Hepatic Arterial Infusion Chemotherapy Combined with Tyrosine Kinase Inhibitors and PD-1 Inhibitors in Hepatocellular Carcinoma

doi:10.21203/rs.3.rs-2632584/v1

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Hepatic Arterial Infusion Chemotherapy Combined with Tyrosine Kinase Inhibitors and PD-1 Inhibitors in Hepatocellular Carcinoma

https://doi.org/10.21203/rs.3.rs-2632584/v1

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Purposes: To compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with tyrosine kinase inhibitors (TKIs) and anti-programmed cell death protein-1 (PD-1) immunotherapy versus combination therapy of transarterial chemotherapy (TACE), TKIs and PD-1 inhibitors in the treatment for hepatocellular carcinoma (HCC).

Methods: The data of 302 patients with HCC receiving HAIC combined with TKIs and PD-1 inhibitors (HAIC-TP group) and 446 patients receiving TACE combined with TKIs and PD-1 inhibitors (TACE-TP group) were retrospectively collected. The progression-free survival (PFS), overall survival (OS), tumor response and adverse events were compared between two groups. Propensity-score matching (PSM) analysis were utilized to minimize the bias.

Results: HAIC-TP group exhibited longer PFS (17.1 months versus 8.9 months, P < 0.001), longer OS (not reached versus 14.3 months, P < 0.001) and better objective response rate (RECIST: 33.1% versus 7.8%, P < 0.001; mRECIST: 51.4% versus 17.5%, P < 0.001) than TACE-TP group. Nausea, diarrhea and abdominal pain were more frequent in the HAIC-TP group, while liver dysfunction occurred more common in the TACE-TP group. PSM analysis showed the same results.

Conclusions: In patients with HCC, the combination of HAIC with TKIs and anti-PD-1 immunotherapy is an effective and safe therapeutic regimen over TACE-based combination therapy. A prospective study with a large sample size is needed to validate the efficacy and safety of the combination therapy.

hepatocellular carcinoma

hepatic arterial infusion chemotherapy

tyrosine kinase inhibitors

anti-programmed cell death protein-1 immunotherapy

Hepatocellular carcinoma (HCC), accounting for about 90%, is the most common pathological type of primary liver cancer [1]. Liver resection is the first choice of treatment for patients with early-stage HCC and is associated with survival above 60% at 5 years [1, 2]. For patients at intermediate and advanced stages, transarterial therapies and systemic therapies were recommended [2]. The common transarterial therapies include transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC). TACE is a therapy consisting of intra-arterial chemotherapy and selected embolization, while HAIC is the interventional therapy with administration of chemotherapeutic drug repeatedly without using embolic materials via hepatic arteries [3]. In a recent phase III trial, HAIC was reported to significantly improve overall survival (OS) over TACE in patients with unresectable large HCC [4].

Since variety of factors should be considered in the selection of therapeutic strategy for HCC, including tumor stage, the function of the remaining liver parenchyma, the future liver remnant volume and the patients’ general condition, a multidisciplinary treatment method is needed to improve patients’ outcomes. HAIC-based combination treatment has been proposed and it was reported that HAIC combined with sorafenib, one of the tyrosine kinase inhibitors (TKIs), yielded favorable OS compared with sorafenib alone for patients with advanced HCC [5–8]. Considering the different anti-tumor effect of TKIs, programmed cell death protein-1 (PD-1) inhibitors and HAIC, it may lead to promising treatment efficacy when combining these three therapeutic methods in the treatment for HCC. A combination therapy of Lenvatinib (a TKI), toripalimab (a PD-1 inhibitors) plus HAIC has been reported to have acceptable toxic effects and encouraging antitumor activity in patients with advanced HCC [9, 10].

To investigate the therapeutic efficacy and safety of HAIC combined with TKIs and PD-1 immunotherapy in HCC, we conducted a retrospective analysis of patients with HCC who were treated with this combination therapy and compared with patients with HCC receiving the combination of TACE with TKIs and anti-PD-1 agents in our institution.

