Lenvatinib plus TACE versus Sorafenib plus TACE for advanced hepatocellular carcinoma: A systematic review and meta-analysis

doi:10.21203/rs.3.rs-3579907/v1

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Lenvatinib plus TACE versus Sorafenib plus TACE for advanced hepatocellular carcinoma: A systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-3579907/v1

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Objective

The goal of this systematic review was to compare the effectiveness and safety of the treatment of advanced hepatocellular carcinoma (HCC) with lenvatinib plus transarterial chemoembolization (TACE) versus sorafenib plus TACE.

Method

A comprehensive search was conducted across multiple databases, including PubMed, Web of Science, Cochrane Library, Embase, CNKI, Wangfangdate, and CBM. We computed pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess overall survival (OS), progression-free survival (PFS), and time to progression (TTP). Additionally, we determined pooled risk ratios (RRs) and their 95% CIs to evaluate the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs).

Result

The analysis comprised a total of 7 studies with 682 patients as the sample size. The results of our study indicate that the combination of lenvatinib and TACE demonstrated significantly improved OS (HR = 0.594, 95% CI: 0.484–0.730, p < 0.001), PFS (HR = 0.417, 95% CI: 0.302–0.574, p < 0.001), TTP (HR = 0.603, 95% CI: 0.442–0.824, p = 0.001), ORR (RR = 1.820, 95% CI: 1.272–2.605, p = 0.001), and DCR (RR = 1.333, 95% CI: 1.040–1.708, p = 0.023) compared to the combination of sorafenib and TACE in patients with advanced HCC. Additionally, there was no significant difference found in the overall adverse events of all-grade (RR = 1.054, 95% CI: 0.984–1.128, p = 0.136) and grade 3/4 (RR = 1.062, 95% CI: 0.875–1.289, p = 0.542) between the two groups.

Conclusion

Lenvatinib plus TACE improved OS, PFS, TTP, ORR, and DCR compared with sorafenib plus TACE in advanced HCC with an acceptable safety profile.

hepatocellular carcinoma

lenvatinib

sorafenib

transarterial chemoembolization

meta-analysis

Hepatocellular carcinoma (HCC) is the predominant histological subtype of liver cancer, constituting roughly 90% of liver cancer cases[1] and representing a significant contributor to cancer-related mortality on a global scale[2]. The well-known Barcelona Clinical Liver Cancer (BCLC) staging system determines the therapeutic regimen for people with HCC diagnoses[3]. Most patients are diagnosed with intermediate advanced HCC, precluding the feasibility of radical intervention. Transarterial chemoembolization (TACE) has been established as the preferred treatment modality for individuals diagnosed with BCLC stage B HCC[4]. Nevertheless, the occurrence of hypoxia following embolization has the potential to induce tumor angiogenesis and collateral circulation formation, which may subsequently lead to local tumor recurrence[5, 6].

The integration of TACE with additional locoregional therapeutic modalities or systemic therapy is prioritized in practical clinical settings. Sorafenib, a multi-target tyrosine kinase inhibitor (TKI), was the initial pharmaceutical agent authorized for the therapeutic management of advanced hepatocellular carcinoma (aHCC)[7]. Numerous trials substantiated that the combination of TACE with sorafenib yielded a significant improvement in survival outcomes compared to TACE used as a standalone therapy[8–10]. Nevertheless, only around 30% of patients exhibit a positive response to sorafenib[7, 11], acquired resistance often emerges within six months[11].

Currently, there is a growing interest in the novel oral multikinase inhibitor Lenvatinib. The findings of REFLECT research indicate that lenvatinib was comparable to sorafenib in terms of overall survival (OS). Additionally, the lenvatinib arm exhibited statistically significant improvements in all secondary efficacy measures when compared to sorafenib[12]. As a result, lenvatinib has been granted approval as an alternative first-line treatment for aHCC in various countries.

It is anticipated that the concurrent administration of TACE with lenvatinib will confer supplementary advantages in terms of patient survival. Multiple clinical trials have been conducted to evaluate the efficacy of lenvatinib plus TACE versus sorafenib plus TACE in patients with aHCC[13–16]. However, the findings from these trials have not yet provided compelling and adequate data to support a survival advantage. Although a similar meta-analysis was published by Liu[17], the sample size of studies included in this meta is small and lacking the study by Xu[18] et al. Moreover, the study was not registered with PROSPERO. Therefore, we conducted this meta-analysis to assess the efficacy and safety of TACE combined with levatinib versus TACE combined with sorafenib in patients diagnosed with unresectable HCC.

