Abstract
Background:
The benefits of transarterial chemoembolization (TACE) plus lenvatinib in advanced hepatocellular carcinoma (HCC) remain controversial. Therefore, we performed a meta-analysis to evaluate the efficacy and safety of TACE plus lenvatinib in the treatment of advanced HCC.
Methods:
Up to February 26, 2023, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang were searched, and clinical studies of TACE plus lenvatinib (experimental group) versus TACE or lenvatinib (control group) in the treatment of advanced HCC were included. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included literature. Revman5.4 software was used for meta-analysis.
Results:
A total of 1855 patients were included in 18 studies. The results of the meta-analysis showed that TACE plus lenvatinib could increase the objective response rate (ORR) (odds ratio [OR] = 3.25, 95% confidence interval [CI]: 2.46–4.31; OR = 3.55, 95%CI: 2.53–4.97) and disease control rate (DCR) (OR = 3.27, 95%CI: 2.44–4.38; OR = 3.45, 95%CI: 2.28–5.24), 12-month (OR = 3.43, 95%CI: 2.08–5.65; OR = 2.78, 95%CI: 1.90–4.05) and 18-month (OR = 2.97, 95%CI: 1.77–5.00; OR = 2.62, 95%CI: 1.54–4.47) progression-free survival (PFS) rate, 12-month (OR = 2.34, 95%CI: 1.53–3.58; OR = 3.64, 95%CI: 2.65–5.01) and 18-month (OR = 2.27, 95%CI: 1.48–3.48; OR = 3.23, 95%CI: 2.33–4.48) overall survival (OS) rate compared with TACE or lenvatinib alone. In addition, the experimental group could significantly reduce the expression levels of serum alpha-fetoprotein (AFP) (standard mean difference [SMD] = 1.22, 95%CI: 0.67–1.78) and vascular endothelial growth factor (VEGF) (SMD = 1.27, 95%CI: 0.87–1.67). In terms of adverse events of drugs, the incidence of grade ≥ 3 hypertension and elevated aspartate aminotransferase and alanine aminotransferase in the experimental group was higher than that in the control group (P < .05).
Conclusion:
Compared with TACE or lenvatinib alone, TACE plus lenvatinib has achieved remarkable efficacy in patients with advanced HCC, and the efficacy versus risk need to be carefully balanced in clinical application.
Keywords: hepatocellular carcinoma, lenvatinib, meta-analysis, transarterial chemoembolization
1. Introduction
According to the annual statistics of GLOBOCAN 2020, hepatocellular carcinoma (HCC) has become the sixth most common malignant tumor in the world with the third highest mortality rate.[1] HCC often has an insidious onset and rapid progression. Clinically, more than 70% of patients are already in the advanced stage when diagnosed, which means that they have lost the opportunity to undergo radical surgery.[2] Transarterial chemoembolization (TACE) is a common method for the treatment of advanced HCC, which mainly blocks the blood supply vessels of the tumor through the infusion of chemotherapy drugs, resulting in the necrosis of tumor cells due to ischemia and hypoxia.[3] However, clinical studies have shown that TACE can not completely kill tumor cells, and may stimulate vascular endothelial growth factor (VEGF) in the residual lesions and induce tumor angiogenesis.[4] Lenvatinib is an oral small-molecule multikinase inhibitor that effectively inhibits tumor proliferation and tumor angiogenesis, and has been approved as a first-line therapy for advanced HCC in several countries.[5] In recent years, there are many reports about TACE combined with lenvatinib in the treatment of advanced HCC, but the conclusions of its efficacy and safety are not completely consistent. Therefore, we conducted a meta-analysis to systematically evaluate the efficacy and safety of TACE plus lenvatinib in the treatment of advanced HCC, to provide an evidence-based basis for clinically rational drug use.
