resected Non-small Cell Lung Cancer. J Natl Compr Canc Netw. 2018;16(5):508–16.29752325
17. Wang Y Liu S Yang Z Algazi AP Lomeli SH Wang Y Othus M Hong A Wang X Randolph CE Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy Cancer Cell 2021 39 10 1375 e13876 10.1016/j.ccell.2021.07.023 34416167
Wang Y, Liu S, Yang Z, Algazi AP, Lomeli SH, Wang Y, Othus M, Hong A, Wang X, Randolph CE, et al. Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy. Cancer Cell. 2021;39(10):1375–e13876.34416167
18. Heimbach JK Kulik LM Finn RS Sirlin CB Abecassis MM Roberts LR Zhu AX Murad MH Marrero JA AASLD guidelines for the treatment of hepatocellular carcinoma Hepatology 2018 67 1 358 80 10.1002/hep.29086 28130846
Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, Zhu AX, Murad MH, Marrero JA. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358–80.28130846
19. Hermanek P Wittekind C Residual tumor (R) classification and prognosis Semin Surg Oncol 1994 10 1 12 20 10.1002/ssu.2980100105 8115781
Hermanek P, Wittekind C. Residual tumor (R) classification and prognosis. Semin Surg Oncol. 1994;10(1):12–20.8115781
20. Vogel A Martinelli E ESMO Guidelines Committee Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice guidelines Ann Oncol 2021 32 6 801 5 10.1016/j.annonc.2021.02.014 33716105
Vogel A, Martinelli E, ESMO Guidelines Committee. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice guidelines. Ann Oncol. 2021;32(6):801–5.33716105
21. Zhou J, Sun H, Wang Z, Cong W, Wang J, Zeng M, Zhou W, Bie P, Liu L, Wen T et al. Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition). Liver Cancer. 2020; 9(6):682–720.
22. Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R Dancey J Arbuck S Gwyther S Mooney M New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 2 228 47 10.1016/j.ejca.2008.10.026 19097774
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.19097774
23. National Cancer Institute. common terminology criteria for adverse events, version 5.0. [ Jun;2020 ]; https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf
24. Tomokazu Kawaoka H Aikata H Hyogo R Morio K Morio M Hatooka T Fukuhara T Kobayashi N Naeshiro D Miyaki Comparison of hepatic arterial infusion chemotherapy versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma J Dig Dis 2015 16 9 505 12 10.1111/1751-2980.12267 26121102
Tomokazu Kawaoka H, Aikata H, Hyogo R, Morio K, Morio M, Hatooka T, Fukuhara T, Kobayashi N, Naeshiro D, Miyaki, et al. Comparison of hepatic arterial infusion chemotherapy versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma. J Dig Dis. 2015;16(9):505–12.26121102
25. Choi JH Chung WJ Bae SH Song DS Song MJ Kim YS Yim HJ Jung YK Suh SJ Park JY 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 78 10.1007/s00280-018-3638-0 29982870
Choi JH, Chung WJ, Bae SH, Song DS, Song MJ, Kim YS, Yim HJ, Jung YK, Suh SJ, Park JY, 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):469–78.29982870
26. He MK Liang RB Zhao Y Xu YJ Chen HW Zhou YM Lai ZC Xu L Wei W Zhang YJ Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma Ther Adv Med Oncol 2021 13 17588359211002720 10.1177/17588359211002720 33854567
He MK, Liang RB, Zhao Y, Xu YJ, Chen HW, Zhou YM, Lai ZC, Xu L, Wei W, Zhang YJ, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2021;13:17588359211002720.33854567
27. Xu YJ Lai ZC He MK Bu XY Chen HW Zhou YM Xu L Wei W Zhang YJ Chen MS Toripalimab Combined with hepatic arterial infusion Chemotherapy Versus Lenvatinib for Advanced Hepatocellular Carcinoma Technol Cancer Res Treat 2021 20 15330338211063848 10.1177/15330338211063848 34898313
