Abstract
The safety and therapeutic efficiency of tyrosine kinase inhibitors (TKIs) and programmed death-1 (PD-1) inhibitors in combination with hepatic artery infusion chemotherapy (HAIC) for patients with unresectable/advanced hepatocellular carcinoma (HCC) require further investigation. This meta-analysis aimed to thoroughly investigate the safety and efficacy of this triple combination therapy based on currently available research. PubMed, Embase, Cochrane Library, Web of Science, VIP, Wan Fang, and China National Knowledge Infrastructure were searched. Outcomes included complete response (CR), partial response (PR), stable disease, overall survival, progression-free survival, and treatment/laboratory-related adverse events. Stata15.1 software was used for random/fixed-effect model analysis. Ten studies with 1108 patients were incorporated in the analysis. For efficacy, the triple combination therapy achieved an improved CR rate [relative risk (RR): 2.76, 95% confidence interval (CI): 1.43–5.33] and PR rate (RR: 1.70, 95% CI: 1.01–2.86) than the control group. Moreover, the triple combination therapy decreased the 44% risk of death [hazard ratio (HR): 0.56, 95% CI: 0.46–0.67] and 37% risk of disease progression (HR: 0.63, 95% CI: 0.53–0.75) compared with the control group. The triple combination therapy group and the control group did not exhibit a statistical difference in treatment- or laboratory-related adverse events. In the management of unresectable/advanced HCC, HAIC in conjunction with PD-1 inhibitors and TKI exhibits both safety and efficacy, providing a scientific basis for clinical practice.
Keywords: efficacy, HAIC, PD-1 inhibitors, safety, TKIs, unresectable/advanced hepatocellular carcinoma
Introduction
As a serious malignant tumor, hepatocellular carcinoma (HCC) ranks sixth among the most common malignant tumors and third in cancer-related mortality globally [1]. Nearly 70% of patients receive a diagnosis at the advanced stage, thereby precluding the possibility of surgical resection, and their overall survival (OS) is only 4.2–7.9 months [2]. For unresectable liver cancer in the middle and late stages, therapies including hepatic artery infusion chemotherapy (HAIC), tyrosine kinase inhibitors (TKIs), and programmed death-1 (PD-1) inhibitors can be adopted [3–5]. Although a single therapy achieves certain therapeutic effects, the improvement in OS is still not ideal [5,6].
Studies have indicated that combination therapy may be beneficial for patients with HCC in terms of time to progression, OS, and tumor response rates [7,8]. Combining HAIC with TKI and anti-PD-1 immunotherapy has demonstrated good efficacy and safety, with a 63.0% response rate, 92.6% disease control rate, and no treatment-related deaths [9]. Chen et al. [10] found that compared with TKI and anti-PD-1 [OS: 12.6 months, progression-free survival (PFS): 6.8 months], this triple combination therapy extended the median OS to 17.7 months and PFS to 10.9 months for advanced HCC. A study conducted by Lin et al. [11] found that the median OS and median PFS in the triple combination therapy group were significantly increased than in the patients treated with HAIC and TKI (OS: 16.0 vs. 9.0 months, PFS: 11.0 vs. 6.0 months). The tolerable safety of the triple combination therapy has also been reported [8,12]. Mei et al. [12] found that there was no statistical significance between the triple combination therapy and TKI, and PD-1 inhibitors were observed in the treatment-related adverse events. No significant difference in adverse events was found by Pan et al. [8] between the triple combination therapy and systemic therapy; however, the separate original studies may have some limitations, such as the small sample size.
Meta-analysis combines results from two or more separate studies to strengthen the evidence level [13,14]. Therefore, we perform a meta-analysis to comprehensively evaluate the efficacy and safety of combining HAIC with TKI and anti-PD-1 therapy in patients with unresectable/advanced HCC based on the previously published studies.
Materials and methods
Strategy of searching
PubMed, Embase, Cochrane Library, Web of Science, VIP, Wan Fang, and China National Knowledge Infrastructure were systematically searched from August 2023 to September 2023. Two independent researchers conducted the literature search, and the third person provided the consultation if conflicts existed. Supplementary File S1, Supplemental digital content 1, https://links.lww.com/EJGH/B176 contains a list of search terms in both English and Chinese.
