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ABSTRACT
Malignant ascites is frequently found in OC, with about 10% of patients suffering from recurrent OC. More than a third
of ovarian cancer patients have ascites at diagnosis, and nearly all have ascites at recurrence. The presence of ascites
correlates with peritoneal spread of ovarian cancer and is associated with a poor prognosis of the disease. Malignant
ascites acts as a reservoir of a complex mixture of soluble factors and cellular components that provide a tumor-
stimulating microenvironment for tumor cells. Ascites -derived malignant cells represent a major source of morbidity
and mortality in ovarian cancer patients. Subpopulations of these tumor cells have increased resistance to therapy
and the ability to distal metastasis and recurrence. The anti-angiogenic targeted agents bevacizumab and pazopanib
also showed good effects in the symptomatic treatment of malignant ascites OC, significantly prolonging the time to
the next paracentesis. Thus, we conclude that further large-scale studies are needed to find out whether the reduction
in ascites with these targeted drugs leads to an increase in the duration of tumor-related survival or not.
KEYWORDS
Ovarian cancer, ascites, targeted therapy, bevizumab, pazopanib.
Research Article
ASCYTE IN OVARIAN CANCER: NEW OPPORTUNITIES FOR RESEARCH
Submission Date:
October 01, 2022,
Accepted Date:
October 07, 2022,
Published Date:
October 21, 2022
Crossref doi:
https://doi.org/10.37547/ijmscr/Volume02Issue10-05
Rakhimov Nodir Makhammatkulovich
Samarkand State Medical University, Uzbekistan
Shakhanova Shakhnoza Shavkatovna
Samarkand State Medical University, Uzbekistan
Abdurakhmonov Zhurabek Amrilloevich
Samarkand State Medical University, Uzbekistan
Journal
Website:
https://theusajournals.
com/index.php/ijmscr
Copyright:
Original
content from this work
may be used under the
terms of the creative
commons
attributes
4.0 licence.
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INTRODUCTION
Inclusive literature search was carried out by cross -
referencing by keywords and then using literature
references classified in preliminary sequence in the
second stage to reduce the search volume. After
documenting this core compendium of studies, the
inclusion and exclusion criteria were formulated. The
study included literature on targeted therapy in the
treatment of ovarian cancer ascites ; the relevance of
targeted therapy for the treatment of the disease;
specifics of targeted therapy in the treatment of
ovarian cancer; assessment of response after
treatment; ongoing surveillance and recurrence of
ovarian cancer. Evaluation terms included : ovarian
cancer ascites, targeted therapy in the evaluation of
ovarian cancer, recent innovations in targeted therapy
for the treatment of ovarian cancer.
Epithelial ovarian cancer (OC) is the eighth most lethal
gynecological malignancy in the world and the leading
cause of gynecological cancer death in industrialized
countries [21]. It is characterized by the spread of the
tumor into the peritoneum and the development of
malignant ascites, as well as the absence of specific
symptoms in the early stages of the disease [35]. More
than 200,000 cases of ovarian cancer are diagnosed
each year , but 120,000 deaths are due to late
detection [3]. Almost 70% of all patients have stage III
and IV disease, although late detection of OC is not
associated with the absence of symptoms, but the
symptoms are rather nonspecific. Most patients suffer
from pain in the abdomen, gastrointestinal tract,
urination or pelvis, which rarely attracts the attention
of the attending physician. This is the reason for the
late detection of OC [36].
Currently, aggressive cytoreductive surgery followed
by carboplatin and paclitaxel based on adjuvant
chemotherapy is the “gold standard” [28]. However,
the majority of patients will have disease progression
with the development of resistance to chemotherapy
in the future, which prompted us to explore new
therapeutic methods, since the overall survival for
patients who undergo surgery with adjuvant
chemotherapy is only approximately 30% [13]
According to Simpson-Abelson MR et all. h anniy
metatase in OC occurs through the direct spread of the
tumor to areas adjacent to the primary tumor [38].
The epithelial-mesenchymal transition is involved in the
formation of metastases, which leads to the migration
of tumor cells to distant sites, after which the
mesenchymal-epithelial
transition
occurs
to
accumulate in the tissue where the metastasis is
located [1].
