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Abstract

Background:

The efficacy and safety of transarterial chemoembolization (TACE) combined with immune checkpoint inhibitors (ICIs) and anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) have been established. However, it remains unclear whether the addition of TACE to systemic therapies exacerbates liver function deterioration and increases mortality risk.

Objectives:

To assess liver function changes and their impact on prognosis in patients with advanced hepatocellular carcinoma (HCC) treated with ICIs and anti-VEGF antibody/TKIs with or without TACE as first-line therapy.

Design:

This is a real-world retrospective cohort study.

Methods:

Patients with advanced HCC treated with TACE combined with ICIs and anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or ICIs and anti-VEGF antibody/TKIs alone (ICI-VEGF) from January 2018 to June 2024 were retrospectively included. The primary outcomes were changes in albumin-bilirubin (ALBI) score and time to deterioration (TTD) of liver function. The secondary outcomes included overall survival (OS), progression-free survival (PFS), and the relationship between TTD and prognosis.

Results:

A total of 111 patients were included, with 54 and 57 patients receiving TACE-ICI-VEGF and ICI-VEGF, respectively. Changes in ALBI score were similar between groups (difference in least squares mean, −0.075; 95% confidence interval (CI): −0.298 to 0.148). TTD was also comparable (median for TACE-ICI-VEGF 9.7 months vs. ICI-VEGF 8.5 months; hazard ratio (HR) = 1.19 (95% CI: 0.71–2.01); p = 0.512). TACE-ICI-VEGF group demonstrated a significantly improved median OS (18.3 vs. 11.8 months; HR = 0.60 (95% CI: 0.37–0.98); p = 0.041) and a trend toward prolonged median PFS (14.7 vs. 11.2 months; HR = 0.76 (95% CI: 0.47–1.25); p = 0.278). Patients with liver function deterioration had an increased risk of mortality (median OS: 13.2 vs. 17.0 months; HR = 1.44 (95% CI: 0.88–2.35); p = 0.139).

Conclusion:

TACE combined with ICIs plus anti-VEGF antibodies/TKIs as first-line treatment generally did not adversely affect liver function. Liver function deterioration was associated with an increased risk of mortality.

Keywords

albumin-bilirubin score hepatocellular carcinoma liver function systemic therapies transarterial chemoembolization

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related mortality worldwide.¹ Despite improvements in HCC detection, over 50% of patients are diagnosed at an advanced-stage (Barcelona Clinic Liver Cancer (BCLC) Stage C), at which point curative treatments are generally not feasible.^2,3 For patients with advanced-stage HCC, systemic therapy is the recommended first-line treatment, whereas transarterial chemoembolization (TACE) may be considered in select circumstances.^2,4–6

Recent advancements in molecular targeted therapies and immune checkpoint inhibitors (ICIs) have made the combination of TACE and systemic therapy a research focus.^7,8 The rationale for combining TACE with ICIs, anti-vascular endothelial growth factor (anti-VEGF) antibodies, and tyrosine kinase inhibitors (TKIs) in the treatment of HCC lies in TACE’s ability to remodel the tumor immune microenvironment, while anti-VEGF antibody/TKIs can inhibit tumor angiogenesis, potentially yielding a synergistic antitumor effect.^9,10 Several randomized controlled trials have demonstrated the efficacy of TACE combined with systemic therapy. The LAUNCH trial revealed that the addition of TACE to Lenvatinib significantly improved the clinical outcomes in patients with advanced HCC. Entering the era of targeted and immune therapies, the LEAP-012 and EMERALD-1 trials consecutively confirmed that the combination of TACE, ICIs, and anti-VEGF antibodies/TKIs resulted in promising outcomes for HCC patients compared with ICIs and anti-VEGF antibodies/TKIs alone.^11,12 In real-world settings, a national multicenter retrospective cohort study conducted in China, the CHANCE2201 study, demonstrated that the combination of TACE with ICIs and anti-VEGF antibodies/TKIs improved the prognosis of patients with advanced HCC.¹³