This systematic review and meta-analysis was performed in conformity to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Additionally, the protocol of the study was submitted to the PROSPERO (CRD42023438814).

Inclusion and exclusion criteria

The inclusion criteria were as follows:

studies comparing lenvatinib plus TACE with sorafenib plus TACE in advanced HCC patients

the study design was limited to randomized control trials (RCTs), retrospective or prospective cohort studies, and case-control studies

studies reporting at least one evaluable survival outcome

The exclusion criteria were as follows:

sample size less than 10 patients

duplicate studies and studies reporting incomplete or inconsistent outcomes

article type: case report, review, conference abstract, and cell or animal study.

Search Strategy and Study Selection

A comprehensive review of the existing literature was conducted by searching many databases, including the Cochrane Library, PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Chinese Biological Medicine (CBM) Database, Wanfang Database, and Wipro Periodicals Chinese Journal Platform. The search was undertaken until August 2023. The main search terms were “lenvatinib,” “sorafenib,” “transarterial chemoembolization,” “TACE,” “advanced,” “hepatocellular carcinoma,” and “HCC.” Two researchers independently screened the retrieved studies according to the inclusion and exclusion criteria set beforehand, with disagreements revolved by group discussion with a third researcher.

Data Extraction

Two investigators (LM and DP) independently made the study selection. If there were any differences between them, the third author (ZH) would discuss them together. The following information was collected: study characteristics (first author, publication year, study design, country), patients and tumor characteristics (number of patients for each group, age, gender, Eastern Cooperative Oncology Group Performance Status [ECOG] score, Barcelona Clinic Liver Cancer [BCLC] stage, albumin-bilirubin [ALBI] grade, maximum tumor size, HBV/HCV virology status, Child-Pugh score, α-fetoprotein [AFP] level, portal vein tumor thrombus [PVTT], extrahepatic spread), treatment protocols and outcomes (OS, progression-free survival [PFS], time to progression [TTP], objective response rate [ORR], disease control rate [DCR], adverse events [AEs]). The HRs and their corresponding 95% confidence intervals (CIs) were obtained directly from the articles or calculated from the Kaplan-Meier curves using Engauge Digitizer version 4.1.

Quality Assessment

The Cochrane Risk of Bias Tool was employed in order to evaluate the methodological rigor of randomized controlled trials (RCTs). This assessment was based on several key criteria, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, handling of incomplete outcome data, selective reporting, and identification of any other potential biases. Each assessment involves the application of three levels of judgment: high (indicating a high risk of bias), low (indicating a low risk of bias), and unclear (indicating an uncertain risk of bias). The outcomes were plotted and evaluated using Review Manager 5.3. The assessment of the methodological quality of the observational study was conducted using a modified version of the Newcastle-Ottawa scale (NOS).

Statistical analysis

Combined hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for the effects of lenvatinib plus TACE versus sorafenib plus TACE on OS, PFS, and TTP. The results of ORR, DCR, and AEs were reported as combined risk ratios (RRs) with their respective 95% confidence intervals (95% CIs). Heterogeneity was assessed using Cochran’s Q test and I2 statistics, with I2 values of more than 25%, 50%, and 75% representing low, medium, and high heterogeneity, respectively. If the heterogeneity was not significant (I2 < 50% and p > 0.10), a fixed-effects model (FEM) was used. Conversely, if the heterogeneity was found to be significant, the random-effects model (REM) was utilized. Sensitivity analyses were performed in order to examine the impact of each individual study on the overall estimate of effect size. Publication bias was tested by Begg’s and Egger’s tests. All p -values were two-sided, and p < 0.05 was considered statistically significant. All analyses were performed with STATA, version 15.0.

Search results

We identified 218 studies through the database search, 103 of which were duplicate studies. 29 articles were discarded after reviewing their abstracts or titles. The remaining articles were reviewed based on our inclusion criteria. Following reading the full text, 79 studies were further excluded for the following reasons: different intervention (n = 8), non-comparative studies (n = 12), insufficient data (n = 17), full text unavailable (n = 19), failed quality assessment (n = 23). Ultimately, 7 eligible studies (1 RCT[16] and 6 observational studies[13–15, 18–20]), including 682 patients, were included in the current meta-analysis. Figure 1 depicts the flow chart for the literature selection procedure.