Patient cohorts

This was a retrospective study that was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center. The medical records of patients who were diagnosed with unresectable HCC and treated with HAIC combined with TKIs and anti-PD-1 agents (HAIC-TP group) or TACE combined with TKIs and anti-PD-1 agents (TACE-TP group) at the Department of Hepatic Surgery of Fudan University Shanghai Cancer Center were reviewed for eligibility. Patients were included based on the following specific criteria: age ≥ 18 years, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1, Child-Pugh class A/B liver function, at least one measurable intrahepatic lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [11], and adequate organ function [absolute neutrophil count ≥ 1.2 × 10⁹/L, platelet account ≥ 60 × 10⁹/L, total bilirubin (T-BIL) < 30 µmol/L, albumin (ALB) ≥ 30 g/L, aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5 × upper limit of the normal, creatinine clearance rate of ≤ 1.5 × upper limit of the normal, and left ventricular ejection ≥ 45%]. Patients were excluded if they received other interventional therapies before or during the combination therapy. Patients were also excluded if they were diagnosed with other malignant tumors or their medical information and follow-up data were incomplete.

Treatment protocol

The Seldinger technique was used to puncture the femoral artery, and a catheter was inserted into the feeding hepatic artery using digital subtraction angiography guidance. Chemotherapeutic agents (20 mg of Hydroxycamptothecin and 60 mg of Pirarubicin) were injected and then embolization was performed with iodized oil (3-5ml) in the procedure of TACE, while the chemotherapeutic regimen of HAIC (oxaliplatin 85/m² from hour 0 to 2 on day 1; leucovorin 400 mg/m² from hour 2 to 3 on day 1; 5-fluorouracil 400 mg/m² bolus at hour 3; and 2400 mg/m² over 46h on days 1 and 2) was infused via the catheter in the ward. HAIC was repeated every 3 weeks, while whether TACE was repeated depended on the accumulation of iodized oil which was evaluated by plain computed tomography (CT). TKIs [Lenvatinib: a dose of 12 mg/day (for bodyweight ≥ 60 kg) or 8 mg/day (for bodyweight < 60 kg); Apatinib: a dose of 250 mg/day; Donafenib: a dose of 200 mg twice daily] were administered above 1 week prior to the initial interventional therapy, and discontinued from one day before each session of the interventional therapy to the time of withdrawing the catheter. Anti PD-1 agents (Tislelizumab: 200 mg/3 weeks, Sintilimab: 200 mg/3 weeks, Toripalimab: 240 mg/3 weeks) were administrated intravenously within 2 days after the start of the interventional therapy. Dose reduction and treatment interruption depended on disease progression, unacceptable toxicity, patients’ withdrawal of consent or changes of treatment plan and technical difficulties in repeating the interventional therapy. Enhanced CT or magnetic resonance imaging (MRI) was performed to evaluate the therapeutic efficacy every 6 weeks after treatment began.

Data collection and study objectives

Clinical and radiological data for analysis were retrospectively collected from the medical record. The following data were collected and analyzed: age, sex, ECOG PS score, negative or positive of hepatitis B surface antigen (HBV) and hepatitis C antibody (HCV), ⍺-fetoprotein (AFP), albumin-bilirubin (ALBI) grade, ALB, T-BIL, ALT, AST, Child-Pugh class, tumor number, maximum tumor diameter, presence or absence of portal vein tumor thrombus (PVTT) and extrahepatic metastasis, Barcelona Clinic Liver Cancer (BCLC) stage.

The primary endpoints were objective response rate (ORR), defined as the proportion of patients with complete response (CR) or partial response (PR) that was maintained for at least 4 weeks, and disease control rate (DCR), defined as the proportion of patients with ORR plus stable disease (SD). The ORR and DCR were evaluated according to both RECIST version 1.1 and modified RECIST [11, 12]. The second endpoints were progression-free survival (PFS), defined as the time from the commencement of the treatment to progression or death from any cause, and OS, defined as the time from the commencement of the treatment to death from any cause. Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

Propensity-score matching analysis

A PSM analysis was performed to minimize the uneven distribution of covariates in two groups. The matching algorithm included age, sex, ECOG PS score, negative or positive of HBV and HCV, AFP level, ALBI grade, ALB, T-BIL, ALT, AST, Child-Pugh class, tumor number, maximum tumor diameter, presence or absence of PVTT and extrahepatic metastasis, BCLC stage. The “MatchIt” package of R (version 4.1.2) was used for the PSM analysis. Caliper width was 0.05 and the one-to-one match between two groups was obtained by the nearest neighbor matching.