Regarding treatment safety, however, most studies have primarily focused on monitoring adverse events (AEs) occurring during treatment,¹⁴ and limited research has been conducted on the long-term effects of treatment on liver function. Post hoc analyses of the SHARP, KEYNOTE-240, and IMbrave150 trials have confirmed the maintenance of liver function over the course of treatment with sorafenib, pembrolizumab, and atezolizumab plus bevacizumab (Atez/Bev);^15–17 however, the available evidence for the combination of TACE with ICIs and anti-VEGF antibodies/TKIs remains insufficient. Moreover, although previous studies have indicated that baseline liver function is an independent prognostic factor for various treatment modalities for HCC, including TACE combined with systemic therapy,^16–21 the relationship between changes in liver function during treatment and prognosis remains unclear. Consequently, whether the combination of TACE with ICIs and anti-VEGF antibodies/TKIs exacerbates the deterioration of liver function and increases the risk of mortality remains an area that warrants further investigation.

The Child-Pugh (CP) class and albumin-bilirubin (ALBI) grade are commonly used to evaluate liver function. The ALBI grade, based on serum bilirubin and albumin levels, demonstrated comparable or superior performance to that of the CP class.²² Compared with the CP class, the ALBI grade eliminates the subjective influence of ascites and hepatic encephalopathy severity, providing a more objective assessment of liver function status.²³

Therefore, we conducted a single-center retrospective cohort study to evaluate changes in liver function during treatment using the ALBI score and assess its impact on prognosis in patients with advanced HCC receiving ICIs and anti-VEGF/TKIs with or without TACE as first-line therapy.

Materials and methods

Patients

Patients with advanced HCC who received either TACE combined with ICIs and anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or ICIs combined with anti-VEGF antibody/TKIs (ICI-VEGF) as the first-line therapy at our hospital between January 2018 and June 2024 were screened and enrolled. We ensured that patient data remained strictly confidential.

The study inclusion criteria were as follows: (1) age ⩾18 years; (2) pathologically or clinically confirmed diagnosis of HCC at BCLC stage C; (3) at least one measurable intrahepatic lesion based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; (4) CP grade A or B, without uncontrolled ascites or hepatic encephalopathy; (5) Eastern Cooperative Oncology Group performance status (ECOG PS) ⩽1; and (6) first-line treatment with either ICI-VEGF or TACE-ICI-VEGF combination therapy. Definition of Combination Therapy: Anti-VEGF antibody/TKIs and ICIs were to be administered within 1 week, while TACE could be performed concurrently with or up to 3 months before or after ICI-VEGF therapy. Patients in the TACE-ICI-VEGF group were required to receive at least one cycle of ICI-VEGF therapy before or after the first TACE session. The exclusion criteria were: (1) prior systemic ICIs or anti-VEGF antibody/TKIs treatment, or local treatments using chemotherapeutic agents such as hepatic arterial infusion chemotherapy or TACE; (2) failure to meet combination therapy criteria; and (3) concurrent malignancies under active treatment.

Treatments

A multidisciplinary discussion was conducted before determining the individualized treatment regimen. The potential benefits, complications, and costs of each option were thoroughly discussed with the patient and their family, and the final decision was made collaboratively, ultimately resting with the patient and their family.

All patients received first-line ICI-VEGF combination therapy until disease progression or the occurrence of unacceptable toxicity. Agents were administered according to the recommended doses and schedules of the manufacturer’s instructions (detailed in Tables S1 and S2). In cases of unacceptable AEs deemed related to the agents, dose reduction was allowed for TKIs, but not typically for ICIs, bevacizumab, or its biosimilars. If necessary, the affected agents were temporarily interrupted.

For patients receiving TACE, either conventional TACE or drug-eluting beads TACE was standardly performed in “on demand” mode.²⁴ All TACE procedures employed super-selective catheterization and embolization techniques to improve tumor control while minimizing TACE-related complications, adhering to the current clinical guidelines.²⁵ Repeat TACE was considered when viable tumors or intrahepatic recurrence were detected through follow-up imaging, according to the relevant clinical protocols,²⁵ but was discontinued under any of the following conditions: (1) liver function deteriorated to CP grade C; (2) targeted intrahepatic lesions progressed after three consecutive TACE sessions, or (3) ECOG PS exceeded 2. The detailed TACE procedure is described in the Supplemental Material, pages 1 and 2.

