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www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 12), pp: 20510-20515
Signicant ecacy and well safety of apatinib in an advanced
liver cancer patient: a case report and literature review
Peisi Kou
1,2,*
, Yan Zhang
2,*
, Wenbo Shao
4
, Hui Zhu
2
, Jingze Zhang
2
, Haiyong Wang
2
,
Li Kong
2
and Jinming Yu
2,3,1
1
Department of Radiation Oncology, The First Aliated Hospital of Zhengzhou University, Zhengzhou, China
2
Department of Radiation Oncology, Shandong Cancer Hospital Aliated to Shandong University, Jinan, China
3
School of Medicine and Life Sciences, University of Jinan - Shandong Academy of Medical Sciences, Jinan, China
4
Department of Intervention, Shandong Cancer Hospital Aliated to Shandong University, Jinan, China
*
These authors have contributed equally to this work
Correspondence to: Jinming Yu, email: zzuyujm@163.com
Keywords: hepatocellular carcinoma, apatinib, targeted therapy
Received: September 06, 2016 Accepted: January 04, 2017 Published: January 18, 2017
ABSTRACT
Apatinib is a novel and highly selective tyrosine kinase inhibitor of vascular
endothelial growth factor receptor-2. Previous studies have suggested that apatinib
is safe and eective in some solid tumors. We report one case with advanced
hepatocellular carcinoma (HCC), who received apatinib combined with transhepatic
arterial chemotherapy and embolization (TACE), and chemotherapy respectively. TACE
was administered three times once a month, using lipiodol 10ml, oxaliplatin 150mg,
and tegafur 1g. The dose of apatinib was 500 mg/d from day 4 to 24. After TACE, the
patient received chemotherapy of regimen FOLFOX4, oxaliplatin intravenously at 85
mg/m
2
on day 1, calcium levofolinate 200 mg/m
2
on day 1 and 2, 5-uorouracil 400
mg/m
2
intravenously and 5-uorouracil 600 mg/m
2
intravenously pumped for 22h on
day 1 and 2, cycled every two weeks for seven cycles. He took concurrently apatinib
with a dose of 500mg daily from 1 to 10 days per cycle. He was conrmed as partial
response (PR) by the Response Evaluation Criteria in Solid Tumors (RECIST). The level
of serum alpha-fetoprotein (AFP) decreased from 60500 ng/ml to 12.7 ng/ml, and
the progression free survival (PFS) time was more than eight months. It indicated
that apatinib may be a superior choice for HCC patients.
INTRODUCTION
Liver cancer ranks the fourth in the morbidity rate
of cancers in China, and it is the third leading cause of
cancer death among both men and women [1]. Therapeutic
methods of liver cancer contain surgery, interventional
therapy, radiofrequency ablation, microwave ablation,
chemotherapy, radiation therapy, targeted therapy and
liver transplantation. Nowadays, with the development
of precision medicine, targeted therapy gained more and
more attention.
Apatinib is the rst generation of oral
antiangiogenesis drug. As the tyrosine kinase inhibitor
of vascular endothelial growth factor receptor-2, apatinib
could prevent the growth of tumor. Some clinical trials
have proved the eect of apatinib on advanced gastric
cancer [2, 3] and hepatocellular carcinoma (HCC) [4].
Here we report one case using apatinib combined with
transhepatic arterial chemotherapy and embolization
(TACE) and chemotherapy on treatment of liver cancer
in our hospital.
CASE REPORT
In November 2015, a 45-year-old man was referred
to our hospital with complains of diarrhea and fever
for one month. He had a history of chronic hepatitis B
for more than ten years and drank for twenty years,
but no family history of hepatitis and cancers. Physical
examination showed no positive sign, and Eastern
Cooperative Oncology Group (ECOG) performance
status was 1. The concentration of serum alpha-fetoprotein
(AFP) exceeded 60500 ng/ml (normal range: 0-7), which
was the upper limit of our laboratory. But he didn’t appear
Case Report
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jaundice and the initial liver function was Child-Pugh B.
The patient underwent abdominal computed tomography
(CT), which demonstrated three irregular and low density
masses in the liver. These masses located at the top and
right lobe of the liver, with a maximum volume of 6 cm
× 8 cm × 10 cm (Figure 1A). In addition, portal vein
tumor thrombosis was shown on CT (Figure 1B). He was
performed liver puncture and conrmed histologically
as HCC, C stage (Barcelona Clinic Liver Cancer staging
system, 2010) (Figure 2).
