Antony, 2001

Copyright #ERS Journals Ltd 2001
Eur Respir J 2001; 18: 402–419 European Respiratory Journal

Printed in UK – all rights reserved ISSN 0903-1936
ERS ATS STATEMENT
Management of malignant pleural effusions
V.B. Antony*, R. Loddenkemper#, P. Astoul}, C. Boutin}, P. Goldstrawz, J. Hott*,

F. Rodriguez Panadero §, S.A. Sahn ƒ
CONTENTS
Aetiology and pathogenesis . . . . . . . . . . . . . . 402 Treatment of pleurodesis failure. . . . . . . . . . . 410

Diagnostic approaches . . . . . . . . . . . . . . . . . . . . 403 Other treatments . . . . . . . . . . . . . . . . . . . . . 410
Clinical manifestations . . . . . . . . . . . . . . . . . 403 Malignant pleural effusions in specific diseases . . . 411
Imaging techniques. . . . . . . . . . . . . . . . . . . . 403 Lung carcinoma . . . . . . . . . . . . . . . . . . . . . . 411
Diagnostic thoracentesis . . . . . . . . . . . . . . . . 404 Mesothelioma . . . . . . . . . . . . . . . . . . . . . . . 411
Closed pleural biopsy . . . . . . . . . . . . . . . . . . 405 Breast carcinoma . . . . . . . . . . . . . . . . . . . . . 412
Medical thoracoscopy . . . . . . . . . . . . . . . . . . 405 Lymphoma, leukaemia, and multiple myeloma . . 412
Bronchoscopy . . . . . . . . . . . . . . . . . . . . . . . 406 Factors affecting prognosis . . . . . . . . . . . . . . 413
Surgical biopsy. . . . . . . . . . . . . . . . . . . . . . . 406 Future directions for research . . . . . . . . . . . . . 413
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406 Definitions of success or failure of pleurodesis . . 413
Indications and contraindications . . . . . . . . . 406 Prospects for clinical studies . . . . . . . . . . . . . 413
Therapeutic thoracentesis . . . . . . . . . . . . . . . 407 Gene therapy . . . . . . . . . . . . . . . . . . . . . . . . 413
Chemical pleurodesis . . . . . . . . . . . . . . . . . . 407 Cellular basis of malignant effusions and
Talc pleurodesis . . . . . . . . . . . . . . . . . . . . . . 408 pleurodesis. . . . . . . . . . . . . . . . . . . . . . . . . . 414
Malignant pleural effusions are a common clinical 5–10% of malignant effusions, no primary tumour is
problem in patients with neoplastic disease. In one identified [12, 13]. The incidence of mesothelioma
post mortem series, malignant effusions were found in varies according to the geographical location.
15% of patients who died with malignancies [1]. Post mortem studies suggest that most pleural
Although there have been no epidemiological studies, metastases arise from tumour emboli to the visceral
the annual incidence of malignant pleural effusions in pleural surface, with secondary seeding to the parietal
the United States is estimated to be w150,000 cases pleura [1, 20]. Other possible mechanisms include
(table 1) [2–17]. Malignant pleural effusion is also one direct tumour invasion (in lung cancers, chest wall
of the leading causes of exudative effusion; studies neoplasms, and breast carcinoma), haematogenous
have demonstrated that 42–77% of exudative effusions spread to parietal pleura, and lymphatic involvement.
are secondary to malignancy [18, 19]. A malignant tumour can cause a pleural effusion,
both directly and indirectly. Interference with the
integrity of the lymphatic system anywhere between
Aetiology and pathogenesis the parietal pleura and mediastinal lymph nodes can
result in pleural fluid formation [12, 20]. Direct
Nearly all neoplasms have been reported to involve tumour involvement with the pleura may also
the pleura. In most studies, however, lung carcinoma contribute to the formation of pleural effusions.
has been the most common neoplasm, accounting for Local inflammatory changes in response to tumour
approximately one-third of all malignant effusions. invasion may cause increased capillary permeability,
Breast carcinoma is the second most common. with resultant effusions [21].
Lymphomas, including both Hodgkin9s disease and The term "paramalignant effusions" is reserved for
non-Hodgkin9s lymphoma, are also an important those effusions that are not the direct result of
cause of malignant pleural effusions. Tumours less neoplastic involvement of the pleura but are still
commonly associated with malignant pleural effusions related to the primary tumour (table 2) [22]. Impor-
include ovarian and gastrointestinal carcinomas. In tant examples include: postobstructive pneumonia,
*VA Medical Centre, Indianapolis, IN, USA, #Lungenklinik Heckeshorn, Berlin, Germany, }Hôpital de la Conception, Marseille, France,
z §
Royal Brompton Hospital, London, UK, El Mirador, Seville, Spain, ƒMedical University of South Carolina, Charleston, SC, USA.
Correspondence: R. Loddenkemper, Lungenklinik Heckeshorn, Zum Heckeshorn 33, D-14109 Berlin, Germany. Fax: 49 3080202286.