Follow-up and assessments

The last follow-up was conducted on December 31, 2024. Laboratory tests were performed every 3–4 weeks, alongside assessments of vital signs, clinical symptoms, and treatment-related AEs. Radiological examinations by contrast-enhanced computed tomography or magnetic resonance imaging were performed every 9–12 weeks. The treatment response was evaluated by two independent radiologists, each with at least 10 years of experience. Second-line therapies were administered following disease progression.

Outcomes

The primary outcomes of this study were a change in ALBI score from baseline to disease progression, and time to deterioration (TTD; defined as the time from baseline to a ⩾0.5-point increase in ALBI score sustained across two visits, or to disease progression) of liver function. Secondary outcomes included overall survival (OS) and progression-free survival (PFS). OS was defined as the time from the initiation of combination therapy to death from any cause or end of follow-up (December 31, 2024). PFS was defined as the time from the initiation of combination therapy to the first tumor progression assessed by the modified RECIST (mRECIST), death from any cause, or the end of follow-up.

Statistical analysis

The baseline ALBI score was calculated using the most recent albumin and bilirubin levels before the initiation of combination therapy. Albumin and bilirubin levels were monitored at each follow-up until disease progression. The ALBI scores were calculated as follows: log10 (bilirubin (µmol/L) × 0.66) + (albumin (g/L) × −0.085). ALBI grades were classified as follows: grade 1 (⩽−2.60), grade 2 (>−2.60 to ⩽−1.39), and grade 3 (>−1.39).²²

The change in ALBI score from baseline to the last measurement before disease progression between the two groups was assessed using ANCOVA, which evaluates whether the adjusted mean changes in ALBI score differ between groups while controlling for the effect of the baseline ALBI score. The least squares mean (LSM), adjusted for baseline effects, was derived from the ANCOVA model for each group. The difference in LSM between groups, along with 95% CIs and p-values, was reported.

The TTD curve was estimated using the Kaplan-Meier method for censored data. Hazard ratios (HRs) with corresponding 95% CIs were calculated using an unstratified Cox regression model with Efron’s method for handling tied values, including baseline ALBI grade as a covariate.

A sensitivity analysis was performed to assess the robustness of the aforementioned findings using an alternative liver function evaluation criterion: time to ALBI grade increase, which was defined as the time from the initiation of combination therapy to the first ALBI measurement that was ⩾1 grade higher than baseline, or disease progression. The Kaplan-Meier method was used to estimate the time to ALBI grade increase curve, and Cox regression analysis was applied to calculate the HRs.

The median OS and PFS for each treatment group were estimated using the Kaplan-Meier method. The HRs and 95% CIs were calculated using an unstratified Cox regression model. An exploratory analysis was performed to compare OS between patients with and without liver function deterioration, defined as a ⩾0.5-point increase in the ALBI score, in the overall population and across treatment groups.

All statistical analyses were conducted using the R software (version 4.4.2; R Project for Statistical Computing, http://www.r-project.org). All comparisons were two-tailed, and p-values were calculated using the log-rank test for survival analysis, with a significance threshold of p < 0.05. The reporting of this study conforms to the STROBE statement (Table S3).²⁶

Results

Patients characteristics

A total of 111 patients were included in this analysis, with 54 and 57 patients in the TACE-ICI-VEGF and ICI-VEGF groups, respectively (Figure 1). Of the 111 patients, 28 had baseline ALBI grade 1 (TACE-ICI-VEGF, n = 13; ICI-VEGF, n = 15), 81 had baseline ALBI grade 2 (TACE-ICI-VEGF, n = 40; ICI-VEGF, n = 41), and 2 had baseline ALBI grade 3 (TACE-ICI-VEGF, n = 1; ICI-VEGF, n = 1). Data for patients with ALBI grade 3 were excluded from the analysis because of the limited sample size and inability to assess ALBI grade increase.

Figure 1.