Study Characteristics

In our meta-analysis, a total of 304 patients underwent the combination therapy of lenvatinib and TACE, and 378 received the combination therapy of sorafenib and TACE. Table 1 presents an overview of the key attributes pertaining to the studies and patients that were included in the analysis. All studies were published between 2020 and 2023. Five studies were conducted in China, while the remaining two were carried out in Japan and Korea, respectively. The sample sizes of the studies included in the analysis varied from 64 to 150 participants.

Quality Assessment

As detailed in the Cochrane Handbook, one RCT was evaluated with the Cochrane Risk of Bias Tool (Fig. 2). Because of problems such as treatment and ethics, double blindness is difficult to achieve in studies of this type. Furthermore, given the conditions of the patients, their own constitutions, their familial situations, and other factors, the selection bias in allocation cannot be disregarded. The six cohort studies were assessed with the NOS (Table 2). The scores of these studies are all greater than or equal to 6 points.

Table 2

The Newcastle-Ottawa Scale (NOS) quality assessment of the eligible studies in the meta-analysis.
First author	Year of publication	Selection				Comparability	Outcome			Total score
First author	Year of publication	Representativeness of the exposed cohort	Selection of the non-exposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was not present at start of study	Comparability of cohorts on the basis of the design or analysis	Assessment of outcome	Was follow-up long enough for outcomes t ooccur	Adequacy of follow u pof cohorts
XUE M	2021	✮	✮	✮	✮	✮✮	✮	✮	✮	9
XU R	2023	✮	✮	✮	✮	✮	✮	-	-	6
SHIMOSE S	2020	✮	✮	✮	✮	✮	✮	-	✮	7
LEE J	2020	✮	✮	✮	✮	✮	✮	✮	✮	8
YANG B	2021	✮	✮	✮	✮	✮	✮	✮	✮	8
ZHANG J X	2022	✮	✮	✮	✮	✮	✮	✮	✮	8

Primary Endpoints: ORR and OS

The primary outcome measures for this meta-analysis were the ORR and OS. The ORR was reported in all seven investigations, which included 682 patients. Moderate heterogeneity was identified among the trials (p = 0.008, I2 = 65.2%); hence, a random-effects model was employed to conduct the meta-analysis. Meta-analysis showed that lenvatinib plus TACE was associated with a significantly higher ORR than sorafenib plus TACE (RR = 1.820, 95% CI: 1.272–2.605, p = 0.001) (Fig. 3A).

Six studies[13, 15, 16, 18–20] including 596 patients, compared the OS between the patients who received lenvatinib plus TACE and sorafenib plus TACE. No statistically significant heterogeneity was found among the trials (p = 0.136, I2 = 40.5%). Therefore, a fixed-effects model was employed for the meta-analysis. The pooled HR demonstrated that the lenvatinib plus TACE group had a significantly better OS than the sorafenib plus TACE group (HR = 0.594, 95% CI: 0.484–0.730, p < 0.001) (Fig. 3B).

Secondary Endpoints: DCR, PFS, TTP, and AEs

Secondary outcome measures included the DCR, PFS, TTP, and AEs. All of the studies analyzed the outcome of DCR. A meta-analysis by pooling seven studies showed the lenvatinib plus TACE group was superior to the sorafenib plus TACE group in terms of the DCR (RR = 1.333, 95% CI: 1.040–1.708, p = 0.023; I2 = 89.9%), with high heterogeneity. A random-effects model was used (Fig. 3C).

Five studies[14, 15, 18–20] were pooled for the analysis of PFS. The pooled HR demonstrated that patients receiving lenvatinib plus TACE showed significantly longer PFS than patients receiving sorafenib plus TACE (HR = 0.417, 95% CI: 0.302–0.574). The heterogeneity analysis suggested moderate heterogeneity between studies (I2 = 52.5%, p = 0.077). A random-effects model was used (Fig. 3D).

A total of two investigations[13, 16] documented the TTP outcome. We observed no heterogeneity among the trials (p = 0.456, I2 = 0.0%). Consequently, a fixed-effects model was employed for the meta-analysis. The combined findings demonstrated a significant increase in TTP among patients who were administered lenvatinib in conjunction with TACE (HR = 0.603, 95% CI: 0.442–0.824, p = 0.001) (Fig. 3E).