The patient received TACE on day 1, using
oxaliplatin 150mg, tegafur 1g, lipiodol 10ml, and took
orally apatinib with a dose of 500 mg/d from day 4 to
24. He accepted the treatment for three times once a
month from November 2015. The CT scan after therapy
exhibited that the lesions were much smaller (Figure 3A).
And the serum AFP concentration decreased to 2099
ng/ml (normal range: 0-7). He was evaluated as partial
response (PR) by the Response Evaluation Criteria
in Solid Tumors (RECIST). Subsequently, the patient
Figure 2: Hematoxylin and eosin staining of a tumor section (×200). The pathological diagnosis is HCC.
Figure 1: Abdomen CT images show that one of the lesions is located in the top of liver. A. In the venous phase, the mass is
low density and irregular. B. The arrow represents tumor thrombus in the left branch of portal vein.
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received chemotherapy of regimen FOLFOX4, oxaliplatin
intravenously at 85 mg/m
2
on day 1, calcium levofolinate
200 mg/m
2
on day 1 and 2, 5-uorouracil 400 mg/m
2
intravenously and 5-uorouracil 600 mg/m
2
intravenously
pumped for 22h on day 1 and 2, cycled every two weeks
for seven cycles. He took concurrently apatinib with
a dose of 500 mg daily from 1 to 10 days per cycle.
After the therapy, the CT scan showed the lesions were
similar to latest images (Figure 3B), and the serum AFP
concentration has been persistently decreasing to 12.7 ng/
ml (Figure 4). Finally, the case was conrmed as PR by
RECIST.
The patient experienced some toxicities, including
hand-foot syndrome (grade 3), diarrhea (grade 2),
hypertension (grade 1), decline of leucocyte (grade 1) and
platelet (grade 2), and short-lived elevated blood bilirubin
and aminotransferase (grade 1). But these adverse eects
were controllable and tolerable.
Now, the patient is still taking apatinib as single
agent for maintenance therapy with mild toxic eects.
And the progression-free survival (PFS) time is more than
eight months.
The study was approved by the institutional review
board of Radiation Oncology, Shandong Cancer Hospital
Figure 3: Tumor shrinkage was conrmed. CT scan on March 2016 A. and on May 2016 B. showed that tumor was smaller after
using apatinib.
Figure 4: The level of serum AFP keeps falling during treatment.
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and Institute. The patient provided written informed
consent.
DISCUSSION
For local and early HCC patients, surgery is
the gold-standard treatment, often complemented by
interventional therapy or radiofrequency ablation. But, in
advanced HCC patients, therapy options are complicated,
and the clinical ecacy is always unsatisfactory, due to the
relapse, metastasis and patients’ poor performance status.
According to the results of the current studies, targeted
therapy serves as an important role on the advanced HCC
patients, such as sorafenib [5, 6].
Angiogenesis is mediated by vascular endothelial
growth factor (VEGF) and act as an important role in
the process of tumor growth [7]. When VEGF combines
with vascular epidermal growth factor receptor (VEGFR),
the downstream signals will be active to stimulate the
proliferation of vascular endothelium. VEGFR family
proteins are membrane receptor tyrosine kinases, including
VEGFR-1, VEGFR-2 and VEGFR-3 [8]. VEGFR-2,
which are mainly expressed on endothelial cells, mediates
the angiogenic, mitogenic and permeability-enhancing
eects of VEGF [9]. It is considered that blockage of
VEGFR-2 could be a promising strategy to inhibit tumor-
induced angiogenesis.
Apatinib is the latest inhibitor of VEGFR-2 targeting
the intracellular ATP-binding site of the receptor, which
could inhibit VEGF-stimulated endothelial cell migration
and proliferation, decrease tumor microvascular density,
and promote apoptosis [10-12]. There are several pre-
clinical and clinical trials proving the eect and safety of
apatinib. A phase I study was conducted for patients with
advanced solid tumors, and turned out that the maximum-
tolerated dose was 850 mg once daily [13]. The adverse
events of apatinib contained hand-foot syndrome in 46%
of patients, proteinuria in almost 50% of patients, and
hypertension in about 70% of patients. A phase II study in
metastatic gastric cancer patients displayed that apatinib
obviously improved PFS comparing with placebo (3.67
months vs. 1.40 months) [2]. The toxicities included
fatigue, hypertension and hand-foot syndrome, which were
well controlled. In patients with advanced or metastatic
adenocarcinoma of the stomach or gastroesophageal
junction, it was also veried that median overall survival
(OS) was signicantly improved in the apatinib group
compared with the placebo group (6.5 months vs. 4.7
months, P = 0.0149), the same as PFS (2.6 months vs.