Xu YJ, Lai ZC, He MK, Bu XY, Chen HW, Zhou YM, Xu L, Wei W, Zhang YJ, Chen MS, et al. Toripalimab Combined with hepatic arterial infusion Chemotherapy Versus Lenvatinib for Advanced Hepatocellular Carcinoma. Technol Cancer Res Treat. 2021;20:15330338211063848.34898313
28. Shukui Qin Y Bai HY Lim S Thongprasert Y Chao J Fan T-S Yang V Bhudhisawasdi WK Kang Y Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia J Clin Oncol 2013 31 28 3501 8 10.1200/JCO.2012.44.5643 23980077
Shukui Qin Y, Bai HY, Lim S, Thongprasert Y, Chao J, Fan T-S, Yang V, Bhudhisawasdi WK, Kang Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013;31(28):3501–8.23980077
29. Qin S Cheng Y Liang J Shen L Bai Y Li J Fan J Liang L Zhang Y Wu G Efficacy and safety of the FOLFOX4 regimen versus doxorubicin in Chinese patients with advanced hepatocellular carcinoma: a subgroup analysis of the EACH study Oncologist 2014 19 11 1169 78 10.1634/theoncologist.2014-0190 25223462
Qin S, Cheng Y, Liang J, Shen L, Bai Y, Li J, Fan J, Liang L, Zhang Y, Wu G, et al. Efficacy and safety of the FOLFOX4 regimen versus doxorubicin in Chinese patients with advanced hepatocellular carcinoma: a subgroup analysis of the EACH study. Oncologist. 2014;19(11):1169–78.25223462
30. Liang RB Zhao Y He MK Wen DS Bu XY Huang YX Lai ZC Xu YJ Kan A Wei W Hepatic Arterial Infusion Chemotherapy of Oxaliplatin, Fluorouracil, and Leucovorin with or without Sorafenib as initial treatment for Advanced Hepatocellular Carcinoma Front Oncol 2021 11 619461 10.3389/fonc.2021.619461 34055599
Liang RB, Zhao Y, He MK, Wen DS, Bu XY, Huang YX, Lai ZC, Xu YJ, Kan A, Wei W, et al. Hepatic Arterial Infusion Chemotherapy of Oxaliplatin, Fluorouracil, and Leucovorin with or without Sorafenib as initial treatment for Advanced Hepatocellular Carcinoma. Front Oncol. 2021;11:619461.34055599
31. Wu JS Hong TC Wu HT Lin YJ Chang TT Wang CT Liu WC Hsieh MT Wu IC Chen PJ Hepatic arterial infusion chemotherapy and immune checkpoint inhibitors, alone or in combination, in advanced hepatocellular carcinoma with macrovascular invasion: a single-centre experience in Taiwan J Gastrointest Oncol 2023 14 2 849 62 10.21037/jgo-22-858 37201085
Wu JS, Hong TC, Wu HT, Lin YJ, Chang TT, Wang CT, Liu WC, Hsieh MT, Wu IC, Chen PJ, et al. Hepatic arterial infusion chemotherapy and immune checkpoint inhibitors, alone or in combination, in advanced hepatocellular carcinoma with macrovascular invasion: a single-centre experience in Taiwan. J Gastrointest Oncol. 2023;14(2):849–62.37201085
32. Pan Y Zhu X Liu J Zhong J Zhang W Shen S Jin R Liu H Ye F Hu K China Liver Cancer Study Group Young Investigators (CLEAP) Systemic therapy with or without transcatheter intra-arterial therapies for unresectable hepatocellular carcinoma: a real-world, multi-center study Front Immunol 2023 14 1138355 10.3389/fimmu.2023.1138355 37180173
Pan Y, Zhu X, Liu J, Zhong J, Zhang W, Shen S, Jin R, Liu H, Ye F, Hu K, China Liver Cancer Study Group Young Investigators (CLEAP). Systemic therapy with or without transcatheter intra-arterial therapies for unresectable hepatocellular carcinoma: a real-world, multi-center study. Front Immunol. 2023;14:1138355.37180173
33. Zang M, Hu X, Yuan G, Li R, Li W, Pang H, Li Q, Chen J. Tyrosine kinase inhibitors, immune checkpoint inhibitors combined with hepatic arterial infusion of oxaliplatin and raltitrexed versus oxaliplatin, 5-fluorouracil and leucovorin for intermediate and advanced hepatocellular carcinoma: a retrospective study. Int Immunopharmacol. 2023;125, (Part A):111019.