Four studies[13, 16, 19, 20] provided data on the occurrence of AEs of any grade and severe grade 3/4 AEs. In contrast, two studies[14, 15] solely presented information on the incidence of severe grade 3/4 AEs, while one study[18] exclusively reported the occurrence of AEs of any grade. The occurrence of all-grade anemia (RR = 4.000, 95% CI: 1.246–12.842, p = 0.020), hypertension (RR = 1.439, 95% CI: 1.072–1.933, p = 0.015), anorexia or reduced appetite (RR = 1.266, 95% CI: 1.044–1.535, p = 0.016), ascites (RR = 1.989, 95% CI: 1.117–3.541, p = 0.020), and proteinuria (RR = 2.645, 95% CI: 1.445–4.841, p = 0.002) was notably greater in the lenvatinib plus TACE group compared to the sorafenib plus TACE group. Conversely, the frequency of all-grade fever (RR = 0.826, 95% CI: 0.693–0.984, p = 0.033) and hand-foot skin reactions (RR = 0.752, 95% CI: 0.570–0.994, p = 0.045) was significantly higher in the sorafenib plus TACE group (Table 3). The occurrence of hypertension (RR = 3.030, 95% CI: 1.473–6.231, p = 0.003) and proteinuria (RR = 6.118, 95% CI: 1.771–21.138, p = 0.004) was found to be higher in the lenvatinib plus TACE group compared to the sorafenib plus TACE group, as observed in the grade 3/4 adverse events. However, the incidence of hand-foot skin reactions was significantly lower in the lenvatinib plus TACE group (RR = 0.478, 95% CI: 0.264–0.866, p = 0.015) (Table 3). In addition, comparing the total number of adverse events for all-grade (RR = 1.054, 95% CI: 0.984–1.128, p = 0.136) and grade 3/4 (RR = 1.062, 95% CI: 0.875–1.289, p = 0.542) demonstrated that there was no statistically significant differences in adverse events caused by the two treatment regimens.