To date, there has not yet been a single consensus and
opinion regarding the specific treatment of malignant
ascites in patients with OC [12].
According to the National Cancer Institute, malignant
ascites is defined by the accumulation of fluid
containing cancer cells in the abdominal cavity [28].
Malignant ascites also typically has high levels of
lactate dehydrogenase compared to non-malignant
peritoneal effusions, indicating a high rate of tumor cell
proliferation and rapid disease progression [5].
Malignant ascites is more common in OC than in any
other tumor type; OC is known to cause intraperitoneal
metastases [33].
There are several traditional treatment options for
ascites, including salt restriction, diuretics, radioactive
isotopes, paracentesis, and shunt placement.
However, these methods have only a limited
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therapeutic effect and can cause significant toxic and
side effects [12].
When the ovarian tumor capsule breaks down and the
malignant cells disperse into the abdominal cavity, the
cells survive as single cells or as free-floating
multicellular inclusions in ascites called spheroids [2].
These spheroids adhere to the mesothelial
extracellular matrix, which allows them to be fixed as
secondary lesions of the pelvic organs [37]. Tumor cells
in OC-associated malignant ascites trigger the
recurrence of the disease. Mortality of patients is
mainly associated with widespread metastasis of
serous surfaces and concomitant peritoneal or pleural
effusion [6]. The effusion accumulates as a result of
lymphatic obstruction, activation of native mesothelial
cells by a metastatic process, and increased vascular
permeability
indirectly
triggered
by
vascular
endothelial growth factor ( VEGF ) and interleukins of
the 6th and 8th orders [14]. In addition, tumor cells
themselves accumulate on the surface of the
peritoneum, causing mechanical obstruction and
preventing the absorption of intraperitoneal fluid. In
malignant ascites, peritoneal fluid secretion is
enhanced by VEGF stimulation [8].
A study by Schön-Günter and Mannel to evaluate the
incidence of malignant ascites in ovarian malignancies
found that although malignant ascites is rare in FIGO
stage I OC (17%), it is found in the vast majority of
patients with stage II/III tumor in 89% [35]. However,
this study did not distinguish between epithelial and
non-epithelial
neoplasms.
Commonly
reported
symptoms of malignant ascites include anorexia,
bloating, dyspnea and respiratory distress, fatigue,
insomnia, and abdominal pain [11].
Normal treatment of malignant ascites is generally
unsatisfactory.
Repeated
paracentesis
of
intraperitoneal fluid provides only temporary relief and
is not satisfactory due to the lack of causal therapy,
which requires repeated drainage, depending on the
severity of ascites. Protein loss and hypovolemia also
increase the incidence of circulatory disorders. Finally,
the risk of bowel perforation during paracentesis is
certainly higher if performed more frequently [43].
Thus, advances in understanding the mechanisms that
trigger malignant OC-associated effusion and the
development of new therapies are imperative to
improve the outcome of patients with malignant
ascites.
Targeted therapy has recently been developed as a
promising alternative treatment option for malignant
ascites. Since angiogenesis is known to be a significant
contributor to the formation of ascites, anti-angiogenic
agents have been tested for this purpose.
Bevacizumab and the novel VEGF agent pazopanib
have been investigated and clinical efficacy has been
proven in cohorts of patients with heavy pretreatment
[10]
Pathophysiological aspects of malignant ascites .
Under normal physiological conditions, the capillary
membranes of the abdominal cavity continuously
release free fluid to maintain lubrication of the serous
surfaces of the peritoneal membrane, so that a
solution easily passes between the peritoneum and
adjacent organs. Two-thirds of this peritoneal fluid is
reabsorbed into the lymphatic channels of the
diaphragm and pushed into the right subclavian vein by
negative intrathoracic pressure [15]. In cases of
disseminated intra -abdominal cancer, tumors cause a
further increase in peritoneal fluid production due to
increased tumor microvasculature leakage and
lymphatic obstruction [4]. As a result, the
accumulation of fluid in the abdominal cavity exceeds
the reabsorption of fluid, which leads to the
accumulation of ascites. It is assumed that the
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circulation of ascitic streams in the abdominal cavity
dictates the ways in which ovarian cancer spreads [42].
