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INVITED REVIEW
Clinical implications of pleural effusions in ovarian cancer
JOSÉ M. PORCEL,1 JOHN P. DIAZ2 AND DENNIS S. CHI3
1
Pleural Diseases Unit, Department of Internal Medicine, Arnau de Vilanova University Hospital, Biomedical
Research Institute of Lleida, Lleida, Spain, 2Division of Gynecologic Oncology, Department of Obstetrics and
Gynecology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami,
Florida, and 3Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center,
New York, USA
ABSTRACT
The pleural cavity constitutes the most frequent extra-
abdominal metastatic site in ovarian carcinoma (OC).
In patients with OC and pleural effusions, a positive
fluid cytology is required for a stage IV diagnosis.
Unfortunately, about 30% of malignant pleural effu-
sions exhibit false-negative cytological pleural fluid
results. In those circumstances, exploratory video-
assisted thoracoscopic surgery (VATS) serves as a diag-
nostic, staging and even therapeutic modality. Maximal
(no visible disease) or, at least, optimal (no residual
implant greater than 1 cm) cytoreduction should be
the primary surgical goal in stage IV OC patients.This is
due to residual tumour after cytoreductive surgery
being one of the most important factors impacting
on survival. Although malignant pleural effusions do
not preclude abdominal surgical debulking, excision
of gross pleural nodules may be necessary to achieve
optimal cytoreduction.VATS quantifies pleural tumour
The Authors: Dr José M. Porcel is a Professor of Medicine,
Chief of the Department of Internal Medicine at Arnau de Vil-
anova University Hospital and Head of the Pleural Diseases Unit
at the Biomedical Research Institute in Lleida, Spain (IRBLLEIDA).
He is the ACCP Regent for Spain, Deputy Editor for Respirology
and Editor of the International Pleural Newsletter. His clinical and
research interests focus primarily on pleural effusions. Dr John P.
Diaz is an Assistant Professor of Obstetrics and Gynecology in
the Division of Gynecologic Oncology at the Sylvester Compre-
hensive Cancer Center, University of Miami Miller School of
Medicine, Miami, FL, USA. He is interested in novel surgical
techniques in the management of gynaecologic malignancies. Dr
Dennis S. Chi is the Deputy Chief of the Gynecology Service,
Director of the Gynecologic Oncology Fellowship, Pelvic Recon-
struction Clinical Research Fellowship, and International Gyne-
cologic Oncology Fellowship programs at the Memorial
Sloan-Kettering Cancer Center of New York. He has published
extensively on surgical procedures for treating gynaecologic
malignancies and is an internationally recognized authority in
the field.
Correspondence: José M. Porcel, Department of Internal Medi-
cine, Arnau de Vilanova University Hospital, Avda Alcalde Rovira
Roure 80, 25198 Lleida, Spain. Email: jporcelp@yahoo.es
Received 3 February 2012; invited to revise 6 March 2012;
revised 11 March 2012; accepted 19 March 2012 (Associate
Editor: Ioannis Kalomenidis).
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
burden and allows for intrathoracic cytoreduction or,
if the latter is not feasible, ensures that abdominal
surgery is not unnecessarily performed on women in
whom gross tumour would still remain in the pleural
space afterwards. Taxane-platinum neoadjuvant che-
motherapy should be offered to this group. Patients
with tumour extension into the pleural space have a
median overall survival of 2 years.
Key words: malignant pleural effusion, ovarian cancer,
pleurodesis, thoracoscopy.
INTRODUCTION
Worldwide, ovarian is the eighth most common
cancer among women, following breast, colorectal,
cervical, lung, stomach, uterine and liver.1 In 2008,
there were an estimated 225 500 new cases, and
140 200 women died of ovarian cancer (OC).1
Epithelial OC, which accounts for over 90% of all
ovarian malignancies, is primarily a disease of post-
menopausal women, with a median age at diagnosis
of 63 years.2 The majority of OC occurs sporadically,
and less than 10% are familial. Somatic mutations in
one of two DNA repair genes, the BRCA1 (chromo-
some 17q12-21) or BRCA2 (chromosome 13q12-13),
potently impact lifetime risk of ovarian and breast
cancer. In a series of 1342 unselected patients with
invasive OC, 176 (13%) carried a mutation in BRCA1,
BRCA2 or both.3 Notably, the mutation was seen in
34% of women with a first-degree relative with breast
or OC. BRCA1 and BRCA2 mutations are inherited in
an autosomal dominant manner. Early prophylactic
bilateral salpingo-oophorectomy in carriers of these
germ-line mutations, once childbearing is no longer
an issue, dramatically reduces the risk for developing
both cancer types.4
Approximately 75% of patients with OC are diag-
nosed at advanced stages (III-IV), which include
tumour spread into the pleural space.2 The presence
of pleural effusions poses a diagnostic challenge and,
if malignant, may influence therapeutic strategies, as
discussed in this review.
