Am J Transl Res 2023;15(3):1973-1981
www.ajtr.org /ISSN:1943-8141/AJTR0147925
Original Article
Effectiveness and safety of mono-anlotinib mono
therapy or in combination with chemotherapy in
platinum-resistant recurrent ovarian cancer:
a single-center retrospective study
Yue Wu1,2*, Ping Li1,2*, Yaodong Zhu1,2, Fengli Zhang1,2, Li Su1,2, Yingquan Ye1,2, Yi Huang3
, Mei Zhang1,2
1
Oncology Department of Integrated Traditional and Western Medicine, The First Affiliated Hospital of Anhui
Medical University, Hefei 230022, Anhui, China; 2The Traditional and Western Medicine (TCM)-Integrated
Cancer Center of Anhui Medical University, Hefei 230032, Anhui, China; 3Anhui University of Traditional Chinese
Medicine, Hefei 230038, Anhui, China. *Equal contributors.
Received November 21, 2022; Accepted February 9, 2023; Epub March 15, 2023; Published March 30, 2023
Abstract: Objective: To evaluate the clinical efficacy of mono-anlotinib therapy by itself or in combination with che
motherapy in platinum-resistant recurrent ovarian cancer (PROC). Methods: The clinical data of 35 patients with
platinum-resistant recurrent ovarian cancer admitted to the First Affiliated Hospital of Anhui Medical University
from March 2019 to July 2020 were retrospectively analyzed. All the patients received anlotinib mono- or combined
chemotherapy. The effectiveness and adverse events (AEs) were analyzed by RECIST1.1 and CTCAE5.0. Results:
In the 35 patients, the median follow-up was 9.80 (95% CI: 3.83-15.77) months. The median progression free
survival (mPFS) achieved 6.50 (95% CI: 2.02-10.98) months, the objective response rate (ORR) achieved 17.14%,
and disease control rate (DCR) achieved 60.00%. ORR and DCR were 12.50% and 25.0% for monotherapy, 18.52%
and 70.37% for combined chemotherapy. The PFS of combined chemotherapy was longer than that of monotherapy
(log-rank P = 0.003). thirty-four patients (97.14%) were in a third-line therapy or above, and their ORR and DCR
were 14.71% and 58.82%, respectively. Two patients discontinued treatment because of intolerable AEs. No cases
of grade 4-5 AEs have been reported. Conclusion: Anlotinib had promising effectiveness and tolerable safety in pa
tients with PROC, even in patients who accepted anlotinib as a third-line or above therapy or with a history of other
antiangiogenic drugs.
Keywords: Angiogenesis inhibitors, anlotinib, ovarian epithelial carcinoma, ovarian neoplasms, combination drug
therapy
Introduction
Ovarian cancer (OC) is a highly malignant afflic
tion of the female reproductive system, with
considerable mortality, and a high incidence,
ranking first among gynecological tumors [1]. In
China, over 50,000 cases of OC are diagnos
ed every year, and more than 70% of them
already are at an advanced stage at the initial
diagnosis [2]. The treatment of OC mainly relies
on cytoreductive surgery and platinum-based
chemotherapy, however, resistance to chemo
therapeutic drugs and recurrence are still high.
According to the US NCCN guidelines, recurrent
OC (ROC) is classified as platinum-sensitive,
platinum-resistant, biochemically recurrent,
and refractory. About 80% patients relapse
within 1 to 2 years after initial treatment and
gradually progress to platinum-resistance re
current OC (PROC), accompanied by significant
ly shortened survival [2]. PROC shows poor
response to chemotherapy, and non-platinum
based chemotherapy recommended in the
above guidelines produces limited therapeutic
benefit, with an effective rate of only 10%-25%
[3]. Thus, it is vital to identify novel drugs that
can help improve the prognosis of PROC
patients.
One of the critical factors in the development of
solid tumors is abnormal angiogenesis [4]. Anlotinib alone or in combination with chemotherapy for PROC
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Am J Transl Res 2023;15(3):1973-1981
Vascular endothelial growth factor (VEGF) and
its receptors have been targets for antitumor
treatment [5], and anti-angiogenic drugs can
exert beneficial effects in patients with PROC
[6, 7]. Several anti-angiogenic drugs, such as
bevacizumab, were ratified by the Food and
Drug Administration (FDA) for the treatment of
ROC, and combined therapy with antiangiogen
ic agents and non-platinum-based chemother
apy has gradually become the predominant
mode of PROC treatment [7].
