Comparison analysis of different doses bevacizumab plus ICIs and interventional therapy in unresectable hepatocellular carcinoma: a real-world study

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the fifth leading cause of cancer-related death worldwide (1). Most patients are diagnosed with intermediate or advanced HCC and the prognosis remains poor due to limited treatment options. The median survival for intermediate HCC patients is 40 months (2), while the median survival time is only 11.2 months for patients with advanced HCC with extrahepatic metastasis (3). The emergence of systemic therapies such as bevacizumab combined with atezolizumab or sintilimab has improved the outcomes for unresectable HCC (4,5). However, the median progression-free survival (PFS) of patients with unresectable HCC treated with bevacizumab and atezolizumab in the Chinese subpopulation is only 5.7 months, and the objective response rate (ORR) is only 24.6% (4). Therefore, exploring efficient therapeutic strategies for advanced HCC is urgent to improve patients’ prognoses.

Recently, early experiences of bevacizumab plus immune checkpoint inhibitors (ICIs) combined with hepatic arterial infusion chemotherapy (HAIC) or transcatheter arterial chemoembolization (TACE) in patients with unresectable HCC have gradually attracted attention and revealed significant therapeutic effects. This combination strategy is reasonable. On one hand, TACE may lead to increased hypoxia-inducible factor-1 (HIF-1) expression and induce upregulated expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor because of an ischemic or hypoxic state caused by TACE (6,7). This might enhance the effects of bevacizumab. On the other hand, TACE may cause immunogenic cell death leading to the release of tumor-specific antigens, and may increase the number of immune cells in the tumor microenvironment which leads to enhanced antigen presentation and triggers an immune response (8). Therefore, TACE combined with bevacizumab and ICIs is likely to create synergistic effects. Retrospective study found that the combinations of HAIC and bevacizumab plus ICIs in advanced HCC demonstrated higher disease control rates (DCRs) than dual therapy of bevacizumab and ICIs (9). For advanced HCC patients who received triple therapy of atezolizumab plus bevacizumab combined with HAIC, the ORR based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria was 44.2%, and the median PFS was 10.6 months [95% confidence interval (CI): 8.37–13.8] (10). Similarly, study in triple therapy of TACE, atezolizumab, and bevacizumab for patients with intermediate-stage HCC beyond up-to-seven criteria showed encouraging efficacy, with an ORR of 42.9% (11). More prospective studies are already underway (12-14).

In China, most HCC patients are accompanied by liver fibrosis or cirrhosis (15). The combination therapy may increase the risk of gastrointestinal tract hemorrhage (16) and other toxicities, such as aspartate aminotransferase (AST) elevation, alanine aminotransferase (ALT) elevation, fever, etc. It is still unclear whether patients can tolerate the adverse events (AEs) of the combination therapy. In clinical practice, some patients receive half-dose bevacizumab (7.5 mg/kg) rather than full-dose bevacizumab (15 mg/kg) in combined therapy in order to reduce AEs such as gastrointestinal tract hemorrhage. However, it is still unclear whether the reduction of bevacizumab in combination therapy can achieve the full effect and improve safety.

This real-world analysis evaluates the efficacy and safety of full-dose (15 mg/kg) versus half-dose (7.5 mg/kg) bevacizumab in triple therapy (bevacizumab, ICIs, and TACE/HAIC) for unresectable HCC. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-962/rc).

Methods

Study population

Between December 2020 and July 2023, patients diagnosed with unresectable HCC who received triple therapy of bevacizumab, atezolizumab/sintilimab, and TACE/HAIC as first-line therapy from Zhongshan Hospital, Fudan University were included in this study. The number of cases in the hospital during the study period determined the sample size. Criteria for eligible patients were as follows: (I) aged 18 years or older; (II) pathologically confirmed HCC or HCC diagnosed according to the European association for the study of the liver; (III) with no prior treatment or initial recurrence after radical resection beyond 6 months; (IV) Barcelona Clinic Liver Cancer (BCLC) B-C who were unsuitable for surgery (17); (V) treated with triple therapy of bevacizumab, atezolizumab/sintilimab, and TACE/HAIC as first-line treatment; (VI) at least one measurable target lesion that can be assessed by RECIST 1.1 (18); (VII) adequate organ and hematologic function; (VIII) Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0–1. The exclusion criteria included: (I) a history of other malignant tumors; (II) previously received anti-tumor therapy; (III) combination with other anti-tumor treatments; (IV) incomplete medical information. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics Committee of Zhongshan Hospital, Fudan University (approval No. B2023-219R). Informed consent was obtained from all patients.