Respirology (2012) 17, 1060–1067
doi: 10.1111/j.1440-1843.2012.02177.x
Pleural effusion in ovarian cancer
DIFFERENTIAL DIAGNOSIS OF
CONCOMITANT ASCITES AND
PLEURAL EFFUSION
One common OC presentation is increasing abdomi-
nal girth and difficulty of breathing owing to ascites
formation and/or pleural effusion. However, the
combination of ascites and pleural effusion should
bring to mind not only the possibility of OC but also
disseminated carcinomatosis from another primary
source (e.g. stomach, colon, pancreas, breast),
cirrhosis, and less commonly, heart failure, benign
ovarian tumours, tuberculosis, constrictive pericar-
ditis, endometriosis and ovarian hyperstimulation
syndrome.
Three pivotal features help frame the differential
diagnosis of the main entities, namely clinical data,
analysis of pleural and peritoneal taps, and imaging. A
history of chronic hepatitis C or B, excessive chronic
alcohol use, or the finding upon physical examination
of encephalopathy, dilated abdominal wall veins or
spider angiomas increase the probability of cirrhosis.
In cirrhosis, the gradient between serum albumin
level and the ascitic fluid albumin level is >1.1 g/dL,5
and more than 80% of hepatic hydrothoraces meet
Light’s criteria for transudates.6 In contrast, when the
serum-ascites albumin gradient is <1.1 g/dL and the
pleural fluid is an exudate, malignant causes should
be considered. The serum level of CA-125 (>35 kU/L)
is elevated in greater than 80% of patients with
advanced OC, but lacks specificity,7 as this tumour
marker can also be high in other malignancies (e.g.
non-small cell lung cancer, gastrointestinal, endome-
trial, breast) and many benign conditions, such as
liver disease, inflammation of the peritoneal lining,
benign ovarian tumours, and uterine leiomyomata.
Human epididymis protein 4, a new tumour marker
for OC, has a significantly higher diagnostic specific-
ity than CA-125.8 Finally, solid or bilateral ovarian
masses, and peritoneal nodules on the ultrasound or
computed tomography (CT) are more likely to indi-
cate malignancy. A woman with a pelvic mass and
ascites has OC until proven otherwise. In a study of
125 women with pelvic masses, of which 45% were of
malignant origin, the presence of ascites on physical
examination or imaging had a positive predictive
value of 95% for OC.9
A particularly challenging situation in patients with
an identifiable pelvic mass, ascites and pleural effu-
sion is Meig’s syndrome, which refers to any benign
gynaecological neoplasms causing a non-malignant
serosal fluid formation with exudative characteris-
tics.10 Typically, their surgical removal results in the
permanent disappearance of the ascites and pleural
effusions. Very rarely, metastases to the ovaries from
colorectal,11 gastric12 or breast13 primaries, referred to
as Krukenberg tumours,14 may cause a pseudo-Meig’s
syndrome, in which the ascites and pleural effusion
resolve after extirpation of the ovarian masses.
OC sometimes manifest initially with a pleural effu-
sion. In a retrospective analysis of 123 women with
malignant pleurisy, the effusion was the presenting
manifestation of cancer in 36 (29%), while the
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
1061
remaining 87 subjects had a known history of malig-
nancy and subsequently developed pleural
metastases.15 Lung and ovarian tumours (10 patients
each) accounted for most of the effusions among the
former group, whereas breast cancer (62 patients) led
the second group.