Such regimens may prolong the survival of the
patients with PROC; however, the problems of
drug resistance and adverse reactions remain.
To improve the overall survival of OC patients,
reducing the frequency of side effects of grade
3 or higher side effects is a priority. Anlotinib, a
small-molecular multitargeted tyrosine kinase
inhibitor, is an orally available antiangiogenic
drug that was developed in the People’s
Republic China, and which can achieve good
efficacy in the therapy of various solid tumors
[8-10]. Currently, the FDA approves anlotinib
as an orphan drug for the therapy of OC.
Observational studies have indicated its effec
tiveness and safety in monotherapy or in com
bination chemotherapy in ROC [11-13], howev
er, respective evidence for PROC is still
insufficient.
The present retrospective study was conducted
by analyzing clinical data to assess the effec
tiveness and security of anlotinib in patients
with PROC.
Methods
Patients
We used data of patients who were diagnosed
with PROC and received treatment with anlo
tinib in the First Affiliated Hospital of Anhui
Medical University between March 2019 and
July 2021. This retrospective study was app
roved by the ethics committee of the First
Affiliated Hospital of Anhui Medical University
(Ethical Review-Kuai-PJ2019-03-19).
Inclusion criteria were: (1) patients aged
between 20-80 years old; (2) patients diag
nosed with epithelial OC by histopathology
and previous tumor cytoreductive surgery; (3)
patients with platinum-based chemotherapy as
first-line treatment; (4) patients with platinum
resistant recrudescence (disease progression
within six months after platinum chemothera
py); (5) patients with at least two cycles of anlo
tinib treatment (monotherapy or combined
therapy) after recurrence; (6) patients with
Eastern Cooperative Oncology Group (ECOG)
score of 0-2 points; (7) patients with presence
of assessable lesions.
Exclusion criteria were: (1) patients combined
with another tumor; (2) patients with severe
acute or chronic diseases that may have a
marked impact on antitumor therapy and prog
nosis, such as acute infection, immune defi
ciency diseases, infection with human immuno
deficiency virus, and uncontrolled hyperten
sion; (3) patients with incomplete data (such as
lost to follow-up).
Treatment
All patients were administered 12 mg anlo
tinib once per day in addition to combination
chemotherapy or as monotherapy for two con
secutive weeks (21 days per treatment cycle).
At the same time, based on the combined che
motherapy (albumin-binding taxol, irinotecan,
gemcitabine, doxorubicin liposomes, cyclo
phosphamide tablets, etoposide soft capsules,
capecitabine tablets, and tegio capsules, all of
which are recommended non-platinum based
chemotherapy agents without previous cross
resistance) in the 2019 or 2020 CSCO OC diag
nosis and treatment guidelines.
Patients who were intolerant to chemotherapy
received anlotinib monotherapy with individual
ized dosages. Doses were reduced to 8 mg
anlotinib once per day when severe intolerable
adverse reactions occurred.
Data compilation and definition
The compilation data included age, pathologi
cal type, International Federation of Gyneco
logy and Obstetrics (FIGO) stage, Karnofsky
performance scale (KPS), complicating diseas
es, ascites, size of recurrence, number of recur
rent lesions, metastasis, previous treatment,
therapy lines, treatment regimen, and anlotinib
discontinuation.