Selection criteria
The criteria of inclusion were defined in accordance with the patients, intervention, comparison, outcomes, and study principle as follows: (a) patients: patients with unresectable/advanced HCC; (b) intervention: HAIC combining with TKI and anti-PD-1 immunotherapy; (c) control: other therapies [including lenvatinib (LEN), LEN + PD-1 inhibitor, LEN + HAIC, LEN + PD-1 inhibitor + transarterial chemoembolization (TACE), LEN + PD-1 inhibitor + HAIC + transhepatic arterial embolization]; (d) outcomes: tumor response, survival, adverse events (including treatment- and laboratory-related adverse events); (e) studies: cohort studies, randomized controlled trials (RCTs).
Tumor responses [complete response (CR), partial response (PR), and stable disease) were assessed by the Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1) for solid tumors [15] and modified RECIST (mRECIST) for HCC [16] per independent imaging review.
Survival included 1-year OS, 1-year PFS, median OS, median PFS, OS, and PFS.
Treatment-related adverse events comprised hypertension, fever, abdominal pain, nausea, diarrhea, fatigue, pain, palmar-plantar erythrodysesthesia syndrome, hypothyroidism, and proteinuria.
Laboratory-related adverse events comprised decreases in white blood cell (WBC), neutrophil count, and platelet count, or increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood bilirubin, and hypoalbuminemia.
Exclusion criteria: (a) animal studies, and models; (b) non-English or non-Chinese articles; (c) studies not meeting the topic; (d) editorial materials, comments, errata, letters, notes, conference abstracts, case reports, case series, trial registration records, trial protocols, guidelines, consensuses, review, and meta-analysis; (e) retracted articles.
Data extraction
Following items were extracted using a predesigned form: publication year, author, country, study design, treatments, sample size, sex, age, eastern cooperative oncology group performance status, number and size of tumor, HCC etiology, alpha-fetoprotein, Barcelona Clinic Liver Cancer, liver cirrhosis, tumor thrombus, extrahepatic metastasis, and outcomes. Data extraction was performed independently by two authors.
Quality assessment
Cohort study quality was assessed using the Newcastle–Ottawa Scale (NOS). The NOS consisted of nine points and categorized the studies into three quality levels: low quality (≤3 points), moderate quality (4–6 points), and high quality (7–9 points) [17]. Similarly, the quality of RCTs was assessed using the modified Jadad scale, a seven-point scale that categorized the studies into two quality levels: low quality (1–3 points) and high quality (4–7 points) [18].
Statistical analysis
For outcome measurement, relative risk (RR) and a 95% confidence interval (CI) were used for categorical data, while weighted mean difference (WMD) and a 95% CI were used for continuous data. The merged hazard ratio (HR) was represented as HR and 95% CI. Heterogeneity tests were conducted for the effect size of each outcome. When I2 was 50% or higher, a random-effects model was applied for analysis; if I2 was below 50%, a fixed-effects model was used. Subgroup analysis is based on the study design or previous therapy. The robustness of the pooled results for each outcome was assessed by sensitivity analysis. All statistical analysis was performed using Stata15.1 software (StataCorp, College Station, Texas, USA).
Results
Study search and the characteristics of included studies
First, 4401 studies were searched in several databases. Removed the duplicates, 2633 studies were identified. Screened based on titles and abstracts, 2550 articles were not eligible because of reviews/meta-analyses (n = 492), editorial materials, comments, errata, letters, notes (n = 47), conference abstracts (n = 684), not relevant to the topic (n = 911), case reports, case series (n = 202), animal experiments, models (n = 49), not published in English or Chinese (n = 27), trial registry records, trial protocols (n = 118), guidelines, consensuses (n = 19), and retraction (n = 1). Further, screened based on full texts, 73 articles were excluded for lack of relevance (n = 66) and editorial materials (n = 7). Finally, the meta-analysis included 10 studies involving 1108 patients [6,8,10–12,19–23] (Fig. 1).
Fig. 1.
Literature screening process. CNKI, China National Knowledge Infrastructure.
Table 1 displays the characteristics of the included studies and the results of the quality assessment. There were eight cohort studies and two RCTs. Of these, there were four, five, and one studies of high, moderate, and low quality.
Table 1.
