ALBI Grade Analyses of TACE Combined with Anti-Angiogenesis Therapies Plus PD-1 Inhibitors versus Anti-Angiogenesis Therapies Plus PD-1 Inhibitors in Advanced HCC

Introduction

Liver cancer ranks among the most prevalent risk of cancer-related deaths globally, with hepatocellular carcinoma (HCC) accounting for 75–85% of all diagnosed cases.^1,2 Despite advancements in early detection methods for HCC, approximately 80% of individuals are still identified as having intermediate-to-advanced stages upon initial evaluation in the majority of regions globally.^3,4 Transarterial chemoembolization (TACE) stands as the frontline therapy recommended by the Barcelona Clinic Liver Cancer (BCLC) staging system for patients with intermediate-stage HCC. Moreover, TACE is frequently utilized in clinical practice to treat advanced HCC.^3,5–7

The CHANCE001 study demonstrated that TACE plus PD-(L)1 inhibitors and anti-angiogenesis therapies yielded significantly superior clinical outcomes for advanced HCC compared to TACE alone in real-world clinical scenarios.⁸ Meanwhile, the EMERALD-1 Phase III trial demonstrated that TACE plus durvalumab and bevacizumab strongly improved progression-free survival (PFS) versus TACE monotherapy to manage unresectable HCC.⁹ Furthermore, a Phase II study, assessing the effectiveness and safety of TACE plus lenvatinib and sintilimab in advanced HCC, showed favorable antitumor potential with a tolerable safety profile.¹⁰ Furthermore, some studies have indicated that the combination of TACE plus PD-1 inhibitors and anti-angiogenesis therapies correlated with enhanced OS when compared to dual systemic treatment being the primary therapy approach for unresectable HCC.^11–13

The underlying liver function is a critical determinant of patient’s prognosis.¹⁴ Assessment of liver function is typically based on established markers, including the Child-Pugh (CP) classification as well as the Albumin-Bilirubin (ALBI) grading system.¹⁵ The ALBI grade offers a superior objective evaluation of liver function versus the CP classification, with demonstrated efficacy that is equivalent to or surpasses that of the CP class.¹⁵ The baseline ALBI classification serves as a critical prognostic marker for HCC patients undergoing surgical resection,¹⁶ sorafenib,¹⁷ lenvatinib,¹⁸ and atezolizumab plus bevacizumab.¹⁹ Beyond its prognostic significance, ALBI grading offers a nuanced assessment of hepatic function throughout the course of treatment for advanced HCC patients.²⁰ Nevertheless, the influence of baseline ALBI classification on the therapeutic benefits of advanced HCC patients receiving TACE plus anti-angiogenesis therapies and PD-1 inhibitors remains to be definitively established. Consequently, the design of the current study was to evaluate the ALBI grade’s role in advanced HCC undergoing TACE plus anti-angiogenesis therapies and PD-1 inhibitors versus anti-angiogenesis therapies plus PD-1 inhibitors.

Materials and Methods

With ethical approval granted by the institutional review board of Affiliated Hospital 2 of Nantong University (No. 2022KT269), this study was performed under the principles of the Declaration of Helsinki. Considering the research’s retrospective design, the need for informed consent from participants was waived, and we stated that patient data was strictly confidential, aligning with standard procedures for such research. Advanced HCC treated with TACE plus anti-angiogenesis therapies and PD-1 inhibitors (TACE+TP group) or anti-angiogenesis therapies plus PD-1 inhibitors (TP group) between January 2019 and June 2023 at three hospitals were enrolled. A multidisciplinary discussion was performed before treatment to assess whether TACE+TP or TP alone would be the most appropriate treatment option for the patient. The potential advantages and disadvantages of both treatments were explained to the patients. The final decision on the treatment choice was made by the patients or their relatives. The study’s inclusion criteria included: 1) confirmation of the diagnosis of HCC, either through histological examination or clinical assessment; 2) an identifiable lesion, including multinodular HCC; 2) BCLC stage C; 4) patients with HCC-related therapy histories such as curative resection, ablation, or TACE were permitted. 5) CP grade A or B; 6) Administration of anti-angiogenesis agents and PD-1 inhibitors was begun within a four-week window before or subsequent to TACE in the TACE+TP group and PD-1 inhibitors were introduced within four weeks after the commencement of anti-angiogenesis agents in the TP group. Patients lacking complete follow-up data or with missing information were excluded.

