Hindawi

Journal of Oncology
Volume 2020, Article ID 3852373, 6 pages
https://doi.org/10.1155/2020/3852373

Research Article
An Oral Small Molecule VEGFR2 Inhibitor, Apatinib, in
Patients with Recurrent or Refractory Cervical Cancer: A Real
World Study

Ning Li ,1 Ziyi Wang,2 Guangwen Yuan,1 Yangchun Sun,1 Rong Zhang,1 Xiaoguang Li,1
Nan Li,1 Jing Wang,2 and Lingying Wu 1
1
Department of Gynecologic Oncology, National Cancer Center/Cancer Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
2
Department of Gynecologic Oncology, Hunan Cancer Hospital, 283 Tongzipo Road, Yuelu District, Changsha,
Hunan 410013, China

Correspondence should be addressed to Lingying Wu; [email protected]

Received 10 March 2020; Revised 25 April 2020; Accepted 3 June 2020; Published 22 June 2020

Academic Editor: Philippe Gascard

Copyright © 2020 Ning Li et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
To evaluate the efficacy and safety of apatinib, an oral antiangiogenic drug, in patients with recurrent or refractory cervical cancer
as salvage treatment, we retrospectively analyzed the medical records of recurrent or refractory cervical cancer patients admitted
to the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Hunan Cancer Hospital, from October
1, 2016, to December 31, 2017. Patients who progressed within 6 months after the last treatment were given apatinib orally at a
dose of 250 mg daily until disease progression or unacceptable toxicity. Twenty-nine patients were enrolled in our retrospective
study. Up to February 1, 2019, the median follow-up time was 18 months. The median progression-free survival was 128 days (95%
confidence interval (CI): 20–540 days), and the median overall survival was 9 months (95% CI: 4–23 months). The longest period
of apatinib administration was 540 days. No complete response was observed, 5 (17.2%) patients achieved partial response, and 11
(37.9%) achieved stable disease. The objective response rate and disease control rate were 17.2% and 55.1%, respectively. The most
common adverse events were hypertension (G1, 65.5%, 19/29), mucositis (G1, 55.2%, 16/29), hand-foot syndrome (G1-2, 44.8%,
13/29), and proteinuria (G1-2, 20.7%, 6/29). Grade 3 proteinuria occurred in only one patient (3.4%, 1/29). Apatinib single-agent
use might be an effective and tolerable choice as salvage therapy for patients with recurrent or refractory cervical cancer.

1. Introduction the chemotherapy, and their quality of life is poor. Therefore,

there is an increasing need for targeted, novel therapies with
Cervical cancer is the most common gynecological cancer in low toxicity to serve as monotherapy or adjuvant therapy for
developing countries. The incidence of cervical cancer in recurrent or refractory cervical cancer.
China is 13.3 cases per 100,000 [1]. Early stage cervical Angiogenesis is critical for the development and pro-
cancer can be cured by radical surgery or concurrent che- gression of tumor, and antiangiogenic therapy has been
moradiation. However, recurrent and persistent cervical demonstrated to be effective in multiple cancers, including
cancer remains incurable with limited treatment choices. cervical cancer [5]. In cervical cancer, human papillomavirus
Palliative chemotherapy is the current standard of care for (HPV) mediates the activation of VEGF-VEGFR pathway by
most recurrent cervical cancer with relatively low response promoting the expression of VEGFA, thus promoting tumor
rate (17–30%) and short duration, especially for the patients angiogenesis [6]. Many studies showed that the upregulation
who have received previous chemotherapy [2–5]. Most of all, of VEGFR2 and the increased intratumoral microvessel
a majority of patients with recurrent disease cannot tolerate density (MVD) were associated with poor prognosis and
2 Journal of Oncology