Study cohort.

The baseline demographics and disease characteristics were generally similar in both groups. The median age was 61 years (IQR, 52–66), 90 patients (81.1%) were male, and 81 patients (73.0%) had HBV-related infection. Compared with the ICI-VEGF group, patients in the TACE-ICI-VEGF group had a comparable tumor burden (beyond the up-to-seven criteria: 43 (79.6%) vs. 40 (70.2%)), a similar proportion of vascular invasion (37 (68.5%) vs. 39 (68.4%)), and a lower proportion of extrahepatic spread (25 (46.3%) vs. 34 (59.6%)); none of these differences were statistically significant. Fewer patients in the TACE-ICI-VEGF group had undergone previous HCC-related treatments (curative resection, 5 (9.3%) vs. 19 (33.3%); ablation, 0 (0.0%) vs. 2 (3.5%)), contributing to an imbalance in baseline characteristics (Table 1). Patient characteristics according to the baseline ALBI grades are shown in Table 2.

Table 1.

Patient baseline characteristics.

Characteristics	TACE-ICI-VEGF (n = 54)	ICI-VEGF (n = 57)	p Value
Age (median (IQR))	61 (55, 66)	60 (50, 66)	0.314
Gender			0.534
Female	12 (22.2)	9 (15.8)
Male	42 (77.8)	48 (84.2)
ECOG PS			1.000
0	24 (44.4)	26 (45.6)
1	30 (55.6)	31 (54.4)
Etiology			0.080
Hepatitis B virus^a	44 (81.5)	37 (64.9)
Others^b	10 (18.5)	20 (35.1)
Child-Pugh class			0.897
A	44 (81.5)	48 (84.2)
B	10 (18.5)	9 (15.8)
ALBI grade			0.964
1	13 (24.1)	15 (26.3)
2	40 (74.1)	41 (71.9)
3	1 (1.9)	1 (1.8)
Up-to-seven criteria			0.354
Beyond	43 (79.6)	40 (70.2)
Within	11 (20.4)	17 (29.8)
Vascular invasion			1.000
Absent	17 (31.5)	18 (31.6)
Present	37 (68.5)	39 (68.4)
Extrahepatic spread			0.223
Absent	29 (53.7)	23 (40.4)
Present	25 (46.3)	34 (59.6)
Serum AFP level			0.207
⩽200 ng/mL	33 (61.1)	27 (47.4)
>200 ng/mL	21 (38.9)	30 (52.6)
HCC-related treatment history			0.004
Absent	49 (90.7)	38 (66.7)
Present	5 (9.3)	19 (33.3)
Surgery	5 (9.3)	19 (33.3)	0.004
Ablation	0 (0.0)	2 (3.5)	0.500

Hepatitis B virus infection was defined as hepatitis B surface antigen positivity and/or detectable HBV DNA.

Includes hepatitis C, schistosomal liver disease, and absence of any history of liver disease.

AFP, alpha-fetoprotein; ALBI, albumin-bilirubin; ECOG PS, Eastern Cooperative Oncology Group performance status; HCC, hepatocellular carcinoma; ICIs, immune checkpoint inhibitors; ICI-VEGF, ICIs plus anti-VEGF antibody/TKIs; TACE, transarterial chemoembolization; TACE-ICI-VEGF, TACE with ICIs plus anti-VEGF antibody/TKIs; TKIs, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor.

Table 2.

Patient characteristics according to baseline ALBI grade.