Table 3

Adverse events
	All grades adverse events							Grade 3/4 adverse events
		Lenvatinib + TACE group		Sorafenib + TACE group					Lenvatinib + TACE group		Sorafenib + TACE group
	No.	Event	Noevent	Event	Noevent	RR (95%CI)	p	No.	Event	Noevent	Event	Noevent	RR (95%CI)	p
Hematology
Decreased WBC/NEUT/PLT count	7	71	248	74	347	1.266 (0.946–1.694)	0.112	6	12	264	13	367	1.271 (0.589–2.743)	0.541
Anemia	1	12	20	3	29	4.00 (1.246–12.842)	0.020	1	0	32	0	32	-	-
Cardiovascular system
Hypertension	5	72	165	61	228	1.439 (1.072–1.933)	0.015	6	24	258	10	346	3.030 (1.473–6.231)	0.003
Constitutional symptoms
Fatigue	4	87	91	124	108	0.915 (0.755–1.108)	0..362	4	9	171	13	231	0.939 (0.410–2.147)	0.881
Hoarseness	2	9	82	2	87	4.401 (0.978–19.805)	0.054	2	1	90	0	89	2.945 (0.121–71.095)	0.508
Fever	3	62	39	142	49	0.826 (0.693–0.984)	0.033	3	15	120	24	167	0.884 (0.482–1.621)	0.691
Weight loss	2	17	65	15	117	1.824 (0.965–3.451)	0.064	2	0	82	1	131	0.534 (0.022–12.958)	0.670
Pain	1	29	24	24	35	1.345 (0.907–1.994)	0.140	1	6	47	6	53	1.113 (0.382–30242)	0.844
Dermatologic events
Hand-foot skin reaction	5	58	179	94	195	0.752 (0.570–0.994)	0.045	6	14	268	37	319	0.478 (0.264–0.866)	0.015
Alopecia	5	25	71	24	76	1.085 (0.668–1.763)	0.742	1	0	53	0	59	-	-
Rash	5	27	210	35	254	0.941 (0.587–1.508)	0.800	4	1	193	6	242	0.213 (0.026–1.755)	0.151
Gastrointestinal events
Digestive tract reaction	1	22	21	19	22	1.104 (0.711–1.715)	0.659						-	-
Anorexia / Decreased appetite	3	85	50	95	96	1.266 (1.044–1.535)	0.016	5	9	184	11	288	1.268 (0.535–3.002)	0.590
Nausea and/or vomiting	5	92	134	119	161	0.958 (0.778–1.180)	0.685	5	11	215	10	270	1.363 (0.589–3.151)	0.469
Diarrhea	5	62	175	64	225	1.181 (0.872–1.601)	0.283	6	12	270	13	343	1.165 (0.540–2.514)	0.697
Abdominal pain	2	65	17	97	35	1.079 (0.928–1.254)	0.325	2	13	69	19	113	1.101 (0.575–2.019)	0.771
Cholecystitis	1	0	59	1	56	0.322 (0.013–7.750)	0.485	1	0	59	1	56	0.322 (0.013–7.750)	0.485
Hepatic function
Liver dysfunction	2	32	61	51	90	0.9651 (0.666–1.358)	0.784	1	4	46	6	94	1.333 (0.394–4.511)	0.644
Elevated ALT/AST	4	102	74	108	72	0.966 (0.812–1.149)	0.695	6	14	150	27	261	0.566 (0.303–1.055)	0.073
Hyperbilirubinemia	2	27	64	25	64	1.021 (0.646–1.612)	0.930	3	6	128	2	142	3.224 (0.662–15.698)	0.147
Decreased serum albumin	1	23	9	15	17	1.533 (1.000-2.352)	0.05	1	1	31	0	32	3.000 (0.127–70.997)	0.496
Ascites	2	21	61	17	115	1.989 (1.117–3.541)	0.020	3	3	124	4	181	1.093 (0.249–4.799)	0.907
Hepatic encephalopathy	1	2	30	1	31	2.000 (0.191–20.969)	0.563	2	4	71	3	84	1.547 (0.358–6.691)	0.560
Liver abscess	1	1	58	0.	57	2.900 (0.121–69.749)	0.512	1	0	59	0	57	-	-
Renal function
Bleeding	1	5	54	3	54	1.610 (0.403–6.428)	0.500	2	2	102	2	108	1.058 (0.152–7.372)	0.955
Proteinuria	2	23	59	14	118	2.645 (1.445–4.841)	0.002	4	13	157	3	237	6.118 (1.771–21.138)	0.004
Others
Oral ulcer	2	4	108	3	113	1.381 (0.316–6.032)	0.668	2	1	111	0	116	3.106 (0.128–75.456)	0.486
Hypothyroidism	2	12	73	8	83	1.606 (0.690–3.736)	0.272	2	0	84	0	91	-	-
Infection	1	5	27	4	28	1.250 (0.369–4.234)	0.720	1	5	27	4	28	1.250 (0.369–4.234)	0.720
Total		1052	2328	1242	2962	1.054 (0.984–1.128)	0.136		180	3566	215	4537	1.062 (0.875–1.289)	0.542

Subgroup analysis

Subsequently, multiple subgroup analyses were conducted in order to investigate the comparative DCR of levatinib plus TACE in comparison to sorafenib plus TACE. These subgroup analyses were stratified based on various factors, including the research design method (retrospective or prospective), whether the study was a randomized controlled trial (RCT) or not, the country where the study was conducted, the sample size, the type of TACE embolic material used, the Child-Pugh grade, and whether the patients had been previously treated or not. As Table 4 shows, there were no subgroups in which statistically significant differences between the groups were observed.

