Survival and Pathological Outcomes of Neoadjuvant Therapy Plus Surgery versus Direct Surgery in CNLC Ib–IIIa Hepatocellular Carcinoma

Technical Summary: Survival and Pathological Outcomes of Neoadjuvant Therapy Plus Surgery versus Direct Surgery in CNLC Ib–IIIa Hepatocellular Carcinoma

Problem Statement

Primary hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with a particularly high burden in China due to hepatitis B virus (HBV) prevalence and liver cirrhosis. While radical surgical resection (R0 resection) is the most effective curative modality, approximately 50% of patients present with locally advanced disease, and even after curative resection, the 5-year postoperative recurrence rate can reach 80%. There is an urgent clinical need to identify strategies that reduce postoperative recurrence and improve long-term prognosis, particularly for patients at high risk of recurrence (e.g., those with microvascular invasion, large tumors, or multifocal lesions). While preoperative neoadjuvant therapy has shown promise in shrinking tumors and eliminating occult micrometastases, systematic research on its efficacy specifically for resectable HCC patients with high-risk recurrence factors remains limited.

Methodology

This study employed a retrospective cohort design involving 114 patients with CNLC stage Ib–IIIa HCC who underwent R0 resection at Peking University People's Hospital between January 2017 and May 2025.

• Cohort Division: Patients were categorized into two groups: a Neoadjuvant Therapy Group (n=20), who received preoperative triple therapy followed by surgery, and a Direct Surgery Group (n=94), who underwent immediate hepatectomy.
• Neoadjuvant Regimen: The therapy group received a combination of Transarterial Chemoembolization (TACE), anti-angiogenic targeted agents (lenvatinib or apatinib), and immune checkpoint inhibitors (PD-1 inhibitors such as camrelizumab, sintilimab, or tislelizumab). Treatment efficacy was evaluated using mRECIST criteria 3 months post-initiation.
• Statistical Analysis: To mitigate selection bias arising from baseline imbalances (specifically gender distribution), the study utilized Propensity Score Matching (PSM) with a caliper of 0.02. Variables matched included age, gender, comorbidities, AFP levels, liver function, CNLC staging, tumor size, and portal vein tumor thrombus (PVTT) status.
• Endpoints: The primary endpoints were Overall Survival (OS) and Recurrence-Free Survival (RFS). Secondary endpoints included postoperative pathological features (microvascular invasion, liver capsule invasion, tumor differentiation) and pathological response rates (pCR, pPR).

Key Contributions

• Comparative Efficacy Analysis: The study provides a direct comparison of survival outcomes and pathological characteristics between patients receiving preoperative triple neoadjuvant therapy versus those undergoing upfront surgery for high-risk resectable HCC.
• Pathological Correlation: It links preoperative triple therapy to specific improvements in postoperative pathological indicators, specifically the reduction of microvascular invasion (MVI) and liver capsule invasion, which are established risk factors for recurrence.
• Response Quantification: The study quantifies the pathological response rates (complete and partial) achieved by the triple therapy regimen in a real-world retrospective setting.

Results

• Survival Outcomes:
  • Before PSM: The neoadjuvant group demonstrated significantly superior Recurrence-Free Survival (RFS) compared to the direct surgery group (median RFS: 29 months vs. 18 months; P=0.004). No significant difference was observed in Overall Survival (OS).
  • After PSM: The superiority in RFS persisted in the matched cohort (12 pairs). The median RFS for the neoadjuvant group was "not reached," compared to 20 months for the direct surgery group (P=0.001).
  • Multivariate Analysis: Neoadjuvant therapy was identified as an independent protective factor for survival (HR=0.15, 95% CI: 0.04–0.56, P<0.01).
• Pathological Findings:
  • The neoadjuvant group exhibited significantly lower rates of high-risk pathological indicators. Before PSM, microvascular invasion was 20.00% in the neoadjuvant group versus 60.64% in the direct surgery group (P<0.05). Liver capsule invasion was 25.00% vs. 64.89% (P<0.05). These differences remained statistically significant after PSM.
• Therapeutic Response:
  • Among the 20 patients in the neoadjuvant group, 3 achieved Pathological Complete Response (pCR, 15%), and 10 achieved Pathological Partial Response (pPR, 50%). No patients experienced progressive disease (PD).

Significance and Claims

The authors conclude that preoperative neoadjuvant therapy, specifically the combination of TACE, targeted agents, and immune checkpoint inhibitors, significantly prolongs recurrence-free survival and optimizes pathological characteristics in HCC patients undergoing R0 resection. The study posits that this strategy not only improves survival outcomes but also modifies tumor biological behavior by reducing critical risk factors like microvascular and capsule invasion.

The paper suggests that this approach serves as an important strategy for improving the long-term prognosis of patients with CNLC stage Ib–IIIa HCC who are at high risk of recurrence. The authors acknowledge limitations, including the retrospective nature of the study, the relatively small sample size, and the lack of standardized neoadjuvant regimens, but maintain that the findings support the role of neoadjuvant therapy in optimizing clinical decision-making for this patient population.