Transarterial chemoembolization combined with lenvatinib and sintilimab vs lenvatinib alone in intermediate-advanced hepatocellular carcinoma

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC) is the most common form of liver cancer that has limited treatment options and a poor prognosis. Transarterial chemoembolization (TACE) is the first-line treatment for intermediate-stage HCC but can induce tumour hypoxia, thereby promoting angiogenesis. Recent studies suggested that combining TACE with anti-angiogenic therapies and immunotherapy might improve efficacy. Lenvatinib, a tyrosine kinase inhibitor, has demonstrated superior outcomes compared to sorafenib, while immune checkpoint inhibitors such as sintilimab show potential when combined with TACE. However, the efficacy and safety of TACE combined with lenvatinib and sintilimab (TACE + SL) compared to TACE with lenvatinib alone (TACE + L) in patients with intermediate-advanced HCC has not yet been investigated.

AIM

To evaluate the efficacy and safety of TACE + SL therapy in comparison to TACE + L therapy in patients with intermediate-advanced HCC.

METHODS

A retrospective analysis was performed on patients with intermediate-advanced HCC who received TACE plus lenvatinib with or without sintilimab between September 2019 and September 2022. Baseline characteristics were compared, and propensity score matching was applied. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were evaluated between the two groups, and adverse events were analyzed.

RESULTS

The study included 57 patients, with 30 in the TACE + SL group and 27 in the TACE + L group. The TACE + SL group demonstrated significantly improved median PFS and OS compared to the TACE + L group (PFS: 14.1 months vs 9.6 months, P = 0.016; OS: 22.4 months vs 14.1 months, P = 0.039), along with a higher ORR (70.0% vs 55.6%). After propensity score matching, 30 patients were included, with the TACE + SL group again showing longer median PFS and a trend toward improved OS (PFS: 14.6 months vs 9.2 months, P = 0.012; OS: 23.9 months vs 16.3 months, P = 0.063), and a higher ORR (73.3% vs 53.3%). No severe adverse events were reported.

CONCLUSION

TACE + SL demonstrated superior outcomes in terms of OS and PFS, compared to TACE + L. These findings suggest that the addition of sintilimab might enhance the therapeutic response in patients with intermediate-advanced HCC.

Key Words: Hepatocellular carcinoma; Transarterial chemoembolization; Sintilimab; Lenvatinib; Immunotherapy; Programmed cell death 1; Prognosis

Core Tip: This study evaluates the efficacy and safety of combining transarterial chemoembolization (TACE) with lenvatinib and sintilimab compared to TACE with lenvatinib alone in patients with intermediate-advanced hepatocellular carcinoma. The results indicate that TACE with lenvatinib and sintilimab significantly improves overall survival (22.4 months vs 14.1 months) and progression-free survival (14.1 months vs 9.6 months), with a higher objective response rate (70% vs 55.6%). Notably, no severe adverse events were reported, suggesting that the combination therapy is effective and safe. These findings support the inclusion of sintilimab in hepatocellular carcinoma treatment regimens.

INTRODUCTION

Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is a leading cause of cancer-related mortality worldwide[1,2]. Due to its usually asymptomatic in its early stages, HCC is frequently diagnosed at advanced stages, resulting in limited therapeutic options and a poor prognosis. Transarterial chemoembolization (TACE) is the recommended first-line treatment for intermediate-stage HCC[3]; however, it can induce tumour hypoxia, promoting angiogenesis and tumour progression[4]. Recent studies indicate that combining TACE with anti-angiogenic therapy and immunotherapy can improve treatment efficacy for advanced HCC[5]. Lenvatinib, a tyrosine kinase inhibitor, is approved as a first-line treatment for HCC and has demonstrated superior outcomes compared to sorafenib[6,7]. Additionally, the combination of immune checkpoint inhibitors, including programmed cell death 1 (PD-1) inhibitors such as sintilimab, with TACE has demonstrated promising results across various solid tumours, including liver cancer[8-13]. Sintilimab, with a favourable safety profile compared to other treatments, has shown efficacy in clinical trials, improving overall survival (OS) and objective response rates (ORRs) in patients with advanced HCC, making it a compelling choice for combination therapy in this population[14]. The effectiveness of combining TACE, lenvatinib, and immunotherapy (e.g., sintilimab) in patients with intermediate-advanced HCC remains uncertain. This retrospective study aims to evaluate the potential benefits and prognostic impact of this combination therapy in improving patient outcomes. Specifically, the efficacy and safety of combining TACE with lenvatinib and sintilimab (TACE + SL) and TACE combined with lenvatinib alone (TACE + L) were compared.