Treatment procedure

Eligible patients received ICIs (atezolizumab 1,200 mg or sintilimab 200 mg) plus bevacizumab (15 or 7.5 mg/kg) intravenously every 3 weeks, and HAIC or TACE was received on demand. Usually, HAIC was performed every 3–6 weeks. During the procedure, a 4-Fr catheter or a 2.7-Fr microcatheter was placed into the hepatic artery, and chemotherapeutic agents (FOLFOX) were infused into the hepatic artery through the catheter: oxaliplatin (85 mg/m²) d1, leucovorin (400 mg/m²) d1, fluorouracil (400 mg/m²) d1, and fluorouracil (2,400 mg/m²) civ46h d1. TACE was performed every 2–3 months as needed. The procedure of TACE was as follows: a 4-Fr catheter was inserted into the celiac trunk, superior mesenteric artery, or hepatic artery for arteriography, and a 2.7-Fr microcatheter was super selectively placed into the feeding arteries of the tumor. Chemoembolization agents were used according to the institutional protocol described previously (19). All patients received guideline-recommended interventional therapies (TACE/HAIC) based on tumor burden, macrovascular invasion, liver function, and ECOG PS score (20). To ensure the safety of treatment, the interval of interventional therapy may be extended and dose adjustment of chemotherapeutic agents may be happened. Bevacizumab and ICIs may be transiently or permanently discontinued in case of grade 3–4 AEs.

Follow-up and outcomes

Patients’ clinical baseline characteristics and follow-up data were collected and analyzed through medical records. Tumor response was assessed by contrast-enhanced magnetic resonance imaging​(MRI) or computed tomography (CT) every 8–9 weeks based on RECIST 1.1 which were measured by two imaging specialists with more than 10 years of working experience to avoid bias in tumor assessment. The last follow-up of this study was on Nov 20, 2023. The primary endpoints were PFS, ORR, and DCR. PFS refers to the time from the beginning of the initial combination therapy to the progression of the disease or death. The ORR was referred to as the sum of partial response (PR) and complete response (CR). The DCR was referred to as the sum of PR, CR, and stable disease (SD). The secondary endpoints were overall survival (OS) and the incidence of AEs. OS refers to the time interval from initial combination therapy to death from any cause. AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Statistical analysis

Quantitative data were expressed as the median and interquartile range (IQR), whereas categorical data were expressed as a number (percentage). Kaplan-Meier analysis was used to estimate the PFS and OS. Patients were divided into two subgroups according to the dosage of bevacizumab. Propensity score matching (PSM) was used to control for confounding. The two groups were 1:1 matched using the nearest neighbor approach with a caliper width of 0.01 on the PS scale. Controls were individually matched to cases by age, gender, tumor state, liver function, and medication cycle. All the statistical analyses were performed using IBM SPSS Statistics 22 or R language (version 3.5.2; R Package for Statistical Computing; www.r-project.org). Differences were considered statistically significant when the two-tailed P value was less than 0.05.

Results

Clinicopathological characteristics

A total of 66 eligible patients with unresectable HCC receiving triple therapy (ICIs, bevacizumab, and HAIC/TACE) were enrolled in this study (Figure 1). Among them, 36 patients received 15 mg/kg bevacizumab (full-dose group), whereas 30 patients received 7.5 mg/kg bevacizumab (half-dose group). Most of the patients were men and were with hepatitis B virus infection. The average size of the maximum tumor was 71.2±42.3 mm. Twenty-seven (40.9%) patients had portal vein tumor thrombus, and 15 (22.7%) patients had extrahepatic metastasis. In the half-dose group, 21 patients received sintilimab plus bevacizumab and 9 received atezolizumab plus bevacizumab, while in the full-dose group, 27 patients received sintilimab plus bevacizumab and 9 received atezolizumab plus bevacizumab, with no statistically significant difference between the two groups (P=0.65). There were no significant differences in the baseline features between the two groups.