MANAGEMENT OF MALIGNANT PLEURAL EFFUSIONS 403
Table 1. – Incidence of malignant pleural effusions (MPEs)

Patients Patients with Origin of primary Annual cancer Estimated cases?yr-1
with MPE (all disseminated tumour from deaths in the of MPE
stages)* % disease or at cytology USAz in the USA
autopsy with MPE# % reviews} %
Lung cancer 8–15 20–46 25–52 160,000 32,000–73,600§

Breast cancer 2–12 36–65 3–27 44,000 15,840–28,600§
Lymphoma 7 29–30 12–22 25,000 7,250–7,500§
Other malignancies 29–46 330,000 23,600–47,000ƒ
Total 78,700–156,700
*: [2–7]; #: [8–11]; }: [12–16]; z: [17]; §: percentage of patients with MPE (disseminated/autopsy) 6 cancer deaths; ƒ: assumes
30% of MPE are from "other malignancies".
with a subsequent parapneumonic effusion; obstruc- been clearly elucidated, but several factors may be
tion of the thoracic duct, with the development of involved, including a decrease in the compliance of the
a chylothorax; pulmonary embolism; and transuda- chest wall, contralateral shifting of the mediastinum, a
tive effusions secondary to postobstruction atelectasis decrease in the ipsilateral lung volume, and reflex
and/or low plasma oncotic pressures secondary to stimulation from the lungs and chest wall [23].
cachexia. Treatment of the primary tumour can also Additional symptoms may be related to specific
result in pleural effusions. Important causes in this conditions. Chest pain, commonly seen in mesothe-
category include radiation therapy and such drugs as lioma, is typically localized to the side of the effusion,
methotrexate, procarbazine, cyclophosphamide, and and is described as dull and aching rather than
bleomycin. Finally, concurrent nonmalignant disease, pleuritic [24]. A history of haemoptysis in the presence
such as congestive heart failure, may account for an of a pleural effusion is highly suggestive of broncho-
effusion seen in a patient with cancer. genic carcinoma. A prior history of malignancy is
obviously important, as are any relevant occupational
exposures, especially to asbestos or other carcinogens.
Diagnostic approaches Most patients presenting with malignant effusions
have large enough effusions to cause the chest
Clinical manifestations examination to be abnormal. Other clinically relevant
findings may include cachexia and adenopathy [12].
Dyspnoea is the most common presenting symptom
in patients with malignant effusions, occurring in
more than half the cases [12]. Because of the advanced Imaging techniques
stage of their primary disease, many patients also
present with generalized symptoms such as weight Most patients presenting with malignant pleural
loss, anorexia, and malaise. The pathogenesis of effusions have some degree of dyspnoea on exertion
dyspnoea caused by a large pleural effusion has not and their chest radiographs show moderate-to-large
Table 2. – Causes of paramalignant pleural effusions

Cause Comment
Local effects of tumour

Lymphatic obstruction Predominant mechanism for pleural fluid accumulation
Bronchial obstruction with pneumonia Parapneumonic effusion; does not exclude operability in lung cancer
Bronchial obstruction with atelectasis Transudate; does not exclude operability in lung cancer
Trapped lung Transudate; due to extensive tumour involvement of visceral pleura
Chylothorax Disruption of thoracic duct; lymphoma most common cause
Superior vena cava syndrome Transudate; due to increased systemic venous pressure
Systemic effects of tumour
Pulmonary embolism Hypercoagulable state
Hypoalbuminemia Serum albumin v1.5 g?dL-1; associated with anasarca
Complications of therapy
Radiation therapy
Early Pleuritis 6 weeks to 6 months after radiation completed
Late Fibrosis of mediastinum
Constrictive perficarditis
Vena caval obstruction
Chemotherapy
Methotrexate Pleuritis or effusion; with or without blood eosinophilia
Procarbazine Blood eosinophilia; fever and chills
Cyclophosphamide Pleuropericarditis
Mitomycin/bleomycin In association with interstitial disease
404 V.B. ANTONY ET AL.
pleural effusions ranging from y500–2,000 mL in nonmalignant disease, most notably congestive heart
volume [12]. While only 10% of patients have massive failure [12, 35, 36]. This does not suggest that every
pleural effusions on presentation, malignancy is the individual with a transudative pleural effusion should
most common cause of massive pleural effusion [25]. have pleural fluid cytological examination. However,
Massive pleural effusions are defined as those effu- in the appropriate clinical setting and the absence of
sions occupying the entire hemithorax. About 15% of congestive heart failure or a pleural fluid LDH level
patients, however, will have pleural effusionsv500 mL near the exudative range, determination of pleural
in volume and will be relatively asymptomatic. An fluid cytology is suggested.
absence of contralateral mediastinal shift in these Although malignancy is a common cause of bloody
large effusions implies fixation of the mediastinum, effusions, at least half are not grossly haemorrhagic
mainstem bronchus occlusion by tumour (usually [31]. The pleural fluid nucleated cell count typically
squamous cell lung cancer), or extensive pleural shows a predominance of either lymphocytes or other
involvement (as seen with malignant mesothelioma). mononuclear cells [37, 38]. The presence of w25%
Computed tomography (CT) of patients with lymphocytes is unusual; pleural fluid eosinophilia does
malignancies may identify previously unrecognized not exclude a malignant effusion [37, 39, 40].
small effusions. They may also aid in the evaluation of Approximately one-third of malignant effusions
patients with malignant effusions for mediastinal have a pleural fluid pH of v7.30 at presentation [41,
lymph node involvement and underlying parenchymal 42]; this low pH is associated with glucose values of
disease, as well as in demonstrating pleural, pulmo- v60 mg?dL-1 [43]. The cause of these low-glucose,
nary, or distant metastases [26]; identification of low-pH malignant effusions appears to be an
pleural plaques suggests asbestos exposure. Ultraso- increased tumour mass within the pleural space
nography may aid in identifying pleural lesions in compared with those with a higher pH effusion,
patients with malignant effusions and can be helpful resulting in decreased glucose transfer into the pleural
in directing thoracentesis in patients with small space and decreased efflux of the acidic by-products of
effusions and avoiding thoracentesis complications glucose metabolism, carbon dioxide (CO2), and lactic
[27]. The role of magnetic resonance imaging (MRI) in acid, due to an abnormal pleural membrane [44, 45].