2. Materials and methods
2.1. Publication search
This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.[6] The systematic literature search was performed through PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang Database, covering all articles published up to February 26, 2023. The following keywords were used to retrieve articles: “hepatocellular carcinoma,” “liver neoplasms,” “liver cancer,” “chemoembolization, therapeutic,” “transcatheter arterial chemoembolization,” “transarterial chemoembolization,” “TACE,” and “lenvatinib.” References of the retrieved publications were also screened. The search strategy for PubMed is described as follows:
#1 “Liver Neoplasms” [Mesh]
#2 “Neoplasms, Liver” OR “Liver Cancer” OR “Hepatic Neoplasm” OR “Hepatic Cancer” OR “hepatocellular carcinoma” OR “Hepatocellular Cancer” OR “Hepatocellular Neoplasm” OR “Cancer of Liver” [Title/ Abstract]
#3 #1 OR #2
#4 “Chemoembolization, Therapeutic” [Mesh]
#5 “Therapeutic Chemoembolization” OR “transcatheter arterial chemoembolization” OR “transarterial chemoembolization” OR “TACE” [Title/ Abstract]
#6 #4 OR #5
#7 “lenvatinib” [Title/ Abstract]
#8 #3 AND #6 AND #7
Other database databases use similar search formulas.
2.2. Literature inclusion and exclusion criteria
2.2.1. Inclusion criteria.
Participants: Advanced HCC patients who have lost the opportunity for radical surgery; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; expected survival time more than 3 months; No previous systemic therapy.
Type of study: Prospective or retrospective clinical study.
Intervention: The experimental group was treated with TACE plus lenvatinib, and the control group was treated with TACE or lenvatinib alone.
Outcome indicators: Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) rate, overall survival (OS) rate, expression levels of serum alpha-fetoprotein (AFP) and VEGF, and grade ≥ 3 adverse events. The results were divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) according to the modified Response Evaluation Criteria in Solid Tumors. The ORR was calculated as the sum of the CR and PR rates. The DCR was calculated as the sum of the CR, PR, and SD rates.
2.2.2. Exclusion criteria.
Reviews, case reports, conference abstracts, and repeated studies; single-arm studies without control groups; studies with incomplete data and unable to obtain original data.
2.3. Data extraction and literature quality evaluation
Data were independently screened, extracted, and cross-checked by 2 authors (DLL and PZ). If there is any disagreement in the process, the decision will be made through discussion or by referring to the opinions of the third author (SQL). The extracted data mainly include first author name, country, year of publication, Barcelona clinic liver cancer (BCLC) stage, sample size, age, chemo embolic drugs and dose, oral dose of lenvatinib, treatment cycle, and outcome indicators. If there is a lack of important information in the study, try to contact the first author or corresponding author by email to further obtain unpublished data. The Cochrane risk of bias tool[7] was used to evaluate the quality of each randomized controlled trial (RCT) included. The risk of bias was evaluated from 7 items: selection bias (random sequence generation, allocation concealment), performance bias, detection bias, attrition bias, reporting bias, and other biases. Each item was classified as “low risk of bias,” “unclear risk of bias,” and “high risk of bias.” In addition, the Newcastle-Ottawa scale[8] was used to evaluate the quality of the included retrospective study. Studies with a maximum of 9 stars and a score of more than 5 stars were judged to be of high quality, based on 3 parameters of selection, comparability, and outcome.
2.4. Statistical analysis
Statistical analyses were performed using the Review Manager version 5.4 software. For dichotomous data, odds ratio (OR) and 95% confidence intervals (CI) were used as evaluation indexes. For continuous variables, standard mean difference (SMD) and 95% CI were used for effect pooled analysis. All P values were 2-sided, and P < .05 was considered statistically significant. The heterogeneity was tested by Q and I2 tests. When the heterogeneity exists (I2 > 50% or P < .1), the random-effects model was used for a meta-analysis, otherwise, the fixed-effects model was used. Sensitivity analysis was carried out by removing each study in turn. Potential publication bias was assessed by visual examination of the funnel plots.
