Introduction
Ovarian cancer (OC) is the eighth most common type
of malignant tumor and cause of death among women
worldwide.[] Epithelial OC (EOC) constitutes approximately 85%-90% of all diagnosed ovarian tumors and
typically occurs in women from 55-65 years old.[] Diagnosis
is typically delayed because patients with earlystage
EOC do not present significant symptoms.[] The
standard initial treatment approach for advanced EOC is cytoreductive surgery followed by chemotherapy using
platinum and taxane-based regimens.[,] Despite
high response rates following initial treatment of advanced-
stage EOC, recurrence occurs in approximately
80% of cases within five years.[] Treatment of recurrent
EOC depends on the amount of time since the
previous platinum-based treatment. Patients who experience
recurrence or progression within six months
of completing platinum-containing chemotherapy are
classified as platinum-resistant and exhibit a median
overall survival (OS) of approximately 12-18 months.
Patients who remain free from disease progression for
at least six months after completing platinum-containing
treatment are considered platinum-sensitive; they
tend to respond favorably to platinum-based drugs.
However, patients with platinum-resistant disease or
allergic reactions to platinum compounds respond
poorly to alternative single-agent chemotherapy regimens.[,] Thus, there is a critical need for new treatment
options for patients with platinum-resistant EOC.
Angiogenesis promotes tumor growth and metastasis;
bevacizumab, a monoclonal antibody that targets
vascular endothelial growth factor A (VEGF-A), is a key
factor in this pathway.[] Studies have shown that the
combination of single-agent chemotherapy with bevacizumab
is an effective treatment strategy for patients diagnosed
with platinum-resistant or -allergic metastatic
EOC. In particular, the AURELIA study showed that
single-agent chemotherapy with paclitaxel, topotecan,
and pegylated liposomal doxorubicin (PLD) in combination
with bevacizumab was effective in a cohort of
361 patients diagnosed with platinum-resistant EOC.
The overall response rate (ORR), as well as the durations
of progression-free survival (PFS) and OS, significantly
improved when bevacizumab was included in chemotherapy.
Moreover, the results were slightly better in the
paclitaxel group compared to the others.[]
Few studies have assessed the efficacy of various
chemotherapies combined with bevacizumab in patients
with platinum-resistant or -allergic metastatic
EOC. Therefore, this study aimed to compare the effectiveness
of chemotherapy agents used with bevacizumab
in these patients.
Methods
Patient Demographics and Data Collection
This retrospective cross-sectional study was approved
by both the academic and ethical committees of our
institution. It was conducted in adherence to the principles outlined in the Declaration of Helsinki. The study
included patients who were monitored at an oncology
center's outpatient clinic between 2010 and 2022. Participants
were identified within the institution"s database.
All patients diagnosed with recurrent platinum-resistant
or -allergic EOC and who received non-platinum,
single-agent chemotherapy in combination with bevacizumab
were assessed. Patients with insufficient data for
statistical analysis were excluded from the study. Demographic
and clinical information, such as age at diagnosis,
family history (in accordance with the International
Federation of Gynecology and Obstetrics classification),
cancer stage, histological characteristics, prior adjuvant
or neoadjuvant chemotherapy, number of bevacizumab
cycles administered, number of chemotherapy cycles
administered, radiotherapy treatments, surgical procedures,
and recorded toxicities, were scrutinized from
the medical database. This information was systematically
documented and archived for subsequent analysis.
Treatment-related responses were evaluated through
a combination of clinical assessments and radiological
examinations conducted every 2-3 months. Following
the Response Evaluation Criteria in Solid Tumors (RECIST
1.1) guidelines, treatment responses were categorized
into four groups: complete response (CR), partial
response (PR), stable disease (SD), and progressive disease
(PD). These classifications were used to determine
the best possible response achieved by patients. The
ORR was calculated by summing the CR and PR cases.
The disease control rate (DCR) was determined by considering
not only CR and PR but also SD cases. Adverse
events associated with the treatment were documented
during each patient"s visit. The severity of these events
was systematically assessed and graded in accordance
with the Common Terminology Criteria for Adverse
Events, version 5. PFS was defined as the duration from
the initiation of bevacizumab with chemotherapy to
disease progression. OS refers to the time from the start
of bevacizumab-based therapy to death. We also conducted
a univariate analysis to evaluate the influence of
clinical and pathological factors on OS, whose results
were included in a multivariate analysis with factors
previously identified as significant in the literature.