malignant effusions appears limited, but MRI may be Malignant effusions with a low pH and glucose
helpful in evaluating the extent of chest wall involve- concentration have been shown to have a higher
ment by tumour [28–30]. There is little information initial diagnostic yield on cytological examination, a
available on the utilization of fluorodeoxyglucose worse survival, and a worse response to pleurodesis
positron emission tomography (PET) in malignant than those with normal pH and glucose [41–45].
pleural effusions, although it has been reported as However, other investigators have not found an
helpful in evaluating the extent of disease in malignant association between pleural fluid pH in malignant
mesothelioma [31]. effusions and survival or success of pleurodesis
[46–50]. A meta-analysis of patient-level data from
nine sources encompassing w400 patients, found that
Diagnostic thoracentesis pleural fluid pH was an independent predictor of
survival. A pleural fluid pH threshold ¡7.28 had
Malignancy should be considered and a diagnostic the highest accuracy for identifying poor 1-, 2-, and
thoracentesis performed in any individual with a 3-month survivals. Only 55% of patients identified by
unilateral effusion or bilateral effusion and a normal pleural fluid pH ¡7.28, however, die within 3 months.
heart size on the chest radiograph. It is reasonable to The authors concluded that pleural fluid pH has
order the following pleural fluid tests when consider- insufficient predictive accuracy for selecting patients
ing malignancy: nucleated cell count and differential, for pleurodesis on the basis of estimated survival [51].
total protein, lactate dehydrogenase (LDH), glucose, The same investigators also found that pleural fluid
pH, amylase, and cytology. There are no absolute pH had only modest predictive value for predicting
contraindications to performing thoracentesis. Rela- symptomatic failure from pleurodesis [52]. The pleural
tive contraindications include a minimal effusion fluid pH should be used only in conjunction with the
(v1 cm in thickness from the fluid level to the chest patient9s general health, performance status, primary
wall on a lateral decubitus view), bleeding diathesis, tumour type, and response to therapeutic thoracent-
anticoagulation, and mechanical ventilation. There is esis, in deciding appropriateness for pleurodesis [51,
no increased bleeding in patients with mild-to- 53].
moderate coagulopathy or thrombocytopenia (a Elevated pleural fluid amylase levels (salivary
prothrombin time or partial thromboplastin time up isotype) in the absence of oesophageal rupture greatly
to twice the midpoint normal range and a platelet increases the likelihood that the pleural effusion is
count ofw50,000?mL-1). However, patients with serum malignant, most commonly adenocarcinoma of the
creatinine levels of w6.0 mg?dL-1 are at a considerable lung [54, 55]. Although once thought to be helpful in
risk of bleeding [32]. Important complications of the diagnosis of mesothelioma, hyaluron levels have
thoracentesis include pneumothorax, bleeding, infec- limited diagnostic importance because they can be
tion, and spleen or liver laceration. Almost all malig- elevated in other malignant effusions as well as in
nant pleural effusions are exudates [33, 34]; a few are, benign pleural processes [56].
however, transudates. Paramalignant effusions are Pleural fluid cytology is the simplest definitive
caused by mediastinal node involvement, endobron- method for obtaining a diagnosis of malignant pleural
chial obstruction with atelectasis, or concomitant effusion. The diagnostic yield is dependent on such
factors as extent of disease and the nature of the chest tube insertion by means of a trocar, the
primary malignancy. Therefore, studies have shown a difference being that, in addition, the pleural cavity
large variation in diagnostic yields ranging from can be visualized and biopsies can be taken from all
62–90% [13, 14, 16, 57, 58]. The diagnostic yield of areas of the pleural cavity including the chest wall,
cytology for mesothelioma is 58%. diaphragm, mediastinum, and lung. Medical thoraco-
Other procedures, such as immunohistochemical scopy can be performed either under direct visual
staining with monoclonal antibodies to tumour mar- control through the optical shaft of the thoracoscope,
kers and chromosome analysis, have been proposed to or indirectly by video transmission, which allows
aid further in diagnosis. Because of their relatively low demonstration to assistants and others as well as an
sensitivities and specificities, they cannot be relied on appropriate documentation. Medical thoracoscopy is
for definitive diagnosis; they may nevertheless be of primarily a diagnostic procedure. Indicators for its use
some benefit in certain circumstances. Identification of include the evaluation of exudative effusions of
deoxyribonucleic acid (DNA) aneuploidy by flow unknown cause, staging of malignant mesothelioma
cytometry may add to routine cytology by detecting or lung cancer, and treatment of malignant or other
false negatives in the initial cytological screening, recurrent effusions with talc pleurodesis. Another
warranting further review by the cytopathologists [59]. purpose may be biopsy of the diaphragm, lung,
Chromosome analysis may be useful in cases of mediastinum, or pericardium [77–79].