Statistics analysis

The clinicopathological characteristics and AEs of two group were compared using Chi-squared tests or Fisher’s exact tests. The results related to tumor response were analyzed using ordinal logistic regression. PFS and OS were calculated utilizing the Kaplan-Meier method and compared using log-rank tests. Factors with P-value < 0.05 in the univariate analysis were candidates for entry into a multivariable Cox proportional-hazards model. All P values were two-sided, with P values < 0.05 considered significant. SPSS (version 26.0) and R (version 4.1.2) were used to performed the analyses.

Patient characteristics

Between December 2020 and July 2022, 748 HCC patients were enrolled in this study: 302 patients were treated with HAIC combined with TKIs and anti-PD-1 immunotherapy, while 446 patients received the combination of TACE with TKIs and PD-1 inhibitors. The clinicopathological characteristics were shown in Table 1. The patients in the HAIC-TP group were younger than those in the TACE-TP group (median: 54.5 vs. 57.0 years old, P < 0.001). Besides, more patients were classified to ECOG PS 0 or exhibited HBV infection status in the HAIC-TP group (33.8% vs. 21.3%, P < 0.001; 82.1% vs. 74.2%, P = 0.014). Several characteristics of laboratory examination such as AFP (P = 0.002), T-BIL (P = 0.003) and AST (P < 0.001) were significantly different between two groups. Moreover, significant differences were observed in some tumor characteristics, including tumor number (P < 0.001), maximum tumor diameter (P < 0.001), PVTT (P < 0.001) and BCLC stage (P < 0.001).

Table 1

Clinicopathological characteristics before and after PSM.
	before PSM
	HAIC-TP (n = 302)	TACE-TP (n = 446)	P value	HAIC-TP (n = 232)	TACE-TP (n = 232)	P value
Age, years			< 0.001			0.987
<50	105 (34.8)	105 (23.5)		72 (31.0)	73 (31.5)
≥50	197 (65.2)	341 (76.5)		160 (69.0)	159 (68.5)
Sex			0.445			1.000
Male	266 (88.1)	383 (85.9)		202 (87.1)	202 (87.1)
Female	36 (11.9)	63 (14.1)		30 (12.9)	30 (12.9)
ECOG PS			< 0.001			1.000
0	102 (33.8)	95 (21.3)		69 (29.7)	69 (29.7)
1	200 (66.2)	351 (78.7)		163 (70.3)	163 (70.3)
HBV			0.014			0.650
Positive	248 (82.1)	331 (74.2)		185 (79.7)	180 (77.6)
Negative	54 (17.9)	115 (25.8)		47 (20.3)	52 (22.4)
HCV			0.057			0.416
Positive	5 (1.7)	20 (4.5)		5 (2.2)	9 (3.9)
Negative	297 (98.3)	426 (95.5)		227 (97.8)	223 (96.1)
AFP, ng/ml			0.002			0.642
≤400	146 (48.3)	267 (59.9)		123 (53.0)	117 (50.4)
>400	156 (51.7)	179 (40.1)		109 (47.0)	115 (49.6)
ALBI grade			0.087			0.960
1	177 (58.6)	289 (64.8)		142 (61.2)	139 (59.9)
2/3	125 (41.4)	157 (35.2)		90 (38.8)	93 (40.1)
Albumin, g/l			0.950			0.487
<36	57 (18.9)	85 (19.1)		43 (18.5)	50 (21.6)
≥36	245 (81.1)	361 (80.9)		189 (81.5)	182 (78.4)
T-BIL, µmol/L			0.003			1.000
≤17	185 (61.3)	320 (71.7)		154 (66.4)	154 (66.4)
>17	117 (38.7)	126 (28.3)		78 (33.6)	78 (33.6)
ALT, U/L			0.525			1.000
≤50	226 (74.8)	344 (77.1)		173 (74.6)	172 (74.1)
>50	76 (25.2)	102 (22.9)		59 (25.4)	60 (25.9)
AST, U/L			< 0.001			0.924
≤40	104 (34.4)	228 (51.1)		92 (39.7)	90 (38.8)
>40	198 (65.6)	218 (48.9)		140 (60.3)	142 (61.2)
Child-Pugh class			0.133			1.000
A	298 (98.7)	431 (96.6)		229 (98.7)	230 (99.1)
B	4 (1.3)	15 (3.4)		3 (1.3)	2 (0.9)
Tumor number			< 0.001			0.786
Single	9 (3.0)	57 (12.8)		8 (3.4)	6 (2.6)
Multiple	293 (97.0)	389 (87.2)		224 (96.6)	226 (97.4)
Maximum tumor diameter, cm			< 0.001			0.623
≤7	178 (58.9)	326 (73.1)		151 (65.1)	157 (67.7)
> 7	124 (41.1)	120 (26.9)		81 (34.9)	75 (32.3)
PVTT			< 0.001			1.000
Presence	126 (41.7)	90 (20.2)		70 (30.2)	69 (29.7)
Absence	176 (58.3)	356 (79.8)		163 (69.8)	162 (70.3)
Extrahepatic metastases			0.378			0.707
Presence	44 (14.6)	77 (17.3)		36 (15.5)	40 (17.2)
Absence	258 (85.4)	369 (82.7)		196 (84.5)	192 (82.8)
BCLC stage			< 0.001			0.820
B	152 (50.3)	312 (70.0)		143 (61.7)	140 (60.3)
C	150 (49.7)	134 (30.0)		89 (38.4)	92 (39.7)
PSM, propensity score matching; HAIC-TP, hepatic artery infusion chemotherapy combined with tyrosine kinase inhibitor and anti-PD-1 agents; TACE-TP, transarterial chemotherapy combined with tyrosine kinase inhibitor and anti-PD-1 agents; ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; HCV, hepatitis C virus; AFP, ⍺-fetoprotein; ALBI, albumin-bilirubin; T-BIL, Total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PVTT, portal vein tumor thrombus; BCLC stage, Barcelona Clinic Liver Cancer stage