TACE Procedure

Patients in the study were treated with two types of TACE: conventional TACE or drug-eluting beads TACE, with procedural details reported in earlier studies.²¹ Briefly, all TACE procedures in this study were expertly executed using super-selective chemoembolization by interventional physicians with extensive experience. Repeated TACE was performed based on the “on demand” mode. Evaluation for repeated TACE was performed if contrast-enhanced CT/MRI presented progression of the treated lesion(s) or new lesions for the patient. Repeated TACE was considered until: 1) liver function deteriorated to CP-C; 2) Eastern Cooperative Oncology Group (ECOG) performance status >2; and 3) progression of targeted intrahepatic lesions after three consecutive TACE sessions.

Administration of Anti-Angiogenesis Agents and PD-1 Inhibitors

Anti-angiogenesis agents and PD-1 inhibitors, including combinations of sorafenib/lenvatinib with camrelizumab, or bevacizumab with sintinimab, were started in close proximity to TACE therapy, specifically within a one-month timeframe before or after the procedure. Dosing of camrelizumab or sintinimab at 200 mg was performed intravenously at three-week intervals. Patients received oral sorafenib at 800 mg or lenvatinib dosed at 8 mg for those weighing less than 60 kg and 12 mg for those over 60 kg, with daily administration recommended. Bevacizumab was given intravenously at a dose of 15 mg/kg, also on a three-weekly schedule. In cases of disease progression or intolerable adverse events that persist despite dose reduction, treatment was escalated to regorafenib, considering the individual patient’s clinical status and treatment preferences. Apart from anti-tumor therapies, antiviral therapies with entecavir or tenofovir were recommended for patients with detectable HBV-DNA or positive hepatitis B surface antigen (HBsAg) through the entire duration of treatment for HCC.

Assessments and Outcomes

Imaging surveillance was conducted using contrast-enhanced CT and/or MRI at intervals of 2 to 3 months to monitor tumor response and progression. Laboratory assessments were completed prior to each therapy and at regular follow-up visits to evaluate individuals’ health status. Whenever serious complications developed or patients experienced discomfort and required a hospital visit for follow-up, they were instructed to return to the hospital. Furthermore, all patients underwent continuous follow-up, concluding either upon their death or the study’s endpoint on December 31, 2023. Assessment of imaging response was conducted following the current Modified Response Evaluation Criteria in Solid Tumors (mRECIST), with evaluations performed independently by two senior radiologists at each involved medical center.²² ALBI scores were calculated using the formula: (log10 bilirubin [in µmol/L] × 0.66) + (albumin (in g/L) × −0.085). ALBI grading is classified into three levels: grade 1 for scores ≤ −2.60, grade 2 for scores > −2.60 to ≤ −1.39, and grade 3 for scores > −1.39.¹⁵

The primary outcomes were time to progression of the ALBI grade and change in ALBI score between the initial baseline and the final assessment point available. Time to progression of the ALBI grade was measured between the ALBI assessment at baseline and the first subsequent measurement that indicated an increase of at least one grade above the baseline level. The secondary outcomes encompassed overall survival (OS) and PFS. OS was identified as the duration from the commencement of the initial treatment to death due to any cause. PFS was identified as the interval between the start of the initial therapy and the earliest occurrence of tumor progression or death due to any cause.

Statistical Analysis

The patient characteristics were reported utilizing means with standard deviations for continuous data, and utilizing frequencies with percentages for categorical data. Student’s t test was applied to analyze continuous data. Fisher exact test or the χ² test was applied to analyze categorical data. The correlation between change in ALBI score from the initial assessment to the final available evaluation and treatment was evaluated utilizing analysis of Covariance (ANCOVA). ANCOVA was employed to ascertain whether the average changes in ALBI scores, when adjusted for the baseline scores, were consistent between the two treatment cohorts, thereby statistically controlling for the initial ALBI score’s impact. The ANCOVA model yielded adjusted least squares means for each treatment group, accounting for the baseline ALBI score’s influence. The differences in these adjusted means between the two treatment arms, along with their respective 95% CIs, were reported to provide a comprehensive statistical comparison. OS and PFS were evaluated utilizing the Kaplan–Meier method, and survival curves were compared utilizing a Log rank test to assess differences between groups. A two-tailed P-value of less than 0.05 was determined statistically significant. All analyses were performed utilizing SPSS (version 26.0, IBM, New York).