3. Results
3.1. Literature search and study characteristics
A total of 573 articles were retrieved, and 244 repeated articles were excluded by title, year of publication, and author information. Then after reading abstracts and full-text screening, 311 articles that did not meet the criteria were excluded and finally included 18 studies[9–26] (Fig. 1). There were 1855 patients with advanced HCC, of which 902 patients received TACE plus lenvatinib, and 953 patients received TACE or lenvatinib alone.
Figure 1.
Literature screening flow chart.
The quality evaluation of the included studies is shown in Tables 1 and 2. The characteristics of the included studies are summarized in Table 3. Of these, thirteen studies are TACE plus lenvatinib vs TACE alone, and the other 5 studies are TACE plus lenvatinib vs lenvatinib alone.
Table 1.
The methodological quality of the included randomized controlled trials were assessed using the Cochrane “Risk of Bias” tool.
| Study | Selection bias | Performance bias | Detection bias | Attrition bias | Reporting bias | Other bias | |
|---|---|---|---|---|---|---|---|
| Random sequence generation | Allocation concealment | ||||||
| ZW Peng 2022 | + | ? | + | + | + | + | ? |
| MY Zhong 2022 | ? | ? | ? | ? | + | + | ? |
| M Zhang 2022 | + | ? | ? | ? | + | + | ? |
| FQ Zhang 2022 | ? | ? | ? | ? | + | + | ? |
| X Huang 2020 | + | ? | ? | ? | + | + | ? |
? = unclear risk of bias; + = low risk of bias; - = high risk of bias.
Table 2.
The included retrospective cohort studies were scored according to the NOS scale.
| Category | Entries | Study | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ① | ② | ③ | ④ | ⑤ | ⑥ | ⑦ | ⑧ | ⑨ | ⑩ | ⑪ | ⑫ | ⑬ | ||
| Representation of the exposure cohort | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | |
| Section | Representation of the non-exposed cohort | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ |
| Determination of exposure | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | |
| No outcome event occurred before the study began | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | |
| Comparability | Comparability of cases and controls on the basis of the design and analysis |
☆ ☆ |
☆ ☆ |
☆ ☆ |
☆ ☆ |
☆ | ☆ ☆ |
☆ ☆ |
☆ | ☆ | ☆ | ☆ | ☆ | ☆ |
| Results determination method | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | |
| Outcome | Adequate follow-up time | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ||||||
| Complete follow-up | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | |
| Total scores | 9 | 9 | 8 | 9 | 8 | 9 | 9 | 7 | 8 | 7 | 7 | 7 | 7 | |
①YX Chen 2022; ②Ando 2021; ③QY Xie 2022; ④WZ Fan 2022; ⑤ZG Fu 2021; ⑥DD Xia 2022; ⑦Kuroda 2022;
⑧LK Dong 2022; ⑨J Liu 2022; ⑩HY Wang 2020; ⑪N Ai 2022; ⑫YH Liu 2022; ⑬B Li 2022.
NOS = Newcastle-Ottawa scale.
Table 3.
Basic characteristics of included literature.