lymphoma and leukaemia [60]. In some cases differ- In cases of undiagnosed exudative effusions with a
entiating between reactive mesothelial cells, meso- high clinical suspicion for malignancy, some clinicians
thelioma, and adenocarcinoma can be problematic. may proceed directly to thoracoscopy if the facilities
Tumour markers such as carcinoembryonic antigen for medical thoracoscopy are available. The procedure
(CEA), Leu-1, and mucin, may be helpful in establish- should be performed for diagnosis and possible talc
ing the diagnosis, as they are frequently positive poudrage. Diagnostic yields of nonsurgical biopsy
in adenocarcinomas (50–90%) but rarely seen with methods for malignant pleural effusions were studied
mesothelial cells or mesothelioma (0–10%) [61–71]. in 208 patients, each of whom underwent all studied
procedures [79]. Diagnoses included 58 malignant
Closed pleural biopsy mesotheliomas, 29 bronchogenic carcinomas, and 116
metastatic pleural effusions (28 breast cancers, 30
In malignant effusions, closed pleural biopsies are cancers of various other organs, and 58 of undeter-
less sensitive than pleural fluid cytology. These blind mined origin), and five lymphomas. The diagnostic
percutaneous biopsies of the costal (parietal) pleura yield was 62% by pleural fluid cytology, 44% by closed
report a diagnostic yield of 40–75% [15, 57, 58, 72, 73]. pleural biopsy, and 95% by medical thoracoscopy
If abnormalities of the pleura are identified with CT, (fig. 1). The sensitivity of medical thoracoscopy was
as in mesothelioma, a CT-guided biopsy is performed higher than that of cytology and closed pleural biopsy
[74]. The relatively low yield of blind pleural biopsy is combined (96 versus 74%, pv0.001). The combined
due to several factors, including early stage of disease methods were diagnostic in 97% of the malignant
with minimal pleural involvement, distribution of pleural effusions. In 6 of the 208 cases (2.8%), an
tumour in areas not sampled during blind biopsy, and underlying neoplasm was suspected at thoracoscopy,
operator inexperience [75]. However, studies have but confirmed only by thoracotomy or autopsy. Simi-
shown that 7–12% of patients with malignant effu- lar results have been reported by other investigators
sions may be diagnosed by pleural biopsy when fluid [80–83].
cytology is negative [15, 58]. The reasons for false-negative thoracoscopy in-
Contraindications to pleural biopsy include bleed- clude insufficient and nonrepresentative biopsies that
ing diathesis, anticoagulation, chest wall infection, depend largely on the experience of the thoracoscopist
and lack of patient cooperation. Important compli- [80, 84] and the presence of adhesions that prevent
cations include pneumothorax, haemothorax, and access to neoplastic tissue [77, 80]. Adhesions are often
vasovagal reactions. Postbiopsy pneumothoraces are a consequence of repeated therapeutic thoracenteses
frequently due to air entry from the needle during [77, 85].
the procedure and do not often require intervention.
A rapid clinical deterioration or increased postproce-
dure effusion should alert the clinician to possible Closed pleural Fluid Medical
haemothorax [76]. biopsy cytology thoracoscopy
44 62 95
Medical thoracoscopy
Medical thoracoscopy as compared with surgical 74 96

thoracoscopy (which is more precisely known as
video-assisted thoracic surgery (VATS; see also surgi-
cal biopsy) has the advantage that it can be performed
under local anaesthesia or conscious sedation, in an 97
endoscopy suite, using nondisposable rigid instru- Fig. 1. – Malignant pleural effusions: sensitivity (%) of different
ments. Thus, it is considerably less invasive and less biopsy methods (cytological and histological results combined).
expensive than VATS. The technique is similar to Presented is a prospective simultaneous comparison (n=208).
provide easier identification of primary tumour [80],

100 including hormone receptors in breast cancer [94], and
improved morphological classification in lymphomas
80 [95].
Medical thoracoscopy is of further value in exclud-
60 ing malignancy and tuberculosis in undiagnosed
effusions [79]. After thoracoscopy, v10% of effusions
Sensitivity %
remain undiagnosed [80, 83, 96, 97]; whereas with

40 pleural fluid analysis and closed needle biopsy, more
than 20% remained undiagnosed [98–100]. In the few
20 cases in which thoracoscopy is not possible (or
diagnosis remains elusive even after thoracoscopy),
VATS or exploratory thoracotomy may be indicated
0 [101].
Lung Non-lung Mesothelioma Total
cancer primary
Bronchoscopy
Fig. 2. – Diagnostic sensitivity of cytology (h) and medical thora-
coscopy (r) in malignant pleural effusions. n-numbers are as The diagnostic yield of bronchoscopy is low in
follows: lung cancer, 67; non-lung primary, 154; mesothelioma, 66; patients with undiagnosed pleural effusions and
total, 287.
should not be undertaken routinely [102–104]. How-
The diagnostic sensitivity of medical thoracoscopy ever, it is indicated when endobronchial lesions are
is similar for all types of malignant effusions (fig. 2). suspected because of haemoptysis, atelectasis, or large
The diagnostic sensitivity in 287 cases was 62% for effusions without contralateral mediastinal shift.
cytology and 95% for medical thoracoscopy; the Bronchoscopy should also be performed to exclude
sensitivity of cytology and thoracoscopy did not endobronchial obstruction before attempting pleuro-
vary among lung carcinomas (67 versus 96%), extra- desis when there is absence of lung expansion after
thoracic primaries (62 versus 96%), and diffuse therapeutic thoracentesis.
malignant mesotheliomas (58 versus 92%) [79].