The outcomes included: progression-free sur
vival (PFS), objective response rate (ORR). Di-Anlotinib alone or in combination with chemotherapy for PROC
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Am J Transl Res 2023;15(3):1973-1981
sease control rate (DCR), and safety. The out
comes were evaluated by the investigators
according to the Response Evaluation Criteria
in Solid Tumors 1.1 (RECIST1.1), graded by the
and malignant mesodermal mixed tumor (1
case; 2.86%). Most patients (n = 34, 97.14%)
received anlotinib as third-line therapy or high
er, of whom 28 (80.00) was treated with above
Table 1. Demographic and baseline clinical characteris
tics of the patients
Total (N = 35)
Age, years, median (range)
53 (29-77)
Histology, n (%)
Serous
25 (71.43)
Mucinous
4 (11.42)
Clear-cell
5 (14.29)
Malignant mesodermal mixed tumor
1 (2.86)
International FIGO stage, n (%)
IIIA
6 (17.14)
IIIC
8 (22.86)
IV
21 (60.00)
KPS, median (range), n (%)
80 (60-90)
Complicating disease, n (%)
6 (17.14)
Complicated with ascites, n (%)
8 (22.86)
Size of recurrence, n (%)
≤ 5 cm
21 (60.00)
> 5 cm
14 (40.00)
Number of recurrent lesions, n (%)
Multiple
28 (80.00)
Single
6 (17.14)
NE
1 (2.86)
Peritoneal metastasis, n (%)
20 (57.14)
Lymphatic metastasis, n (%)
23 (65.71)
Viscera metastasis, n (%)
25 (71.43)
Previous other anti-angiogenic therapy, n (%)
24 (68.57)
Current treatment lines, n (%)
2
1 (2.86)
3
6 (17.14)
> 3
28 (80.00)
Therapeutic regimen, n (%)
Anlotinib
8 (22.86)
Anlotinib + etoposide + cyclophosphamide
3 (8.57)
Anlotinib + capecitabine
3 (8.57)
Anlotinib + etoposide
4 (11.43)
Anlotinib + irinotecan
5 (14.29)
Anlotinib + liposomal doxorubicin
3 (8.57)
Anlotinib + cyclophosphamide
3 (8.57)
Anlotinib + nab-paclitaxel
3 (8.57)
Anlotinib + pemetrexed
3 (8.57)
Federation of Gynecology and Obstetrics (FIGO), Karnofsky perfor
mance scale (KPS).
severity of toxic effects based on the
National Cancer Institute Common
Terminology Criteria for Adverse Events
(CTCAE5.0).
Follow-up
Imaging examination (CT or MRI) and
clinical evaluation was performed every
2 cycles. The last follow-up was July 1,
2021.
Statistical analysis
Statistical analyses were conducted
using SPSS 22.0 software (IBM Corp.,
Armronk, NY, USA). Survival curves were
produced using GraphPad Prism7
(GraphPad Software, San Diego, CA,
USA). Categorical data (case, %) were
tested using a Chi-squared test or
Fisher’s exact test. Statistical signifi
cance was reported at P < 0.05.
Results
Baseline data
A total of 35 patients with PROC were
included in this study, all of whom were
diagnosed with terminal OC (6 at st
age IIIA, 8 at stage IIIB, and 21 at st
age IV). Twenty-seven (77.14%) patients
received anlotinib in combination with
chemotherapy, and 8 (22.86%) patients
received anlotinib monotherapy due to
chemotherapy intolerance. The median
follow-up period was 9.80 months (95%
CI: 3.83-15.77), as of July 1, 2021.
Fifteen patients discontinued the treat
ment until the last follow-up.
The baseline characteristics of all
the patients are described in Table 1.
The median age was 53 (29-77) years
old. The pathological subtypes included
serous carcinoma (25 cases; 71.43%),
mucinous carcinoma (4 cases; 11.42%),
clear cell carcinoma (5 cases; 14.29%)Anlotinib alone or in combination with chemotherapy for PROC
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Am J Transl Res 2023;15(3):1973-1981
apy, 5 of which (18.52%) achieved PR, 14
(51.85%) achieved SD state, and 8 (29.63%)
exhibited PD. Thus, ORR was 12.50% and
18.52%, with DCR of 25.0% and 70.37% in
those who received anlotinib monotherapy or
anlotinib combined with chemotherapy, res
pectively (Table 3). The mPFS of monotherapy
was 1.20 months (95% CI: 0.96-1.42), and the
mPFS of combined therapy was 6.80 months
(95% CI: 5.89-7.71). The PFS of combined ther
apy was longer than that of monotherapy (log
rank P = 0.003; Figure 3).
Figure 1. PFS of the patients with PROC. Progression-free survival (PFS),
platinum-resistant recurrent ovarian cancer (PROC).