| Study | Country | Study type | Intervention | Sample size | Gender (male/female) | Age (Yr) | Child-Pugh class: A/B | ECOG score: 0–1/2 | BCLC stage: B/C | Hepatitis B virus | Outcome indicators |
|---|---|---|---|---|---|---|---|---|---|---|---|
| YX Chen 2022 | China | RCS | TACE + Lenvatinib vs TACE | 34 68 |
33/1 66/2 |
60.1 ± 10.8 61.4 ± 11.8 |
31/3 65/3 |
27/7 57/11 |
NA | 31 58 |
①②③④⑥ |
| Ando 2021 | Japan | RCS | TACE + Lenvatinib vs Lenvatinib | 19 19 |
18/1 17/2 |
74 (46–84) 72 (57–88) |
19/0 19/0 |
NA | 19/0 19/0 |
NA | ①②③④⑥ |
| QY Xie 2022 | China | RCS | TACE + Lenvatinib vs TACE | 53 51 |
41/12 38/13 |
56.6 ± 5.7 56.8 ± 5.7 |
42/11 39/12 |
NA | NA | 45 42 |
①②④⑤⑥ |
| WZ Fan 2022 | China | RCS | TACE + Lenvatinib vs Lenvatinib | 78 78 |
70/8 71/7 |
51 ± 10 51 ± 11 |
66/12 64/14 |
78/0 78/0 |
0/78 0/78 |
67 67 |
①②④⑥ |
| ZW Peng 2022 | China | RCT | TACE + Lenvatinib vs Lenvatinib | 170 168 |
139/31 132/36 |
54 (46–64) 56 (48–63) |
170/0 168/0 |
170/0 168/0 |
NA | 148 144 |
①②③④⑥ |
| ZG Fu 2021 | China | RCS | TACE + Lenvatinib vs TACE | 60 60 |
50/10 55/5 |
60 (25–76) 60 (33–81) |
56/4 57/3 |
NA | 33/25 26/31 |
48 48 |
①②③④⑥ |
| DD Xia 2022 | China | RCS | TACE + Lenvatinib vs Lenvatinib | 58 58 |
NA | NA | NA | 58/0 58/0 |
NA | NA | ①②③④⑥ |
| Kuroda 2022 | Japan | RCS | TACE + Lenvatinib vs Lenvatinib | 63 63 |
51/12 53/10 |
70.4 ± 9.6 69.6 ± 8.9 |
56/7 57/6 |
63/0 63/0 |
27/36 32/31 |
11 15 |
③④⑥ |
| LK Dong 2022 | China | RCS | TACE + Lenvatinib vs TACE | 26 26 |
16/10 17/9 |
51.0 ± 8.8 52.1 ± 8.7 |
18/8 15/11 |
NA | 13/13 15/11 |
NA | ①②⑤ |
| J Liu 2022 | China | RCS | TACE + Lenvatinib vs TACE | 52 51 |
48/4 43/8 |
53.5 ± 12.0 50.0 ± 12.7 |
38/14 43/8 |
39/13 38/13 |
8/44 8/43 |
NA | ①②③④ |
| HY Wang 2020 | China | RCS | TACE + Lenvatinib vs TACE | 30 30 |
23/7 25/5 |
65.6 ± 5.5 65.3 ± 5.9 |
NA | NA | 21/9 20/10 |
NA | ①②⑤⑥ |
| N Ai 2022 | China | RCS | TACE + Lenvatinib vs TACE | 23 23 |
18/5 16/7 |
53.1 ± 12.1 54.2 ± 11.8 |
9/14 8/15 |
17/6 18/5 |
9/14 11/12 |
20 19 |
①② |
| MY Zhong 2022 | China | RCT | TACE + Lenvatinib vs TACE | 30 30 |
28/2 26/4 |
43.5 ± 7.8 40.3 ± 6.4 |
24/6 26/4 |
NA | NA | NA | ①②⑤ |
| M Zhang 2022 | China | RCT | TACE + Lenvatinib vs TACE | 48 48 |
41/7 39/9 |
56.1 ± 10.3 54.4 ± 8.3 |
48/0 48/0 |
NA | NA | NA | ①② |
| YH Liu 2022 | China | RCS | TACE + Lenvatinib vs TACE | 54 50 |
34/20 37/13 |
59.2 ± 10.4 58.4 ± 9.4 |
NA | NA | NA | NA | ①② |
| FQ Zhang 2022 | China | RCT | TACE + Lenvatinib vs TACE | 40 40 |
32/8 31/9 |
56.3 ± 5.6 55.3 ± 6.3 |
NA | NA | 22/18 21/19 |
NA | ①②⑤ |
| B Li 2022 | China | RCS | TACE + Lenvatinib vs TACE | 34 60 |
19/15 33/27 |
69.2 ± 3.2 69.2 ± 3.3 |
20/14 34/26 |
NA | NA | NA | ①②④⑤ |
| X Huang 2020 | China | RCT | TACE + Lenvatinib vs TACE | 30 30 |
20/10 21/9 |
56.5 ± 5.6 56.3 ± 5.3 |
NA | NA | NA | NA | ①② |
AFP = alpha-fetoprotein, BCLC = Barcelona clinic liver cancer, DCR = disease control rate, ECOG = eastern cooperative oncology group, NA = not available, ORR = objective response rate, OS = overall survival, PFS = progression-free survival, RCT = randomized controlled trial, RCS = retrospective cohort study, TACE = transarterial chemoembolization, VEGF = vascular endothelial growth factor.