MATERIALS AND METHODS

Patients

This retrospective analysis included all patients with intermediate-advanced HCC treated at the First Affiliated Hospital of Nanjing Medical University who received TACE plus lenvatinib, with or without sintilimab, between September 2019 and September 2022. The study was approved by the Institutional Ethics Review Boards and conducted in accordance with the World Medical Association Declaration of Helsinki. Inclusion criteria were Barcelona Clinic Liver Cancer (BCLC) stage B or C, Child-Pugh class A5, A6, or B7, Eastern Cooperative Oncology Group performance status ≤ 1, at least one assessable lesion, and ≥ 1 cycle of TACE plus lenvatinib with/without sintilimab. Exclusion criteria included < 1 month of lenvatinib or sintilimab treatment, secondary primary malignancies, follow-up < 6 months, incomplete clinical data, or loss to follow-up. Informed consent was waived due to the retrospective nature of the study.

TACE procedure

TACE was initiated before the administration of lenvatinib and sintilimab. A percutaneous femoral or radial artery approach was used for intubation, followed by angiography to identify the tumour-feeding artery. Chemoembolization was performed using super-selective emulsions of epirubicin and iodised oil via microcatheters, followed by the injection of gelatine sponge fragments to embolise the blood vessels supplying the tumour. Post-TACE syndrome was recorded, and liver function indicators were assessed within 1 week of each TACE treatment.

Lenvatinib and sintilimab administration

Lenvatinib was administered orally at a daily dose of 12 mg for patients weighing ≥ 60 kg or 8 mg for those weighing < 60 kg. Sintilimab was administered intravenously at a dose of 200 mg within 1 week of the initial TACE procedure, followed by subsequent doses every 3 weeks. In the event of severe adverse events (AEs), sintilimab and lenvatinib doses were adjusted through dose reduction, suspension, or discontinuation to ensure patient safety and manage treatment-related toxicities.

Follow-up and assessment

Patients were followed up every 6-8 weeks until the end of the study (June 30, 2023) or death. Follow-up assessments included routine physical examinations, laboratory blood tests, and contrast-enhanced computed tomography/magnetic resonance imaging scans to monitor treatment-related AEs. Tumour progression was assessed using the modified Response Evaluation Criteria in Solid Tumours. OS was defined as the time from treatment initiation to death from any cause or the most recent follow-up. Progression-free survival (PFS) was measured from treatment initiation to the date of disease progression. The ORR was calculated as the sum of complete responses and partial responses, while the disease control rate (DCR) included complete responses, partial responses, and stable disease.

Statistical analyses

All statistical analyses were performed using IBM SPSS Statistics 26 software and R 4.1.2 software. Propensity score matching (PSM) was applied to minimize selection bias and reduce the influence of potential confounding factors. Due to the small sample size, continuous variables were dichotomised to ensure comparability between the groups. Baseline variables were compared using the χ² test or Fisher’s exact test for categorical variables, and the Student’s t-test or Mann-Whitney U test for quantitative data, as appropriate. Survival analysis was conducted using the Kaplan-Meier method, with the log-rank test used to compare survival curves between groups. Univariate Cox regression analysis was performed, and factors with a P-value of < 0.2 were included in the multivariate regression using a backward stepwise selection approach (P < 0.05 for significance). A P-value of < 0.05 was considered statistically significant.