DISEASE STAGING
According to the International Federation of Gynecol-
ogy and Obstetrics nomenclature, OC is divided into
four stages, with the first three representing the
cancer being confined to the ovaries, to the pelvis
and to the peritoneal cavity, respectively.2 Stage IV
is defined as when the cancer has spread to the
liver parenchyma or outside the abdomen. The
most common extra-abdominal site of disease is
the pleural surface, pleural effusions being present in
more than one-third of stage IV patients.16 The 5- and
10-year survival rates for stage IV are around 20% and
<5%, respectively.17
Imaging studies performed in patients with sus-
pected OC include abdominopelvic ultrasonography
for documenting adnexal masses and ascites, and
chest radiograph or ultrasound to look for pleural
effusions. CT of the abdomen and pelvis may be
helpful for evaluating the remainder of the peritoneal
cavity, though it is not mandatory. The predictive
capacity of CT for staging OC and determining
tumour resectability is at most moderate.17 Pleural
fluid should be tapped and examined for the presence
of malignant cells. Nevertheless, preoperative
work-up is usually limited because surgical interven-
tion for definitive diagnosis, staging and treatment is
necessary. Some studies suggest that in patients with
involvement of the diaphragmatic peritoneum, a sur-
gical exploration of the chest cavity may be justified
because the pleural space frequently harbours undi-
agnosed disease.18,19 Thus, a study found that 27 (36%)
of 75 patients with apparent stage IIIC OC, diaphrag-
matic involvement and no preoperative pleural effu-
sions on imaging were upgraded to stage IV after the
demonstration of pleural metastases through a trans-
diaphragmatic thoracoscopy.19 Of note, only three
(4%) patients had pleural disease that would have
resulted in leaving residual disease greater than 1 cm.
PLEURAL EFFUSION
CHARACTERISTICS
Malignant pleural effusions in OC most probably
result from the pleural invasion from contiguous
structures, such as the diaphragm, or the transdia-
phragmatic migration of malignant cells thorough
pleuroperitoneal communications.20 Metastases to
the parietal pleura via a haematogenous route might
also be considered as a potential pathogenetic
mechanism.
To illustrate pleural effusion characteristics in
women with OC, selective unpublished data from
all hospitalized patients who have undergone a
Respirology (2012) 17, 1060–1067
1062
diagnostic thoracentesis in the Arnau de Vilanova
University Hospital (Lleida, Spain) during the last
17 years is presented herein. The leading aetiologies
of 742 malignant pleural effusions were lung (273
patients, 37%), breast (127 patients, 17%), haemato-
logic malignancies (74 patients, 10%), unknown
primary (72 patients, 10%), ovary (50 patients, 7%),
gastrointestinal (48 patients, 6.5%) and mesothelioma
(21 patients, 3%). However, if only the 364 women of
this series are considered, OC represents the third
most common cause, accounting for 14% of all malig-
nant effusions, after breast (34%) and lung (14.5%)
primaries.
The median age of the 50 women with OC metasta-
sizing the pleural surfaces was 67 years (quartiles
54–75 years). Pleural effusions were unilateral in 77%
of the cases (60% on the right side) and bilateral in
23% based on chest radiographs. Two thirds of the
effusions occupied half or more of the hemithorax. All
these patients presented with shortness of breath.
The effusions invariably met Light’s criteria for exu-
dates. In 85% of the pleural fluid differential leukocyte
counts, the predominant cells were lymphocytes.
Using 100% specific cut-off levels for malignancy, it
was found that 68% and 64% of 36 patients from
whom data was available exhibited pleural fluid levels
of CA-125 >2800 U/mL and CA-15-3 >75 U/mL,
respectively. The percentages of elevated CA-125 and
CA-15-3 tumour markers in the fluids from 307 and
449 patients with malignancies other than ovarian
carcinoma were significantly lower (16% and 29%,
respectively; P < 0.0001).
The yield of the pleural fluid cytological examina-
tion was 72% in women with OC as compared with
58% in 695 malignant effusions from other origins
(P = 0.047). That cytological tests are more frequently
positive in patients with OC than in other tumour
types was also exemplified in a study of 556 malignant
effusions submitted to thoracoscopy.21 Pleural fluid
cytology had 83% sensitivity in 27 patients with OC,
but only 57% in lung cancer, 41% in mesothelioma
and 18% in lymphoma.21
Immunocytochemistry assists in reducing the
number of false-negative cytology results in effusions
caused by misclassification of adenocarcinoma cells
as reactive mesothelial cells. In addition, immunocy-
tochemistry plays an important role in distinguishing
adenocarcinoma from malignant mesothelioma as
well as in determining the primary site of the meta-
static carcinoma. Evaluating published articles on
Respirology (2012) 17, 1060–1067
JM Porcel et al.