①=ORR, ②=DCR, ③=PFS, ④=OS, ⑤=AFP and (or) VEGF, ⑥= grade ≥ 3 adverse events.
3.2. ORR
Seventeen studies[9–15,17–26] provided ORR data, of which thirteen studies[9,11,14,17–26] were TACE plus lenvatinib vs TACE alone, and the other 4 studies[10,12,13,15] were TACE plus lenvatinib vs lenvatinib alone. Based on the heterogeneity test results (P = .89, I2 = 0%; P = .21, I2 = 33%). Fixed-effects model analysis showed that the ORR of patients with advanced HCC in the TACE plus lenvatinib group was significantly higher than that in the TACE or lenvatinib group (OR = 3.25, 95%CI: 2.46–4.31, P < .00001; OR = 3.55, 95%CI: 2.53–4.97, P < .00001). See Figure 2.
Figure 2.
ORR forest plot of the experimental group versus the control group. ORR = objective response rate.
3.3. DCR
Seventeen studies[9–15,17–26] provided DCR data, of which thirteen studies[9,11,14,17–26] were TACE plus lenvatinib vs TACE alone, and the other 4 studies[10,12,13,15] were TACE plus lenvatinib vs lenvatinib alone. Based on the heterogeneity test results (P = .70, I2 = 0%; P = .17, I2 = 44%). Fixed-effects model analysis showed that the DCR of patients with advanced HCC in the TACE plus lenvatinib group was significantly higher than that in the TACE or lenvatinib group (OR = 3.27, 95%CI: 2.44–4.38, P < .00001; OR = 3.45, 95%CI: 2.28–5.24, P < .00001). See Figure 3.
Figure 3.
DCR forest plot of the experimental group versus the control group. DCR = disease control rate.
3.4. PFS rate
Seven studies[9,10,13–16,18] provided 6-month, 12-month, and 18-month PFS rate data, of which 3 studies[9,14,18] were TACE plus lenvatinib versus TACE alone, and the other 4 studies[10,13,15,16] were TACE plus lenvatinib versus lenvatinib alone. The results of the heterogeneity test showed that the heterogeneity among the studies was small (P > .1, I2 < 50%). Fixed-effects model analysis showed that compared with TACE or lenvatinib alone, TACE plus lenvatinib could significantly increase the 6-month (OR = 3.42, 95%CI: 2.06–5.67, P < .00001; OR = 3.83, 95%CI: 2.66–5.53, P < .00001), 12-month (OR = 3.43, 95%CI: 2.08–5.65, P < .00001; OR = 2.78, 95%CI: 1.90–4.05, P < .00001), and 18-month (OR = 2.97, 95%CI: 1.77–5.00, P < .0001; OR = 2.62, 95%CI: 1.54–4.47, P = .0004) PFS rate in patients with advanced HCC. See Figure 4.
Figure 4.
PFS rate forest plot of the experimental group versus the control group. (A) 6-mo PFS rate, (B) 12-mo PFS rate, (C) 18-mo PFS rate. PFS = progression-free survival.