Medical thoracoscopy may be more useful than Surgical biopsy
thoracotomy in staging patients with lung cancer and
diffuse malignant mesothelioma. In patients with lung VATS procedures usually require general anaes-
cancer, thoracoscopy can help determine whether the thesia and single-lung ventilation. The surgeon may
effusion is malignant or paramalignant. As a result, it undertake a more extensive procedure than medical
may be possible to avoid exploratory thoracotomy thoracoscopy, using several ports, and often combin-
for tumour staging. WEISSBERG et al. [86] performed ing diagnosis with treatment. VATS is contraindicated
medical thoracoscopy in 45 patients with lung cancer and open biopsy is preferred when the patient cannot
and a pleural effusion, and found pleural invasion in tolerate single-lung ventilation (e.g. patient under-
37, mediastinal disease in three, and no metastatic going mechanical ventilation, prior contralateral
disease in five (11%) and therefore, no contraindica- pneumonectomy, or abnormal airway anatomy pre-
tion to resection [86]. CANTÓ et al. [87] found no cluding placement of double-lumen endotracheal
thoracoscopic evidence of pleural involvement in eight tube), if the pleural space contains adhesions that
of 44 patients; six proceeded to resection with no would prevent the safe insertion of the examining
pleural involvement found. A more recent study by thoracoscope, and if there is insufficient expertize to
CANTÓ et al. [88] demonstrated that diagnostic deal with the complications of the procedure [105].
sensitivity of malignancy was associated with the size Adhesions may be evident preoperatively on chest
of the effusion. radiographs or on pleural ultrasound and may lead to
In diffuse malignant mesothelioma, medical thora- the decision to undertake open biopsy. Often, how-
coscopy can provide earlier diagnosis, better histo- ever, this situation is appreciated for the first time at a
logical classification than closed pleural biopsy VATS examination, and the surgeon must therefore
because of larger and more representative biopsies, be ready to convert to an open procedure. Adhesions
and more accurate staging [89–91]. In addition, frequently result from previous pleurodesis attempts
fibrohyaline or calcified, thick, pearly white pleural but may also follow repeated thoracentesis for
plaques may be found, diagnosing benign asbestos diagnosis or therapy.
pleural effusion (BAPE) and excluding mesothelioma
or malignancies [92]. Thoracoscopic lung biopsies, as
well as biopsies from lesions on the parietal pleura Treatment
[93], may demonstrate high concentrations of asbestos
fibres, providing further support for a diagnosis of Indications and contraindications
asbestos-induced disease.
A further advantage of medical thoracoscopy in With the diagnosis of a malignant pleural effusion,
metastatic pleural disease is that biopsies of the palliative therapy should be considered, necessitating
visceral and diaphragmatic pleura are possible under evaluation of the patient9s symptoms, general health
direct observation. The thorascopic biopsies can and functional status, and expected survival. The
major indication for treatment is relief of dyspnoea. The volume of fluid that can be safely removed
The degree of dyspnoea is dependent on both the from the pleural space during a therapeutic thoracent-
volume of the effusion and the underlying condition esis is unknown. Ideally, monitoring of pleural fluid
of the lungs and pleura. pressure during the procedure should determine that
Therapeutic thoracentesis should be performed in volume. If pleural fluid pressure does not decrease
virtually all dyspnoeic patients with malignant pleural below -20 cmH2O, fluid removal can usually be con-
effusions to determine its effect on breathlessness and tinued safely [106]. As most clinicians do not measure
rate and degree of recurrence. In some dyspnoeic pleural pressure during therapeutic thoracentesis, it is
patients with a large effusion and contralateral recommended that only 1–1.5 L of fluid is removed at
mediastinal shift, some clinicians may choose to one sitting, as long as the patient does not develop
proceed directly to chest tube drainage and chemical dyspnoea, chest pain, or severe cough. When a patient
pleurodesis or thoracoscopy with talc poudrage. with contralateral mediastinal shift on chest radio-
Rapid recurrence of the effusion dictates the need graph tolerates thoracentesis without chest tightness,
for immediate treatment; stability and absence of cough, or dyspnoea, removal of several litres of
symptoms may warrant observation. If dyspnoea is pleural fluid is probably safe. Neither patient nor
not relieved by thoracentesis, other causes should be operator, however, may be aware of a precipitous
investigated, such as lymphangitic carcinomatosis, decrease in pleural pressure. In patients without
atelectasis, thromboembolism, and tumour embolism. contralateral or with ipsilateral mediastinal shift, the
Before attempting pleurodesis, complete lung likelihood of a precipitous fall in pleural pressure is
expansion should be demonstrated. Failure of com- increased, and either pleural pressure should be
plete lung expansion occurs with mainstem bronchial monitored during thoracentesis or only a small
occlusion by tumour or trapped lung due to extensive volume of fluid (v300 cm3) should be removed. In
pleural tumour infiltration. If a contralateral medi- patients with ipsilateral mediastinal shift, it is unlikely
astinal shift is not observed on the chest radiograph that removal of pleural fluid will result in significant
with a large pleural effusion, or the lung does not relief of dyspnoea, because there is either mainstem
expand completely after pleural space drainage, an bronchial occlusion or a trapped lung. Re-expansion
endobronchial obstruction or trapped lung should be pulmonary oedema can occur after rapid removal
suspected and can be diagnosed with bronchoscopy or of air or pleural fluid from the pleural space and is
thoracoscopy, respectively. An initial pleural fluid not necessarily related to the absolute level of nega-
pressure of ¡-10 cmH2O at thoracentesis makes tive pleural pressure. The mechanism of oedema is
trapped lung likely [43, 106, 107]. Cut-off points believed to be increased capillary permeability; the
of ¡-19 cmH2O with the removal of 500 mL [107] of injury may be related to the mechanical forces causing
fluid and of ¡-20 cmH2O with the removal of 1 L of vascular stretching during re-expansion [114] or to
fluid [106] are predictive of trapped lung in the ischaemia-reperfusion.
absence of endobronchial obstruction.