PSM analysis was performed to minimize the bias. After PSM, 232 patients were selected from each of the two groups and there were no significant differences between characteristics of the two groups.

Therapeutic efficacy

The tumor responses were listed in Table 2. Before PSM, the DCR and ORR were significantly higher in the HAIC-TP group than those in the TACE-TP group based on the RECIST criteria (77.8% vs. 47.1%, P < 0.001; 33.1% vs. 7.8%, P < 0.001). According to the mRECIST criteria, HAIC-TP group also exhibited higher DCR and ORR than TACE-TP group (77.8% vs. 47.1%, P < 0.001; 51.4% vs. 17.5%, P < 0.001). After PSM, higher DCR and ORR were observed in the HAIC-TP group based on both RECIST and mRECIST criteria (RECIST: 79.7% vs. 40.1%, P < 0.001; 34.5% vs. 8.6%, P < 0.001; mRECIST: 79.7% vs. 40.1%, P < 0.001; 52.5% vs. 15.9%, P < 0.001). In addition, more patients in the HAIC-TP group were performed curative surgery owing to tumor shrinkage or downstaging either before PSM or after PSM than those in the TACE-TP group (before PSM: 11.3% vs. 1.6, P < 0.001; after PSM: 11.6% vs. 1.7%, P < 0.001). CT or MRI scans of ten representative patients who were treated with the combination of HAIC with TKIs and anti-PD-1 agents were shown in Supplementary Fig. 1.

Table 2

Summary of response before and after PSM.
	before PSM			after PSM
	HAIC-TP (%)	TACE-TP (%)	P value	HAIC-TP (%)	TACE-TP (%)	P value
RECIST	n = 302	n = 446		n = 232	n = 232
CR	0 (0.0)	0 (0.0)	-	0 (0)	0 (0)	-
PR	100 (33.1)	35 (7.8)	< 0.001	80 (34.5)	20 (8.6)	< 0.001
SD	135 (44.7)	175 (39.2)	0.154	105 (45.3)	74 (31.5)	0.002
PD	67 (22.2)	236 (52.9)	< 0.001	47 (20.3)	138 (59.9)	< 0.001
ORR	33.1%	7.8%	< 0.001	34.5%	8.6%	< 0.001
DCR	77.8%	47.1%	< 0.001	79.7%	40.1%	< 0.001
	before PSM			after PSM
	HAIC-TP (%)	TACE-TP (%)	Pvalue	HAIC-TP (%)	TACE-TP (%)	Pvalue
mRECIST	n = 302	n = 446		n = 232	n = 232
CR	9 (3.0)	0 (0.0)	< 0.001	8 (3.4)	0 (0.0)	0.004
PR	143 (47.4)	78 (17.5)	< 0.001	114 (49.1)	37 (15.9)	< 0.001
SD	83 (27.5)	132 (29.6)	0.531	63 (27.2)	56 (24.1)	0.457
PD	67 (22.2)	236 (52.9)	< 0.001	47 (20.3)	139 (59.9)	< 0.001
ORR	51.4%	17.5%	< 0.001	52.5%	15.9%	< 0.001
DCR	77.8%	47.1%	< 0.001	79.7%	40.1%	< 0.001
PSM, propensity score matching; RECIST, Response Evaluation Criteria in Solid Tumors; HAIC-TP, hepatic artery infusion chemotherapy combined with tyrosine kinase inhibitor and anti-PD-1 agents; TACE-TP, transarterial chemotherapy combined with tyrosine kinase inhibitor and anti-PD-1 agents; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, overall response rate; DCR, disease control rate.