The physiological factors that govern this process are
gravity, diaphragmatic pressure, organ mobility, and
depressions formed by key anatomical structures [34].
The three most common intra-abdominal sites of
ovarian cancer metastasis are the greater omentum,
right subdiaphragmatic region, and pouch of Douglas,
areas that have easy access to ascites. Detached
ovarian tumor cells, either singly or in the form of
multicellular spheroids, are largely colonized in these
distant sites by the flow of ascites; however, little is
known about the effect of ascites flow on the
heterogeneity of metastatic ovarian tumors that
colonize at distant sites [34].
In a study by Latifi et al . It has been demonstrated
that both adherent and non-adherent tumor cells are
present in malignant ascites. The aim of their study was
to separate these two types in culture. Interestingly,
adherent tumor cells in ascitic fluid expressed rather
mesenchymal features, while non-adherent cells had
an epithelial phenotype, as they expressed epithelial
cell adhesion molecule (EpCAM) and cytokeratin-7 (
Latifi A et all conducted an experiment with mice
injected intraperitoneally with either adherent or non-
adherent cells.Mice injected with non-adherent cells
developed tumors and malignant ascites within 12-14
weeks.In contrast, mice injected with adherent cells
remained tumor-free for 20 weeks [26].
In a study by Simpson-Abelson MR et all. ovarian
tumor-associated ascitic fluid has been shown to
inhibit T-cell-induced nuclear factor-kappa-B (NF-
κB)
receptor and activated T-cell signaling nuclear factor
(NFAT) in T-cell-associated tumors. In fact, the T cells
present in ovarian tumor ascites do not respond
properly to stimulation through the T cell receptor.
Thus, NF-
κB and NFAT activation is reduced, as is the
proliferation of these immunosuppressed T cells.
Interestingly, T cell anergy in ascites is due to fluid
soluble factors. Since these T cells are analyzed in the
absence of ascites, they acquire their normal function,
and this effect is quickly restored when ascitic fluid is
added to the T cells. This may explain why human
tumors grow despite the presence of T cells and other
immune response cells. The immunosuppressive effect
of cellular or soluble biological factors on T cells and
the accumulation of these immunosuppressed cells in
tumors has already been proven by Simpson - Abelson
MR et all . also demonstrated that the delay in NF-
κB
and NFAT signaling is located upstream of
phospholipase C, as the signaling phosphorylation
pattern of normal T cell receptors was compared to
that of T cells in ascites. In addition, T cells derived from
normal donated peripheral blood were incubated with
(cirrhotic) ascitic fluid and showed the same T cell
receptor signaling. Thus, it is assumed that ascitic fluid
has an immunosuppressive effect on T cells, causing
them to become anergic to various stimuli. Targeting
soluble factors that induce T cell immunosuppression
will undoubtedly be a future therapeutic option for the
treatment of OC . [38].
Davidson
and
colleagues
investigated
active
biochemical events in malignant ascites and pleural
effusion. Patients with malignant effusion due to OC
were included in this study . Expression and activation
of selected signaling proteins in effusion samples were
studied using protein microarrays using antibodies
[9]. Malignant effusions (>80% malignant cells) were
differentiated from benign effusions . Malignant
effusion samples were characterized by higher
expression of protein kinase B, activated extracellular
signal kinase, cyclic adenosine monophosphate-
responsive element binding protein, and N- terminal
kinase c-JUN. Interestingly, there were no differences
in signal profiles between pleural effusion and ascites.
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In group 1 patients, high p38 expression and a high
ratio of phosphorylated to non-phosphorylated
epidermal growth factor receptor (EGFR) were
associated with poor survival, while the amount of N-
terminal phospho-c-JUN kinase was associated with
poor outcome in group 2. This The study shows that
there is a clear dysregulation in proliferation, survival,
and apoptotic signaling in OC effusion samples , and
that some of the signaling proteins may influence
patient outcome. With this knowledge, the authors
wanted to accelerate the invention of new targeted
therapeutic agents against ascites associated with OC
[9].