Figure 2. Short-term effectiveness of the patients who received assessment
according RECIST1.1. Response Evaluation Criteria in Solid Tumors 1.1 (RE
CIST1.1).
third-line therapy. Twenty-four
patients (68.57%) had previ
ously used other antiangio
genic agents (such as beva
cizumab).
Effectiveness assessment
Among all patients, the medi
an PFS (mPFS) was 6.50
months (95% CI: 2.02-10.98;
Figure 1), and none of pa
tients died until the last
follow-up.
Regarding short-term effec
tiveness, 6 patients (17.14%)
achieved partial response
(PR), 15 patients (42.86%)
reached a stable disease
(SD) state, and 14 patients
(40.00%) exhibited progres
sive disease (PD; Figure 2
and Table 2). The ORR and
DCR were 17.14% (95% CI:
6.56-33.65), and 60.00%
(95% CI: 42.11-76.13; Table
2).
Effectiveness of anlotinib as
monotherapy and in combina
tion with chemotherapy
Among the 35 patients who
were assessed for short-term
effectiveness, 8 were treated
with anlotinib monotherapy,
of whom 1 (12.50%) achieved
PR, 1 (12.50%) achieved SD,
and 6 (75.0%) exhibited PD.
The remaining 27 patients
were treated with anlotinib in
combination with chemother
Table 2. Short-term effectiveness of all the
patients
Anlotinib (N = 35)
PR, n (%)
6 (17.14)
SD, n (%)
15 (42.86)
PD, n (%)
10 (28.57)
NE, n (%)
4 (11.43)
ORR (%, 95% CI)
17.14 (6.56, 33.65)
DCR (%, 95% CI)
60.00 (42.11, 76.13)
Objective response rate (ORR), disease control rate
(DCR), partial response (PR), stable disease (SD).Anlotinib alone or in combination with chemotherapy for PROC
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Am J Transl Res 2023;15(3):1973-1981
Effectiveness in various subgroups
Grouping the data according to previous use of
anti-angiogenic agents (Table 4) showed that
11 patients had received no other anti-angio
genic therapy previously, 3 of whom (27.27%)
achieved PR, 5 (45.45%) achieved SD, and 3
(27.27%) showed PD. Among those who previ
ously received other anti-angiogenic therapy
(n = 24), 5 (20.83%) achieved PR, 8 (33.33%)
reached SD state, and 11 (45.83%) experi
enced PD. Thus, in patients who received anlo
tinib as the first anti-angiogenic agent or after
previous administration of other anti-angiogen
ic agents, the ORR was 27.27% and 20.53%,
with a DCR of 72.72% and 54.17%, respective
ly. Moreover, 34 patients used anlotinib as
third-line or above therapy, of which 5 (14.71%)
achieved PR, 15 (44.12%) reached SD, and 14
chemotherapy intervals of < 6 months or those
developing progression during chemotherapy,
options for treatments are limited and their
efficacy is mostly unsatisfactory. One of the
main difficulties in current clinical practice is
the insidious onset of OC in most cases, thus
typically precluding early detection [14, 15].
According to statistical date from the China
Cancer Center, the incidence of OC in China is
increasing annually, and survival rates have not
markedly improved [16], mostly because some
patients show recurrence within a short time
after initial treatment, and gradually developed
into PROC [17]. High expression of VEGF pre
dicts the median survival time of patients with
OC [15, 18-20], and high expression of platelet
derived growth factor (PDGF), fibroblast growth
factor (FGF), and their receptors are similarly
poor prognostic factors in OC [21, 22]. Thus,
Table 3. Short-term effectiveness of mono-anlotinib therapy and in
combination with chemotherapy (n = 35)
Anlotinib monotherapy
(n = 8)
Anlotinib + chemotherapy
(n = 27)
P
CR, n (%)
0
0
PR, n (%)
1 (12.50)
5 (18.52)
SD, n (%)
1 (12.50)
14 (51.85)
PD, n (%)
6 (75.00)
8 (29.63)
ORR (%)
12.50%
18.52%
0.96433
DCR (%)
25.0%
70.37%
0.1473
Objective response rate (ORR), disease control rate (DCR), partial response (PR),
stable disease (SD).