Therapeutic thoracentesis Chemical pleurodesis
Therapeutic thoracentesis may serve as the primary Chemical pleurodesis is accepted palliative therapy
therapeutic modality in some patients. In patients for patients with recurrent, symptomatic malignant
with far advanced disease, poor performance status, pleural effusions. Various chemicals have been used in
and low pleural fluid pH (pH ¡7.2) relief can be an attempt to produce pleurodesis. Adequate assess-
provided by periodic outpatient therapeutic thora- ment of the efficacy of specific chemical agents has
centeses in lieu of hospitalization for more invasive been problematic because reported trials have evalu-
and morbid procedures. Animal studies suggest that ated small numbers of patients, employed different
pleural effusions tend to increase the volume of the techniques, used conflicting success criteria, and/or
hemithorax more than they compress lung tissue [108]. monitored subjects for varying periods of time.
It is therefore not surprising that after thoracentesis, Progression of disease is variable, and death has
total lung capacity (TLC) increases by approximately sometimes occurred during the first month after
one-third the volume of fluid removed, and the forced pleurodesis. Not all chemical agents have undergone
vital capacity (FVC) increases by one-half the increase direct comparison under similar conditions in the
in TLC [109]. The improvement in FVC and TLC same patient population. In some studies, adverse
after thoracentesis is variable and is greatest in effects have been addressed casually, making compar-
patients with high lung compliance. isons difficult.
Intrapulmonary shunt is the main mechanism WALKER-RENARD et al. [115] reviewed all published
underlying the arterial hypoxaemia associated with a articles in the English language from 1966–1992
large pleural effusion. Thoracentesis has short-term describing patients with recurrent, symptomatic
effects on pulmonary gas exchange [110]. The effect on malignant pleural effusions who were treated with
arterial oxygen tension (Pa,O2) is variable, and it can chemical pleurodesis. A total of 1,168 such patients
increase, remain the same, or decrease [109–112]. were analysed for complete success of pleurodesis
After therapeutic thoracentesis, there appears to be (defined as nonrecurrence of the effusion, as deter-
delayed lung volume re-expansion, with or without mined by clinical examination or chest radiograph) and
the coexistence of minimal pulmonary oedema [113]. 1,140 patients assessed for drug toxicity. Chemical
Table 3. – Complete success rates of commonly used pleurodesis agents

Chemical agent Total patients n Successful n Successful % Dose
Talc 165 153 93 2.5–10 g

Corynebacterium parvum 169 129 76 3.5–14 mg
Doxycycline 60 43 72 500 mg (often multiple doses)
Tetracycline 359 240 67 500 mg–20 mg?kg-1
Bleomycin 199 108 54 15–240 units
Adapted from [115].
pleurodesis produced a complete response in 752 suction be applied to the chest tube until the 24-h
(64%) of the 1,168 patients. output from the chest tube is v150 cm3.
The complete success rate with fibrosing agents
(nonantineoplastic drugs) was 75% (557 of 770), Doxycycline. For many years, tetracycline was the
compared with a complete success rate of only 44% sclerosing agent of choice. However, when it became
(175 of 398) for antineoplastic agents. Talc (2.5–10 g) commercially unavailable, alternative agents were
was the most effective agent, with a complete success investigated. Doxycycline, a tetracycline analogue,
rate of 93% (153 of 165 patients) (table 3) [115]. The has been recommended as a replacement for tetra-
efficacy of talc in the control of malignant pleural cycline. Although there are no direct studies compar-
effusions has been found to be superior to that of ing doxycycline with tetracycline, pleurodesis studies
bleomycin and tetracycline [116–118]. The most have demonstrated clinical success rates with doxy-
commonly reported adverse effects were pain and cycline that are similar to those with tetracycline
fever. Adverse reactions varied among the different (historical data), with a success rate of up to 80–85% in
agents (table 4) [115]. If the patient undergoing carefully selected patients [120, 126, 127]. Most studies
pleurodesis is receiving corticosteroid therapy, the have recommended the utilization of 500 mg of
drug should be stopped or the dose reduced if possible doxycycline mixed with 50–100 cm3 of sterile saline
because of concerns of decreased efficacy of pleuro- [120, 127]. As pain is the most common complication
desis [119]. associated with doxycycline pleurodesis, narcotic
Patients selected for pleurodesis should have analgesic and/or conscious sedation is often recom-
significant symptoms that are relieved when pleural mended [126].
fluid is evacuated. There should be evidence of
complete re-expansion of the lung without evidence Bleomycin. Another agent frequently recommended
of bronchial obstruction or fibrotic trapped lung. for pleurodesis is bleomycin. Most studies have used a
Most commonly, pleurodesis is performed via a dose of 60 IU of bleomycin mixed with 50–100 cm3 of
standard tube thoracostomy. However, some studies sterile saline. Unlike doxycycline, bleomycin has been
directly compared with tetracycline. Most of these
have reported similar success rates with small-bore
studies demonstrated similar or higher success rates
(3–5 mm) catheters [120–125]. Ideally, the chest tube is
when utilizing bleomycin as a sclerosing agent,
directed posteriorly toward the diaphragm. Radio-
compared with tetracycline [117, 128, 129]. A direct
graphical confirmation is then obtained to demon- study comparing doxycycline with bleomycin pleuro-
strate complete re-expansion of the lung in evacuation desis utilizing a small-bore catheter, demonstrated
of the fluid. At this point, intravenous narcotic similar success rates (72% with bleomycin, 79%
analgesics and/or sedation are often recommended with doxycycline) [120]. As stated previously, direct
because of the pain associated with many sclerosing studies comparing talc and bleomycin have demon-
agents. The sclerosing agent of choice is then added strated a superior pleurodesis success rate with talc
to the chest tube, typically in a solution of 50–100 cm3 [115, 116, 130]. An important criticism of bleomycin
of sterile saline. The chest tube is then clamped for as a sclerosing agent involves its relative expense as
1 h, without rotation of the patient being required. compared with other sclerosing agents such as talc
The chest tube is then subsequently reconnected to or doxycycline [129, 131]. However, studies utilizing
20 cmH2O suction. It is then recommended that small-bore catheters and bleomycin have demon-
strated successful pleurodesis [120, 121] and therefore
Table 4. – Adverse effects of commonly used pleurodesis a potential overall cost saving when factors such as
agents hospitalization, duration, and procedure costs are
included.
