A Proposal for a Simple Subclassification of Advanced Hepatocellular Carcinoma in Systemic Treatment

1. Introduction

Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide. Primary liver cancer includes hepatocellular carcinoma (HCC), which accounts for 75–85% of cases, and intrahepatic cholangiocarcinoma, which accounts for 10–15%, along with other less common types of liver cancer [1]. HCC arises from hepatocytes and typically develops in the presence of chronic liver conditions such as chronic hepatitis B or C infection, alcohol abuse, or metabolic dysfunction-associated steatotic liver disease [2,3,4,5]. Symptoms of HCC include fatigue, abdominal pain or swelling, unexplained weight loss, and jaundice. However, most patients with HCC exhibit no symptoms in the early stages of the disease. Therefore, regular screening tests such as ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and blood tests are essential for individuals with chronic liver disease [6,7]. The treatment of HCC depends on the stage of cancer, liver function, and the patient’s overall health status. Treatment options for early-stage HCC include ablation, resection, radiation, transarterial chemoembolization, and liver transplantation. However, the treatment options for advanced-stage HCC are generally limited to systemic therapy [8,9,10].

Advances in systemic treatment have resulted in significant changes in the treatment outcomes of unresectable HCC [11,12,13]. With the advent of immune checkpoint inhibitors and other tyrosine kinase inhibitors, multiple drug treatments have become available, and the indications for each are rapidly evolving [14,15,16,17,18,19]. The Barcelona Clinic Liver Cancer (BCLC) staging system is widely used as a treatment guideline for HCC [20]. In this classification, advanced HCC (BCLC-C) is defined as "patients presenting with vascular invasion or extrahepatic spread who are still relatively fit," with an expected survival period of about 2 years. However, in clinical practice, the prognosis of advanced HCC varies significantly. At the same time, some patients live well beyond 2 years, while many have a prognosis of less than 6 months [21,22,23]. Therefore, a precise subclassification of advanced HCC based on treatment outcomes is highly desirable. In this study, we focused on the presence or absence of vascular invasion and extrahepatic spread when initiating systemic treatment. We identified a simple subclassification associated with treatment outcomes.

2. Materials and Methods

2.1. The Study Population

We retrospectively collected clinical data from patients who received first-line systemic treatment between 2011 and 2024 at the Nagoya University Hospital in Aichi, Japan. Baseline characteristics, including age, sex, underlying liver disease, laboratory data, and tumor-specific factors, such as the duration of drug administration, tumor stage based on the BCLC classification, macrovascular and portal vein invasion, and extrahepatic spread, were retrospectively assessed. This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Nagoya University Hospital (No. 2021-0247).

2.2. HCC Diagnosis

HCC was primarily diagnosed using hemodynamic imaging techniques, including contrast-enhanced CT, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI, and/or contrast-enhanced ultrasonography with perflubutane [24,25,26]. Pathological diagnosis was performed only in inconclusive cases.

2.3. Liver Function Assessment

Liver function was assessed using the Child–Pugh classification and the albumin–bilirubin (ALBI) score. In brief, the ALBI score was calculated based on laboratory data using the following formula: ALBI score = log10 bilirubin (µmol/L) × 0.66 + albumin (g/L) × −0.085 [27].

2.4. Systemic Therapy

Patients received systemic therapy until disease progression was confirmed, unacceptable adverse events occurred, consent was withdrawn, or a physician decided to discontinue the treatment based on the patient's condition and clinical data. Sorafenib was administered until February 2018 [14,15], lenvatinib between March 2018 and October 2020 [16], atezolizumab plus bevacizumab from November 2020 [17,18], and tremelimumab plus durvalumab from January 2023 [19]. However, the choice of agent was also influenced by complications. The systemic therapy regimens were as follows: 400 mg sorafenib orally twice daily, 12 mg lenvatinib daily for patients weighing ≥60 kg, or 8 mg daily for those weighing <60 kg; 1200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously every 3 weeks; and 300 mg tremelimumab intravenously once plus 1500 mg durvalumab intravenously every 4 weeks.

2.5. Assessment of Treatment Effects and Adverse Events

Treatment effects were typically assessed every 2–4 months using contrast-enhanced CT or Gd-EOB-DTPA-enhanced MRI, following the RECIST and mRECIST criteria [28]. Tumor markers, such as alpha-fetoprotein and des-γ-carboxy prothrombin, were also evaluated at each patient visit. Adverse events were graded using the Common Terminology Criteria for Adverse Events version 5.0 [29]. Drugs were discontinued or interrupted according to the manufacturer’s instructions.

2.6. Statistical Analysis

Categorical variables, described as numbers, were compared using the chi-square test, and continuous variables, described as means (minimum to maximum), were compared using a one-way analysis of variance. Multiple comparisons were performed using Tukey's multiple comparison test. Overall survival (OS) was analyzed using the Kaplan–Meier method and compared using the log-rank test. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals (CIs). For all tests, statistical significance was set at P < 0.05. GraphPad Prism 9 (GraphPad Software, San Diego, CA, USA), R (version 4.1.2, R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org/), and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R, were used for the statistical analyses [30].