Survival outcomes

The follow-up was completed on October 2022. At the time of analysis, there were 67 patients (22.2%) who were evaluated as progression and 37 patients (12.3%) had died in the HAIC-TP group, while 236 (52.9%) patients had disease progression and 156 (35.0%) patients had died in the TACE-TP group. Before PSM, the median PFS and OS in the HAIC-TP group was 17.1 months and not reached, compared with 8.9 months and 14.3 months in the TACE-TP group (P < 0.001; Fig. 1A and 1B). Subgroup analysis showed that except for patients with albumin < 36 g/l or extrahepatic metastases, patients in the HAIC-TP group had better survival outcomes than those in the TACE-TP group (Fig. 1C and 1D). After PSM, the median PFS and OS of the HAIC-TP group was 17.1 months and not reached, which were also significantly longer than those of the TACE-TP group (PFS: 6.9 months, OS: 12.5 months, P < 0.001; Fig. 2A and 2B). Furthermore, patients in the HAIC-TP group exhibited longer survival compared to those in the TACE-TP group in the subgroup analysis (Fig. 2C and 2D).

Univariate and multivariate analysis of survival

Multivariate analysis demonstrated that the independent risk factors for PFS before PSM were type of treatment (HAIC-TP vs. TACE-TP, HR: 0.293, 95% CI: 0.221–0.389; P < 0.001), AFP (≤ 400 vs. >400 ng/ml, HR: 0.631, 95% CI: 0.498-0.800; P < 0.001), maximum tumor diameter (≤ 7 vs. >7 cm, HR: 0.719, 95% CI: 0.563–0.918; P = 0.008), and BCLC stage (B vs. C, HR: 1.362, 95% CI: 1.034–1.793; P = 0.028). Moreover, multivariate analysis showed that type of treatment (HAIC-TP vs. TACE-TP, HR: 0.249, 95% CI: 0.171–0.363; P < 0.001), AFP level (≤ 400 vs. >400 ng/ml, HR: 0.707, 95% CI, 0.523–0.955; P = 0.024), maximum tumor diameter (≤ 7 vs. >7 cm, HR: 0.718, 95% CI: 0.559–0.922; P = 0.002) and BCLC stage (B vs. C, HR: 0.626, 95% CI: 0.429–0.915; P = 0.015) were also the independent risk factors for OS (Supplementary Table S1).

After PSM, type of treatment (HAIC-TP vs. TACE-TP, HR: 0.267, 95% CI: 0.191–0.373; P < 0.001) and AFP (≤ 400 vs. >400 ng/ml, HR: 0.707, 95% CI: 0.526–0.950; P = 0.021) were the independent risk factors for PFS. Furthermore, only type of treatment (HAIC-TP vs. TACE-TP, HR: 0.199, 95% CI: 0.124–0.319; P < 0.001) was the independent risk factor for OS (Table 3).

