Treatment options for advanced HCC are limited, usually improving overall survival rather than curing the disease. These options include chemotherapy, radio-embolization, immune check-point therapy, and anti-angiogenic therapy.44

Anti-angiogenic therapy was developed with the rationale that these drugs lead to destruction of the abnormally structured blood vessels resulting in tumor hypoxia and shrinkage.45 However, Jain et al introduced the vascular normalization hypothesis that anti-angiogenic therapy restores the integrity and structure of the tumor-induced blood vessels without destroying these vessels.46

Anti-angiogenic induced reduction in tumoral vascular burden induces hypoxic tumoral microenvironment. This hypoxia leads to accumulation of certain chemokines including programmed death receptor ligand 1 (PD-L1) which suppress immune cells and induces resistance to anti-angiogenic therapy, recent advances include the combination of immune checkpoint therapy with anti-angiogenic therapy to treat advanced HCC.47,48

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To date, the US Food and Drug Administration (FDA) has approved few anti-angiogenic drugs for HCC. Table 1 summarizes these drugs and their indications.49–58

Table 1

Sorafenib is an oral multi-kinase inhibitor that targets the activity of VEGF-2, PDGFR-β, and other signaling cascades, and has been the only approved systemic therapy for HCC for over a decade. Sorafenib upregulates P53 and decreases expression of matrix metalloprotease-2 (MMP-2) which suppresses cellular proliferation and invasion.59,60 It is the only anti-angiogenic drug incorporated into the American Association for the Study of Liver Diseases (AASLD) guidelines for treatment advanced HCC (unresectable HCC).44,61,62 (Figure 1). Although its indication of use is still vague, it is the first line of treatment in advanced HCC (with macro-vascular invasion or metastatic disease).44

Figure 1

Lenvatinib is a more potent anti-angiogenic drug than Sorafenib, which acts through multi-kinase inhibition of VEGFR (more potent than Sorafenib), FGF receptors and PDGFR. Dual suppression of VEGF and FGF pathways results in concomitant suppression of both neo-angiogenesis and tumor growth. Lenvatinib is used in unresectable HCC with comparable results in overall survival between both Lenvatinib and Sorafenib.63 Lenvatinib provides an advantage over Sorafenib with a longer time to progression as well as progression-free survival in patients enrolled in the trial.64

Regorafenib and Cabozantinib are tyrosine kinase inhibitors which are the only anti-angiogenic drugs that were seen to be advantageous as a second-line therapy in patients who progressed on Sorafenib. Regorafenib and Cabozantinib show statistically significant improvement in overall survival and progression-free survival over the use of placebo in these patients.54,55,65

Ramucirumab is a monoclonal antibody that inhibits the VEGF axis through blocking the activation of VEGFR-2. The FDA recently approved the use of Ramucirumab based on Phase 3 trial (REACH-2) that demonstrated effectiveness of this drug in patients who progressed on Sorafenib with AFP ≥ 400 ng/mL. It showed an increase in overall survival and progression-free survival with comparable results as Cabozantinib and Regorafenib.57,58

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