The characteristics and quality assessment of included studies
| Author | Country | Study design | Treatments | Sample size | Sex (male/female) | Age (years) | ECOG performance status | Tumor number | Tumor size (cm) | HCC etiology | AFP (ng/ml) | BCLC | Liver cirrhosis | Tumor thrombus | Extrahepatic metastasis | Outcomes | Quality score |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Chen et al. [10] | China | Retrospective cohort | Lenvatinib + pembrolizumab + HAIC | 84 | 72/12 | 52 (42–67)a | 0, 38 1, 46 |
Metastatic sites < 3, 7 ≥3, 64 Unclear, 13 |
HBV, 45 HCV, 22 Without viral hepatitis, 17 |
3984.0 (82.0–49 534.0)a | B, 22 C, 62 |
Absent, 27 Present, 57 |
Absent, 35 Branch of portal vein, 36 Main portal vein, 13 |
Absent, 64 Present, 20 |
CR, PR, SD, OS, median OS, median PFS, AE | 8 | |
| Lenvatinib + pembrolizumab | 86 | 71/15 | 53 (43–69)a | 0, 35 1, 51 |
Metastatic sites < 3, 6 ≥3, 68 Unclear, 12 |
HBV, 48 HCV, 26 Without viral hepatitis, 12 |
4022.0 (79.0–51 462.0)a | B, 21 C, 65 |
Absent, 28 Present, 58 |
Absent, 31 Branch of portal vein, 44 Main portal vein, 11 |
Absent, 62 Present, 24 |
||||||
| Tao [23] | China | Retrospective cohort | Lenvatinib + camrelizumab + HAIC | 21 | 17/4 | ≥55, 10 <55, 11 |
≥2, 13 1, 8 |
Largest tumor diameter ≥ 10, 9 <10, 12 |
HBV negative, 1 HBV positive, 20 |
≥400, 15 <400, 6 |
A, 3 B, 3 C, 15 |
Absent, 12 Present, 9 |
PVTT Absent, 12 Present, 9 |
CR, PR, SD, AE | 6 | ||
| Lenvatinib + camrelizumab + TACE | 20 | 19/1 | ≥55, 7 <55, 13 |
≥2, 16 1, 4 |
Largest tumor diameter ≥ 10, 10 <10, 10 |
HBV negative, 6 HBV positive, 14 |
≥400, 9 <400, 11 |
A, 3 B, 5 C, 12 |
Absent, 11 Present, 9 |
PVTT Absent, 11 Present, 9 |
|||||||
| Liang et al. [22] | China | RCT | Lenvatinib + sintilimab + HAIC | 40 | 32/8 | 55.26 ± 8.32b | 0, 32 1, 4 2, 4 |
≥5, 34 <5, 6 |
HBV, 38 | ≥400, 24 <400, 16 |
B, 24 C, 16 |
Absent, 6 Present, 34 |
Absent, 36 Present, 4 |
CR, PR, SD | 4 | ||
| Lenvatinib + sintilimab + TACE | 40 | 30/10 | 54.78 ± 10.55b | 0, 32 1, 2 2, 6 |
≥5, 30 <5, 10 |
HBV, 36 | ≥400, 26 <400, 14 |
B, 26 C, 14 |
Absent, 11 Present, 9 |
Absent, 34 Present, 6 |
|||||||
| Jia et al. [21] | China | RCT | Lenvatinib + PD-1 inhibitor + HAIC | 25 | 20/5 | 57.08 ± 6.67b | 0, 20 1, 0 2, 5 |
≥5, 21 <5, 4 |
HBV, 22 | ≥400, 10 <400, 15 |
Absent, 2 Present, 23 |
PVTT, 25 | Absent, 21 Present, 4 |
CR, PR, SD, AE | 3 | ||
| Lenvatinib + PD-1 inhibitor | 25 | 18/7 | 52.84 ± 12.61b | 0, 14 1, 3 2, 8 |
≥5, 19 <5, 6 |
HBV, 18 | ≥400, 11 <400, 14 |
Absent, 5 Present, 20 |
PVTT, 25 | Absent, 23 Present, 2 |
|||||||
| Chen et al. [20] | China | Retrospective cohort | Lenvatinib + tislelizumab + HAIC | 50 | 46/4 | 0, 38 1, 12 |
≥2, 41 1, 9 |
14.2 ± 2.5b | HBV, 45 HCV, 4 Others, 1 |
≤400, 18 >400, 32 |
PVTT, 50 | Absent, 16 Present, 34 |
CR, PR, SD, median OS, median PFS, AE | 8 | |||
| Lenvatinib + tislelizumab + HAIC + TAE | 50 | 42/8 | 0, 40 1, 10 |
≥2, 40 1, 10 |
14.1 ± 2.9b | HBV, 45 HCV, 2 Others, 3 |
≤400, 14 >400, 36 |
PVTT, 50 | Absent, 16 Present, 34 |
||||||||
| Lin et al. [11] | China | Retrospective cohort | Lenvatinib + PD-1 inhibitor + HAIC | 75 | 66/9 | 55.3 ± 9.5b | >3, 70 ≤3, 5 |