1.8 months, P < 0.01) [3]. Qin et al. [4] reported that
apatinib was ecient for patients with advanced HCC
as the rst line therapy. In their study, advanced HCC
patients were randomized into two groups in which they
took apatinib 850 mg or 750 mg daily respectively until
progression of the disease. The time to progression (TTP)
was 4.21 and 3.32 months in 850 mg and 750 mg groups
(P > 0.05), respectively. And adverse events were similar
in the two groups. They preferred to recommend 750 mg
once daily for the next clinical study. Recently, apatinib
also shown satisfactory ecacy in non-small cell lung
cancer [14], breast cancer [15, 16], malignant brous
histiocytoma [17], intrahepatic cholangiocarcinoma [11],
and extrahepatic bile duct carcinoma [12].
According to the treatment guideline, TACE
and chemotherapy are dominating managements for
advanced HCC patient. But targeted therapy has been
a hot topic in multidisciplinary therapy of HCC. Huang
et al. [18] performed a study in intermediate stage HCC
patients, and the therapeutic regimen was metronomic S-1
chemotherapy in combination with TACE. The median
TTP was 6 months. A phase II study of the combination
of TACE and sorafenib in patients with unresectable
HCC showed that the median TTP was 5.1 months [19].
Hu et al. compared TACE plus sorafenib with TACE
alone in Barcelona Clinic Liver Cancer stage C patients,
and the TTP was longer in the combined group (2.6
months vs. 1.9 months, P = 0.001) [20]. Abou-Alfa et
al. [21] analized the dierence between sorafenib plus
doxorubicin and doxorubicin alone, which showed an
apparent improvement in both PFS (6.0 months vs. 2.7
months, P = 0.006) and OS (13.7 months vs. 6.5 months,
P = 0006). Assenat E et al. [22] compared sorafenib plus
gemcitabine/oxaliplatin with sorafenib alone as the rst
line therapy for patients with advanced HCC. The study
declared that DCR and RR were 77% vs. 16%, and 70%
vs. 9%, respectively. A lot of data suggested that targeted
therapy combined with TACE or chemotherapy might
develop synergetic eects. However, the expensive cost
and toxicities of sorafenib limited the utilization. Although
apatinib showed notable ecacy in some solid tumors,
there is no data about apatinib combined with TACE and
chemotherapy in HCC. For this case, based on previous
datas of apatinib in HCC, we attempted to administrate
him multidisciplinary therapy including apatinib combined
with TACE and chemotherapy. In our clinical experience,
many gastric cancer patients could not tolerate the toxicity
of apatinib alone with the dose of 850 mg daily. In this
case, we prescribed him 500 mg daily combined with
TACE or chemotherapy. However, he still suered hand-
foot syndrome and diarrhea at the rst cycle, and we had
to interrupt the medicine for two days. In the follow-up
cycles, the adverse events were tolerable gradually and the
therapy remained ceaselessly. The patient was evaluated
as partial response and the PFS were 8 months until now,
which was much longer than that of previous studies [4,
18-21]. This case suggested that the combined therapy
of apatinib and TACE followed chemotherapy displayed
challenging ecacy. It illuminated that apatinib might
cooperate superiorly with TACE and chemotherapy for
advanced HCC.
In conclusion, apatinib may provide an additional
option for the treatment of liver cancer. Our study
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indicates that the multiple therapeutics strategies of
apatinib combined with other therapies, such as TACE
and chemotherapy, should be developed in future clinical
trials. Moreover, how to nd biomarkers to predict drug
ecacy is also one of the challenges with antiangiogenic
therapy. Further large-scale prospective studies are
required to prove the eect of apatinib in liver cancer.
ACKNOWLEDGMENTS
This study was supported by research program from
the National Natural Science Foundation of China (Grant
No. 81472812). Informed patient consent was obtained for
publication of this case report. The authors thank all the
treatment group of Shandong Cancer Hospital.
CONFLICTS OF INTEREST
The authors declare no conicts of interest.
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