Table 4

HRs for DCR by subgroup
parameters	No. of studies	Cases	HR (95% CI) of PFS	P	I²(%)	Ph	Effect model
Research design method (retrospective vs. Prospective)
Retrospective	5	538	1.377 (1.133–1.672)	0.001	63.6	0.027	Random
Prospective	2	140	1.164 (0.694–1.951)	0.565	92.4	0.000	Random
Research design method (RCT or not)
RCT	1	64	1.381 (1.050–1.817)	0.021	-	-	-
Non-RCT	6	618	1.329 (1.004–1.760)	0.047	91.2	0.000	Random
Country
China	5	486	1.184 (0.973–1.440)	0.092	81.5	0.000	Random
non-China	2	196	1.868 (1.186–2.942)	0.007	60.7	0.111	Random
Sample size
༜100	4	336	1.494 (0.806–1.769)	0.202	96.6	0.000	Random
≥ 100	3	346	1.207 (1.060–1.374)	0.004	0.0	0.560	Fixed
TACE embolic material
Drug-eluting beads (DEB)	1	150	1.118 (0.910–1.373)	0.289	-	-	-
Embosphere	2	148	1.282 (1.075–1.530)	0.006	0.0	0.488	Fixed
Gelatin sponge particle	2	174	1.256 (0.757–2.743)	0.568	97.4	0.000	Random
Polyvinyl alcohol particle	1	112	1.330 (1.044–1.693)	0.021	-	-	-
unknown	1	98	2.460 (1.436–4.215)	0.001	-	-	-
Child-Pugh grade
A/B	5	486	1.184 (0.973–1.440)	0.092	81.5	0.000	Random
A	2	196	1.868 (1.186–2.942)	0.007	60.7	0.111	Random
Previously treated or not
TACE	2	196	1.868 (1.186–2.942)	0.007	60.7	0.111	Random
none	4	374	1.150 (0.938–1.410)	0.179	79.6	0.002	Random
unknown	1	112	1.333 (1.040–1.708)	0.021	-	-	-

Sensitivity Analysis

To analyze the source of heterogeneity, we performed a sensitivity analysis of the DCR. The combined results did not change significantly after sensitivity analysis with the removal of one study at a time, which indicated that our conclusions were relatively stable (Fig. 4). The causes of heterogeneity may be related to the different sample sizes of the included studies, the different types of study designs, the diverse techniques and protocols employed during the TACE procedure, and the different baseline characteristics of the patients.

Publication Bias

Begg’s funnel plot and Egger’s test were performed to detect publication bias. As shown in Fig. 5, p values of Begg’s test and Egger’s test were 0.452 and 0.765, respectively. The funnel diagram was roughly symmetrical, indicating that the comprehensive analysis results were unlikely to be wrong due to publication bias.

The prevalence of HCC has exhibited a consistent upward trend, with a majority of HCC patients being diagnosed at intermediate (BCLC stage B) or advanced (BCLC stage C) stages, where curative interventions are no longer viable. Treatment of such patients suggests local therapy (e.g., TACE) in combination with systemic therapy (e.g., TKI or immunotherapeutic agents)[21]. On the one hand, The TACE procedure involves the utilization of chemotherapeutic medications and embolic agents to impede the blood supply to the tumor. This results in the occurrence of tumor ischemia and hypoxia, which effectively hinder the growth of the tumor and facilitate the processes of tumor necrosis and apoptosis[22]. On the other hand, the occurrence of hypoxia following embolization has the potential to induce increased expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)[6, 23]. TKIs target VEGF, which inhibits tumor revascularization and slows tumor progression. At present, lenvatinib and sorafenib are widely acknowledged as standard treatments for BCLC stage B HCC[12, 24].

Sorafenib targets VEGF[25], the TACTICS trial found that sorafenib in combination with TACE improved PFS (25.2 vs. 13.5 months) and ORR (71.3% vs. 61.8%) in patients with unresectable hepatocellular carcinoma (uHCC) (18 at BCLC stage C)[8]. However, activation of FGF family members weakens Sorafenib's antitumor activeness, thereby escaping anti-VEGF therapy[26]. Levatinib, a novel oral multikinase inhibitor targeting VEGFR 1–3, FGFR 1–4, platelet-derived growth factor receptor (PDGFR) α, as well as proto-oncogenes RET and KIT[27], possesses both anti-angiogenic and direct anti-tumor effects[28]. Its application has eliminated the original position of sorafenib as the only first-line TKI therapy for advanced HCC[29]. Compared to sorafenib, lenvatinib involves a unique mechanism of action with distinct inhibition of the FGF/FGF receptor pathway and stronger inhibition of the VEGF/VEGF receptor pathway[30, 31]. The FGF signaling pathway is critical in cancer angiogenesis and is considered to underlie the escape mechanism of anti-VEGF drugs[28]. Furthermore, other signaling pathways with pro-angiogenic effects, such as PDGF, another inhibitory pathway unaffected by sorafenib, provide potential escape mechanisms[32]. The combination of lenvatinib with TACE maximizes inhibition of tumor neovascularization and enhances anti-tumor activity to a greater extent[30]. The variances in the specific kinases that sorafenib and lenvatinib target, as well as the varying levels of intensity with which they act, have the potential to exacerbate the disparities in treatment outcomes among HCC patients who undergo transarterial therapy. Moreover, lenvatinib demonstrates anti-tumor efficacy through the synergistic modulation of effector T cell function within the tumor microenvironment (TME) and the reciprocal regulation of tumor vascular normalization[33]. The modulation of the TME induced by lenvatinib has the potential to enhance the effectiveness of TACE therapy. The results of the phase III REFLECT trial showed an OS of 13.6 and 12.3 months for lenvatinib and sorafenib, respectively, with patients in the lenvatinib group demonstrating longer TTP (8.9 vs. 3.7 months), PFS (7.2 vs. 4.6 months), and higher ORR (21.4% vs. 9.2%) compared to sorafenib[34, 35]. Nevertheless, previous meta-analyses have had small sample sizes, inadequate search strategies, and a number of high-quality studies have been published in recent years. To the extent of our knowledge, our study is the most comprehensive meta-analysis that includes high-quality studies with clinical relevance through sound quality assessment and subgroup analyses.