Figure 1 (a) Pleural fluid: cellular
evidence of adenocarcinoma (Papa-
nicolaou, 400¥). (b) Positive Wilms’
tumour antigen 1 (WT-1) immun-
ostain on the cell block is consistent
with an ovarian carcinoma (WT-1,
400¥) (courtesy of Dr Ramón Egido,
Pathology Department, Arnau de Vil-
anova University Hospital, Lleida,
Spain).
the immunocytochemistry profile of OC in pleural
effusions is difficult because many studies have
analysed adenocarcinomas of various origins, with
only few primary tumours from the ovary. As in
most adenocarcinomas, OC cells in pleural effusions
are positive for non-specific epithelial markers, such
as Ber-EP4, B72.3 and LeuM1.22 However, specific
immunocytochemistry markers used for adenocarci-
noma cells found in pleural effusions, when OC is a
consideration, are estrogen receptors, CA-125 and
Wilms’ tumour antigen 1.22 A positive nuclear stain-
ing with estrogen receptor employing the antibody
estrogen receptor-1D5 (Dako, Glostrup, Denmark)
points to a breast or ovary (with the exception of the
mucinous subtype) origin of the metastatic pleural
cells, although some pulmonary adenocarcinomas
may also express estrogen receptor.23 CA-125 stains
ovarian and lung adenocarcinomas. Finally, nuclear
Wilms’ tumour antigen 1 staining in pleural effusions
suggests three potential diagnoses: OC (Fig. 1), breast
cancer or mesothelioma.23
If initial cytological studies are normal but the diag-
nosis of pleural malignancy is strongly suspected on
clinical grounds (e.g. other diagnosis less likely than
malignancy, predominantly lymphocytic exudative
effusion), a thoracoscopic examination of the pleural
space for taking biopsies is indicated. In one study,
four (36%) of 11 patients with OC and a negative cyto-
logical examination of pleural fluid had macroscopic
pleural malignancy on thoracoscopy.24 The rationale
behind the use of invasive procedures as a last resort
is that the poor prognosis associated with malignant
effusions may affect the management plan.
Certain radiological characteristics point to the
diagnosis of probable malignant effusion. In a retro-
spective series, 38 patients with OC and preoperative
pleural effusions detected on the upper most images
of an abdominal-pelvis CT underwent a diagnostic
thoracentesis.25 Based on the results of pleural fluid
cytology, 16 (42%) were classified as malignant effu-
sions and 22 (58%) as nonmalignant. The three radio-
logical predictors of malignant pleuritis were an
effusion of moderate-to-large size (81% vs 9%), supra-
diaphragmatic lymph node enlargement of >1 cm
(75% vs 9%) and pleural nodules of >3 mm (50% vs
0%) (Fig. 2).25 The main limitation of the study was
that true malignant effusions with false-negative
cytological results could not be confidently ruled out
(imperfect reference standard). Another retrospective
analysis of 44 patients with stages III/IV, for whom a
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
Pleural effusion in ovarian cancer
Figure 2 (a) Sagittal computed tomography (CT) image
showing a pleural effusion in a patient with an adnexal
mass (asterisk). (b) Axial CT demonstrating a right-sided
pleural effusion and nodular pleural thickening (white
arrow) in a woman with ovarian cancer (courtesy of
Dr Marina Pardina, Radiology Department, Arnau de
Vilanova University Hospital, Lleida, Spain).