Chemical agent Total Chest pain Fever
patients n % %
Talc pleurodesis
Talc 131 7 16
Corynebacterium parvum 169 43 59 Talc from chemical supply houses is asbestos free
Doxycyline 60 40 31 [132], with variable particle size generally v50 mm.
Tetracycline 359 14 10
Bleomycin 199 28 24 Although talc is not packaged aseptically by the
manufacturer, limitation of the number of micro-
Adapted from [115]. organisms is a part of the specifications, and the total
bacterial count cannot exceed 500 organisms?g-1 of pulmonary circulation after application of the scle-
talc. In one study, bacillus species were cultured from rosing agent [142]. Other possible causes of acute
six different supplies of unsterilized talc; dry heat, respiratory failure with talc pleurodesis include sepsis
c-irradiation, and ethylene oxide gas all proved effec- due to nonsterile or endotoxin-containing talc, exces-
tive sterilization methods [133]. The cost of sterilizing sive talc dosing, active air leak, excessive periproce-
a 5-g packet of talc (about 10 cm3) isy£3, £5 or £10 for dure medications, severe underlying lung disease, and
dry heat, ethylene oxide, and c-irradiation, respectively re-expansion pulmonary oedema.
[114]. Sterilized talc remains culture-negative on the Twenty-two to 35 yrs after talc poudrage of
pharmacy shelf for w1 yr [134]. pneumothorax, TLC averaged 89% of predicted in
A review of published series found a 93% success 46 patients, whereas TLC was 97% of predicted in 29
rate (153 of 165 patients) for talc pleurodesis in the patients treated with tube thoracostomy alone [143].
treatment of pleural effusions, the majority of them None of the poudrage group developed mesothelioma
malignant [115]. Success was variably defined in these over the 22- to 35-yr follow-up. Although talc
studies but was based primarily on 16 clinical criteria poudrage may result in minimally reduced total
or radiographical findings. In some studies, complete capacity, as well as pleural thickening on chest
and persistent absence of fluid was the determinant, radiography, these changes appear to be clinically
where as in others, the lack of need for further pleural unimportant. Short-term follow-up after talc poud-
drainage was the sole criterion. Follow-up times were rage for pneumothorax revealed no difference in lung
also variable, and in these studies, doses ranged function when compared with other patients who had
1–14 g. When analysed by the method of administra- thoracotomy without talc poudrage [144, 145]. A link
tion, poudrage and slurry pleurodesis methods between talc and cancer has been reported in those
resulted in similar success rates of 91%: 418 of 461 who mine and process talc [146], but this association is
for talc poudrage and 168 of 185 for slurry [116–118, attributed to asbestos, which is commonly found with
135–137]. In a small series of 57 patients randomized talc, rather than to talc itself. No increase in lung
to receive talc slurry through a chest tube or talc cancers was found in a group of patients who had talc
poudrage with VATS, using 5 g of talc, no significant pleurodesis for pneumothorax and had long-term
difference was found in recurrence: one of 28 with follow-up [147].
poudrage and three of 29 with slurry [138]. A large Talc is an inexpensive and highly effective pleuro-
randomized multicentre trial addressing the efficacy of desis agent when administered by either poudrage or
talc poudrage versus talc slurry is near completion in slurry in patients with malignant pleural effusions.
the North American Cooperative Oncology Groups. The most common short-term adverse effects include
A defined rate of clinically important complications fever and pain. Development of respiratory failure is
was observed with thoracoscopic talc poudrage and reported and may be related to dose and particle size,
no deaths were related to the procedure in a series of or other factors related to its instillation [148, 149].
360 patients [139]. A similarly low rate of complica- Investigation of this issue is ongoing and physicians
tions was observed by VIALLAT et al. [140], who used and patients should be aware of a potential for
either local anaesthesia plus conscious sedation or respiratory failure, which has not been described with
general anaesthesia in a two-center study that other agents. Long-term safety does not appear to be
included 360 patients. Fever up to 102.4u F after talc an issue with the asbestos-free product, especially in
pleurodesis has been reported to occur in 16–69% of patients with malignant pleural effusions. Because the
patients [141]. Fever characteristically occurs 4–12 h response to talc has not been studied over a wide dose
after talc instillation and may last for 72 h. Empyema range and serious adverse effects tend to occur with
has been reported with talc slurry in 0–11% of higher doses [150], it is recommended that no more
procedures, whereas talc poudrage is associated with than 5 g of talc be used, and that bilateral simulta-
an incidence rate of 0–3% of patients [141]. Local neous pleurodesis not be attempted.