The study reported the pooled analyses of seven studies (one RCT and six observational studies) that compared lenvatinib plus TACE with sorafenib plus TACE for advanced HCC patients. The findings from our meta-analysis indicate that lenvatinib plus TACE resulted in a significant improvement in OS (HR = 0.594, 95% CI: 0.484–0.730, p < 0.001), PFS (HR = 0.417, 95% CI: 0.302–0.574, p < 0.001), TTP (HR = 0.603, 95% CI: 0.442–0.824, p = 0.001), ORR (RR = 1.820, 95% CI: 1.272–2.605, p = 0.001), and DCR (RR = 1.333, 95% CI: 1.040–1.708, p = 0.023) when compared to sorafenib plus TACE. With the exception of the absence of heterogeneity in the pooled TTP analysis (I2 = 0.0%), the studies examining OS, PFS, ORR, and DCR demonstrated moderate to high levels of heterogeneity. The application of meta-regression analyses was not feasible due to the inclusion of fewer than 10 studies in the meta-analysis. Subgroup analyses were employed in order to investigate the origins of heterogeneity. Given the restricted number of studies included, it is advisable to exercise caution when interpreting the results. The subgroup analyses conducted for DCR, utilizing the research design method, country, sample size, TACE embolic material, Child-Pugh grade, and previous treatment status as variables, did not yield statistically significant results. Our hypothesis posits that the observed heterogeneity could potentially be attributed to variations in the baseline characteristics of the participants, different drug doses as well as the diverse techniques employed during the TACE procedure. A uniform dosage regimen was administered to the majority of patients across the seven studies. Specifically, sorafenib was administered at an initial dose of 400 mg twice daily, while lenvatinib was administered at a dose of 12 mg once daily for patients weighing 60 kg or more and 8 mg once daily for patients weighing less than 60 kg. Nevertheless, the exact dosing regimen will need to be decided on a patient-by-patient basis. The utilization of a novel TACE technique involves the incorporation of a balloon, drug-eluting beads (DEB), and advanced micro-catheters that exhibit enhanced drug absorption and release rates when compared to conventional iodine oil and gelatin granules[36, 37]. The validation of these results is currently hindered by the limited number of studies available. Yet, future research in this area, once more abundant, will provide additional support and enhance the credibility of these findings. The reliability of the current findings was confirmed through the implementation of sensitivity analyses. Additional research is required to validate the most effective TACE embolic material, determine the appropriate dosage regimen for lenvatinib or sorafenib, and establish the optimal treatment sequence for combination therapy.