Table 3

Univariate and multivariate analysis of progression-free survival and overall survival after PSM
	Progression-free survival			Overall survival
	Univariate	Multivariate		Univariate	Multivariate
	P value	HR (95% CI)	P value	P value	HR (95% CI)	P value
Group (HAIC-TP vs. TACE-TP)	< 0.001	0.267 (0.191–0.373)	< 0.001	< 0.001	0.199 (0.124–0.319)	< 0.001
Age (< 50 vs. ≥50)	0.004		0.464	0.070
Sex (Male vs. Female)	0.807			0.565
ECOG PS (0 vs.1)	0.012		0.805	0.070
HBV (Positive vs. Negative)	0.130			0.502
AFP, ng/ml (≤ 400 vs. >400)	0.007	0.707 (0.526–0.950)	0.021	0.131
ALBI grade (1 vs. 2/3)	0.912			0.501
Tumor number (Single vs. Multiple)	0.271			0.885
Maximum tumor diameter, cm (≤ 7 vs. >7)	0.661			0.042		0.134
PVTT (Presence vs. Absence)	0.094			0.945
Extrahepatic metastases (Presence vs. Absence)	0.035		0.364	0.003		0.285
BCLC stage (B vs. C)	0.615			0.007		0.252
PSM, propensity score matching; HR, hazard ratio; CI, confidence interval; HAIC-TP, hepatic artery infusion chemotherapy combined with tyrosine kinase inhibitor and anti-PD-1 agents; TACE-TP, transarterial chemotherapy combined with tyrosine kinase inhibitor and anti-PD-1 agents; ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; AFP, ⍺-fetoprotein; ALBI, albumin-bilirubin; PVTT, portal vein tumor thrombus; BCLC stage, Barcelona Clinic Liver Cancer stage

Safety

No treatment-related death was observed in two groups and the treatment-related AEs were listed in the Supplementary Table S2 and Table 4. Any grade nausea (46.4% vs. 34.3%, P = 0.001; 46.6% vs. 36.6%, P = 0.030), diarrhea (25.2% vs. 13.2%, P < 0.001; 25.4% vs. 15.1%, P = 0.006) and abdominal pain (33.1% vs. 23.8%, P = 0.006; 34.5% vs. 25.0%, P = 0.025) occurred more frequently in the HAIC-TP group than in the TACE-TP group either before or after PSM. Furthermore, more patients in the HAIC-TP group exhibited grade 3/4 diarrhea (4.3% vs. 1.1%, P = 0.011; 4.3% vs. 1.3%, P = 0.049) than in the TACE-TP group. Before PSM, any grade vomiting (28.1% vs. 21.5%, P = 0.047), and grade 3/4 abdominal pain (5.6% vs. 2.5%, P = 0.041) were observed more in the HAIC-TP group. Any grade and grade 3/4 liver dysfunction, including elevated ALT, elevated AST, hyperbilirubinemia and hypoalbuminemia were less frequent in the HAIC-TP group than in the TACE-TP group.

Table 4

Treatment-related Adverse Events after PSM
	HAIC-TP (n = 232), No. (%)		TACE-TP (n = 232), No. (%)		P value
	Any grade	Grade 3/4	Any grade	Grade 3/4	Any grade	Grade 3/4
Neutropenia	68 (29.3)	11 (4.7)	80 (34.5)	9 (3.9)	0.232	0.648
Thrombocytopenia	75 (32.3)	11 (4.7)	72 (31.0)	5 (2.2)	0.765	0.127
Fatigue	131 (56.5)	5 (2.2)	144 (62.1)	3 (1.3)	0.219	0.476
Hypertension	75 (33.1)	8 (3.3)	72 (31.0)	9 (3.9)	0.765	0.805
Weight loss	63 (27.2)	6 (2.6)	66 (28.4)	2 (0.9)	0.756	0.154
Hand foot skin reaction	76 (32.8)	9 (3.9)	70 (30.2)	15 (6.5)	0.549	0.208
Rash	25 (10.8)	2 (0.9)	21 (9.1)	5 (2.2)	0.534	0.253
Nausea	108 (46.6)	15 (6.5)	85 (36.6)	12 (5.2)	0.030	0.552
Vomiting	67 (28.9)	6 (2.6)	56 (24.1)	7 (3.0)	0.247	0.778
Diarrhea	59 (25.4)	10 (4.3)	35 (15.1)	3 (1.3)	0.006	0.049
Abdominal pain	80 (34.5)	15 (6.5)	58 (25.0)	7 (3.0)	0.025	0.081
Sensory neuropathy	33 (14.2)	2 (0.9)	33 (14.2)	3 (1.3)	1.000	0.653
Proteinuria	59 (25.4)	4 (1.7)	40 (17.2)	3 (1.3)	0.031	0.703
Elevated ALT	107 (46.1)	22 (9.5)	146 (62.9)	38 (16.4)	< 0.001	0.027
Elevated AST	100 (43.1)	41 (17.7)	150 (64.7)	56 (24.1)	< 0.001	0.087
Hyperbilirubinemia	83 (35.8)	5 (2.2)	123 (53.0)	14 (6.0)	< 0.001	0.035
Hypoalbuminemia	102 (44.0)	8 (3.4)	138 (59.5)	17 (7.3)	0.001	0.064
Fever	37 (15.9)	5 (2.2)	82 (35.3)	5 (2.2)	< 0.001	1.000
Anemia	80 (34.5)	5 (2.2)	78 (33.6)	1 (0.4)	0.845	0.100
Elevated creatinine	10 (4.3)	1 (0.4)	11 (4.7)	2 (0.9)	0.823	0.562
PSM, propensity score matching; HAIC-TP, hepatic artery infusion chemotherapy combined with tyrosine kinase inhibitor and anti-PD-1 agents; TACE-TP, transarterial chemotherapy combined with tyrosine kinase inhibitor and anti-PD-1 agents; ALT, alanine aminotransferase; AST, aspartate aminotransferase