34. Correale P Cusi MG Del Vecchio MT Aquino A Prete SP Tsang KY Micheli L Nencini C La Placa M Montagnani F Dendritic cell-mediated cross-presentation of antigens derived from colon carcinoma cells exposed to a highly cytotoxic multidrug regimen with gemcitabine, oxaliplatin, 5-fluorouracil, and leucovorin, elicits a powerful human antigen-specific CTL response with antitumor activity in vitro J Immunol 2015 175 2 820 8 10.4049/jimmunol.175.2.820
Correale P, Cusi MG, Del Vecchio MT, Aquino A, Prete SP, Tsang KY, Micheli L, Nencini C, La Placa M, Montagnani F, et al. Dendritic cell-mediated cross-presentation of antigens derived from colon carcinoma cells exposed to a highly cytotoxic multidrug regimen with gemcitabine, oxaliplatin, 5-fluorouracil, and leucovorin, elicits a powerful human antigen-specific CTL response with antitumor activity in vitro. J Immunol. 2015;175(2):820–8.
35. Wang X Li M Ren K Xia C Li J Yu Q Qiu Y Lu Z Long Y Zhang Z On-Demand autophagy Cascade amplification nanoparticles precisely enhanced Oxaliplatin-Induced Cancer Immunotherapy Adv Mater 2020 32 32 e2002160 10.1002/adma.202002160 32596861
Wang X, Li M, Ren K, Xia C, Li J, Yu Q, Qiu Y, Lu Z, Long Y, Zhang Z, et al. On-Demand autophagy Cascade amplification nanoparticles precisely enhanced Oxaliplatin-Induced Cancer Immunotherapy. Adv Mater. 2020;32(32):e2002160.32596861
36. Finn RS Ikeda M Zhu AX Sung MW Baron AD Kudo M Okusaka T Kobayashi M Kumada H Kaneko S Phase ib study of Lenvatinib Plus Pembrolizumab in patients with Unresectable Hepatocellular Carcinoma J Clin Oncol 2020 38 26 2960 70 10.1200/JCO.20.00808 32716739
Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, Okusaka T, Kobayashi M, Kumada H, Kaneko S, et al. Phase ib study of Lenvatinib Plus Pembrolizumab in patients with Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2020;38(26):2960–70.32716739
37. D’Alessio A Fulgenzi CAM Nishida N Schönlein M von Felden J Schulze K Wege H Gaillard VE Saeed A Wietharn B Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and child-pugh A and B cirrhosis: a real-world study Hepatology 2022 76 4 1000 12 10.1002/hep.32468 35313048
D’Alessio A, Fulgenzi CAM, Nishida N, Schönlein M, von Felden J, Schulze K, Wege H, Gaillard VE, Saeed A, Wietharn B, et al. Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and child-pugh A and B cirrhosis: a real-world study. Hepatology. 2022;76(4):1000–12.35313048
38. Scheiner B Pomej K Kirstein MM Hucke F Finkelmeier F Waidmann O Himmelsbach V Schulze K von Felden J Fründt TW Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score J Hepatol 2022 76 2 353 63 10.1016/j.jhep.2021.09.035 34648895
Scheiner B, Pomej K, Kirstein MM, Hucke F, Finkelmeier F, Waidmann O, Himmelsbach V, Schulze K, von Felden J, Fründt TW, et al. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. J Hepatol. 2022;76(2):353–63.34648895
39. Guan R Mei J Lin W Deng M Li S Guo R Is the CRAFITY score a superior predictor of prognosis and adverse events in hepatocellular carcinoma patients treated with locoregional-immunotherapy? Hepatol Int 2023 17 5 1279 88 10.1007/s12072-023-10535-8 37129721
Guan R, Mei J, Lin W, Deng M, Li S, Guo R. Is the CRAFITY score a superior predictor of prognosis and adverse events in hepatocellular carcinoma patients treated with locoregional-immunotherapy? Hepatol Int. 2023;17(5):1279–88.37129721
40. Li Q Wei Y Zhang T Che F Yao S Wang C Shi D Tang H Song B Predictive models and early postoperative recurrence evaluation for hepatocellular carcinoma based on gadoxetic acid-enhanced MR imaging Insights Imaging 2023 14 1 4 10.1186/s13244-022-01359-5 36617581
Li Q, Wei Y, Zhang T, Che F, Yao S, Wang C, Shi D, Tang H, Song B. Predictive models and early postoperative recurrence evaluation for hepatocellular carcinoma based on gadoxetic acid-enhanced MR imaging. Insights Imaging. 2023;14(1):4.36617581