Figure 1 Flowchart of the study. DCR, disease control rate; HCC, hepatocellular carcinoma; HAIC, hepatic arterial infusion chemotherapy; ICIs, immune checkpoint inhibitors; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TACE, transcatheter arterial chemoembolization.

After PSM, 60 patients were retained: 30 with half-dose bevacizumab triple therapy and 30 with full-dose bevacizumab triple therapy. All baseline characteristics were well balanced (Table 1).

Treatment efficacy

In the overall population, patients in the half-dose group received 4.7±4.4 cycles of ICIs plus bevacizumab and 2.5±1.8 cycles of HAIC/TACE at the data cut-off (Nov 2023), while patients in the full-dose group received 5.9±5.0 cycles of ICIs plus bevacizumab and 2.5±1.6 cycles of HAIC/TACE, respectively. Tumor response was evaluated based on RECIST 1.1. The best tumor responses of the two groups were shown in Table 2. Twenty patients achieved CR/PR in the full-dose group and 11 patients achieved CR/PR in the half-dose group. While there was a trend toward higher ORR (55.6% vs. 36.7 %, P=0.13) and DCR (88.9% vs. 83.3%, P=0.51) in full-dose group compared to half-dose group, this did not achieve statistical significance. The detailed tumor responses of the two groups were presented in Figure 2A. After PSM, patients of the full-dose group received 5.9±5.1 cycles of ICIs plus bevacizumab and 2.5±1.7 cycles of HAIC/TACE during the study, respectively. The ORR and DCR were 36.7%, 83.3% in the half-dose group, and 53.3%, 86.7% in the full-dose group, respectively (Table 2, Figure 2B). Despite the numerically higher ORR and DCR in the full-dose cohort, the intergroup difference lacked statistical significance (P=0.19 and 0.72), which were consistent with findings from the general population.

Figure 2 Best tumor response according to RECIST 1.1 before and after PSM. (A) Best tumor response according to RECIST 1.1 before PSM. (B) Best tumor response according to RECIST 1.1 after PSM. CR, complete response; PD, progressive disease; PR, partial response; PSM, propensity score matching; RECIST, response evaluation criteria in solid tumors; SD, stable disease.

Overall, patients receiving full-dose bevacizumab showed markedly improved survival outcomes, with significantly prolonged PFS compared to the half-dose group (median PFS: not attained vs. 8.0 months; P<0.001; Figure 3A). The full-dose group also demonstrated superior PFS rates compared to the half-dose group at all timepoints: 100% vs. 67% at 3 months (P<0.001), 86% vs. 46% at 6 months (P=0.001), and 74% vs. 40% at 12 months (P=0.02; Table 2). The median OS was not reached with a 1-year OS rate of 86% in the full-dose group and 83% in the half-dose group (Figure 3B). Results remained consistent after PSM (Table 2). The full-dose bevacizumab triple therapy also prolonged median PFS relative to the half-dose bevacizumab triple therapy (median PFS not attained vs. 8 months, P=0.004, Figure 3C). The 1-year OS rate reached 83% in both the two groups (Figure 3D).

Figure 3 Kaplan-Meier-estimated PFS and OS curves in HCC patients receiving different therapies. (A,B) PFS and OS before PSM. (C,D) PFS and OS after PSM. **, P<0.01; ***, P<0.001. HCC, hepatocellular carcinoma; OS, overall survival; PFS, progression-free survival; PSM, propensity score matching.

Safety

Treatment related AEs were evaluated based on frequency and severity according to CTCAE version 5.0. The most common AEs before and after PSM were shown in Tables 3,4. In the overall cohort, hypertension (13.3%), proteinuria (10.0%), decreased appetite (10.0%), and hypothyroidism (10.0%) were the most common AEs in the half-dose group, contrasting with proteinuria (13.9%), gastrointestinal hemorrhage (13.9%), diarrhea (13.9%), and fatigue (13.9%) in the full-dose group. The most common grade 3 or 4 AEs were gastrointestinal hemorrhage (11.1%), followed by abnormal liver function (5.6%) in full-dose group. No treatment-related deaths occurred in both the two groups. While full-dose group exhibited a numerically higher occurrence of AEs (any grade) than half-dose group (n=34 vs. 20), no statistically significant differences were observed in the frequency of individual AE subtypes (all P>0.05, Table 3).