3.5. OS rate
Ten studies[9–16,18,25] provided 6-month OS rate data, of which 5 studies[9,11,14,18,25] were TACE plus lenvatinib versus TACE alone, and the other 5 studies[10,12,13,15,16] were TACE plus lenvatinib versus lenvatinib alone. Based on the heterogeneity test results (P = .95, I2 = 0%; P = .52, I2 = 0%). Fixed-effects model analysis showed that the 6-month OS rate of advanced HCC patients in the TACE plus lenvatinib group was significantly higher than that in the lenvatinib group alone (OR = 2.53, 95%CI: 1.61–3.98, P < .0001). However, compared with the TACE group alone, there was no significant advantage in the 6-month OS rate of the TACE plus lenvatinib group (OR = 1.78, 95%CI: 0.89–3.56, P = .10). See Figure 5A. The ten and 9 included studies reported that 12-month[9–16,18,25] and 18-month[9–16,18] OS rates, respectively. The results of the heterogeneity test showed that the heterogeneity among the studies was small (P > .1, I2 < 50%). Fixed-effects model analysis showed that compared with TACE or lenvatinib alone, TACE plus lenvatinib could significantly increase the 12-month (OR = 2.34, 95%CI: 1.53–3.58, P < .0001; OR = 3.64, 95%CI: 2.65–5.01, P < .00001) and 18-month (OR = 2.27, 95%CI: 1.48–3.48, P = .0002; OR = 3.23, 95%CI: 2.33–4.48, P < .00001) OS rates in patients with advanced HCC. See Figure 5B and C.
Figure 5.
OS rate forest plot of the experimental group versus the control group. (A) 6-mo OS rate, (B) 12-mo OS rate, (C) 18-mo OS rate. OS = overall survival.
3.6. AFP and VEGF
The 5 included studies[17,19,21,24,25] reported the expression level of AFP in the serum of the experimental group and the control group before and after treatment, and heterogeneity test results showed significant heterogeneity among studies (P = .0002, I2 = 82%). Random-effects model analysis showed that the experimental group compared with the control group could significantly reduce the level of serum AFP expression in patients with advanced HCC (SMD = 1.22, 95%CI: 0.67–1.78, P < .0001). See Figure 6A. Five other studies[11,17,19,21,24] reported VEGF expression levels in serum before and after treatment in experimental and control groups. Based on the results of the heterogeneity test (P = .02, I2 = 66%), the results of the random-effects model analysis showed that the experimental group could significantly reduce the level of serum VEGF expression in patients with advanced HCC compared with the control group (SMD = 1.27, 95%CI: 0.87–1.67, P < .00001). See Figure 6B.
Figure 6.
Forest plot of tumor marker. (A) AFP, (B) VEGF. AFP = alpha-fetoprotein, VEGF = vascular endothelial growth factor.
3.7. Grade ≥ 3 adverse events
In terms of adverse events of drugs, the incidence of grade ≥ 3 hypertension and elevated aspartate aminotransferase and alanine aminotransferase in the experimental group was higher than that in the control group (P < .05). There was no significant difference in the incidence of grade ≥ 3 hyperbilirubinemia, fatigue, diarrhea, abdominal pain, hand-foot skin reaction, leukopenia or thrombocytopenia, decreased appetite, albuminuria, hoarseness, fever, nausea and vomiting, weight decrease, rash, and constipation between the 2 groups (P > .05). See Table 4.
Table 4.
Comparison of grade ≥ 3 adverse events between the experimental group and the control group.