RESULTS

Patients’ characteristics

This study enrolled 57 patients with HCC who met the inclusion criteria between September 2019 and September 2022 (Figure 1). The patients were divided into two groups: The TACE + SL group (n = 30) and the TACE + L group (n = 27), with ages ranging from 37 years to 80 years. The median follow-up duration was 19.2 months for the TACE + SL group and 17.5 months for the TACE + L group. Table 1 presents the clinical characteristics of the patients. PSM at a 1:1 ratio yielded 15 matched pairs. After matching, no statistically significant differences were observed in baseline characteristics between the two groups.

Figure 1 Flow diagram of patient enrollment. HCC: Hepatocellular carcinoma; TACE: Transarterial chemoembolization; BCLC: Barcelona Clinic Liver Cancer.

Table 1 Patient characteristics before and after propensity score matching.

Characteristic		Before PSM			After PSM
		TACE + L	TACE + SL	P value	TACE + L	TACE + SL	P value
Gender				1.00			1.00
	Female	3	3		2	1
	Male	24	27		13	14
Age (year)				0.66			1.00
	≥ 60	16	15		8	8
	< 60	11	15		7	7
ECOG				1.00			0.43
	0	7	8		3	6
	1	20	22		12	9
Etiology				0.49			0.65
	HBV	22	21		13	11
	Other	5	9		2	4
Cirrhosis				1.00			1.00
	No	4	4		2	2
	Yes	23	26		13	13
Tumor number				0.35			0.71
	≥ 3	11	17		6	8
	< 3	16	13		9	7
Tumor size (cm)				0.43			1.00
	≥ 7	8	13		4	5
	< 7	19	17		11	10
PVTT				0.05			1.00
	No	22	16		11	11
	Yes	5	14		4	4
Metastases				1.00			0.33
	No	23	26		11	14
	Yes	4	4		4	1
BCLC				0.03			1.00
	B	22	15		11	11
	C	5	15		4	4
Child-Pugh class				1.00			1.00
	A	25	27		14	15
	B	2	3		1	0
AFP (ng/mL)				0.00			1.00
	≥ 100	2	17		2	2
	< 100	25	13		13	13

PSM: Propensity score matching; TACE + L: Transarterial chemoembolization with lenvatinib alone; TACE + SL: Transarterial chemoembolization combined with lenvatinib and sintilimab; ECOG: Eastern Cooperative Oncology Group; PVTT: Portal vein tumour thrombosis; BCLC: Barcelona Clinic Liver Cancer; AFP: Alpha-fetoprotein; HBV: Hepatitis B virus.

Efficacy outcomes

Before PSM, the median OS was 22.4 months for the TACE + SL group and 14.1 months for the TACE + L group (P = 0.039). The median PFS for the TACE + SL group was 14.1 months, compared to 9.6 months for the TACE + L group (P = 0.016) (Figure 2A and B). After PSM, the median OS for the TACE + SL group increased to 23.9 months, while it was 16.3 months for the TACE + L group (P = 0.063). The median PFS remained consistent, with 14.6 months in the TACE + SL group and 9.2 months in the TACE + L group (P = 0.012) (Figure 2C and D). The 1-year and 2-year survival rates for the TACE + SL group were 93.3% and 40.0%, respectively, compared to 80.0% and 13.3% in the TACE + L group (Table 2).

Figure 2 Kaplan-Meier survival for overall survival. A and B: Kaplan-Meier survival for overall survival and progression-free survival before propensity score matching; C and D: Kaplan-Meier survival for overall survival and progression-free survival after propensity score matching. Yellow and blue areas: Confidence intervals. S + L: Sintilimab and lenvatinib; L: Lenvatinib.

Table 2 Tumor response at 1 year based on modified response evaluation criteria in solid tumors, n (%).

	Unmatched group		Matched group
	TACE + L (n = 27)	TACE + SL (n = 30)	TACE + L (n = 15)	TACE + SL (n = 15)
CR	4 (14.8)	6 (20.0)	1 (6.7)	2 (13.3)
PR	11 (40.7)	15 (50.0)	7 (46.7)	9 (60.0)
SD	2 (7.4)	6 (20.0)	1 (6.7)	3 (20.0)
PD	10 (37.0)	3 (10.0)	6 (40.0)	1 (6.7)
ORR	15 (55.6)	21 (70.0)	8 (53.3)	11 (73.3)
DCR	17 (63.0)	27 (90.0)	9 (60.0)	14 (93.3)
1-year OS	19 (70.4)	26 (86.7)	12 (80)	14 (93.3)

TACE + L: Transarterial chemoembolization with lenvatinib alone; TACE + SL: Transarterial chemoembolization combined with lenvatinib and sintilimab; CR: Complete response; PR: Partial response; SD: Stable response; PD: Progressive disease; ORR: Objective response rate; DCR: Disease control rate; OS: Overall survival.