In this retrospective study, we attained the primary evidence on the superiority of HAIC combined with TKIs and anti-PD-1 immunotherapy over the combination of TACE with TKIs and anti-PD-1 immunotherapy in terms of tumor response and survival outcomes in the treatment for HCC. The multivariate analysis indicated that the type of therapy, AFP, maximum tumor diameter and BCLC stage were the prognostic factors of patients with HCC in our study. The HAIC-based combination treatment exhibited acceptable toxicity. The PSM analysis that mimics randomization of a prospective study and reduces the bias caused by confounding variables was performed to substantiate the credibility of these findings [13].

The transarterial therapies, including HAIC and TACE, play an important role in the treatment for HCC [14]. For those carefully selected cases, such as well-compensated liver disease; asymptomatic patients; no vascular invasion; small volume disease, the benefits of TACE were greatest with median survival exceeding 40 months [15, 16]. However, two clinical trials demonstrated that HAIC yielded significantly better treatment response, better survival outcomes and less AEs than TACE in the treatment for massive unresectable HCC [4, 17]. The combination of HAIC with TKIs and anti-PD-1 inhibitors has been reported to be used as a therapeutic method by previous studies with favorable ORR (63.0%-67.6%), DCR (90.1%-92.6%) and PFS (10.6 months-11.63 months) [9, 10, 18]. Moreover, He et al.[10] reported that 9 (12.7%) patients were converted to curative surgical resection owing to tumor shrinkage after the combination therapy. These might indicate that this combination regimen was effective in the treatment for HCC. In this study, TKIs and anti-PD-1 immunotherapy were combined with HAIC or TACE, and it was observed that both the treatment response and survival outcomes in the HAIC-TP group were significantly better than those in the TACE-TP group. In addition, the same results were also observed in subgroup analysis. The possible reason is that the continuously infusion of chemotherapeutic agents in the procedure of HAIC, which is different from TACE, can provide stable local high concentration of agents in the tumors and thus HAIC can promote the anti-tumor effect of TKIs and anti-PD-1 inhibitors better than TACE. Another possible reason is that tumor hypoxia induced by TACE can lead to the upregulation of hypoxia inducible factor-1 ⍺ (HIF-1⍺), which activates the proangiogenic response including upregulation of the expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), and thus increase tumor angiogenesis and influence local tumor recurrence [19–22]. Moreover, more patients in the HAIC-TP group were performed liver resection because of tumor shrinkage or downstaging than those in the TACE-TP group. This result not only demonstrated HAIC-based combination therapy exhibited better efficacy than TACE-based combination therapy but is the reason that longer PFS and OS were observed in patients of the HAIC-TP group compared to the TACE-TP group.

In multivariate analysis, the treatment method was the prognostic factor of survival outcomes, which further indicated that HAIC-TP group exhibited better therapeutic efficacy than TACE-TP group. Serum AFP level exhibited diagnostic and prognostic value in HCC and was reported to predict the response to systemic therapies and survival after liver transplantation [23–25]. In our study, AFP level was the prognostic factor for survival in HCC patients and patients with AFP ≤ 400 ng/ml were associated with better survival outcomes, which were also reported in the study of He et al.[10]. These results demonstrated the importance of AFP level in treatment and prognosis of HCC. In addition, we identified the prognostic significance of maximum tumor diameter and BCLC stage. Therefore, for patients with HCC receiving HAIC- or TACE-based combination therapy, tumor burden and tumor stage play an important role in the survival outcomes. Further studies were needed to validate the conclusion.