chest CT was available before a thoracoscopy, further
supported the association between greater effusion
size (albeit no other radiological features) and the
probability of having malignant disease on biopsy.26
In addition, small thoracoscopic series have demon-
strated the inaccuracy of preoperative CT for identi-
fying pleural-based tumours in women with OC.27,28 A
case in point is that only eight (53%) of 15 patients
noted to have pleural metastases at thoracoscopy, dis-
closed suspicious radiological findings on a previous
chest CT.28
TREATMENT OF STAGE IV-BASED
PLEURAL EFFUSIONS
The standard treatment of advanced epithelial OC
includes primary cytoreductive surgery followed by
adjuvant systemic chemotherapy.29 However, admin-
istration of chemotherapy before surgery (neoad-
juvant chemotherapy) is a valid alternative. A
randomized trial by the European Organization for
Research and Treatment of Cancer compared both
strategies in 632 patients with stage IIIC (regional
lymph nodes metastasis and/or peritoneal implants
beyond pelvis >2 cm) or IV OC, of whom 17% had
malignant pleural effusions.30 It was found that neo-
adjuvant chemotherapy followed by interval debulk-
ing surgery was not inferior to primary debulking
surgery followed by chemotherapy with respect to
survival, adverse effects, quality of life, or postopera-
tive morbidity or mortality. Nevertheless, the median
survival (29–30 months) in this study was significantly
less than that previously reported in other studies
for optimally debulked stage III patients receiving
postoperative intraperitoneal chemotherapy
(66 months).31 Additionally, only 42% of the primary
debulking operations achieved an optimal result,
whereas expert centres often report figures of up to
75%.32
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Respirology © 2012 Asian Pacific Society of Respirology
1063
Another study retrospectively evaluated the
median survival of 242 patients with stage IV OC,
according to the initial therapeutic modality.33 Data
extraction from the subgroup of patients with malig-
nant pleural effusions showed that there was an
equivalent overall survival rate between the 81 who
underwent primary debulking surgery and subse-
quent chemotherapy (26 months), the 20 who were
treated with neoadjuvant chemotherapy followed
by interval debulking surgery (28 months), and the
3 who received only chemotherapy (32 months,
P = 0.8).33 In addition, neoadjuvant chemotherapy
resulted in higher rates of complete resection and
fewer postoperative complications.
Despite the preceding findings, neoadjuvant che-
motherapy has not been fully integrated into the
management of advanced OC. It is generally reserved
for patients who are poor candidates for surgery (poor
performance status, significant comorbidities) or
those whose disease is clearly too extensive to be
resected even by an experienced OC surgical team
(e.g. unresectable liver, lung or pleural metastases,
evidence of bulky disease in the root of the small
bowel mesentery).34,35 If the response to chemo-
therapy is adequate, debulking surgery may then be
attempted. However, chemoresistance implies a poor
prognosis regardless of further therapies, thus usually
making aggressive surgery unnecessary.
If, for whatever reason, cytoreduction was not per-
formed by a highly skilled gynaecologic oncologist
and, consequently, the initial surgery efforts were
submaximal, chemotherapy and interval surgical
reduction may be beneficial.
Abdominal cytoreductive surgery
Whether surgery is the primary treatment or per-
formed after neoadjuvant chemotherapy, the surgical
goal should be to completely remove all gross disease,
leaving little (<1 cm; ‘optimal’ cytoreduction) or no
visibly residual tumour.36 OC is unique in that
maximal surgical cytoreduction of all tumour sites is
associated with increased survival. A meta-analysis
of 53 studies including 6885 patients with stage III or
IV disease reported that every 10% increase in cytore-
duction was associated with a 5.5% increase in
median survival.37 However, the likelihood of com-
plete resection (microscopic residual disease) in stage
IV patients taken to primary surgery is about 10%,
while that of leaving residual disease >1 cm ranges
from 30% to 40%.38 Complete cytoreduction often
requires extensive and/or complicated procedures,
such as bowel, liver or pancreatic resections, splenec-
tomy, or diaphragm surgery, albeit at the expense of
increased complication rates.
Diaphragmatic surgery consists of tumour ablation
through electrocoagulation or excision by either the
stripping of the diaphragmatic peritoneum or a full-
thickness resection, including diaphragmatic muscle
and eventually the pleura. The rate of postoperative
pleural effusions after diaphragmatic surgery at
primary or interval debulking ranges from 2% to
65%,39–44 depending on whether entry into the pleural
Respirology (2012) 17, 1060–1067
1064
cavity occurs during the procedure. For example, the
frequency of postoperative pleural effusions was
significantly higher in 33 patients who underwent
diaphragmatic resection (64%) than in 79 diaphrag-
matic stripping procedures (38%).43 In 87 patients
submitted to diaphragmatic debulking, other authors
showed that the presence of postoperative pleural
effusions correlated with complete liver mobilization
(52% vs 16%) and large diaphragmatic disease (>5 cm)
removal (54% vs 23%).41 Although there is no consen-
sus about the need for inserting chest tubes intraop-
eratively, it may be recommended when the pleural
opening is large (>5 cm), several defects are produced
in the same hemidiaphragm, or the patient undergoes
full-thickness resection or extensive liver mobiliza-
tion.40 Using this strategy, postoperative pleural effu-
sions and pneumothoraces requiring drainage were
reported in only 5% of 63 diaphragmatic stripping or
coagulation procedures.40 In another series, pleural
effusions developed in 37% of 148 patients submitted
to diaphragmatic surgery during which the pleural
space was opened in half the cases.44 However, the
effusions were symptomatic enough to warrant a sec-
ondary chest tube drainage or pleural puncture in just
14% of the subjects.