metastasis of cervical cancer [7]. This evidence indicates that 2.3. Efficacy and Safety Assessments. Disease status was
antiangiogenic therapy may be applied to cervical cancer. assessed by CT or MRI every 8 weeks. The SCC antigen, a
In the randomized, open-label, phase III trial GOG 240, widely used tumor marker for squamous cell carcinoma, was
bevacizumab in combination with chemotherapy showed tested at every cycle. If SCC doubled compared to the
significant improvement of overall survival (OS) for ad- baseline, imaging was warranted to determine progression.
vanced cervical cancer, demonstrating its activity in this The tumor response was evaluated according to Response
disease [5]. But the high cost of bevacizumab limits its use in Evaluation Criteria in Solid Tumors 1.1 criteria [16]. The
developing or low-income countries. A novel oral small objective response rate (ORR) was defined as the sum of
molecule tyrosine kinase inhibitor targeting VEGFR2, complete response (CR) and partial response (PR). The
apatinib, has been demonstrated to exert an antitumor effect disease control rate (DCR) was defined as the addition of CR,
in a few I/II phase clinical studies of gastric cancer, NSCLC, PR, and stable disease (SD). PFS was defined as the period
ovarian cancer, and breast cancer [8–12]. Additionally, in a from the beginning of apatinib treatment to disease pro-
randomized, double-blinded, placebo-controlled phase III gression or death. OS was defined as the duration from the
trial of apatinib, Li et al. reported that apatinib significantly beginning of apatinib treatment to the date of death for any
improved OS and progression-free survival (PFS) of patients reason or to the last date of follow-up, whichever came first.
with stomach or gastroesophageal junction cancers [13], so it Blood pressure was monitored once every morning. He-
was approved and marketed for the treatment of advanced matology, serum chemistry, routine urine examination,
gastric cancer in China. In vitro and in vivo studies also physical examination, and 12-lead electrocardiogram were
demonstrated that apatinib showed potential efficacy for the assessed every 4 weeks. Adverse events were evaluated by the
treatment of cervical cancer [14]. Moreover, a retrospective National Cancer Institute Common Terminology Criteria
study of apatinib for treating gynecologic malignancies for Adverse Events version 5.0 [17].
including three cervical cancer patients found that apatinib
might be a potential choice for cervical cancer [15]. We
2.4. Statistical Analysis. Statistical analyses were performed
conducted this retrospective study to further evaluate the
using SPSS software, version 22.0 (SPSS Inc., Chicago, IL,
efficacy and safety of apatinib in patients with heavily
USA). Continuous data were expressed as the median
pretreated persistent/recurrent cervical cancer.
(range) and categorical variables as percentages. PFS and OS
were estimated by the Kaplan–Meier method.
2. Materials and Methods
2.1. Patients. Between October 1, 2016, and December 31,
3. Results
2017, patients with recurrent or refractory cervical cancer at 3.1. Patient Characteristics. A total of 29 patients were ret-
the National Cancer Center/Cancer Hospital, Chinese rospectively enrolled in the study (Table 1). The median age
Academy of Medical Sciences Institution and Hunan Cancer was 48 years (range 38–61 years). Twenty-five (86.2%) pa-
Hospital, were enrolled. Inclusion criteria included (1) age tients were diagnosed with cervical squamous cell carcinoma,
>18 years; (2) pathologically confirmed cervical cancer; (3) three (10.3%) patients with cervical small cell carcinoma, and
progression within 6 months after the last treatment or one (3.4%) patient with cervical adenocarcinoma. The pri-
during the last therapy including chemotherapy, radio- mary treatment was radical surgery ± adjuvant therapy for 9
therapy, or chemoradiotherapy; (4) at least 1 measurable (31.0%) patients with stage IB2-IIA2 disease, while 20 (69.0%)
lesion according to CT or MRI; and (5) the recurrent disease patients with stage IIB-IVB disease underwent concurrent
not suitable for secondary surgery or radiotherapy. Patients radiochemotherapy. No patient had received prior anti-
were excluded for any of the following reasons: (1) prior angiogenic therapy. Thirteen (44.8%) patients exhibited dis-
antiangiogenic treatment; (2) uncontrolled hypertension; (3) ease progression during previous treatment, and the other 16
proteinuria >1 g/24 hours; (4) vaginal bleeding; and (5) (55.2%) recurred within 6 months after the previous treat-
arterial embolism or thrombosis. Informed consent was ment. The median number of prior chemotherapy regimens
obtained from all the patients before the start of apatinib was 3 (range 1 to 5). The main regimens of prior chemo-
therapy. This study was approved by the Institutional Review therapy included cisplatin, 5-FU + cisplatin, paclitax-
Board of Cancer Hospital, Chinese Academy of Medical el + cisplatin, and topotecan. The median treatment-free
Sciences. Data including demographic information, clinical- interval before the start of apatinib was 2 months. Seven
pathologic information, treatment history, disease status, (24.1%) patients exhibited recurrent disease within the pre-
survival status, and adverse events were collected for viously irradiated field, 17 (58.6%) patients exhibited outside
analysis. of the previously irradiated field or without previous radiation
history, and 5 (17.2%) patients exhibited multiple recurrences
both within and outside of the irradiated field.
2.2. Treatment. Apatinib was administered at a daily dose of
250 mg p.o., for a cycle of 4 weeks. Treatment interruption
up to 14 days was allowed if intolerable toxicities developed. 3.2. Efficacy. At the time of the last follow-up on February 1,
Patients discontinued oral administration of apatinib if they 2019, with a median follow-up time of 18.0 months, all
experienced disease progression or unacceptable toxicity patients had discontinued administration, and the longest
after the dose interruption of >14 days. time of apatinib administration was 540 days (Figure 1(a)).
Journal of Oncology 3