Characteristics	ALBI grade 1			ALBI grade 2
	TACE-ICI-VEGF (n = 13)	ICI-VEGF (n = 15)	p value	TACE-ICI-VEGF (n = 40)	ICI-VEGF (n = 41)	p value
Age (median (IQR))	61 (55, 66)	59 (49, 66)	0.661	62(55, 66)	61(50, 66)	0.458
Gender			1.000			0.546
Female	2 (15.4)	2 (13.3)		10 (25.0)	7 (17.1)
Male	11 (84.6)	13 (86.7)		30 (75.0)	34 (82.9)
ECOG PS			0.243			0.424
0	9 (69.2)	6 (40.0)		15 (37.5)	20 (48.8)
1	4 (30.8)	9 (60.0)		25 (62.5)	21 (51.2)
Etiology			0.910			0.082
Hepatitis B virus^a	9 (69.2)	9 (60.0)		34 (85.0)	27 (65.9)
Others^b	4 (30.8)	6 (40.0)		6 (15.0)	14 (34.1)
Child-Pugh class			1.000			0.738
A	13 (100.0)	14 (93.3)		31 (77.5)	34 (82.9)
B	0 (0.0)	1 (6.7)		9 (22.5)	7 (17.1)
Up-to-seven criteria			0.638			0.625
Beyond	9 (69.2)	8 (53.3)		33 (82.5)	31 (75.6)
Within	4 (20.4)	7 (29.8)		7 (17.5)	10 (24.4)
Vascular invasion			0.173			0.579
Absent	2 (15.4)	7 (46.7)		14 (35.0)	11 (26.8)
Present	11 (84.6)	8 (53.3)		26 ( 65.0)	30 (73.2)
Extrahepatic spread			0.140			0.581
Absent	8 (61.5)	4 (26.7)		21 (52.5)	18 (43.9)
Present	5 (38.5)	11 (73.3)		19 (47.5)	23 (56.1)
Serum AFP level			0.910			0.220
⩽200 ng/mL	9 (69.2)	9 (60.0)		24 (60.0)	18 (43.9)
>200 ng/mL	4 (30.8)	6 (40.0)		16 (40.0)	23 (56.1)
HCC-related treatment history			0.173			0.025
Absent	11 (84.6)	8 (53.3)		37 (92.5)	29 (70.7)
Present	2 (15.4)	7 (46.7)		3 (7.5)	12 (29.3)
Surgery	2 (15.4)	7 (46.7)	0.173	3 (7.5)	12 (29.3)	0.025
Ablation	0 (0.0)	1 (6.7)	1.000	0 (0.0)	1 (2.4)	1.000

Hepatitis B virus infection was defined as hepatitis B surface antigen positivity and/or detectable HBV DNA.

Includes hepatitis C, schistosomal liver disease, and absence of any history of liver disease.

During the treatment period, patients in the TACE-ICI-VEGF and ICI-VEGF groups received a median of 8 (IQR, 4–15) and 6 (IQR, 4–14) cycles of ICIs (p = 0.31), and median treatment durations of 7.1 months (IQR, 3.9–14.0) and 5.2 months (IQR, 2.8–11.0) with anti-VEGF antibodies/TKIs (p = 0.23), respectively. The TACE-ICI-VEGF group underwent a median of two sessions of TACE procedures (IQR, 1–3).

Change in ALBI score from baseline

The ALBI score changes from baseline to the last measurement before disease progression were comparable between the TACE-ICI-VEGF and ICI-VEGF groups (difference in LSM, −0.075 (95% CI, −0.298 to 0.148), p = 0.51). In subgroup analysis, the between-group difference in LSM was comparable in both groups when analyzed by ALBI grade (0.080; 95% CI: −0.366 to 0.525; p = 0.72 for ALBI grade 1 and −0.117; 95% CI: −0.375 to 0.142; p = 0.37 for ALBI grade 2).

TTD of liver function

At the data cutoff of December 31, 2024, the median follow-up duration was 13.2 months overall (IQR, 7.4–19.8), 15.0 months in the TACE-ICI-VEGF group (IQR, 9.6–19.9), versus 11.7 months in the ICI-VEGF group (IQR, 5.1–18.1) (p = 0.10). Overall, there was no significant difference in the TTD between the TACE-ICI-VEGF and ICI-VEGF groups (median: 9.7 vs. 8.5 months; HR = 0.84; 95% CI: 0.50–1.41; p = 0.51) (Figure 2). The median TTD of the TACE-ICI-VEGF group showed a modest extension, which indicated that adding TACE to ICI-VEGF therapy did not exacerbate liver function impairment relative to the use of ICI-VEGF alone. Similar results were obtained in the sensitivity analysis. No significant difference was found in the time to ALBI grade increase between the TACE-ICI-VEGF and ICI-VEGF groups (median 8.9 vs. 10.2 months; HR = 1.01; 95% CI: 0.59–1.73; p = 0.99) (Figure 3).

