Hepatic Arterial Chemotherapy Infusion Combined with Tyrosine Kinase Inhibitors and PD-1 Inhibitors for Advanced Hepatocellular Carcinoma with High Risk: A Propensity Score Matching Study

Hepatobiliary System Oncology Medicine
Advanced Hepatocellular Carcinoma Hepatic Arterial Infusion Chemotherapy High Risk Programmed Cell Death Protein-1 Inhibitors Propensity Score Matching Triple Therapy Tyrosine Kinase Inhibitors

Study on the Application of Hepatic Arterial Chemotherapy Combined with Targeted and Immunotherapy in Advanced Liver Cancer

Background

Liver cancer is the sixth most commonly diagnosed cancer globally and the third leading cause of cancer-related deaths. Most patients are diagnosed at an advanced stage, losing the opportunity for surgical resection, with a median survival of only 2.7 to 4.0 months. In recent years, the combination of immune checkpoint inhibitors (such as PD-1 inhibitors) and targeted drugs (such as tyrosine kinase inhibitors, TKIs) has shown significant survival benefits in the treatment of advanced liver cancer. However, for high-risk patients (e.g., those with VP4 portal vein invasion or tumor diameter ≥10 cm), the efficacy of existing systemic therapies is limited. Therefore, researchers have explored the triple therapy of hepatic arterial infusion chemotherapy (HAIC) combined with TKIs and PD-1 inhibitors to improve the prognosis of high-risk advanced liver cancer patients.

Study Source

The study was conducted by Mengxuan Zuo, Guanglei Zheng, Yuzhe Cao, and others from Sun Yat-sen University Cancer Center. It was published online on July 12, 2024, in the International Journal of Surgery. The study was supported by the National Cancer Center of China and adhered to the ethical standards of the Declaration of Helsinki.

Study Design and Process

Study Subjects and Grouping

This multicenter retrospective study included 466 high-risk advanced liver cancer patients treated between October 2014 and April 2022 at five medical centers. Patients were divided into two groups: the triple therapy group (HAIC combined with TKIs and PD-1 inhibitors, n=245) and the dual therapy group (TKIs combined with PD-1 inhibitors, n=221). To reduce bias in baseline characteristics, propensity score matching (PSM) was used, resulting in 194 matched patients in each group.

Treatment Protocol

  • Triple Therapy Group: Patients received 4 to 6 cycles of FOLFOX (oxaliplatin, fluorouracil, and leucovorin)-based HAIC, with each cycle lasting 21 days. Additionally, patients started oral TKIs (e.g., lenvatinib, sorafenib) and intravenous PD-1 inhibitors (e.g., camrelizumab, sintilimab) within 3 days after HAIC.
  • Dual Therapy Group: Patients received only the combination of TKIs and PD-1 inhibitors.

Follow-up and Evaluation

All patients underwent standardized assessments every 3 to 6 weeks, including dynamic contrast-enhanced abdominal MRI/CT, chest CT, and laboratory tests. Tumor response was evaluated according to mRECIST criteria, with the primary endpoints being overall survival (OS) and progression-free survival (PFS), and secondary endpoints being objective response rate (ORR) and safety.

Key Results

Survival Analysis

  • Overall Survival (OS): The median OS in the triple therapy group was 24.6 months, significantly higher than the 11.9 months in the dual therapy group (HR=0.43, p<0.001).
  • Progression-Free Survival (PFS): The median PFS in the triple therapy group was 10.0 months, significantly higher than the 7.7 months in the dual therapy group (HR=0.68, p=0.002).
  • 6-, 12-, and 24-Month Survival Rates: The triple therapy group had rates of 94.2%, 71.0%, and 50.8%, respectively, compared to 75.9%, 49.9%, and 26.8% in the dual therapy group.

Tumor Response

  • Objective Response Rate (ORR): The ORR in the triple therapy group was 57.7%, significantly higher than the 28.9% in the dual therapy group (p<0.001).
  • Conversion from High-Risk to Non-High-Risk: 68.0% of patients in the triple therapy group converted to non-high-risk, compared to 36.6% in the dual therapy group (p<0.001).
  • Salvage Liver Resection or Ablation: 16.5% of patients in the triple therapy group underwent salvage liver resection or ablation, compared to 9.2% in the dual therapy group (p=0.033).

Safety

  • Grade 3⁄4 Adverse Events: The incidence in the triple therapy group was 59.2%, significantly higher than the 47.4% in the dual therapy group (p=0.022). The most common adverse events were hypertension, thrombocytopenia, and neutropenia, all of which were manageable through dose adjustments or temporary treatment interruptions.

Conclusion and Significance

The study demonstrates that FOLFOX-based HAIC combined with TKIs and PD-1 inhibitors significantly improves overall survival and progression-free survival in high-risk advanced liver cancer patients, with a higher objective response rate and manageable safety profile. This provides a potential first-line treatment option for high-risk advanced liver cancer patients, with significant clinical value.

Study Highlights

  1. Breakthrough in High-Risk Patient Treatment: This study is the first to validate the efficacy of triple therapy in high-risk advanced liver cancer patients with a large sample size, addressing the limitations of existing systemic therapies.
  2. Significant Survival Benefits: The triple therapy group showed significantly better median OS and PFS compared to the dual therapy group, with higher rates of conversion to non-high-risk and salvage surgery.
  3. Controlled Safety: Although the triple therapy group had a higher incidence of adverse events, all were manageable through dose adjustments or temporary treatment interruptions, with no treatment-related deaths.

Future Directions

While this study provides a new treatment option for high-risk advanced liver cancer patients, further prospective large-scale randomized controlled trials (RCTs) are needed to validate its efficacy and safety. Additionally, future research could explore the efficacy differences of triple therapy in various patient subgroups and optimize HAIC cycles to enhance treatment outcomes.