Largest tumor diameter 8.3 ± 3.8b |
HBV, 70 HCV, 0 Nonhepatitis B and C, 5 |
≤400, 38 >400, 37 |
B, 44 C, 31 |
Present, 51 Absent, 24 |
Present, 28 Absent, 47 |
CR, PR, SD, PFS, median OS, median PFS, AE | 6 | ||
| Lenvatinib + HAIC | 74 | 60/14 | 56.0 ± 10.5b | ≤7, 69 >7, 5 |
Largest tumor diameter 7.5 ± 3.8b |
HBV, 63 HCV, 0 Nonhepatitis B and C, 11 |
≤400, 41 >400, 33 |
B, 41 C, 33 |
Present, 53 Absent, 21 |
Present, 20 Absent, 54 |
|||||||
| Mei et al. [12] | China | Retrospective cohort | Lenvatinib + PD-1 inhibitor + HAIC | 45 | 38/7 | 49.1 ± 10.6b | Solitary, 9 Multiple, 36 |
Largest tumor diameter 11.2 ± 3.9b |
HBV negative, 8 HBV positive, 37 HCV negative, 44 HCV positive, 1 |
4106.0 (72.8–121 000.0)a | B, 5 C, 40 |
Absent, 5 Present, 40 |
Absent, 9 Branch of portal vein, 20 Main portal vein, 16 |
Absent, 30 Present, 15 |
CR, PR, SD, OS, PFS, AE | 7 | |
| Lenvatinib + PD-1 inhibitor | 25 | 18/7 | 50.1 ± 12.3b | Solitary, 5 Multiple, 20 |
Largest tumor diameter 10.9 ± 4.2b |
HBV negative, 6 HBV positive, 19 HCV negative, 25 HCV positive, 0 |
767.6 (23.3–21 940.5)a | B, 3 C, 22 |
Absent, 7 Present, 18 |
Absent, 7 Branch of portal vein, 6 Main portal vein, 12 |
Absent, 12 Present, 13 |
||||||
| An et al. [19] | China | Retrospective cohort | Lenvatinib + PD-1 inhibitor + HAIC | 58 | 49/9 | 46.6 ± 9.7b | 0, 52 1, 6 |
Single, 15 Multiple, 43 |
Diameter ≤7, 28 >7, 30 |
HBV absence, 2 HBV presence, 56 |
≤400, 21 >400, 36 |
Absence, 23 Presence, 25 |
OS, AE | 6 | |||
| Lenvatinib + HAIC | 87 | 77/10 | 51.5 ± 10.2b | 0, 65 1, 22 |
Single, 38 Multiple, 49 |
Diameter ≤7, 45 >7, 42 |
HBV absence, 10 HBV presence, 77 |
≤400, 23 >400, 64 |
Absence, 39 Presence, 48 |
||||||||
| He et al. [6] | China | Retrospective cohort | Lenvatinib + toripalimab + HAIC | 71 | 59/12 | ≤50, 40 >50, 31 |
0, 14 1, 57 |
>3, 68 ≤3, 3 |
≤10, 26 >10, 45 |
HBsAg positive, 62 HBsAg negative, 9 |
≤400, 26 >400, 45 |
PVTT Absent, 16 Present, 55 HVTT Absent, 45 Present, 26 |
Absence, 55 Presence, 16 |
CR, PR, SD, median PFS, AE | 6 | ||
| Lenvatinib | 86 | 77/9 | ≤50, 42 > 50, 44 |
0, 22 1, 64 |
≤7, 77 >7, 9 |
≤10, 40 >10, 46 |
HBsAg positive, 78 HBsAg negative, 8 |
≤400, 31 >400, 55 |
PVTT Absent, 24 Present, 62 HVTT Absent, 53 Present, 33 |
Absence, 61 Presence, 25 |
|||||||
| Pan et al. [8] | China | Retrospective cohort | TKI + PD-1 inhibitor + HAIC/TACE | 146 | 131/15 | 54.00 (47.50–60.00)a | 0, 100 1, 46 |
Intrahepatic tumor number 1, 67 2–3, 54 ≥4, 25 |
9.859 ± 4.588b | HBV, 129 HCV, 3 Nonhepatitis B and C, 14 |
22 366.19 ± 44 313.27 | B, 20 C, 126 |
HVTT, 31 PVTT, 94 |
OS | 6 |
AE, adverse event; AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CR, complete response; ECOG, Eastern Cooperative Oncology Group; HAIC, hepatic arterial infusion chemotherapy; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HVTT, hepatic vein tumor thrombus; OS, overall survival; PD-1, programmed death-1; PFS, progression-free survival; PR, partial response; PVTT, portal vein tumor thrombus; RCT, randomized controlled trial; SD, stable disease; TACE, transcatheter arterial chemoembolization; TAE, transhepatic arterial embolization; TKI, tyrosine kinase inhibitor.
