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.