1 Introduction
Primary hepatocellular cancer was one of the major threat to human health worldwide, in 2020, primary liver cancer has become the sixth leading malignancy and the third cause of cancer-related deaths worldwide[1]. Hepatocellular carcinoma (HCC), with a five-year survival rate only 18%, accounts for 75%-85% of primary liver cancer cases[2]. Besides, incidence rate of HCC were much higher in Eastern Asia followed by Northern Africa and South-Eastern Asia[3]. For patients diagnosed at early- or intermediate-stage HCC, curative treatments such as surgical procedures, which including whole or partial hepatectomy and liver transplant, and locoregional therapies including radiofrequency ablation, transarterial chemoembolization, and radiation therapy could improve survival[4, 5]. However, more than half of the patients with HCC diagnosed at advanced or incurable stage, making systemic therapy one of few treatments available to improve survival[6, 7].
Great advances in understanding the mechanisms and progression of HCC over the past decades have promoted the development of novel drugs such as tyrosine kinases inhibitors (TKIs) to prolong the survival of patients with advanced HCC. In 2007, FDA approved sorafenib for HCC targeted therapy. Sorafenib was an anticancer agent with multi-targent, it could prevent the proliferation of tumor cells and inhibit cancer angiogenesis by suppressing the RAF/MEK/ERK pathway as well as inhibiting vascular endothelial growth factor receptor 2/3 (VEGFR-2/3) and platelet-derived growth factor receptors (PDGFR)[7, 8].In the SHARP trial[9] and ORIENTAL trial[10], the investigators demonstrated that sorafenib could significantly increased survival of advanced HCC patients with different territories. Thus, sorafenib became the first line systemic therapy approved by european medicines agency(EMA) and FDA. It almost took 10 years until lenvatinib was approved as the second TKI for advanced HCC treatment. It acts as a potent inhibitor of VEGFR1-3 and other receptor tyrosine kinases, including fibroblast growth factor receptor(FGFR), KIT, and RET[11, 12]. The open-label,multicenter, non-inferiority phase III REFLECT trial enrolled 954 aHCC patients, the result demonstrated that lenvatinib was non-inferior compared to sorafenib. Lenvatinib group reached a median overall survival(OS) of 13.6 months compared to 12.3 months in the sorafenib group. Furthermore, lenvatinib group exhibit higher objective response rates(ORR) compared to sorafenib group(24.1% vs 9.2%)[13].The REFLECT study established lenvatinib as first line therapy in systematic treatment of unresectable HCC. Combination of lenvatinib and other immunotherapies has achieved encouraging clinical benefit. In 2017, another TKI small molecular, regorafenib was approved for patients with advanced HCC[14] Regorafenib targets VEGFR, PDGFR, and FGFR, RAF, RET, KIT[15]. In the phase III RESORCE study[16], 573 aHCC patients who tolerated sorafenib in 21 countries were enrolled. Regorafenib improved overall survival with a hazard ratio of 0.63 (95% CI 0.50-0.79; one-sided p<0.0001) and median survival was 10.6 months for regorafenib versus 7.8 months for placebo. Hence, Regorafenib was approved for second line treatment of HCC who have been previously treated with sorafenib. Cabozantinib was another oral multiple tyrosine kinase receptor inhibitor with activity against the VEGFR(VEGFR-1, VEGFR-2, VEGFR-3), RET and KIT. It also inhibits MET and AXL, which have previously been associated with sorafenib resistance[17].In phase III CELESTIAL trail[18], 707 patients with previously treated HCC were enrolled, and the results showed a median OS of 10.62 months in cabozantinib group compared to 8.0 months in the placebo group. Median progression-free survival(PFS) was 5.2 months in cabozantinib group and 1.9 months in placebo (HR for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P < 0.001), demonstrated cabozantinib as a second-line agent in the treatment of HCC. Nowadays, most advanced HCCs could benefit from the sound “transformation therapy”, which indicated that transformed inoperable advanced HCC into resectable cancer with multimodal therapy options, targeted therapy became one of the important strategies.
However, some serious adverse events(AEs) that may induced by TKIs were emerged, some even fatal in cardiac system. Hypertension, QT prolongation, arrhythmias, left ventricular systolic dysfunction, and heart failure were the most common cardiac AEs reported[19-21]. Safety profiles of TKIs were evaluated primarily in clinical trials, which due to the strict study entry criteria, small sample sizes and relatively short length of time, were scattered and insufficient to provide a detailed overview of the risk of cardiac AEs induced by those above four TKIs. Therefore, Pharmacovigilance study using post-marketing safety reports can be an great supplement to the detection of cardiac AEs of TKIs. Currently, the FDA Adverse Events Reporting System (FAERS) was one of the largest global repository of post-marketing drug surveillance. It contains adverse event reports, medication error reports that were submitted to FDA.