Median (interquartile range)
Mean ± SD
Efficacy of triple combination therapy in patients diagnosed as unresectable/advanced hepatocellular carcinoma
No notable distinctions (P > 0.05) were found between the two groups in CR, PR, and stable disease (RECIST version 1.1). Compared with the control group, higher rates of CR (RR: 2.76, 95% CI: 1.43–5.33, I2: 10.9%) (Fig. 2a) and PR (RR: 1.70, 95% CI: 1.01–2.86, I2: 81.4%) (Fig. 2b) were found in the intervention group (assessed by mRECIST). The results of the subgroup analysis displayed that previous therapy was not the source of heterogeneity for the PR rate. The results are shown in Table 2.
Fig. 2.
Meta-analysis results of CR rate (a) and PR rate (b) assessed by mRECIST. CI, confidence interval; CR, complete response; DL, DerSimonian–Laird; mRECIST, modified Response Evaluation Criteria in Solid Tumours; PR, partial response.
Table 2.
The efficiency of combining hepatic artery infusion chemotherapy with tyrosine kinase inhibitor and anti-programmed death-1 therapy in the patients with unresectable/advanced hepatocellular carcinoma
| Outcomes | Number of studies | RR/WMD/HR (95% CI) | P value | I2 (%) |
|---|---|---|---|---|
| Tumor response | ||||
| RECIST version 1.1 | ||||
| Complete response | 2 | 3.55 (0.76–16.65)a | 0.108 | 0.0 |
| Sensitivity analysis | 3.55 (0.76–16.65) | |||
| Partial response | 5 | 1.69 (0.84–3.39)a | 0.141 | 87.3 |
| Sensitivity analysis | 1.69 (0.84–3.39) | |||
| Study design | ||||
| Cohort | 3 | 1.75 (0.58–5.27) | 0.322 | 93.5 |
| RCT | 2 | 1.53 (0.95–2.44) | 0.078 | 0.0 |
| Stable disease | 5 | 0.83 (0.60–1.15)a | 0.263 | 57.9 |
| Sensitivity analysis | 0.83 (0.60–1.15) | |||
| Study design | ||||
| Cohort | 3 | 0.76 (0.48–1.21) | 0.248 | 72.7 |
| RCT | 2 | 0.98 (0.66–1.47) | 0.926 | 0.0 |
| mRECIST | ||||
| Complete response | 6 | 2.76 (1.43–5.33)a | 0.003 | 10.9 |
| Sensitivity analysis | 2.76 (1.43–5.33) | |||
| Partial response | 6 | 1.70 (1.01–2.86)a | 0.045 | 81.4 |
| Sensitivity analysis | 1.70 (1.01–2.86) | |||
| Previous therapy | ||||
| None | 4 | 1.48 (0.77–2.86) | 0.239 | 76.8 |
| TACE | 1 | 1.36 (0.90–2.06) | 0.151 | 0.0 |
| Stable disease | 6 | 0.82 (0.53–1.26)a | 0.363 | 74.2 |
| Sensitivity analysis | 0.82 (0.53–1.26) | |||
| Previous therapy | ||||
| None | 4 | 0.90 (0.53–1.51) | 0.677 | 67.6 |
| TACE | 1 | 1.18 (0.73–1.90) | 0.514 | 0.0 |
| Survival | ||||
| 1-year OS | 3 | 1.28 (0.97–1.70)a | 0.084 | 62.9% |
| Sensitivity analysis | 1.28 (0.97–1.70) | |||
| Median OS | 3 | 4.27 (0.51–8.02)b | 0.026 | 68.9 |
| Sensitivity analysis | 4.27 (0.51–8.02) | |||
| Previous therapy | ||||
| None | 2 | 1.84 (−5.79 to 9.46) | 0.637 | 79.2 |
| TACE | 1 | 7.00 (3.61–10.39) | <0.001 | 0.0 |
| Median PFS | 4 | 3.34 (0.07–6.61)b | 0.046 | 87.4 |
| Sensitivity analysis | 3.34 (0.07–6.61) | |||
| Previous therapy | ||||
| None | 2 | 1.47 (−3.72 to 6.67) | 0.579 | 93.6 |
| TACE | 1 | 5.00 (2.47–7.53) | <0.001 | 0.0 |
| OS | 5 | 0.56 (0.46–0.67)c | <0.001 | 0.0 |
| Sensitivity analysis | 0.56 (0.46–0.67) | |||
| PFS | 4 | 0.63 (0.53–0.75)c | <0.001 | 7.8 |
| Sensitivity analysis | 0.63 (0.53–0.75) | |||
CI, confidence interval; HR, hazard ratio; mRECIST, modified RECIST; OS, overall survival; PFS, progression-free survival; RCT, randomized controlled trial; RECIST, Response Evaluation Criteria in Solid Tumours; RR, relative risk; TACE, transarterial chemoembolization; WMD, weighted mean difference.
