Purpose: We retrospectively evaluated the efficacy and safety of apatinib as a first-line treatment for advanced hepatocellular carcinoma (HCC) and explored whether drug-related hypertension (HTN) could predict its efficacy.
Patients and Methods: This retrospective analysis included patients with advanced HCC who received oral treatment with apatinib. We evaluated the effectiveness by overall survival (OS), progression-free survival (PFS), time to progression (TTP), and disease control rate (DCR), and assessed the safety of the drug based on the occurrence of adverse events. In order to explore whether apatinib-related HTN can be used as a predictor of therapeutic effect, patients were divided into an HTN group and a non-HTN group and adjusted for propensity score-matched (PSM) to reduce mixed deviation. Subgroup analyses of negative prognostic factors for advanced HCC were also performed, including alpha-fetoprotein (AFP), Child–Pugh Score, macrovascular invasion, and extrahepatic metastasis.
Results: A total of 208 patients were analyzed, of which 40.9% (n =85) developed drug-related HTN. For all patients, the OS was 13.4 months (95% CI, 12.2– 14.6), the PFS was 5.7 months (95% CI, 5.1– 6.3), and the TTP was 6.9 months (95% CI, 6.0– 7.8). The OS of the HTN group and the non-HTN group was 17.4 months (m) and 12.5m (p=0.001), and the PFS was 7.4m and 4.7m (p=0.000), respectively. After PSM, the OS (p=0.001) and PFS (p=0.003) of the HTN group were still significantly better than the non-HTN group. Subgroup analysis suggested that overall survival was significantly longer in patients with HTN when serum AFP ≤ 400 μg/L or extrahepatic metastases. Moreover, OS in the HTN group increased significantly with or without macrovascular invasion. In addition, through the analysis of two groups of patients with PFS> 6m and PFS≤ 6m, we know that the patients with drug-related HTN may develop resistance later, so they have longer survival time.
Conclusion: Apatinib demonstrates compelling anti-cancer activity and acceptable safety in advanced HCC. Apatinib-related HTN can potentially predict prolonged survival in patients with advanced HCC.

Keywords: VEGFR-2, HTN, HCC, resistance, liver cancer

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Hepatocellular carcinoma (HCC) is classified as the world’s seventh-highest ranking cancer for morbidity and its fourth-highest for mortality. In 2018, new incidences of liver cancer exceeded 840,000 and the disease caused more than 780,000 deaths.1

About 70% to 85% of HCC is a late or unresectable disease at the time of diagnosis and is not recommended for surgical resection or liver transplantation.2 Therefore, it is imperative to develop comprehensive treatments to improve the overall survival rate of advanced HCC. Because of their remarkable effects on other cancers, anti-angiogenic drugs have received much attention in the treatment of HCC. From the successful Phase III clinical trial of sorafenib in the treatment of HCC in 2008, the recent first-line treatment of lenvatinib and the second-line replacement therapy of regorafenib and cabozantinib have brought new hope to HCC targeted therapy.3–7 Angiogenesis is regulated by a number of growth factors that signal through a variety of tyrosine kinase pathways and bind to specific tyrosine kinase receptors. Vascular endothelial growth factor (VEGF; in particular VEGF-A) and its receptors (VEGFRs; in particular VEGFR-2) play a major pro-angiogenic role.8 VEGF inhibitors inhibit vascular growth by inhibiting the binding of VEGF to VEGFR-2 and their biological activities, which achieves anti-tumor effects.9,10 Considering the overexpression of VEGFR-2 in HCC and its importance in cancer progression, targeting VEGFR-2 might be a good choice.

Apatinib is a highly selective tyrosine kinase inhibitor of VEGFR-2.11 A Phase II clinical study reported at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting showed that apatinib has potential survival benefits in patients with advanced liver cancer.12 Our previous data show that apatinib improves the prognosis of patients with advanced HCC.13 However, there are many adverse events, especially hypertension (HTN) and proteinuria during the treatment of apatinib, which can lead to dose reduction or termination of medication in some patients with a good response. Some studies have shown that HTN induced by VEGF inhibitors (VEGFIs) is not a side effect of treatment, but a mechanism-dependent targeted toxicity. The occurrence of HTN may indicate the effectiveness of VEGF inhibition and may serve as a predictor for the beneficial outcome of VEGFI treatment.14–16

Therefore, our study was designed to assess the efficacy and safety of apatinib in patients with advanced HCC, and evaluate whether apatinib-related HTN can be used as a predictor of its efficacy.

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