Figure 2.

Time to deterioration in liver function.^a

Figure 3.

Time to ALBI grade increase.^a

In the subgroup analysis based on baseline ALBI grade, the median TTD for ALBI grade 1 patients was 2.1 months in the TACE-ICI-VEGF group compared to 6.1 months in the ICI-VEGF group (HR = 1.62; 95% CI: 0.67–3.92; p = 0.27), while for ALBI grade 2 patients, it was not reached in the TACE-ICI-VEGF group versus 8.6 months in the ICI-VEGF group (HR = 0.63; 95% CI: 0.32–1.22; p = 0.17) (Figure 4(a) and (b)). This suggests that in patients with baseline ALBI grade 1, TACE combined with ICI-VEGF may accelerate liver function deterioration compared to ICI-VEGF alone, whereas in patients with baseline ALBI grade 2, it may delay liver function deterioration. A similar trend was observed in the median time to ALBI grade increase between the TACE-ICI-VEGF and ICI-VEGF groups: 1.7 versus 4.2 months (HR = 1.62; 95% CI: 0.77–4.17; p = 0.17) for ALBI grade 1, and 23.4 versus 20.2 months (HR = 0.83; 95% CI: 0.40–1.73; p = 0.62) for ALBI grade 2 (Figure 5(a) and (b)).

Figure 4.

Time to deterioration in liver function by (a) ALBI grade 1 and (b) ALBI grade 2.^a

Figure 5.

Time to ALBI grade increase by (a) ALBI grade 1 and (b) ALBI grade 2.^a

OS and PFS

A significant improvement in OS was observed in the TACE-ICI-TKI group compared to the ICI-VEGF group (median: 18.3 months (95% CI: 15.6–NA) vs. 11.8 months (9.4–16.8); HR = 0.60 (95% CI: 0.37–0.98); p = 0.04) (Figure 6(a)). Median PFS was slightly longer in the TACE-ICI-VEGF group (14.7 months (9.7–20.2) vs. 11.2 months (8.6–16.4); HR = 0.76 (95% CI: 0.47–1.25); p = 0.28), as assessed by mRECIST, although the difference was not statistically significant (Figure 6(b)).

Figure 6.

Kaplan-Meier estimates of (a) overall survival, and (b) progression-free survival assessed by mRECIST.

Impact of liver function deterioration on OS

Overall, deterioration of liver function was associated with an increased risk of mortality. Among patients who experienced a ⩾0.5-point increase in ALBI score from baseline, the median OS was 13.2 months (95% CI: 9.1–22.2), compared to 17.0 months (95% CI: 14.4–NA) in those without such an increase (HR = 1.44; 95% CI: 0.88–2.35; p = 0.14) (Figure 7). In the treatment subgroup analysis, liver function deterioration in the TACE-ICI-VEGF group was associated with worse OS (median: 16.4 months (95% CI: 9.8–NA) for patients with ALBI score increase, vs. 30.8 months (95% CI: 16.3–NA) for patients without ALBI score increase) (HR = 1.93; 95% CI: 0.89–4.18); p = 0.09) (Figure 8(a)). In the ICI-VEGF group, no significant OS difference was observed between patients with deteriorated and preserved liver function (median: 10.2 months (95% CI: 6.5–20.3) versus 11.8 months (95% CI: 11.6–NA) (HR = 1.21; 95% CI: 0.64–2.32); p = 0.55) (Figure 8(b)).

Figure 7.

Impact of liver function during treatment on OS.^a

Figure 8.

Impact of liver function during treatment on OS by (a) TACE-ICI-VEGF group and (b) ICI-VEGF group.^a

Discussion

This retrospective study evaluated the effect of adding TACE to ICIs and anti-VEGF antibodies/TKIs on liver function and its relationship with prognosis. The change in ALBI score from baseline was similar between the TACE-ICI-VEGF and ICI-VEGF groups. Additionally, the TTD of liver function showed no significant difference between the two groups. Regarding efficacy, the TACE-ICI-VEGF combination significantly improved OS and demonstrated a trend toward prolonged PFS. In both the entire cohort and the TACE-ICI-VEGF group, deterioration of liver function during treatment was associated with shorter OS.