Table 1: Patient’s clinical-pathologic characteristics.

Characteristics
Age (years) 48 (30–63)
FIGO stage
IB2-IIA2 9 (31.0%)
IIB-IVB 20 (69.0%)
Histology
Cervical squamous cell carcinoma 25 (86.2%)
Cervical adenocarcinoma 1 (3.4%)
Cervical small cell cancer 3 (10.3%)
Sites of recurrence
Within the irradiated field 7 (24.1%)
Outside the irradiated field 17 (58.6%)
Within and outside the irradiated field 5 (17.2%)
Median number of previous chemotherapy regimens 3 (1–5)
Median interval between last treatment and disease progression (months) 2 (0–6)
FIGO: the International Federation of Gynecology and Obstetrics.

Twenty-six (89.7%) patients discontinued treatment due to critical role of an antiangiogenic agent in cervical cancer
disease progression, and 3 patients with stable disease dis- treatment combining bevacizumab with chemotherapy [5].
continued treatment due to either appendectomy, pneu- Meanwhile, various antiangiogenetic agents such as apatinib
monia fever, or grade 3 proteinuria, respectively. At the end are under investigation in multiple solid tumors including
of the follow-up, 25 patients had died, 2 patients were still cervical cancer.
alive, and the 2 remaining patients have lost to follow-up at 3 Apatinib, as a novel, oral, highly selective tyrosine kinase
and 7 months after discontinuation of apatinib, respectively. inhibitor, blocks downstream signaling of VEGFR2 by
The median PFS was 128 days (95% CI: 20–540 days) targeting its ATP-binding site. Pharmacodynamics studies
(Figure 1(b)), and the median OS was 9 months (95% CI: showed that apatinib could suppress the tyrosine kinase
4–23 months) (Figure 2). None of the patients achieved CR. activity of VEGFR, block the VEGF-induced signal trans-
A total of 5 patients (17.2%, 5/29) achieved PR, and 11 duction, and result in the inhibition of tumor angiogenesis
patients (37.9%, 11/29) achieved SD. ORR and DCR were [18]. Preclinical data also showed that apatinib effectively
17.2% and 55.2% (16/29), respectively. inhibited proliferation, migration, and tube formation of
human umbilical vein endothelial cells. Subsequently, the
use of animal models confirmed that apatinib blocked the
3.3. Safety. Treatment-related adverse events (AEs) are budding of rat aortic ring and inhibited the growth of xe-
summarized in Table 2. The most common AEs were hy- nograft tumors, either alone or in combination with che-
pertension (G1, 65.5%, 19/29), mucositis (G1, 55.2%, 16/29), motherapeutic drugs [19, 20].
hand-foot syndrome (G1, 41.4%, 12/29; G2, 3.4%, 1/29), Apatinib has been rarely reported for the treatment of
neutropenia (G1-2, 27.6%, 8/29), and proteinuria (G1-2, cervical cancer. In two retrospective studies with a limited
20.7%, 6/29). Grade 3 proteinuria occurred in only one number of patients with metastatic or recurrent cervical
patient (3.4%, 1/29) after administration of apatinib for cancers, apatinib showed potential efficacy [21, 22] with a
118 days with full recovery after supportive treatment within median PFS of 3.0 to 7.0 months, a median OS of 7.0 to 16.0
2 weeks. No grade 4 AE was observed in the study. months, an ORR of 15.4 to 16.7%, and a DCR of 57.7 to
67.7%. In the present study, twenty-nine recurrent or re-