Malignant pleural effusions upstage the disease
but are not a contraindication to initial cytoreduc-
tive abdominal surgery. In other words, they do not
predict by themselves a suboptimal debulking. A
report of 58 patients classified as stage IV OC only on
the basis of malignant pleural effusions demonstrated
a survival benefit when the disease was optimally
debulked (residual disease <1 cm) in the abdomen
and pelvis (3.1 years vs 1.3 years).45 In half of these
patients, the pleural space was a site of relapse, while
two thirds had pleural effusions at the time of death.
Therefore, treatment failure is often associated with
the inability to eradicate cancer cells in effusions,
which may need specific management.
Video-assisted thoracoscopic surgery
Demonstration of an unrecognized high pleural
tumour burden may have a substantial influence on
further OC therapy. Because the goal of surgical
cytoreduction is to achieve a state of no visible
residual disease in any location, pleural tumour
debulking should also be theoretically striven for
when feasible. video-assisted thoracoscopic surgery
(VATS) is the optimal method to evaluate and remove
as much disease burden as possible in the pleural
cavity.
In the first series that made use of thoracoscopy for
the management of stage IV OC, the procedure was
mostly performed at the time of the abdominal
surgery by introducing the laparoscope into the chest
cavity through the diaphragm.46 Of 30 patients, 10
(33%) had pleural implants that were excised,
whereas three (10%) had unresectable intrathoracic
disease that lead to abbreviated attempts at abdomi-
nal cytoreduction.46 The significant impact of VATS,
before a planned abdominal exploration, on the
global therapeutic strategy was reinforced in a report
Respirology (2012) 17, 1060–1067
JM Porcel et al.
Figure 3 Video-assisted thoracic surgery showing
diffuse malignant pleural involvement in a patient with
ovarian carcinoma.
of 42 patients with OC and pleural effusions affecting
one third or more of the hemithorax.24 VATS revealed
macroscopic pleural disease in 29 (69%) patients, the
majority (18 patients) having nodules greater than
1 cm. Based on thoracoscopic findings, the primary
management plan (i.e. abdominal cytoreduction)
was altered in 18 (43%) patients: 6 underwent
first intrathoracic cytoreduction and subsequently
abdominal surgery on the same or a later day, whereas
12 received neoadjuvant chemotherapy due to unre-
sectable pleural tumours, followed by interval debulk-
ing.24 The median overall survival for the primary
cytoreductive surgery group (29 patients) was 40
months as compared with 34 months for the neo-
adjuvant group (13 patients), an insignificant differ-
ence probably related to the small sample size.24 To
sum up, in patients with suspected OC and moderate-
to-large pleural effusions, VATS allowed for the selec-
tion of patients who would benefit from intrathoracic
cytoreduction or neoadjuvant chemotherapy (i.e.
those with gross pleural disease not amenable to
optimal debulking) (Fig. 3).
Chemotherapy
Chemotherapy with carboplatin and paclitaxel (or
docetaxel) every 3 weeks for six to eight cycles is
the mainstay of postoperative treatment.29 Concern-
ing the neoadjuvant approach, three courses of
platinum-based chemotherapy followed by interval
debulking surgery and at least three new courses of
chemotherapy are the most common scheme. The
therapeutic role of biological agents, particularly
those involved in the vascular endothelial growth
factor pathway and those targeting the poly (adenos-
ine diphosphate-ribose) polymerase enzyme, is being
investigated.2 Recently, it has been demonstrated that
the addition of bevacizumab, a humanized antivascu-
lar endothelial growth factor monoclonal antibody, to
standard front-line therapy prolongs the median
progression-free survival by about 4 months.47
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
Pleural effusion in ovarian cancer
Pleurodesis
A symptomatic pleural effusion should be drained to
optimize pulmonary function before surgery. Yet, the
best palliative measure is the intrapleural instillation
via chest tube or by insufflation through a thoraco-
scope of a sclerosing agent in order to prevent fluid
reaccumulation.
