First-line use of antiangiogenic agents in unresectable hepatocellular carcinoma: a double-edged sword?

Area of Science:

• Hepatocellular Carcinoma (HCC) Treatment
• Cancer Immunotherapy
• Vascular Endothelial Growth Factor (VEGF) Inhibition

Background:

• Hepatocellular carcinoma (HCC) treatment options, especially for unresectable cases with cirrhosis, were historically limited.
• Initial systemic therapies using vascular endothelial growth factor (VEGF) inhibitors provided modest survival benefits but lacked durable responses.
• Prolonged VEGF blockade raised concerns regarding hepatic/renal toxicities and limited long-term efficacy in liver cancer.

Purpose of the Study:

• To evaluate the paradigm shift from VEGF-centric therapy to immune checkpoint inhibitors (ICIs) in unresectable HCC.
• To assess the impact of dual-ICI regimens on response durability and long-term survival compared to anti-VEGF agents.
• To propose a refined treatment strategy optimizing efficacy and safety for advanced liver cancer.

Main Methods:

• Review of clinical trial data comparing anti-VEGF therapies with immune checkpoint inhibitors (ICIs) for unresectable HCC.
• Analysis of response durability, overall survival, and toxicity profiles of different treatment modalities.
• Evaluation of the potential benefits and drawbacks of combining VEGF inhibition with ICIs.

Main Results:

• Dual-ICI regimens demonstrated more durable responses and higher long-term survival rates in HCC compared to prior VEGF inhibitors.
• Anti-VEGF therapies, while useful for initial tumor reduction, may negatively impact liver regeneration and worsen portal hypertension with prolonged use.
• The efficacy of dual ICIs challenges the traditional VEGF-focused approach, suggesting a potential for more transformative disease control.

Conclusions:

• Dual immune checkpoint inhibitors (ICIs) represent a significant advancement, offering improved long-term outcomes for unresectable hepatocellular carcinoma.
• A refined strategy involving limited-duration VEGF inhibition followed by or combined with ICIs may enhance both efficacy and safety.
• Future research should prioritize identifying predictive biomarkers for ICI response and developing novel regimens for maximizing survival in advanced liver cancer.