Relative risk.
Weighted mean difference.
Hazard ratio.
For survival outcomes, Fig. 3a and b display a 44% risk of death (HR: 0.56, 95% CI: 0.46–0.67, I2: 0.0%) and 37% risk of disease progression (HR: 0.63, 95% CI: 0.53–0.75, I2: 7.8%) were decreased in the intervention group. Moreover, longer median OS (WMD: 4.27, 95% CI: 0.51–8.02, I2: 68.9%) (Fig. 3c) and longer median PFS (WMD: 3.34, 95% CI: 0.07–6.61) (I2: 87.4%; Fig. 3d) were found in the intervention group. Subgroup analysis indicated that heterogeneity came from previous therapy. The comparison of 1-year OS showed no difference in the two groups, with an RR value of 1.28 (95% CI: 0.97–1.70, I2: 62.9%). Mei et al. [12] found that the intervention group achieved longer 1-year PFS (RR: 2.64, 95% CI: 1.01–6.90). The results are shown in Table 2.
Fig. 3.
Meta-analysis results of OS (a), PFS (b), median OS (c), and median PFS (d). CI, confidence interval; DL, DerSimonian–Laird; HR, hazard ratio; IV, inverse variance; OS, overall survival; PFS, progression-free survival; WMD, weighted mean difference.
Safety of triple combination therapy in patients diagnosed as unresectable/advanced hepatocellular carcinoma
Table 3 shows no difference between the two groups in the treatment-related adverse events (hypertension, fever, abdominal pain, nausea, diarrhea, fatigue, pain, palmar-plantar erythrodysesthesia syndrome, hypothyroidism, and proteinuria) (P > 0.05). The statistical differences were also not found between the two groups in the laboratory-related adverse events, including the decrease of WBC, neutrophil count, platelet count, hypoalbuminemia, or the increase of ALT, AST, and blood bilirubin (P > 0.05).
Table 3.
The safety of combining hepatic artery infusion chemotherapy with tyrosine kinase inhibitor and anti-programmed death-1 therapy in the patients with unresectable/advanced hepatocellular carcinoma
| Outcomes | Number of studies | RR (95% CI) | P value | I2 (%) |
|---|---|---|---|---|
| Treatment-related adverse events | ||||
| Hypertension | 6 | 1.19 (0.94–1.50) | 0.151 | 0.0 |
| Sensitivity analysis | 1.19 (0.94–1.50) | |||
| Fever | 5 | 1.08 (0.87–1.36) | 0.482 | 0.0 |
| Sensitivity analysis | 1.08 (0.87–1.36) | |||
| Abdominal pain | 4 | 0.93 (0.53–1.65) | 0.806 | 81.1 |
| Sensitivity analysis | ||||
| Previous therapy | ||||
| None | 2 | 0.55 (0.39–0.78) | 0.001 | 0.0 |
| TACE | 1 | 1.13 (0.82–1.55) | 0.463 | 0.0 |
| Nausea | 6 | 1.20 (0.61–2.35) | 0.593 | 71.0 |
| Sensitivity analysis | 1.20 (0.61–2.35) | |||
| Diarrhea | 7 | 0.94 (0.71–1.25) | 0.685 | 0.0 |
| Sensitivity analysis | 0.94 (0.71–1.25) | |||
| Fatigue | 7 | 1.19 (0.88–1.60) | 0.262 | 51.3 |