Statistical Analysis
Statistical analyses were conducted using SPSS software
version 25. Continuous variables are presented
as medians and the corresponding minimum and
maximum values. Categorical variables are expressed
as numbers and percentages. Survival curves were
constructed using the Kaplan-Meier method. Univariate analysis was performed using the log-rank
test. Multivariate analysis was conducted using the
Cox regression model to assess the independent effects
of various variables on the outcomes of interest.
Results
Patient Characteristics and Treatment Modalities
A total of 60 patients with primary platinum-resistant
or -allergic metastatic EOC were included in this study.
The median age of these patients was 57 years, with a
range from 26 to 76 years. The majority (83%) of patients
were diagnosed with serous adenocarcinoma, whereas
the remaining (17%) were classified into other pathological
subgroups, including clear-cell, endometrioid,
and mucinous subtypes. Table 1 presents an overview
of the clinical and pathological characteristics of the
patient cohort. Notably, 58 out of 60 patients (97%) underwent
primary surgery before initiating bevacizumab-
based treatment. All of them, except for one patient,
received perioperative chemotherapy. Forty-eight patients
(80%) received palliative chemotherapy. Among those who were administered a chemotherapeutic drug
in combination with bevacizumab, 16 (27%), 29 (48%),
and 15 (25%) received PLD, weekly paclitaxel, and gemcitabine
regimens, respectively. The median number of
chemotherapy cycles administered in combination with
bevacizumab was 9, with a range from 2 to 55 cycles.
On average, these patients underwent 10 bevacizumab
cycles, though this number ranged from 1 to 55 cycles.
Table 1 Clinical and pathological features of the patients
Patients were then classified by treatment response:
3 patients (5%) achieved CR, 26 patients (43%)
achieved PR, 11 patients (18%) exhibited SD, and 20
patients (33%) exhibited PD. The ORR was 48%, and
the DCR for all patients was 67% (Table 2). Five patients
(8%) experienced grade >2 hypertension. Gastrointestinal
system (GIS) perforation occurred in one
patient (2%), and another (2%) developed a fistula.
Thromboembolic events, hemorrhage, and heart failure
were reported in three patients (5%), one patient
(2%), and one patient (2%), respectively. Febrile neutropenia
was observed in six patients (10%) (Table 3).
Bevacizumab treatment was discontinued in 50 patients
(83%) due to disease progression, in six patients (10%) due to treatment-related toxicity, and in two patients
(3%) due to an insufficient treatment duration.
Table 2 Responses to bevacizumab based chemotherapy
in recurrent platinum-resistant or -allergic metastatic
EOC
Table 3 Grade >2 side effects of bevacizumab plus
chemotherapy
Survival Outcomes
The median follow-up periods after recurrent disease and
PFS were 40 months and 9.6 months, respectively. The
median PFS was 7.5 months (95% CI: 9.437?11.496) as
shown in Figure 1. The median OS was calculated at 14.4
months (95% CI: 2.579-9.346) as shown in Figure 2. Factors
such as age, pathology type, grade, initial stage, perioperative
chemotherapy, pre-bevacizumab radiotherapy,
and hormone therapy status had no significant (p>0.05)
impact on survival rates. The survival rate of patients with
multiple metastatic sites was significantly lower (p=0.010,
p<0.05) than those with fewer sites. Among those who
underwent different chemotherapy regimens combined
with bevacizumab, no substantial differences in OS were
found between weekly paclitaxel (19.5 months), PLD
(12.6 months), and gemcitabine (18 months) in combination
with bevacizumab (p=0.783, p>0.05) (Tables 4, 5).
Fig. 1. Kaplan-Meier curve of progression-free survival
in patients with platinum-resistant or -allergic
metastatic EOC treated with chemotherapy
plus bevacizumab.
EOC: Epithelial OC.
Fig. 2. Kaplan-Meier curve of overall survival in patients
with platinum-resistant or -allergic metastatic EOC
treated with chemotherapy plus bevacizumab.
Table 4 Univariate analysis for survival analysis
Table 5 Multivariate cox regression analysis for overall survival
Discussion
Carboplatin is the most commonly administered chemotherapeutic
agent for managing metastatic EOC. However,
some patients with recurring EOC do not respond to,
or are allergic to, platinum-based drugs like carboplatin.
