Predictive Role of Liver Functional Reserve, Serum Alpha-Fetoprotein, and Histopathological Grade in Patients Receiving Combination Immunotherapy for Advanced Hepatocellular Carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) is frequently diagnosed at an advanced stage, when impaired hepatic reserve and aggressive tumor biology may adversely affect the efficacy of systemic immunotherapy. Liver functional reserve, serum alpha-fetoprotein (AFP), and histopathological grade may therefore provide important predictive information.

Objective: To determine the predictive role of liver functional reserve, serum AFP, and histopathological grade in patients with advanced HCC receiving combination immunotherapy.

Methods: A prospective observational study was conducted in a tertiary hospital among 100 patients with advanced HCC receiving combination immunotherapy. Baseline liver function was assessed using Child–Pugh classification and albumin-bilirubin (ALBI) grade. Serum AFP, bilirubin, albumin, ALT, AST, and other biochemical parameters were recorded. Histopathological tumor grade was determined according to tumor differentiation. Treatment response was assessed radiologically, while progression-free survival (PFS) and overall survival (OS) were evaluated during follow-up. Associations between baseline variables and treatment outcomes were analyzed using logistic regression and Cox proportional-hazards models.

Results: Among 100 patients, 38 (38.0%) achieved an objective response, including 12 (12.0%) complete and 26 (26.0%) partial responses, while 34 (34.0%) had stable disease and 28 (28.0%) showed progressive disease. Objective response was significantly higher in patients with Child–Pugh class A than class B (45.5% vs. 18.2%, p=0.008) and in patients with ALBI grade 1 compared with grades 2–3 (52.9% vs. 26.0%, p=0.006). Patients with AFP <400 ng/mL demonstrated a significantly higher response rate than those with AFP ≥400 ng/mL (46.8% vs. 22.2%, p=0.011). Poorly differentiated tumors were associated with a lower objective response compared with well/moderately differentiated tumors (20.0% vs. 43.8%, p=0.018). Median PFS was 8.7 months in Child–Pugh A patients compared with 4.6 months in Child–Pugh B patients (p=0.003), while median OS was 18.9 and 10.2 months, respectively (p<0.001). On multivariate analysis, impaired liver functional reserve (HR=2.18, 95% CI: 1.31–3.63, p=0.003), AFP ≥400 ng/mL (HR=1.91, 95% CI: 1.16–3.15, p=0.011), and poor histopathological differentiation (HR=1.84, 95% CI: 1.08–3.14, p=0.025) were independently associated with shorter OS.

Conclusion: Preserved liver functional reserve, lower serum AFP, and favorable histopathological grade were significantly associated with improved response and survival among patients with advanced HCC receiving combination immunotherapy. The combined assessment of hepatic reserve, AFP, and tumor differentiation may provide a useful approach for pretreatment risk stratification and prediction of immunotherapy outcomes.