After PSM, patients in the full-dose group had an increased risk of AEs than those in the half-dose group (n=28 vs. 20). The full-dose group exhibited a 1.5-fold increased risk of grade 3–4 AEs, relative to 6.7% grade 3–4 AEs in the half-dose group. Especially, more gastrointestinal hemorrhage and abnormal liver function occurred in the full-dose group than in the half-dose group (10.0% vs. 3.3%; 6.7% vs. 3.3%). ​However, no statistically significant differences were observed between the two groups (both P>0.99, Table 4).

Discussion

Due to high heterogeneity of advanced HCC, treatment modality from systemic therapy to combined therapy of systemic therapy plus locoregional therapy has attracted more and more attention. Several retrospective and prospective studies have been initiated to assess the efficacy of combination therapies and preliminarily demonstrated potent efficacy, marking it as a viable therapeutic option for advanced HCC (9,12,21-23). Especially, the study of atezolizumab + bevacizumab and TACE-HAIC combined treatment for high tumor burden unresectable HCC patients found it a viable therapeutic option (23). Not to be ignored, interventional therapy may increase risks of complications such as gastrointestinal bleeding and hepatic dysfunction, while targeted therapy is associated with similar AEs. Referring to the general usage and dosage adjustment principles of bevacizumab in the treatment of HCC (14) and previous practical experience of our hospital, half-dose bevacizumab (7.5 mg/kg) may balance efficacy and safety. However, whether dose adjustment of targeted agents is required in combination therapy remains an unresolved question, as no studies have specifically addressed this issue to date. Addressing this knowledge gap constitutes the principal aim of this investigation.

This study is a real-world PSM analysis to evaluate the efficacy and safety of different doses of bevacizumab in the combined therapy of bevacizumab plus ICIs and interventional therapy for unresectable HCC patients. In the present study, full-dose bevacizumab (15 mg/kg) triple therapy demonstrated a statistically significant improvement in PFS relative to half-dose bevacizumab (7.5 mg/kg) triple therapy, while no difference was observed in OS. The full-dose group demonstrated numerically higher ORR and DCR than the half-dose group, but showed no statistical difference. The incidence of AEs was comparable between the two groups, with no statistically significant differences observed. The safety profiles of both the two groups were acceptable, with no severe toxicities.

The study by Wang et al. demonstrated that the ORR and DCR were 42.9% and 100% for intermediate-stage HCC beyond the up-to-seven criteria treated with TACE combined with atezolizumab/bevacizumab according to RECIST 1.1 (11). In parallel, the study by Xiang et al. revealed that the ORR and DCR in the triple therapy of TACE combined with a programmed cell death protein 1 (PD-1) inhibitor and lenvatinib were 64.3% and 85.7% (24). In this study, the ORR reached 53.3% and 36.7% for unresectable HCC patients receiving full-dose bevacizumab and half-dose bevacizumab in the triple therapy respectively, which were similar to previous studies. Full-dose bevacizumab showed promising and favorable results with better ORR and DCR relative to half-dose bevacizumab in triple therapy. However, there were no significant differences between the two groups (P=0.19, 0.72). High response rates may be caused by the synergistic effect of molecular targeting agents (MTAs), ICIs, and TACE/HAIC.

In the present study, the full-dose group showed significantly prolonged PFS compared with half-dose group (median PFS: not attained vs. 8 months, P=0.004). The median OS was not reached with a comparable 1-year OS rate between the two groups (83% vs. 83%, P>0.99). Several prospective and retrospective studies explored the efficacy of combination treatments (including TACE, tyrosine kinase inhibitors, and ICIs) for unresectable HCC have been ongoing recently (12,25,26). Results from a multicenter retrospective study showed that patients staged at BCLC B-C received the treatment of TACE combined with lenvatinib plus sintilimab achieved an ORR of 46.7%, with a median PFS and a median OS of 13.3 months and 23.6 months, respectively (21). The half-dose group in our study demonstrated inferior PFS compared with the previous study. Notably, the median PFS for the full-dose group was not yet reached due to relatively shorter follow-up duration. While direct cross-study comparison was inappropriate, it helpful for interpreting our findings. The IMbrave150 trial showed that the OS rate at 1 year was 67.2% (95% CI: 61.3 to 73.1) for patients with atezolizumab plus bevacizumab and the median PFS was 6.8 months (95% CI: 5.7 to 8.3) (4). Compared with the previous study, our results indicated that full-dose triple therapy inhibited better PFS, while the half-dose triple therapy demonstrated only a marginal improvement in PFS for unresectable HCC patients. These results indicated that locoregional therapies combined with full-dose bevacizumab and ICIs presented impressive efficacy in the treatment of unresectable HCC and might be optimal selection in unresectable HCC patients. Although full-dose group showed better PFS than half-dose group, it didn’t show any advantages in terms of OS. The possible reason may be more AEs occurred in the full-dose group, which affects the prognosis. Moreover, different treatment plans for the posterior line may affect OS. For example, some patients undergo surgical resection when they achieved PR after triple therapy and the OS is longer for these patients.