In patients with chemoresistant disease included in this
study, epithelial, mesenchymal and cancer stem cell
selective markers were examined and compared
between adherent and non-adherent tumor cells. Non-
adherent cells showed increased mRNA expression of
E-cadherin,
epithelial
cell
adhesion
molecule,
transcription signal transducer and activator 3, and
octamer-binding transcription factor 4, while adherent
cells showed increased mRNA expression of
differentiation cluster 44, template metallopeptidase
9, and octamer-binding transcription factor 4.
transcription factor 4. Patients with chemoresistant
tumors had more oncogenic epithelium [26]. It was
also evident that non-adherent epithelial cells had
increased mRNA expression of genes associated with
cancer stem cells. Since cancer cells in OS-associated
ascites are associated with disease recurrence, the
information presented in this study may contribute to
a better understanding of the cellular biology of tumor
cells within ascites.
Angiogenesis of ascites
Antiangiogenic agents for malignant ascites. In healthy
individuals, there is a balance of pro-angiogenic and
anti-angiogenic signals (excluding wound healing and
embryonic development), providing a calm vascular
environment [12]. In the tumor microenvironment, the
pro-angiogenic signaling cascade dominates the anti-
angiogenic pathway, leading to the formation of new
blood vessels [7]. When the tumor diameter exceeds 1
–
2 mm, angiogenesis becomes necessary for tumor
growth [31].
Angiogenesis is mainly regulated by members of the
VEGF family of growth factors and receptors, and
ascites formation is also dependent on VEGF. Tumor
vessels are rather disorganized, twisted and tend to
leak [16]. Since VEGF-dependent signaling is blocked,
the formation of malignant ascites is also reduced [12].
VEGF expression has been detected in OC in various
assays, and in addition, the degree of VEGF expression
has been shown to be associated with poor prognosis
[27].
As cancer cells proliferate, secretion of VEGF occurs,
which
stimulates
neovascularization,
delivering
nutrients to the tumor, promoting metastasis. It has
been shown that during disseminated intra-abdominal
metastasis, cancer cells produce an increased load on
the abdominal fluid and microvascular permeability
increases [39]. This results in significant ascites.
According to Zebrowski and colleagues, VEGF proteins
are increased in malignant peritoneal effusion
compared to non-malignant cirrhotic ascites [44].
It has already been shown in mouse models that
inhibition of VEGF signaling is associated with a
distinct reduction in ascites formation and a reduction
in tumor burden [41]. It has also been evident in animal
models that VEGF production of cancer cells is directly
correlated with tumor cell-induced ascitic fluid
production). Based on these findings, the use of
bevacizumab and pazopanib for the treatment of
malignant ascites was investigated in subjects
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receiving heavy prior therapy and suffering from OC
[23].
Vascular endothelial growth factor is found in high
abundance in the ascites of ovarian cancer patients and
plays a central role in modulating the oncogenic
characteristics of ovarian cancer cells. VEGF is
overexpressed in ovarian tumor cells and is associated
with poor prognosis [ 24 ]. It has been reported that
high VEGF production from primary tumors correlates
with increased metastasis and worse prognosis
compared to tumors with low VEGF secretion [ 40 ].
Retroviral forced expression of VEGF in ovarian cancer
cells has been shown to drastically shorten the onset
of ascites [8]. One of the mechanisms by which VEGF
modulates peritoneal membrane permeability is
through downregulation of the tight junction protein
claudin 5 in peritoneal endothelial cells. In addition, it
has been shown that VEGF induces tyrosine
phosphorylation in the cadherin-catenin complex,
which leads to a decrease in the strength of the
endothelial junction and an increase in permeability
[19]. Several factors have been shown to influence the
production of VEGF by ovarian cancer cells. These
include hypoxia, LPA, tumor necrosis factor, matrix
metalloproteinases,
insulin-like
growth
factor,
epidermal growth factor, platelet-derived growth
factor, and transforming growth factor beta [29]
Consistent with these studies, systemic administration
of VEGF-Trap has been shown to prevent ascites
accumulation and inhibit the growth of disseminated
cancer in a mouse model, suggesting that VEGF
expression is critical for ascites accumulation and
progression of ovarian cancer. Several VEGF-targeting
drugs have been evaluated in phase II trials in women
with recurrent ovarian cancer. Bevacizumab, a
humanized anti-VEGF monoclonal antidiv, is
currently in several Phase III trials with encouraging
results [43].