| Grade ≥ 3 adverse events | Number of studies | Heterogeneity | OR 95%CI | P |
|---|---|---|---|---|
| Elevated ALT | 2 | P = .32, I2 = 0% | 14.43 (3.95–52.80) | <.0001 |
| Elevated AST | 2 | P = .49, I2 = 0% | 14.46 (4.78–43.75) | <.00001 |
| Hyperbilirubinemia | 2 | P = .14, I2 = 53% | 1.96 (0.59–6.45) | .27 |
| Hypertension | 8 | P = .15, I2 = 35% | 1.55 (1.08–2.23) | .02 |
| Fatigue | 6 | P = .58, I2 = 0% | 1.00 (0.46–2.15) | .99 |
| Diarrhea | 7 | P = .96, I2 = 0% | 1.41 (0.70–2.84) | .33 |
| Abdominal pain | 3 | P = .27, I2 = 25% | 2.26 (0.77–6.66) | .14 |
| Hand-foot skin reaction | 6 | P = .59, I2 = 0% | 1.72 (0.58–5.09) | .33 |
| Leukopenia or thrombocytopenia | 4 | P = .98, I2 = 0% | 1.28 (0.55–2.97) | .57 |
| Decreased appetite | 5 | P = .64, I2 = 0% | 0.86 (0.41–1.80) | .70 |
| Albuminuria | 5 | P = .68, I2 = 0% | 0.88 (0.44–1.76) | .71 |
| Hoarseness | 5 | P = .85, I2 = 0% | 0.42 (0.06–2.88) | .38 |
| Fever | 4 | P = .98, I2 = 0% | 3.59 (0.74–17.51) | .11 |
| Weight decrease | 3 | P = .72, I2 = 0% | 0.99 (0.50–1.95) | .98 |
| Rash | 2 | P = .82, I2 = 0% | 2.21 (0.49–9.95) | .30 |
| Nausea and vomiting | 2 | P = .71, I2 = 0% | 0.87 (0.31–2.45) | .79 |
| Constipation | 3 | P = .80, I2 = 0% | 0.74 (0.16–3.34) | .70 |
ALT = alanine aminotransferase, AST = aspartate aminotransferase, CI = confidence interval, OR = odds ratio.
3.8. Sensitivity analysis and publication bias
Sensitivity analysis was performed for each meta-analysis, and the effect size was pooled after eliminating each included study one by one, and there was no significant change in the values of OR, SMD, and 95%CI, indicating that the results of the pooled analysis were stable. The funnel plots with ORR and DCR as indicators were basically symmetric, suggesting no significant publication bias. See Figure 7.
Figure 7.
Funnel plot of ORR (A), DCR (B). DCR = disease control rate, ORR = objective response rate.
4. Discussion
Liver tumor blood supply 75% to 80% from the hepatic artery, TACE can effectively destroy the main focus and sub-focus of the liver tumor by reducing and blocking the tumor blood supply, which has significant short-term efficacy and is one of the most effective ways to treat advanced HCC.[27] However, acute hypoxia caused by TACE can induce up-regulation of VEGF in residual lesions, which may contribute to tumor angiogenesis, promote tumor metastasis, recurrence and spread, and affect long-term efficacy.[28] Tyrosine kinase inhibitor (TKI) inhibits tumor angiogenesis through a variety of pathways, including inhibition of the VEGF receptor, and exerts the effect of anti-tumor cell proliferation.[29] TACE combined with TKI can reduce tumor microvessel density by inhibiting hypoxia-induced VEGF overexpression.[30] Therefore, in theory, TACE combined with TKI can improve the efficacy of patients with advanced HCC.
Sorafenib, as a representative drug of multi-target small molecule TKI, has been the first-line standard drug of advanced HCC in the past 10 years. However, in recent years, several studies have shown that TACE plus sorafenib does not significantly improve the survival outcome of patients with advanced HCC.[31–34] lenvatinib is a TKI that can replace sorafenib in the first-line treatment of advanced HCC.[35] In contrast to Sorafenib, it is characterized by its strong activity against fibroblast growth factor receptors,[36] and recent studies have shown that it also has immunomodulatory activity.[37] In 2018, the REFLECT trial[38] demonstrated that lenvatinib was superior to sorafenib in improving ORR and prolonging PFS. In addition, in a real-world setting, lenvatinib significantly prolonged OS in patients with advanced HCC compared to sorafenib.[39] Therefore, lenvatinib instead of sorafenib combined with TACE may be a more promising treatment.