The CHANCE2201 study demonstrated the efficacy and safety of TACE in combination with ICIs and anti-VEGF antibodies/TKIs.¹³ However, it remains uncertain whether the addition of TACE to systemic therapies exacerbates liver function deterioration, thereby contributing to a poor prognosis. Previous studies have conducted long-term follow-ups to assess the impact of ICIs and/or anti-VEGF antibodies/TKIs on liver function. In CheckMate 459, nivolumab was shown to better preserve liver function than sorafenib, as assessed by the ALBI and CP scores.²⁷ Post hoc analyses of KEYNOTE-240 and IMbrave150, based on ALBI grade, confirmed that both pembrolizumab plus best supportive care and Atez/Bev were associated with favorable liver function preservation.^15,17 In addition, Hatanaka T. et al. found no significant difference in the trend of liver function deterioration between Atez/Bev and Lenvatinib.²⁸ In our study, we also did not observe a more rapid deterioration in liver function induced by triple therapy (TACE-ICI-VEGF) compared to ICI-VEGF alone. However, the subgroup analyses revealed some heterogeneity. In patients with baseline ALBI grade 1, the time to liver function deterioration was shorter in the TACE-ICI-VEGF group compared to the ICI-VEGF group. Conversely, among patients with ALBI grade 2, the TACE-ICI-VEGF group exhibited a longer duration of stable liver function. These trends were consistent with the sensitivity analyses. One possible explanation is that in ALBI grade 1 patients, liver function impairment due to the tumor remains relatively mild, whereas the fluctuations in liver function caused by local ischemia, necrosis, and inflammatory responses following TACE are more pronounced. In contrast, ALBI grade 2 patients had already developed more severe liver dysfunction due to tumor growth, and TACE may help preserve liver function by more effectively controlling tumor progression and potentially reducing tumor burden. Previous studies support this viewpoint. Analysis of ALBI scores from the REACH/REACH2 trials indicated that the increase in the average ALBI score during treatment is likely attributable to disease progression rather than drug-induced hepatotoxicity.²⁹ Meanwhile, analysis of ALBI grades in the KEYNOTE-240 trial observed better preservation of liver function in responders who achieved a complete or partial response.¹⁵ However, owing to the limited sample size within each ALBI subgroup and imbalances in baseline characteristics between subgroups, these results should be interpreted with caution.

Notably, the proportion of patients who had previously received HCC-related treatments, such as curative resection and ablation, was higher in the ICI-VEGF group, leading to an imbalance in baseline characteristics. This imbalance may have compromised the liver function reserve in this group, making it more susceptible to liver function deterioration. Nonetheless, sensitivity analysis demonstrated that the ICI-VEGF group still exhibited a longer time to ALBI grade increase than the TACE-ICI-VEGF group, thereby affirming the credibility of the overall results. In addition, compared with the ICI-VEGF group, patients in the TACE-ICI-VEGF group appeared to receive numerically more cycles of ICIs and longer durations of anti-VEGF antibody/TKIs treatment. Although these differences did not reach statistical significance, they may still affect the accuracy of survival analyses and should therefore be interpreted cautiously.

One of the primary outcomes of this study, TTD, was defined as the time from baseline to a ⩾0.5-point increase in the ALBI score sustained across two visits or to disease progression. Compared to assessing the time to ALBI grade increase, TTD provides continuous liver function evaluation, which not only prevents the oversight of changes within the same ALBI grade but also avoids grade shifts caused by fluctuations near the grade threshold, while minimizing the confounding effects of liver function deterioration caused by tumor progression. During follow-up of albumin and bilirubin levels, researchers observed a transient increase in the ALBI score after TACE, which partially recovered and remained stable over the long term. Previous studies have indicated that liver function damage after TACE occurs in the acute phase (0–29 days) and chronic phase (30–90 days),³⁰ with significant liver function decline observed after the first TACE procedure.³¹ By selecting the TTD as the indicator of liver function, which ensures that the deterioration reflected by biochemical markers is sustained across two visits, the effect of transient liver function deterioration caused by TACE is minimized. Therefore, TTD may be a more reliable indicator of liver function than changes in ALBI grade.