Bevacizumab . In a study by Numnum et al. four
patients with recurrent OC and ascites were treated
with
the
anti-VEGF
monoclonal
antidiv,
bevacizumab. All four patients responded to this
therapy, experiencing symptomatic relief of ascites.
After initiation of bevacizumab therapy, therapeutic
paracentesis was not required, according to a duration
of up to six months [30].
Moreover, Hamilton and colleagues reported a case in
which a patient with progressive, recurrent OC and
severe symptomatic ascites was treated with
intraperitoneal bevacizumab. After administration of
two doses of bevacizumab, the patient experienced
symptomatic relief and improved quality of life [ 20 ].
Two other reports of cases of non-targeted use of
bevacizumab in 10 patients suffering from therapy-
resistant ascites. Symptomatic improvement was
observed in all patients and lasted approximately 2-6
months [23].
El Shami and colleagues conducted a study in which the
safety and tolerability of intraperitoneal bevacizumab
was tested in nine patients with refractory ascites due
to rectal, breast, uterine, and ovarian cancer.
Surprisingly, the malignant effusion was eliminated in
all patients after only one dose, with no recurrence
during a follow-up period of more than two months
[13].
Pazopanib is an oral multitarget tyrosine kinase
inhibitor (TKI) of vascular endothelial growth factor
receptor (VEGFR)-1, -2 and -3, platelet growth factor
receptor (PDGFR) -
α and
-
β. An open
-label Phase II
study evaluated oral monotherapy with pazopanib in
patients with low volume recurrent ovarian cancer
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with a complete CA-125 response to initial platinum-
based chemotherapy and a subsequent increase in CA-
125. Patients were treated with pazopanib (800 mg
once daily) until progressive disease or unacceptable
toxicity. The ORR was 18% in patients with measurable
disease
at
baseline
[17].
The
international
Arbeitsgemeinschaft
Gynaekologische
Onkologie
Studiengruppe Ovarialkarzinom 16 (AGOOVAR 16) was
a phase III randomized control trial evaluating the role
of pazopanib in the maintenance treatment of FIGO
stage II-IV ovarian cancer without progression after
primary therapy consisting of surgery and at least five
cycles platinum/taxane chemotherapy; patients were
randomized 1:1 to receive pazopanib (800 mg once
daily) or placebo for up to 24 months. Maintenance
pazopanib prolonged PFS compared with placebo (17.9
vs. 12.3 months, respectively). Pazopanib maintenance
therapy provided a median PFS improvement of 5.6
months in patients with advanced ovarian cancer who
did not progress after first-line chemotherapy. Data
RAs do not provide any benefits. Grade 3 or 4 side
effects hypertension (30.8%), neutropenia (9.9%), liver-
related toxicity (9.4%), diarrhea (8.2%), fatigue (2.7%),
thrombocytopenia
(2.5%)
and
palmoplantar
erythrodysesthesia (1.9%) were significantly higher in
the pazopanib group. Treatment discontinuation
associated with adverse events was higher among
patients treated with pazopanib (33.3%) compared
with placebo (5.6%) [25]
CONCLUSION
In summary, the new therapeutic approaches for OC -
associated malignant ascites that we discussed in this
review: for the use of targeted therapy in malignant
ascites, it is necessary to carefully select patients and
determine their risk factors in order to minimize the
number of side effects. Further comparative analyzes
and assessment of patient quality of life are the next
steps to be taken before these new drugsYou will be
included in daily clinical practice. In addition, clinical
trials need to be conducted in larger patient series to
see if bevacizumab and pazopanib are useful not only
in relieving symptoms, but also in prolonging tumor-
related overall survival.
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