In recent years, there have been many clinical reports on the treatment of advanced HCC by TACE combined with lenvatinib, but the conclusions are not completely consistent. Therefore, we conducted a meta-analysis to systematically evaluate the efficacy and safety of this combination regimen for advanced HCC. According to the inclusion and exclusion criteria, our study included a total of 18 clinical studies, a total of 1855 patients with advanced HCC. Our meta-analysis showed that compared with TACE or lenvatinib alone, TACE plus lenvatinib could increase ORR, DCR, and 6-month, 12-month, and 18-month PFS rates in patients with advanced HCC, and reduce serum AFP and VEGF expression levels. Compared with TACE alone, TACE plus lenvatinib did not significantly improve the 6-month OS rate, which may be related to the short follow-up period and the long-term survival benefits of the combined regimen have not been fully demonstrated. Further prolonging the follow-up period, our results showed that the combined regimen group significantly improved the 12-month and 18-month OS rate compared with the TACE or lenvatinib group alone. These results strongly suggest that TACE plus lenvatinib is effective. However, in terms of adverse drug events, the combined regimen group had a significantly higher risk of grade 3 and above hypertension, elevated aspartate aminotransferase, and alanine aminotransferase. The occurrence of these severe drug events may lead to drug dose reduction or suspension in clinical treatment, which may affect the benefit of treatment for patients. Therefore, the efficacy versus risk of combination regimens should be carefully balanced in clinical application.
There are some limitations to our study. First of all, the included retrospective studies are mostly single-center and small-sample studies conducted in China, lacking large-sample and global multi-center studies. Second, the differences in the baseline characteristics of the patients included in the study, such as average age, BCLC stage, ECOG score, and etiology, lead to potential heterogeneity. Third, the pattern and frequency of TACE, the drug of chemoembolization and its dose are not completely consistent, which may also be the source of potential heterogeneity. Fourthly, some studies have insufficient follow-up time and lack long-term survival data.
In conclusion, TACE plus lenvatinib in the treatment of advanced HCC is superior to TACE or lenvatinib alone in improving the effective rate, survival rate and reducing the expression of serum AFP and VEGF. However, attention should be paid to the occurrence of adverse events caused by the combination regimen, such as severe hypertension and liver function damage, because it may affect the course of treatment and thus affect the therapeutic efficacy. In addition, due to inconsistent or missing original data provided by the included studies, further analysis could not be conducted according to tumor stage, Child-Pugh class, AFP expression level, treatment duration, and treatment sequence of TACE combined with lenvatinib, and other factors that may affect therapeutic efficacy. Therefore, further validation of this conclusion necessitates meticulously designed large-scale, multi-center RCTs.
Author contributions
Conceptualization: Dailong Li.
Data curation: Dailong Li, Siqi Liu, Chunlai Cheng, Lu Xu, Pingfan Zhao.
Formal analysis: Dailong Li, Siqi Liu, Chunlai Cheng, Pingfan Zhao.
Investigation: Dailong Li.
Methodology: Dailong Li, Siqi Liu, Chunlai Cheng, Lu Xu, Pingfan Zhao.
Software: Dailong Li, Siqi Liu, Chunlai Cheng, Lu Xu, Pingfan Zhao.
Supervision: Pingfan Zhao.
Validation: Dailong Li, Siqi Liu.
Writing – original draft: Dailong Li.
Writing – review & editing: Dailong Li, Siqi Liu, Pingfan Zhao.
Abbreviations:
- AFP
- alpha-fetoprotein
- CI
- confidence interval
- DCR
- disease control rate
- HCC
- hepatocellular carcinoma
- OR
- odds ratio
- ORR
- objective response rate
- OS
- overall survival
- PFS
- progression-free survival
- SMD
- standard mean difference
- TACE
- transarterial chemoembolization
- TKI
- tyrosine kinase inhibitor
- VEGF
- vascular endothelial growth factor
DL and SL contributed equally to this work.
The authors have no conflicts of interest to disclose.
Ethical approval was not necessary, because this article is a meta-analysis and it does not involve the participation of ethics committee.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
How to cite this article: Li D, Liu S, Cheng C, Xu L, Zhao P. Efficacy and safety of transarterial chemoembolization plus lenvatinib in the treatment of advanced hepatocellular carcinoma: A meta-analysis. Medicine 2023;102:35(e34811).
Contributor Information
Dailong Li, Email: 1558983976@qq.com.
Siqi Liu, Email: 1301915712@qq.com.
Chunlai Cheng, Email: 22090947@qq.com.
Lu Xu, Email: xlnick@qq.com.
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