Although patients who are allergic to platinum can undergo
desensitization, this method may not be suitable for all
patients. Desensitization requires access to an advanced
medical center equipped with a skilled and experienced
healthcare team.[] On the other hand, platinum-resistant
patients typically undergo single-agent, nonplatinum
chemotherapies with bevacizumab. Few studies have compared the efficacy of various chemotherapy
agents used in combination with bevacizumab.[-]
The AURELIA trial is the first Phase III clinical trial that
directly compared the combination of bevacizumab with
single-agent chemotherapy against chemotherapy alone
in the context of recurrent, platinum-resistant ovarian
cancer. Chemotherapy agents included weekly paclitaxel,
PLD, or topotecan. Including bevacizumab in the treatment regimen significantly increased PFS to 6.7 months
from 3.4 months in chemotherapy alone. Although the
OS was 16.6 months in the bevacizumab group and 13.3
months in the chemotherapy-alone group, this difference
was not statistically significant. Notably, the true impact
of bevacizumab on OS was obscured and likely diluted by
the fact that 40% of patients in the chemotherapy group
crossed over to receive bevacizumab monotherapy upon experiencing disease progression. Subgroup analysis revealed
that the ORR from combinatorial, bevacizumabbased
therapy was most pronounced in the paclitaxel
group (53.3% ORR compared to 30.2%).
No significant difference in OS was found between
treatments in any of the chemotherapy cohorts. Patients
who received PLD or topotecan in addition to bevacizumab
had slightly higher OS of 14.1 and 13.8 months,
respectively, compared to their single-agent counterparts
of 13.7 and 13.3 months. However, a more pronounced
effect on OS was observed in the paclitaxel cohort (22.4 vs
13.2 months).[] In our study, the median PFS duration
of 7.5 months agreed with the previous trial (6.7 months).
Although not statistically significant, the weekly paclitaxel
regimen had a more positive effect on OS compared
to other regimens. The median OS was 19.5 months for
weekly paclitaxel, 12.5 months for PLD, and 18 months
for gemcitabine (p=0.783, p>0.05). The OS of all patients
in our study was slightly lower at 14.4 months compared
to the 16 months reported in the AURELIA trial. This discrepancy
may be attributed to the fact that our study used
real-world data, whereas the AURELIA study was conducted
on selected patient populations. Another study
assessed the efficacy of the combination of bevacizumab
and PLD against platinum-resistant EOC; the DCR was
73%, and the PFS was six months.[] Our findings were similar: a DCR of 67% and a PFS duration of 7.5 months.
A Phase II clinical trial investigated the combination of
bevacizumab and albumin-bound paclitaxel in patients
with platinum-resistant EOC and reported an ORR of
50% and PFS of eight months,[] similar to the ORR
(48%) and PFS (7.5 months) reported here. In our study,
approximately 8% of patients presented with grade >2
hypertension. Although some complications such as GIS,
thromboembolic events, hemorrhage, and heart failure
were observed in a small number of patients, bevacizumab
was well-tolerated in most cases; only 10% of patients
discontinued treatment due to toxicity. These findings are
consistent with results from previous studies.[]
Limitations of The Study
This study has some limitations. The retrospective design
of our study led to a heterogeneous patient group, and
some data were incomplete or missing. Retrospective and
single-center studies like ours may present selection bias.
Conclusion
In this study, we highlighted the effectiveness and safety
of combining bevacizumab with single-agent chemotherapy
for platinum-resistant or -allergic metastatic EOC.
Overall, there were no significant differences between treatment modalities for recurrent EOC. Bevacizumab
was well-tolerated by most patients and improved patient
outcomes. Ultimately, treatment strategies should
consider factors like the patient"s treatment history, comorbidities,
drug side effects, and related variables.
Ethics Committee Approval: The study was approved by the
Istanbul University Istanbul Faculty of Medicine Clinical Research
Ethics Committee (no: 2022/1652, date: 07/10/2022).
Authorship contributions: Concept - N.K., İ.D., P.S.,
A.Ay.; Design - N.K., İ.D., P.S., A.Ay.; Supervision - N.K.,
İ.D., P.S., A.Ay.; Funding - N.K., N.S.O., A.Y.; Materials -
N.K., N.S.O., A.Y., B.K., A.A.; Data collection and/or processing
- N.K., N.S.O., A.Y., B.K., A.A.; Data analysis and/
or interpretation ? N.K., İ.D., N.S.O., A.A.; Literature search
- N.K., İ.D., N.S.O., A.Y., B.K., A.A.; Writing - N.K., İ.D.,
N.S.O., B.K., A.A.; Critical review - N.K., İ.D., P.S. A.Ay.
Conflict of Interest: All authors declared no conflict of interest.
Use of AI for Writing Assistance: Not declared.
Financial Support: None declared.
Peer-review: Externally peer-reviewed.
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