Tumour responses

Table 3 presents the tumour responses based on modified Response Evaluation Criteria in Solid Tumours. Before PSM, three patients (10.0%) in the TACE + SL group experienced disease progression, resulting in an ORR of 70.0% and a DCR of 90.0%. In contrast, 10 patients (37.0%) in the TACE + L group experienced disease progression, yielding an ORR of 55.6% and a DCR of 63.0%. After PSM, one patient (6.7%) in the TACE + SL group experienced disease progression, with an ORR of 73.3% and a DCR of 93.3%. Conversely, six patients (40.0%) in the TACE + L group experienced disease progression, leading to an ORR of 53.3% and a DCR of 60.0%. The ORR and DCR in the TACE + SL group were consistently higher than those in the TACE + L group before and after PSM.

Table 3 Treatment-related adverse events, n (%).

Adverse events	TACE + SL (n = 30)			TACE + L (n = 27)
Toxicity grade	/	1/2	3/4	/	1/2	3/4
Diarrhea	6 (20.0)	4	2	5 (18.5)	3	2
Transaminitis	14 (46.7)	12	2	13 (48.1)	8	5
Hand-foot skin reactions	10 (33.3)	7	3	7 (25.9)	6	1
Nausea with/without vomiting	23 (76.7)	20	3	17 (63.0)	15	2
Abdominal pain	22 (73.3)	18	4	22 (81.5)	19	3
Fatigue	9 (30.0)	6	3	7 (25.9)	5	2
Fever	23 (76.7)	20	3	17 (63.0)	15	2
Decreased WBC/PLT count	7 (23.3)	5	2	9 (33.3)	7	2
Thrombopenia	8 (26.7)	7	1	3 (11.1)	2	1
Decreased appetite	5 (16.7)	5	0	8 (30.0)	8	0
Hypertension	12 (40.0)	9	3	7 (26.0)	4	3
Hypothyroidism	7 (23.3)	6	1	/	/	/
Proteinuria	0 (0.0)	0	0	1 (3.7)	0	1

TACE + L: Transarterial chemoembolization with lenvatinib alone; TACE + SL: Transarterial chemoembolization combined with lenvatinib and sintilimab; WBC: White blood cell; PLT: Platelet.

Subgroup analysis

The subgroup analyses of factors associated with OS and PFS are presented in Supplementary Figure 1. The TACE + SL regimen demonstrated significantly longer PFS and OS among subgroups of patients with hepatitis B virus infection, absence of distant metastases, BCLC stage B, Child-Pugh class A, and alpha-fetoprotein (AFP) levels of ≤ 100 ng/mL.

Safety outcomes

AEs occurring during treatment were evaluated and classified according to the Common Terminology Criteria for AEs version 5.0, considering their frequency and severity (Table 2). No treatment-related deaths were reported, and all observed toxicities were manageable. In the TACE + SL group, the most commonly reported AEs during TACE included nausea (76.7%), abdominal pain (73.3%), and fever (76.7%). During the administration of lenvatinib and sintilimab, the most common AEs were hand-foot syndrome (33.3%) and hypertension (40.0%). These AEs were generally categorized as mild to moderate.