Figure 3. PFS of mono-anlotinib therapy and in combination with chemo
therapy. Progression-free survival (PFS).
(41.18%) experienced PD.
Thus, the ORR was 14.71%
and the DCR was 58.82%.
Histology, FIGO stage and pre
vious treatment with other
anti-angiogenic drugs were
not associated with PFS (log
rank tests, P > 0.05).
Safety assessment
During follow-up, two patients
aborted treatment due to
intolerable adverse events,
including one patient (2.86%)
showing a grade-3 adverse
reaction (oral mucositis) and
one patient showing gross
hematuria (grade-2). No gr
ade-4 or 5 adverse reactions
occurred.
The most commonly reported
adverse reactions were de
creased appetite (n = 12,
34.29%), fatigue (n = 10,
28.57%), nausea and vomit
ing (n = 8, 22.86%), hand and
foot skin reaction (n = 5,
17.14%), and hypertension
(n = 2, 11.43%).
Discussion
In patients with ROC, especial
ly those with non-platinum Anlotinib alone or in combination with chemotherapy for PROC
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Am J Transl Res 2023;15(3):1973-1981
preventing abnormal blood vessel formation
and persistence and remodeling in the tumor
microenvironment are new directions in the
treatment of OC [15]. Anti-angiogen drugs can
improve the survival of patients with advanced
OC [23, 24]. The current recommended treat
ment for ROC is chemotherapy with or without
targeted therapy [15, 25]. However, there are
several drawbacks, e.g., the duration of recur
rence is gradually shortened in repeated treat
ments, drug resistance may emerge, these
drugs are expensive, and some patients experi
ence intolerable adverse reactions [26, 27].
Anti-angiogenic drugs can also remarkably
improve the prognosis of patients with PROC
[6, 20, 27]. For example, in a massive phase-III
study of chemotherapy in combination with
bevacizumab versus chemotherapy for PROC
(also known as the AURELIA study), the com
bined treatment group exhibited significantly
better results than the chemotherapy group
(mPFS: 6.7 vs 3.4 months; median OS: 16.7 vs
13.3 months) [7]. However, the main target of
bevacizumab is VEGF, it has insufficient effect
on other pathways of angiogenesis. The prog
nosis of PROC patients administered a bevaci
zumab combination treatment is poorer in the
general population than that reported in the
trial, especially in patients receiving multiple
treatments. The survival benefits of this treat
ment are this uncertain. Thus, general applica
bility is limited, and identifying novel respective
drugs is vital.
Anlotinib can act on several targets, including
the VEGFR, PDGFR, FGFR, c-Kit, Ret, and c
Met, to restrain abnormal tumor angiogenesis
and control tumor multiplication and metasta
sis [14, 28]. Furthermore, this compound has
shown remarkable efficacy in the intervention
of many tumor types, e.g., non-small cell lung
cancer [8], soft tissue sarcoma [9], and thyroid
cancer [10], with pronounced antiangiogenic
effects [25]. In the current study, 97.14% of
the included cases were posterior-line pa
tients, with poor response to chemotherapy
and intractable treatment, and it is shown that
anlotinib had promising effectiveness and tol
erable safety, either as monotherapy or in com
bination with chemotherapy. In addition, for
68.57% of the included cases who previously
received bevacizumab or other anti-angiogenic
therapy, anlotinib demonstrated effectiveness.
Some patients continued treatment, as they
had not yet met the PFS evaluation endpoint.
The mPFS calculated for all cases with PD by
the time of data analyses markedly exceeded
that of the currently known chemotherapy
group [7] (6.50 VS 3.4 months) and was similar
to that of the group receiving bevacizumab
combined with chemotherapy (6.80 VS 6.7
months).
In a retrospective study on 15 patients with
PROC, anlotinib showed promising efficacy,
with an ORR of 14.3% and a DCR of 85.7% [13].