| Sensitivity analysis | 1.19 (0.88–1.60) | |||
| Previous therapy | ||||
| None | 4 | 1.24 (0.81–1.90) | 0.313 | 30.0 |
| TACE | 1 | 0.95 (0.63–1.45) | 0.816 | 0.0 |
| Pain | 3 | 1.03 (0.78–1.35) | 0.862 | 4.3 |
| Sensitivity analysis | 1.03 (0.78–1.35) | |||
| Palmar-plantar erythrodysesthesia syndrome | 4 | 1.26 (0.92–1.74) | 0.153 | 0.0 |
| Sensitivity analysis | 1.26 (0.92–1.74) | |||
| Hypothyroidism | 4 | 1.23 (0.73–2.07) | 0.433 | 0.0 |
| Sensitivity analysis | 1.23 (0.73–2.07) | |||
| Proteinuria | 3 | 1.27 (0.89–1.82) | 0.192 | 0.0 |
| Sensitivity analysis | 1.27 (0.89–1.82) | |||
| Laboratory-related adverse events | ||||
| Decrease of white blood cell | 5 | 0.79 (0.50–1.27) | 0.329 | 0.0 |
| Sensitivity analysis | 0.79 (0.50–1.27) | |||
| Decrease of neutrophil count | 4 | 0.99 (0.57–1.72) | 0.969 | 15.3 |
| Sensitivity analysis | 0.99 (0.57–1.72) | |||
| Decrease of platelet count | 6 | 1.60 (0.92–2.78) | 0.095 | 58.0 |
| Sensitivity analysis | 1.60 (0.92–2.78) | |||
| Previous therapy | ||||
| None | 4 | 1.05 (0.68–1.63) | 0.815 | 0.0 |
| TACE | 1 | 1.58 (0.77–3.25) | 0.215 | 0.0 |
| Hypoalbuminemia | 4 | 1.04 (0.72–1.52) | 0.829 | 0.0 |
| Sensitivity analysis | 1.04 (0.72–1.52) | |||
| Increase of ALT | 3 | 1.53 (0.42–5.51) | 0.519 | 91.4 |
| Sensitivity analysis | 1.53 (0.42–5.51) | |||
| Increase of AST | 3 | 1.70 (0.59–4.94) | 0.326 | 90.9 |
| Sensitivity analysis | 1.70 (0.59–4.94) | |||
| Increase of blood bilirubin | 3 | 0.89 (0.62–1.27) | 0.515 | 0.0 |
| Sensitivity analysis | 0.89 (0.62–1.27) | |||
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; RR, relative risk; TACE, transarterial chemoembolization.
Sensitivity analysis and the bias of publication
The sensitivity analysis results indicated that there were no significant alterations in outcomes following the sequential exclusion of individual studies, which suggests the robustness of the results (Tables 2 and 3). When the outcome included equal to or more than 10 studies, publication bias needed to be assessed [24]; however, publication bias was not assessed as no more than 10 studies were included for each outcome.
Discussion
This study performed a meta-analysis of multiple independent studies to analyze the efficacy and safety of HAIC plus TKI plus anti-PD-1 therapy in patients with unresectable/advanced HCC. Compared with the control group, the intervention group had longer OS, median OS, PFS, and median PFS. In the intervention group, both the CR rate and PR rate, as evaluated by mRECIST, were increased than the control group. Regarding safety, no differences were observed in adverse events related to treatment/laboratory between the two groups.