Several studies have confirmed that baseline liver function is an independent prognostic factor for patients with HCC.^32–34 This study conducted an exploratory analysis to compare the prognosis of patients with deteriorated and preserved liver function during treatment. Overall, deterioration of liver function was associated with an increased risk of mortality. For each treatment group, the trend toward shorter OS in patients with liver function deterioration did not reach statistical significance in the TACE-ICI-VEGF group and was negligible in the ICI-VEGF group. These findings suggest that the effect of changes in liver function may differ across treatment regimens. Previous studies have supported these findings to a certain extent. Shen et al. reported that liver injury events were associated with patient mortality when treated with TACE-ICI-VEGF; the median OS of patients without liver injury, with grade 1–2 and grade 3–4 liver injury were undefined, 13.7 and 11.1 months, respectively (p = 0.034).³⁵ Unome et al. found that worsening of the ALBI score within the first 3 months after initiating Atez/Bev therapy was significantly associated with OS.³⁶ However, they also observed a positive correlation between changes in the ALBI score and alterations in PIVKA-II (correlation coefficient t = 0.286, p = 0.034). Therefore, the exact cause of ALBI score deterioration and poor prognosis—whether due to treatment-related AEs or disease progression—remains uncertain and warrants further investigation. Nevertheless, these findings underscore the importance of preserving liver function during treatment.

We acknowledge that the heterogeneity introduced by various drug combinations represents a major limitation of our study. Inspired by the concept of “umbrella trials,” we included drugs with similar targets, all of which are recommended by Western or Chinese guidelines for HCC treatment. In addition, we analyzed the number of patients receiving different systemic treatment regimens within each group and confirmed that there was no significant difference between groups (p = 0.798) (Table S2). Nevertheless, further studies in large, homogeneous populations are warranted. This study has several additional limitations. First, the retrospective nature may have introduced selection bias. Second, the potential influence of concurrent therapies on liver function was not evaluated, which could have confounded the results. Third, previous studies have demonstrated that subsequent-line therapy can improve patient survival,^37–39 however, the impact of subsequent therapies on survival remains unclear in our study, thus limiting the interpretation of long-term outcomes. Finally, the small sample size of this single-center study may limit the generalizability of the findings, emphasizing the need for multicenter studies to strengthen the evidence base.

Conclusion

TACE combined with ICIs plus anti-VEGF antibodies/TKIs as first-line treatment generally did not adversely affect liver function compared to ICIs plus anti-VEGF antibodies/TKIs alone in patients with advanced HCC, as measured by changes in ALBI scores. Improvements in OS and PFS were observed in patients receiving the TACE combination therapy. Furthermore, Liver function deterioration was associated with poor prognosis in the TACE-ICI-VEGF group.

Supplemental Material

sj-docx-1-tam-10.1177_17588359251347363 – Supplemental material for Liver function dynamics in advanced hepatocellular carcinoma receiving immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization

Supplemental material, sj-docx-1-tam-10.1177_17588359251347363 for Liver function dynamics in advanced hepatocellular carcinoma receiving immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization by Chen-You Liu, Meng-Fan Wang, Xiao-Yang Xu, Hao-Dong Wu, Ze Wang, Shuai Zhang, Jian Shen and Xiao-Li Zhu in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

Xiao-Li Zhu, as the corresponding author, is responsible for the content of this paper. Chen-You Liu, Meng-Fan Wang, and Xiao-Yang Xu contributed equally as co-first authors. We sincerely thank all colleagues and collaborators who provided assistance for this study.

Declarations

ORCID iDs

Chen-You Liu

Meng Fan Wang

Xiao-Yang Xu

Supplemental material

Supplemental material for this article is available online.

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