The safety profile observed in our study regarding the combination of TACE and lenvatinib is in line with the established safety profile of TACE and sorafenib in comparable patient cohorts, and no novel safety signals were detected. The group of patients who received lenvatinib in combination with TACE exhibited a lower incidence of hand-foot skin reactions and fatigue of any severity while experiencing a higher occurrence of anemia, hypertension, decreased appetite or anorexia, ascites, proteinuria, and grade 3/4 hypertension and proteinuria in comparison to the group of patients who were treated with sorafenib plus TACE. Among them, hand-foot skin reactions and hypertension were mainly associated with lenvatinib or sorafenib treatment. The observed variations in these effects could potentially be attributed to the distinctive structural characteristics and divergent drug targets of sorafenib and lenvatinib. While other common AEs, such as fever, pain, and elevated ghrelin/glutamine aminotransferase, were mainly associated with the TACE procedure. Furthermore, we discovered a significantly higher incidence of ascites in the lenvatinib plus TACE group, indicating that lenvatinib has greater hepatotoxicity. This is consistent with the results of a previous study that reported a decline in liver function in patients with advanced HCC for a period of time (4 weeks, particularly within 2 weeks) after starting levatinib[38]. Most AE symptoms disappeared after dose reduction and symptomatic treatment. As several trials combine multikinase inhibitors and immune checkpoint inhibitors, safety concerns with lenvainib will become more prominent. The majority of the adverse events in this study were mild to moderate, and no deaths were reported. Overall, there was no significant difference between the two groups in all-grade (RR = 1.054, 95% CI: 0.984–1.128, p = 0.136) or grade 3/4 (RR = 1.062, 95% CI: 0.875–1.289, p = 0.542) AEs, indicating that the safety of the two treatment regimens was comparable, which were resolved or eliminated with appropriate and timely management. Long-term antitumor therapy requires close monitoring of liver function to prevent liver injury, and TACE combined with lenvatinib is feasible with close monitoring of liver function.

The present meta-analysis exhibits several limitations. The present study incorporated a limited number of studies, specifically seven in total, consisting of one RCT and six observational studies. The RCT was an open-label study with a high risk of bias and was prone to biasing the results. Consequently, the overall quality of the evidence can be considered relatively modest. Furthermore, it is worth noting that all the studies included in our meta-analysis were sourced exclusively from Asian regions, with a significant proportion (five studies) originating specifically from China. Given that HCC in China is commonly linked to HBV, as opposed to the prevalence of hepatitis C (HCV) infection in Western nations, it is important to note that the findings of this meta-analysis may not be generalizable to other populations. The credibility of the findings may be subject to scrutiny due to the varied post-disease progression follow-up procedures and the limited number of primary studies included in the subgroup analysis. Finally, both the Risk of Bias Tool and the NOS Scale are subject to researcher subjectivity in the quality assessment process, and survival statistics derived from Kaplan-Meier curves through the use of Engauge Digitizer may exhibit a certain degree of bias, notwithstanding meticulous data handling. In summary, lenvatinib plue TACE has the advantage of prolonging the survival of patients with advanced HCC compared with sorafenib plus TACE. It is imperative to conduct further high-quality randomized controlled trials and studies encompassing diverse racial populations in order to facilitate a more comprehensive comparison between the efficacy of lenvatinib plus TACE and sorafenib plus TACE for HCC.

For patients with advanced HCC, both lenvatinib plus TACE and sorafenib plus TACE are safe and well-tolerated treatments. In terms of OS, PFS, TTP, ORR, and DCR, lenvatinib plus TACE may be significantly superior to sorafenib plus TACE. However, given the limitations of this study, additional prospective studies are required to confirm these findings.

Acknowledgements and Funding Information

This work was supported by Xuzhou Medical Key Talent Cultivation Project [XWRCHT20220068]; Innovation Team Project of Xuzhou Medical University Hospital Development Fund [XYFC2021001]; and Surface Project [XYFM2021014].

Authors Contribution

Conception and design: Z.H., L.M., H.L., D.P., X.Q.,Y.G., X.M; (II) Administrative support: Z.H.; (III) Provision of study materials or patients: L.M., D.P., H.L., A.Y.; (IV) Collection and assembly of data: L.M., H.L., D.P.,D.L., X.Z.; (V) Data analysis and interpretation:L.M. ; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Abbreviations

TACE, transarterial chemoembolization; LEN, lenvatinib; SOR, sorafenib; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinical Liver Cancer; AFP, α-fetoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; OS, overall survival;PFS, progression-free survival; TTP, time to progression.

Data Availability

(II) The original contributions presented in the study are included in the article / Supplementary Material. Further inquiries can be directed to the corresponding authors.

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Table 1 is available in the Supplementary Files section.

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Lenvatinib plus TACE versus Sorafenib plus TACE for advanced hepatocellular carcinoma: A systematic review and meta-analysis

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Quality Assessment

Primary Endpoints: ORR and OS

Secondary Endpoints: DCR, PFS, TTP, and AEs

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