DISCUSSION

This study evaluated the efficacy and safety of the TACE + SL regimen with the TACE + L regimen in treating patients with intermediate-advanced HCC. Our findings indicate that the TACE + SL regimen was associated with improved OS and PFS compared to the TACE + L regimen. These results suggest that the addition of lenvatinib and sintilimab to TACE might offer enhanced therapeutic benefits for patients with intermediate-advanced HCC. The improved outcomes observed in the TACE + SL group could be attributed to several factors. Firstly, lenvatinib, a multi-kinase inhibitor, has demonstrated efficacy as a first-line therapy for unresectable HCC[7,15,16]. Lenvatinib targets multiple angiogenic and oncogenic pathways, resulting in tumour regression and prolonged survival. By combining lenvatinib with TACE, the anti-tumour effect of TACE might be augmented, potentially inhibiting tumour progression[17-19]. Secondly, sintilimab, an anti-PD-1 monoclonal antibody, has shown promising efficacy across various cancers, including HCC[11,20]. By blocking the PD-1/programmed death ligand-1 interaction, sintilimab enhances the immune response, thereby restoring the anti-tumour immune response. When used in combination with TACE, sintilimab might further enhance immune-mediated tumour cell elimination, thereby improving overall treatment response.

Before PSM, baseline differences between the two groups, including portal vein tumour thrombosis (PVTT), BCLC stage, and AFP levels, could have influenced treatment outcomes. It is well established that PVTT, BCLC stage C, and elevated AFP levels are associated with poor prognosis in patients with HCC. Despite having a higher proportion of patients with PVTT, more advanced BCLC stages, and elevated AFP levels, the TACE + SL group exhibited longer OS and PFS compared to the TACE + L group. Subgroup analyses further suggested that the TACE + SL regimen might offer better prognostic outcomes, particularly among patients with hepatitis B virus infection, absence of distant metastases, BCLC stage B, Child-Pugh class A, and AFP ≤ 100 ng/mL. However, given the small sample size, the robustness of these subgroup results might be limited. After PSM, which balanced baseline characteristics between the two groups, no statistically significant difference in median OS was observed between the TACE + SL and TACE + L groups (P = 0.063). This lack of significance may be attributable to the small sample size and the fact that more patients in the TACE + SL group had not yet reached the endpoint due to a shorter follow-up period. However, the TACE + SL group demonstrated superior median PFS compared to the TACE + L group, suggesting the potential for longer OS in further studies. Patients with PVTT, BCLC stage C, and higher AFP levels might benefit more from the TACE + SL regimen compared to the TACE + L regimen. Therefore, large-scale clinical trials and mechanistic studies are required shortly.

The safety profile of the TACE + SL regimen was manageable, with no treatment-related deaths reported. The most common AEs reported during treatment included nausea, abdominal pain, fever, hand-foot syndrome, and hypertension. These AEs were generally mild to moderate in severity and did not significantly affect the patient’s overall well-being. These findings align with those of previous studies on combination therapies for intermediate-advanced HCC[21,22]. Appropriate management and monitoring of these AEs were implemented throughout the study to ensure patient safety and optimize treatment outcomes. This study has certain limitations. First, the retrospective design and relatively small sample size might affect the generalizations and robustness of the findings. To enhance the reliability of these results, future investigations should include larger, multicentre cohorts with extensive follow-up periods, providing more comprehensive data on the long-term efficacy and safety of the combined TACE + SL regimen and strengthening the evidence base for this therapeutic approach. Second, the focus on patients with intermediate-advanced HCC raises concerns about the applicability of the findings to individuals with early-stage disease. Future research should investigate the efficacy and safety of the TACE + SL regimen across different stages of HCC, including early-stage patients. This could involve stratifying populations by disease stage and using randomized controlled trials to draw more definitive conclusions. Addressing these limitations will contribute to a more nuanced understanding of treatment modalities for HCC in subsequent studies.

CONCLUSION

In conclusion, our study demonstrated that the TACE + SL regimen is a promising treatment option for patients with intermediate-advanced HCC. The addition of lenvatinib and sintilimab to TACE improved OS and PFS compared to TACE combined with lenvatinib alone.

ACKNOWLEDGEMENTS

The authors thank the support of Yan Shen for patient recruitment and Zhong-Ling Pei for patient data aggregation. The authors also consulted Hai-Feng Zhou on analytical methodology. The authors thank patients with intermediate-advanced hepatocellular carcinoma at the First Affiliated Hospital of Nanjing Medical University for their immense contribution to this study.