In a different study, 17 PROC patients receiv
ing anlotinib monotherapy produced an ORR of
23.5% and a DCR of 82.3%, whereas in 19
patients receiving this compound in combina
tion with chemotherapy, the ORR was 36.8%
and the DCR was 94.7% [29]. The results of the
present showed comparable short-term effica
cy results. However, the DCR in those who
received anlotinib monotherapy was lower,
compared to the results of the two previous
studies [13, 29], which was likely due to differ
ences in sample size. Of note, the majority of
patients included in this study had previously
received multiline therapy, and some of them
experienced disease progression after using
bevacizumab or other anti-angiogenic drugs,
which emphasizes the effectiveness of anlo
Table 4. Short-term effectiveness of different subgroups
Not use of other anti-angiogenic
therapy previously (n = 11)
After use of ther anti-angiogenic
therapy previously (n = 24)
Anlotinib used as third-line or
above therapy (n = 34)
CR, n (%)
0
0
0
PR, n (%)
3 (27.27)
3 (12.50)
5 (14.71)
SD, n (%)
5 (45.45)
10 (41.67)
15 (44.12)
PD, n (%)
3 (27.27)
11 (45.83)
14 (41.18)
ORR
27.27%
12.50%
14.71%
DCR
72.72%
54.17%
58.82%
Objective response rate (ORR), disease control rate (DCR), partial response (PR), stable disease (SD).Anlotinib alone or in combination with chemotherapy for PROC
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Am J Transl Res 2023;15(3):1973-1981
tinib in the intervention of PROC in the real
world.
The most common adverse effects anti-angio
genic agents are hypertension, proteinuria, and
hand-foot syndrome [17, 18, 26]. The previous
ly reported safety profile of anlotinib-containing
therapy of OC and other tumor types included
hand-foot skin reaction, hypertension, protein
uria, hypothyroidism, leucopenia, and neutro
penia [14]. In the current study the most com
mon adverse reactions were decreased appe
tite, fatigue, nausea and vomiting, hyperten
sion, and hand foot syndrome. One patient
showed grade-3 oral mucositis, two patients
stopped treatment owing to intolerable ad
verse reactions, and most of the other adverse
events were less severe than grade-3 and were
manageable after dose adjustment and symp
tomatic treatment. Therefore, anlotinib demon
strated outstanding efficacy and favorable
safety in the intervention of PROC.
Our study had some limitations, including the
lack of a parallel control, i.e., “no chemothera
py” or “other combination therapy” as a com
parison. Further, most patients had multiple
previous courses of treatment, and limited
subsequent options complicate the stratifica
tion of combination chemotherapy regimens.
The sample size was small, and inter-groups
differences were not pronounced, thus a larg
er sample size would be required for confirma
tion. Some patients were continuing their treat
ment and had not met the PFS evaluation end
point. Moreover, pathological heterogeneity
was not strictly distinguished in this study, but
this is more reflected the diversity of patients
for clinical practice. In the future, it is neces
sary to carry out a prospective study on the
treatment of ovarian cancer with arotinib to
verify it.
Conclusions
To summarize, anlotinib is promising for the
treatment of PROC, either in a monotherapy or
in combined with chemotherapy. This com
pound showed exceptional anti-tumor activity
and offered survival benefits for patients with
PROC, even in patients with a history of treat
ment with other antiangiogenic drugs.
Acknowledgements
The study was supported by the Beijing Medical
and Health Public Welfare Foundation “Medical
Science Research Fund” Project (YWJKJJ
HKYJJ-B183069).
Disclosure of conflict of interest
None.
Abbreviations
PROC, platinum-resistant recurrent ovarian
cancer; AEs, adverse events; Mpfs, median
progression free survival; ORR, objective res
ponse rate; DCR, disease control rate; VEGF,
vascular endothelial growth factor; FDA, Food
and Drug Administration; ECOG, Eastern
Cooperative Oncology Group; FIGO, Internati
onal Federation of Gynecology and Obstetrics;
PFS, progression free survival; PR, partial
response; SD, stable disease; PDGF, platelet
derived growth factor; FGF, fibroblast growth
factor.
Address correspondence to: Mei Zhang, Oncology
Department of Integrated Traditional and Western
Medicine, The First Affiliated Hospital of Anhui
Medical University, No. 218 Jixi Road, Hefei
230022, Anhui, China. Tel: +86-13856990019;
E-mail: zhangmei@ahmu.edu.cn
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