HCC is an inflammatory tumor that often develops from chronic hepatitis and cirrhosis [25]. Immune checkpoint receptors are important in the formation of immune tolerance in liver cancer, which is related to immune escape in the progression of liver cancer [26]. Immune checkpoint inhibitors including PD-1 inhibitors and programmed death ligand 1 inhibitors, exert their antitumor effects by blocking the interaction between checkpoint proteins and their ligands, thereby preventing T-cell inactivation [27]; however, not all patients with HCC are responsive to immunotherapy, single-agent immunotherapy does not significantly improve the OS, and the objective response rate is low [28]. TKIs exert an antiangiogenic effect to inhibit tumor diseases, and can effectively control the fibroblast growth factor receptor and endothelial growth factor receptor, which helps block the new formation of blood vessels, thereby effectively reducing vascular permeability in the tumor microenvironment [4]. A study has revealed that the pairing of immune checkpoint inhibitors and antiangiogenic agents has prominent clinical effects for advanced HCC [29]. To further improve the prognosis of patients with advanced HCC, HAIC was combined with the treatment of immune checkpoint inhibitors and TKIs [10,12]. HAIC refers to the direct delivery of chemotherapy drugs to the supply artery of the tumor through hepatic artery catheterization [22]. HAIC not only kills the tumor cells to the maximum extent by continuously exposing tumors to high concentrations of chemotherapy drugs, but also decreases the systemic toxicity of chemotherapy drugs by the first-pass effect on the liver [22]. Chen et al. [10] have reported that anti-PD-1 plus TKI plus HAIC significantly improved the survival benefits compared with anti-PD-1 plus TKI. Mei et al. [12] have found higher rates of overall response (40.0 vs. 16.0%) and disease control (77.6 vs. 44.0%), along with improved median OS to 15.9 months (vs. 8.6 months) and median PFS to 8.8 months (vs. 5.4 months) in the anti-PD-1 plus TKI plus HAIC group than in the anti-PD-1 plus TKI group. A meta-analysis displayed that OS and PFS of TKI plus anti-PD-1 plus TACE/HAIC were longer than the control group in patients with HCC accompanied by portal vein tumor thrombus [30]. In our meta-analysis, we focused on patients with advanced HCC and further focused on the median OS and median PFS. The results showed that anti-PD-1 plus TKI plus HAIC significantly extended the OS, median OS, PFS, and median PFS, and also increased the CR and PR rate assessed by mRECIST.
Existing studies have reported that the adverse reactions during the treatment process of anti-PD-1 plus TKI plus HAIC were controllable, and the treatment safety was good [10,21]. In this study, we also found that the treatment- and laboratory-related adverse events of anti-PD-1 plus TKI plus HAIC were not different from the control group. Our findings indicated that the triple combination therapy (HAIC plus TKI plus PD-1 inhibitor) for patients with unresectable/advanced HCC was acceptable and safe.
This study comprehensively assessed the efficacy and safety of combined treatment of HAIC, TKI, and PD-1 inhibitors in patients with unresectable/advanced HCC based on published clinical trials, offering a foundation for evidence-based clinical applications. Several limitations of this study should be carefully considered when evaluating the findings. First, retrospective cohort studies are mainly included, and RCTs are fewer. In the future, large-scale and high-quality researches are needed to further verify our results. Second, some results show heterogeneity. Because of limited original studies and extractable data, this study lacks the capacity to conduct subgroup analyses based on varying treatment methods, which limits the exploration of potential sources of heterogeneity. Third, for some outcomes, the limited number of studies included may impact the stability of the results.
Conclusion
Triple combination therapy (HAIC plus PD-1 inhibitors plus TKI) shows an improvement in treatment response, survival benefits, and acceptable toxicities in patients with unresectable/advanced HCC. These findings indicated that this triple combination therapy may be a viable option for patients with unresectable/advanced HCC.
Acknowledgements
Conceived and designed the study: Y.X., X.T., and Ho.Z. Data collection, analyzed, and interpreted the data: Y.X., X.T., Ha.Z., and X.S. Writing of the manuscript: Y.X. and X.T. Providing critical revisions that are important for the intellectual content: Ho. Z. Approved the final version of the manuscript: Y.X., X.T., Ha.Z., X.S., and Ho.Z.
Ethics approval and consent to participate are not applicable because PubMed, Embase, Cochrane Library, Web of Science, VIP, Wan Fang, and China National Knowledge Infrastructure (CNKI) belongs to public databases, the patients involved in the database have obtained ethical approval, users can download relevant data for free for research and publish relevant articles, and our study is based on open-source data, and the Chengwu County People’s Hospital do not require research using publicly available data to be submitted for review to their ethics committee.
The datasets used or analyzed during the current study were publicly available from PubMed: https://pubmed.ncbi.nlm.nih.gov/; Embase: https://www.embase.com/; Cochrane Library: https://www.cochranelibrary.com/; Web of Science: https://www.webofscience.com/; VIP: https://www.cqvip.com/; Wan Fang Data: https://www.wanfangdata.com.cn/; China National Knowledge Infrastructure: https://www.cnki.net/.
Conflicts of interest
There are no conflicts of interest.
Supplementary Material
Footnotes
Yadi Xiao and Xiangbo Tao contributed equally to the writing of this article and are co-first authors.
Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.eurojgh.com.
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