Results

Patient Characteristics

Overall, 183 advanced HCC patients were enrolled in this study, with 100 and 83 patients categorized into the TACE+TP and TP groups, respectively (Figure 1). Data from patients classified with an ALBI classification of 3 were not included in the analysis due to the limited sample size, which precluded a comprehensive evaluation (n = 5). A summary of patient characteristics was available in Table 1. Briefly, the majority of the included individuals were male (n = 153, 80.0%), HBV-related HCC (n = 122, 66.7%), and Child-Pugh grade A (n = 139, 76.0%). The baseline characteristics were similar among the two groups.

Table 1 Baseline Characteristics of Patients

Figure 1 Flowchart of patient selection. Abbreviations: HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization; ALBI, albumin-bilirubin.

Of the 183 patients, 44 were categorized as having an ALBI grade 1 (TACE+TP, n = 23; TP, n = 21) and 139 were categorized as having an ALBI grade 2 (TACE+TP, n = 77; TP, n = 62). The patients’ baseline characteristics were comparable among the two groups irrespective of baseline ALBI classification (Table 2).

Table 2 Baseline Characteristics of Patients According to Baseline ALBI Grade

Time to Progression of ALBI Grade

Overall, the median duration until ALBI grade progression, indicative of liver function deterioration, was comparable between the TACE+TP and TP groups, with no significant difference observed (11.2 vs 19.3 months, P = 0.353) (Figure 2). Comparable findings were noted when evaluating the TACE+TP and TP groups patients initially categorized as ALBI grade 1 (3.5 vs 3.0 months; P = 0.736) and grade 2 (16.6 vs 26.4 months; P = 0.140), which suggested that TACE+TP did not negatively affect liver function than PT.

Figure 2 Kaplan–Meier estimates of time to ALBI grade increase stratified by the group. Abbreviation: ALBI, albumin-bilirubin.

Change from Treatment Baseline in ALBI Score

In aggregate, change in ALBI scores from baseline to the final assessment did not significantly differ between the TACE+TP and TP groups, with a negligible difference in the least squares mean (0.084; 95% CI −0.092−0.261). Likewise, when the change in baseline ALBI scores was stratified by ALBI classification, the difference between these two groups in the least squares mean was minimal and not significantly different for both ALBI grade 1 (0.016; 95% CI −0.375−0.406) and ALBI grade 2 (0.112; 95% CI −0.084−0.308), indicating a comparable trend across both treatment arms.

Efficacy by ALBI Grade

There was an improvement in OS with TACE+TP versus TP independent of baseline ALBI grading. For patients classified with an ALBI grade of 1, TACE+TP group had a significantly superior OS than TP group [median, 30.4 (95% CI 21.0–39.7) vs 14.0 (95% CI 10.8–17.2) months, HR = 0.242 (95% CI 0.071–0.826), P = 0.014, Figure 3A]. In the case of ALBI grade 2 patients, TACE+TP group also had a significantly superior OS than TP group [median, 21.7 (95% CI 16.8–26.5) vs 12.0 (95% CI not reach–not reach) months, HR = 0.593 (95% CI 0.357–0.985), P = 0.041, Figure 3B]. Consistent with the findings for OS, TACE+TP demonstrated a trend toward enhanced PFS across all ALBI grade categories. For patients classified with an ALBI grade of 1, TACE+TP group had a relatively superior PFS trend than TP group [median, 20.0 (95% CI 5.3–34.6) vs 7.8 (95% CI 2.8–12.8) months, HR = 0.602 (95% CI 0.259–1.402), P = 0.234, Figure 4A]. In the case of ALBI grade 2 patients, TACE+TP group also had a relatively superior PFS trend than TP group [median, 13.4 (95% CI 11.2–15.6) vs 9.4 (95% CI 6.4–12.5) months, HR = 0.785 (95% CI 0.499–1.235), P = 0.293, Figure 4B]. In addition, no instances of therapy-related mortality or unexpected serious adverse effects were reported in our study.

Figure 3 Kaplan–Meier estimates of overall survival by (A) ALBI grade 1 and (B) ALBI grade 2. Abbreviation: ALBI, albumin-bilirubin.