TACE was reported to be associated with more serious AEs compared to HAIC in the treatment for HCC [4, 17]. In our study, patients in the HAIC-TP group had significantly higher frequencies of nausea, vomiting, diarrhea and abdominal pain because of the continuously infusion of chemotherapeutic agents. Thus, it may be appropriate to administer antiemetic agents before the infusion of chemotherapeutic agents, as well as utilize painkillers and reduce the oxaliplatin dose when patients occur abdominal pain. However, more patients in the TACE-TP group had elevated ALT, elevated AST, hyperbilirubinemia and hypoalbuminemia, indicating that TACE-based combination therapy can lead to more damage to liver function. Besides, owing to the embolization by iodized oil in the procedure of TACE, more patients had fever in the TACE-TP group. It is worth noting that the abovementioned treatment related AEs were acceptable and manageable by treatment interruption or dose modification.

There were several limitations in this study. First, the retrospective design of the study means it is prone to a variety of bias. Despite of insignificant difference in the baseline characteristics after PSM, there may still be other unrecognized confounders. Second, patients were treated with a variety of TKIs and PD-1 inhibitors and it was difficult to compare the therapeutic efficacy and AEs in patient receiving combination therapy based on the same TKIs and PD-1 inhibitors. Considering these limitations, more multicenter and large-scale clinical trials were needed to explore the role and the mechanisms of HAIC combined with TKIs and anti-PD-1 immunotherapy in the treatment for HCC.

In summary, our retrospective study showed that for patients with HCC, the combination of HAIC of TKIs and anti-PD-1 immunotherapy was effective and safe therapeutic regimen with better treatment response, longer survival outcomes and acceptable AEs, compared to TACE-based combination therapy. Besides the type of treatment, AFP level, maximum tumor diameter and BCLC stage were the most crucial predictors associated with overall survival.

Funding

This work was jointly supported by National Natural Science Foundation of China (81874182), National Science and Technology Major Project (2018ZX10723204-007-004), Shanghai Municipal Health Bureau (201940043), and Shanghai Hospital Development Center (SHDC12019X19).

Conflicts of interests

The authors have no conflicts of interest to declare.

Author contributions

Conception and design: Lu Wang, Bingran Yu; Development of methodology: Bingran Yu, Lu Wang; Acquisition of data (provided clinical data and clinical samples, etc.): Bingran Yu, Ning Zhang, Lu Wang; Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Bingran Yu, Yixiu Wang, Yun Feng, Yongfa Zhang; Writing, review, and/or revision of the manuscript: Bingran Yu, Ti Zhang, Lu Wang; Administrative technical, or material support (i.e., reporting or organizing data, constructing databases): Lu Wang, Ti Zhang; Study supervision: Bingran Yu, Lu Wang, Ti Zhang

Informed consent

Written informed consent was obtained from all patients for being included in the study.

Ethical approval

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center.

Data availability statement

The data during the current study are available from the corresponding author on reasonable request.

Supplementary Figure 1 CT or MRI scans of ten representative patients who were treated with the combination of HAIC with TKIs and anti-PD-1 agents. (A) Patients 1 achieved partial response based on RECIST and mRECIST criteria. PVTT, portal vein tumor thrombus. (B) Patients 2 achieved partial response based on RECIST and mRECIST criteria. IVCTT, inferior vena cana tumor thrombus. (C) Patients 3 achieved partial response based on RECIST and mRECIST criteria. PVTT, portal vein tumor thrombus. (D) Patients 4 achieved partial response based on RECIST and mRECIST criteria. IVCTT, inferior vena cana tumor thrombus; PVTT, portal vein tumor thrombus. (E) Patients 5 achieved partial response based on RECIST and mRECIST criteria. (F) Patients 6 achieved partial response based on RECIST and mRECIST criteria. (G) Patients 7 achieved partial response based on RECIST and mRECIST criteria. (H) Patients 8 achieved partial response based on RECIST and mRECIST criteria. (I) Patients 9 achieved partial response based on RECIST and mRECIST criteria. (J) Patients 10 achieved partial response based on RECIST and mRECIST criteria.

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No competing interests reported.

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Hepatic Arterial Infusion Chemotherapy Combined with Tyrosine Kinase Inhibitors and PD-1 Inhibitors in Hepatocellular Carcinoma

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