Two of the most commonly used agents for sclero-
sis are talc and doxycycline. In a series of 24 malig-
nant effusions secondary to OC, thoracoscopic talc
poudrage was able to prevent recurrence in 22 (92%)
cases for up to 6 months.48 The procedure has been
shown to be safe and effective in this patient popula-
tion.49 Recently, the outcome of 447 thoracoscopic
talc poudrage and 126 bedside doxycycline pleur-
odesis procedures in different tumour types was
reported.50 Complete (i.e. no fluid reaccumulation
until patient’s death) and partial (i.e. partial reaccu-
mulation of fluid without the need for aspiration)
responses to talc poudrage in 25 patients with OC
were 76% and 12%, respectively. The figures for doxy-
cycline pleurodesis among 15 OC cases were 86.7%
and 13.3%. Accordingly, this translated into a pleur-
odesis failure rate of only 12% for talc and 0% for
doxycycline.50
The utility of intrapleural paclitaxel, a chemothera-
peutic agent with intrinsic activity against OC, has
been described in 18 patients (11 OC and 7 breast
cancer) with recurrent malignant effusions.51 The
overall response rate at 2 months was 89% (half
each for complete and partial responses). However,
the need for premedication (dexamethasone, antihis-
tamines), common toxicities (67% chest pain, 56%
fever, 44% infusion extravasation), lack of experience,
and the fact that cheaper and at least equally effective
agents are available preclude paclitaxel from being
recommended.
Lastly, two small series have shown that the con-
comitant presence of ascites does not adversely affect
the response to pleurodesis in patients with gynaeco-
logic malignancies.52,53
PROGNOSIS
One study evaluated prognostic factors and survi-
val in 573 patients with stage IV OC submitted to
standard debulking surgery and postoperative che-
motherapy (platinum and paclitaxel).16 Complete
resection with no macroscopic evidence of residual
tumour in the abdomen was achieved only in 70
(12.3%) patients, while a residual tumour between
1–10 mm and >1 cm were reported in 29.3% and
58.4% of cases, respectively. Median overall survival
for these groups was 54.6, 25.8 and 23.9 months. Of
note, the overall survival of 214 (37.3%) patients with
malignant pleural effusions was 24 months. In the
multivariate analysis, visible residual tumour after
surgery, multiple metastatic sites, poor performance
status and mucinous histological subtype were shown
to negatively impact survival.16
In an earlier study, 21 patients with optimally
debulked stage IV disease based exclusively on malig-
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
1065
nant pleural effusions had a shorter time to recur-
rence (mean 12 months) and decreased overall
survival (median 30 months) compared with 76 opti-
mally debulked patients who had stage III disease (21
and 58 months, respectively, all P < 0.05).54 This prob-
ably reflected a higher tumour burden in the former
group due to pleural-based disease that was not sur-
gically approached. The negative effect of pleural
effusions on survival has been further supported by
one study that evaluated their prognostic importance
in a series of 203 patients with advanced OC, of whom
60 (30%) exhibited pleural effusions on a preoperative
CT.55 Seventy-two percent of the effusions were not
tapped (verification bias), and thus, their malignant
or benign nature was virtually unknown. The authors
found that the presence of moderate-to-large–sized
effusions (i.e. those occupying more than one third of
the hemithorax), as compared with no or small effu-
sions, was independently associated with poorer
overall survival (hazard ratio = 2.27) after controlling
for cytoreductive status.55
CONCLUSIONS
Approximately 15% of women who are newly diag-
nosed with OC present with stage IV disease in which
pleural effusions are characteristic. Even patients in
this advanced stage have an improved prognosis with
optimal debulking. In order to achieve maximal
cytoreduction, any visible tumours need to be surgi-
cally removed. This theoretically includes metastatic
pleural nodules by means of VATS. However, the
impact that extending surgical debulking to the
pleural space may have on quality of life, postopera-
tive morbidity and mortality await prospective inves-
tigations. In any case, the potential benefits of an
Figure 4 Proposed treatment strategy for patients with
ovarian cancer and secondary malignant pleural effusion.
OC, ovarian cancer; VATS, video-assisted thoracic
surgery.
Respirology (2012) 17, 1060–1067
1066
abdominal cytoreduction may be negated if VATS
identifies unresectable pleural disease. In this sce-
nario, patients should be considered for neoadjuvant
chemotherapy. Currently, it is not clear if bulky
intrathoracic disease may be present in OC patients
with small pleural effusions and if VATS could have a
role in this particular subgroup. A treatment algo-
rithm for patients with malignant pleural effusions
due to OC is suggested in Figure 4.
ACKNOWLEDGEMENT
Dr Silvia Bielsa’s assistance in the preparation of the
manuscript was greatly appreciated.
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