3. Results

Approximately, 362 patients with HCC who received first-line systemic therapy were enrolled during the study period. The breakdown of first-line treatments was as follows: sorafenib, 207 cases; lenvatinib, 72 cases; atezolizumab plus bevacizumab, 75 cases; and durvalumab plus tremelimumab, eight cases. By applying the “current” BCLC classification, 207 patients with either vascular invasion or extrahepatic metastasis (advanced group) had significantly worse prognoses than the prognosis of 155 patients without these features (intermediate group), with a median survival of 434 days vs. 658 days (Figure 1a).

Further classification of the advanced group into three subgroups—77 patients with only extrahepatic metastasis (m group), 78 patients with only vascular invasion (v group), and 52 patients with both vascular invasion and extrahepatic metastasis (vm group)—demonstrated that the m group had a significantly better prognosis than the other two groups, with a median survival time of 649 days in the m group, 323 days in the v group, and 187 days in the vm group (Figure 1b). Even among patients with a Child-Pugh score of A for liver function at the initiation of systemic therapy, those in the m group had a significantly better prognosis than those in the other two groups (Figure 1c). These results reveal distinct subgroups of advanced HCC, potentially indicating different prognoses in response to first-line systemic treatments.

A comparison of the clinical backgrounds of the three groups revealed that the m group had significantly better liver function at the time of treatment initiation than the function in the other two groups (Table 1). In addition, intrahepatic lesions were substantially larger in the v group than in the m group. Although no significant differences in progression-free survival among the three groups were observed, the time to treatment failure was significantly longer in the m group than in the other two groups, suggesting better treatment tolerance in the m group (Table 1).

m group, patients with only extrahepatic metastasis; v group, patients with only vascular invasion; vm group, patients with both vascular invasion and extrahepatic metastasis; PS, performance status; SOR, sorafenib; LEN, lenvatinib; AB, atezolizumab DT, durvalumab–tremelimumab PFS, progression-free survival; TTF, time to treatment failure; AFP, alpha-fetoprotein; DCP, des-gamma-carboxy prothrombin; PT-INR, prothrombin time-international normalized ratio; T-bil, total-bilirubin

In a study of 207 patients who received first-line systemic treatment for advanced HCC, those treated with atezolizumab plus bevacizumab had a significantly improved prognosis (Figure 2a). However, in the m group, no significant difference was noted in the prognosis based on the type of initial systemic treatment (Figure 2b). Notably, atezolizumab plus bevacizumab treatment demonstrated significantly better outcomes in the v and vm groups than other systemic treatments (Figure 2c). These results suggest that the improved prognosis following atezolizumab plus bevacizumab treatment in advanced HCC is primarily attributable to the effects of the drugs on the vm and vm groups.

In the univariate analysis of factors associated with survival, the m group, performance status, Child–Pugh score, and initial treatment with immune checkpoint inhibitors were identified as significant (Table 2). In multivariate analysis, which included these factors, the m group was identified as an independent and significant factor (hazard ratio 0.50, Table 2). Taken together, patients with advanced HCC with only extrahepatic metastases represent a distinct subgroup in terms of prognosis after first-line systemic treatment.

4. Discussion

We focused on the presence or absence of vascular invasion and extrahepatic metastasis at the time of first-line systemic therapy for HCC. We identified that the prognosis could be broadly categorized into three groups. Among these, patients with extrahepatic metastasis but no vascular invasion (group m) had a better prognosis after the introduction of systemic therapy than those in the other two groups. Applying this simple sub-classification at the start of systemic therapy can help guide appropriate treatment decisions.

The prognosis of HCC is significantly influenced not only by the stage of the cancer but also by liver function, performance status, and comorbidities, making individual patient evaluation essential. The BCLC system is commonly used to stage HCC, and each stage provides a general prognostic prediction [20]. For cases classified as BCLC-C with vascular invasion or extrahepatic metastasis, the expected survival time is approximately 2 years, and systemic therapy is recommended. Despite recent advancements in systemic therapy for HCC, leading to trends in prolonged OS, the prognosis for HCC cases classified as BCLC-C varies widely, with many cases having a survival time of less than 6 months [21,22,23].

Recently, new subclassifications such as the Bolondi classification and Kinki criteria have been proposed and widely applied in clinical practice for HCC cases classified as BCLC-B (intermediate HCC) [31,32]. However, investigations into the subclassification of BCLC-C cases are limited. Based on our results, we propose a new subclassification for predicting the prognosis of advanced HCC when introducing systemic therapy, focusing on the presence or absence of vascular invasion and extrahepatic metastasis. Owing to the retrospective study design, we could not determine the underlying cause of the improved prognosis in the m group. However, we speculate that the presence of vascular invasion may aggravate liver function, leading to an insufficient relative dose intensity for systemic therapy and/or reduced capacity for subsequent treatments. As this was a single-center, retrospective observational study, further validation in a multicenter setting is necessary. We hope that this proposal contributes to the reclassification of advanced HCC.

5. Conclusions

Advanced HCC with extrahepatic metastases but no vascular invasion represents a new staging category for the initiation of systemic treatments.