The safety of different doses of bevacizumab in triple therapy was also investigated in the present study. The combination therapy might increase the rate of certain toxicities inevitably, but most cases were mild in severity. As shown in Tables 3,4, although the occurrence of AEs was numerically higher in the full-dose group versus the half-dose group, this difference did not reach statistical significance. The most common grade 3 or 4 AEs were gastrointestinal hemorrhage and abnormal liver function in both the full-dose group and half-dose group. High rates of gastrointestinal hemorrhage in both the two groups may be attributed to the combined effects of TACE/HAIC and bevacizumab. Vascular complications are typical complications of bevacizumab (27). As we all know, TACE may increase portal pressure, especially for patients with portal vein tumor thrombosis (PVTT). The combination of TACE and bevacizumab may increase the risk of gastrointestinal hemorrhage (16). Embolization, the use of chemotherapy drugs during TACE/HAIC may lead to liver function damage, while the usage of bevacizumab plus ICIs could increase the risk and worsen liver function. Moreover, most HCC patients have liver cirrhosis, and a lot of patients are accompanied by portal hypertensive gastropathy, esophageal-gastric variables, thrombocytopenia, splenomegaly, and reduced liver reserve function (15,28). Full-dose bevacizumab may worsen the procedure compared to half-dose bevacizumab. While a dose-dependent increase in treatment-related AEs was observed in this study, no statistically significant differences were detected between two groups, with both groups maintaining clinically manageable safety profiles. Protocol optimization strategies could be considered to reduce grade ≥3 toxicities, including pre-TACE/HAIC administration of bevacizumab and ICIs, initiating bevacizumab and ICIs treatment when liver function returns to Child-Pugh class A, dose reduction of bevacizumab, and extending the interval of TACE/HAIC, though prospective validation in controlled trials is required.

There are several limitations in this study. Firstly, this is a single-center retrospective study, potential selection bias may arise from non-randomized patient allocation and modest sample size, particularly in the inclusion of heterogeneous regimens (atezolizumab, sintilimab, and combined TACE/HAIC therapies), though consistent enrollment criteria were applied across different dose cohorts. However, it was inevitable in retrospective studies. PSM methodology was employed to address potential confounding variables. Secondly, substantial variations in subsequence treatments after triple therapy may confound survival outcome interpretations. Thirdly, while PSM was implemented to address confounders, residual bias from unmeasured variables cannot be excluded. Fourthly, the retrospective collection of AEs data from hospital information system might lead to underestimation of AE incidence, particularly for subjective symptoms not systematically documented. Therefore, to determine the optimal treatment dose for unresectable HCC patients, large sample size, multicenter, prospective studies are needed to confirm the efficacy and safety of different doses of bevacizumab in triple therapy.

Conclusions

Full-dose bevacizumab exhibited prolonged PFS, while maintaining comparable in OS and ORR relative to half-dose bevacizumab in unresectable HCC patients treated with triple therapy. Accordingly, the occurrence of treatment-related AEs revealed dose-dependent increases, though no statistical difference was observed between the two groups. AEs of both groups remained acceptable. These data provide a framework for personalized combination therapies in unresectable HCC patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-962/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-962/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-962/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-962/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in compliance with the ethical standards of Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics Committee of Zhongshan Hospital, Fudan University (approval No. B2023-219R). Informed consent was obtained from all patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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