4. Discussion fractory cervical cancer patients received apatinib. We re-
ported that the PFS was 128 days, OS was 9 months, ORR
Patients with recurrent/refractory cervical cancer after was 17.2%, and DCR was 55.2%, which was comparable with
failing multiple-line treatment show very poor response to the results of the above two studies. Currently, cisplatin is
therapy and are intolerant to chemotherapy. Treatment of one of the most effective cytotoxic agents for the treatment of
such patients remains a crucial challenge in cervical cancer recurrent or metastatic cervical cancer, with an ORR ranging
management. Various single-agent or combination thera- from 20–30% and a median OS of 6–9 months [2, 3, 23].
pies have been evaluated in this particular patient pop- Therefore, apatinib might be a valuable choice for recurrent
ulation, yet disease outcome is disappointing, often cervical cancer especially considering the toxicity associated
accompanied by compromised quality of life. Therefore, the with chemotherapy.
identification of a more effective low-toxic therapy is The common adverse events of apatinib, including hy-
paramount. pertension, mucositis, hand-foot syndrome, and proteinuria,
In the past two decades, antiangiogenic agents have seemed to be similar to those observed with other anti-
exhibited promising antitumor efficacy in multiple solid angiogenic agents [24]. Our study further investigated
tumors such as colorectal cancer and ovarian cancer. In apatinib safety profile at a lower dose (250 mg) than that
2014, the GOG 240 trial, for the first time, established the previously reported (500 mg) in consideration of multiple
4 Journal of Oncology

29
27
25
23
21
19
17
15
13
11
9
7
5
3
1
0 100 200 300 400 500 600
(a)

1.0

0.8
Cumulative survival

0.6

0.4

0.2

0.0

0 100 200 300 400 500 600

PFS (days)

PFS
PFS censored
(b)

Figure 1: (a) Duration of apatinib treatment in patients (days). (b) Kaplan–Meier plot for PFS.

lines of pretreatment, poor bone marrow reserve, and weak (grade 1-2) and manageable, thus not requiring treatment
physical conditions of this patient population. Notably, in discontinuation. Moreover, our current study with low-dose
the studies reported by Yu et al. and Chen et al., dose re- apatinib reached comparable PFS and OS to those of Yu’s
duction was as high as 53.8% and 66.7% when adminis- and Chen’s studies. In addition, low-dose apatinib allowed
trating apatinib at a daily dose of 500 mg [21, 22]. Our results increased treatment duration as described in the present
successfully demonstrated an outstanding advantage of a study, i.e., a maximum of 540 days. The sustainability of
low-dose (250 mg) regimen with only one grade 3 AE with apatinib might bring further benefits to declining patients
proteinuria who fully recovered within 2 weeks and no with poor outcome. Therefore, low-dose apatinib might be a
occurrence of grade 4 AE. Most of AEs were relatively mild promising alternative treatment for recurrent or refractory
Journal of Oncology 5

1.0 Acknowledgments
This study was supported by the “CAMS Innovation Fund
for Medical Sciences” (CIFMS) (2016-I2M-1-001).
0.8

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