Figure 4 Kaplan–Meier estimates of progression-free survival by (A) ALBI grade 1 and (B) ALBI grade 2. Abbreviation: ALBI, albumin-bilirubin.

Discussion

In our study, we observed that time to progression of the ALBI grade and change in ALBI score between the initial baseline and the final measurement were comparable between the TACE+TP and TP groups, irrespective of the initial ALBI grade. Furthermore, TACE+TP demonstrated a significant enhancement in OS and a consistent trend toward improved PFS across both ALBI grade 1 and grade 2 subgroups when compared to TP.

The worsening of liver function in HCC patients restricts available treatment options and adversely affects their prognosis, highlighting the critical importance of liver function in managing the disease.²³ TACE is an established therapeutic standard that has been employed for unresectable HCC over numerous years, reflecting its enduring role in oncology. Although TACE could contribute to a decrease in liver function,²⁴ a study has demonstrated that the clinical benefits and safety of CP B (score 7) HCC patients who underwent TACE were comparable to those of CP-A patients.²⁵ Recently, debates have emerged regarding the optimal therapeutic strategy for HCC when liver resection and radiofrequency ablation are not viable options, specifically concerning whether to prioritize TACE or systemic therapy approaches.^26–28 For enhanced prioritization of therapeutic options, the ALBI classification has been recognized as a valuable criterion for evaluating liver function. In instances where TACE fails to elicit a complete response after a single session, it is advisable to contemplate the early integration of systemic therapy prior to re-initiating TACE.

Interestingly, TACE+PT did not adversely influence liver function than PT in HCC patients, which was determined by monitoring time to progression in ALBI grade and observing changes in ALBI scores. The potential reasons might be explained as follows: 1) all patients underwent super-selective TACE, which minimally impaired liver function; and 2) TACE+PT improved clinical efficacy in advanced HCC while reducing the number of repeated TACE.

Previous research assessing the influence of baseline ALBI grading on treatment efficacy in advanced HCC has yielded results that are largely in alignment with our study’s observations. Specifically, in the context of first-line therapy, a post-hoc analysis from the phase III REFLECT trial demonstrated that patients undergoing lenvatinib experienced more favorable clinical benefits (OS and PFS) versus those treated with sorafenib, across all ALBI grade categories.¹⁸ Furthermore, in the second-line therapy context, a post-hoc analysis of the REACH plus REACH-2 trials revealed superior survival outcomes (OS and PFS) with ramucirumab versus placebo, irrespective of the patients’ baseline ALBI classification.²⁹ A consistent finding was revealed in patients receiving cabozantinib.³⁰ Meanwhile, a post-hoc analysis of the KEYNOTE-240 study, evaluating pembrolizumab against placebo after sorafenib as a second-line treatment, indicated a trend toward enhanced OS and PFS with pembrolizumab than placebo, irrespective of the patients’ baseline ALBI grade.³¹ Within the scope of our study, we observed a significant improvement in OS and a noteworthy trend toward enhanced PFS among patients receiving TACE+TP, as compared to those receiving TP alone, across all baseline ALBI grading categories.

Furthermore, HCC patients with a baseline ALBI grade of 1 exhibited more favorable survival benefits versus patients with an ALBI grade of 2 or higher, following treatment with sorafenib³² and ramucirumab.²⁹ The ALBI grade had demonstrated prognostic significance for treatment outcomes in HCC patients, irrespective of whether they received atezolizumab plus bevacizumab or sorafenib alone.¹⁹ These findings underscored the critical importance of preserving liver function to maximize the therapeutic benefits derived by patients undergoing TACE+TP.

The study’s findings should be interpreted with consideration of several inherent limitations. First, the retrospective design might predispose the research to potential biases, underscoring the need for caution in extrapolating these results. Prospective studies would offer a more robust framework for validation. Second, the limited sample size of patients with a baseline ALBI grade of 3 precluded a comprehensive analysis of outcomes for this subgroup. Finally, the analysis employed the ALBI grading system, prioritizing its objectivity over the CP grading system. Unlike the CP system, the ALBI grade did not encompass subjective evaluations of clinical signs, thereby providing a more reliable measure of liver function.

Conclusions

TACE+PT did not negatively affect liver function compared to PT in HCC patients, as indicated by the changes in ALBI scores, while a significant improvement in OS and a promising trend toward enhanced PFS with TACE+PT were observed in both ALBI grade groups.