site infection is uncommon, and the degree of pain
associated with talc has reportedly ranged from Talc poudrage. The most widely reported method of
nonexistent to severe. talc instillation into the pleural space for malignant
Cardiovascular complications such as arrhythmias, effusion is talc poudrage, which is usually performed
cardiac arrest, chest pain, myocardial infarction, or under thoracoscopic guidance. Talc poudrage can be
hypotension have been noted; whether these compli- performed by medical thoracoscopy under local
cations result from the procedures or are related to anaesthesia with conscious sedation or by VATS.
talc per se has not been determined. Acute respiratory Several technical details should be taken into
distress syndrome (ARDS), acute pneumonitis, and account in order to achieve good pleurodesis and
respiratory failure have also been reported to occur avoid complications. All pleural fluid should be
after both talc poudrage and slurry [141]. It is removed before spraying talc. Removal can be easily
doubtful that the method of administration (poudrage accomplished during thoracoscopy, as air is passively
versus slurry) plays a major role in the development of entering the pleural cavity, thus creating a desirable
respiratory failure, although the dose and particle size equilibrium in pressures. Complete collapse of the
of talc may be important. In an experimental study lung is important, affording a good view of the pleural
using talc slurry, KENNEDY et al. [142] found cavity and the opportunity to biopsy suspicious
prominent perivascular infiltrates with mononuclear lesions and also permitting wide distribution of the
inflammation in the underlying lung, and it was talc.
speculated that mediators might spread through the Although an optimal dose of talc for poudrage has
not been established, y5 g (8–12 mL) is usually Repeat pleurodesis may be performed either with
recommended for malignant effusions. After talc instillation of sclerosants through a chest tube or by
insufflation, repeat inspection of the pleural cavity thoracoscopy and talc poudrage. Repeat thoracentesis
should be done to ensure that the powder has been would be the choice for a terminal patient with short
evenly distributed over the pleural surface. expected survival. Pleuroperitoneal shunting or pleuro-
An 8–11 mm chest tube should always be inserted. ectomy may be suitable for patients whose clinical
Graded and progressive suction should be applied and condition is reasonably good and who have experi-
maintained until the amount of fluid aspirated per day enced pleurodesis failure. Other alternatives in failed
is v100 mL. Air leak can occur in patients with pleurodesis include tube drainage into a bag.
necrotic tumour nodules in the visceral pleura,
especially those with prior chemotherapy, even if no
biopsies of this area have been taken. Other treatments
On average, reported success with talc poudrage is
w90% but, as previously noted, reliable guidance on Systemic therapy. In patients with symptomatic
doses remains elusive, and definitions of success have malignant pleural effusions due to tumours likely to
not been standardized [151, 152]. respond to chemotherapy, such as small-cell lung
cancer, systemic treatment should be started if no
Talc slurry. Talc slurry is also an effective pleurodesis contraindications exist and it may be combined with
agent in malignant effusions [136, 138]. Potential therapeutic thoracentesis or pleurodesis. Neoplasms
disadvantages of slurry include lack of uniform that tend to be chemotherapy responsive include breast
distribution, accumulation in dependent areas of the cancer (hormone treatment may also be appropriate),
pleural space possibly leading to incomplete pleuro- small-cell lung cancer, and lymphoma. Effusions
desis and loculations, and decreased direct contact associated with prostate, ovarian, thyroid, and germ-
time with the pleural surface due to the liquid sus- cell neoplasms may also be chemotherapy responsive.
pension with subsequent decrease in effectiveness. When systemic treatment options are unavailable or
The slurry is made by mixing talc with normal contraindicated, or systemic treatment is or has
saline and gently agitating. Various volumes of saline become ineffective, local therapy such as pleurodesis
have been used, ranging from 10–250 mL [136, 138]. may be applied.
The pleurodesis technique is the same as for the
soluble chemical agents [153]. It is recommended that
administration of small doses of an intravenous Surgery. Major surgical procedures, such as parietal
narcotic and anxiolytic-amnestic agent before the pleurectomy, decortication, or pleuropneumonectomy,
procedure. The chest should be drained as completely performed alone, have proved to provide neither
as possible by tube thoracostomy. Standard chest superior palliation nor prospects for cure, compared
tubes (6–8 mm) or small-bore catheters (3–4 mm) with pleurodesis alone. Surgical palliation may,
have been used successfully for talc slurry pleurodesis however, be achieved with talc pleurodesis and/or
[123, 124]. A dose of 4–5 g of talc in 50 mL of normal the insertion of a pleuroperitoneal shunt [156]; such
saline should be instilled through the chest tube when approaches may be undertaken by VATS or limited
the radiograph demonstrates an absence or minimal thoracotomy. Pleurodesis may fail if there is a cortex of
amount of pleural fluid and complete lung expansion. malignant tissue covering the pleural surfaces. The
The chest tube should be clamped for 1 h after talc cortex may be removable by converting to an open
slurry instillation. It is unclear whether talc slurry thoracotomy, and pleurodesis may then prove possible.
disperses as rapidly throughout the pleural space, This procedure has a reported perioperative mortality
compared with tetracycline [154, 155]. Therefore, pati- of 12%, and therefore patient selection is important
ent rotation is recommended until definitive studies [157].
are available. After unclamping of the chest tube, the If expansion of the lung is inadequate after removal
patient should be maintained on -20 cmH2O suction; of an effusion due to a cortex of malignant tissue or
the chest tube should be removed when the 24-h tube fibrosis, a pleuroperitoneal shunt should be inserted.
drainage isv100–150 mL. If, after 48–72 h, chest tube Such a situation may be suggested by lack of
drainage remains excessive (w250 mL?24 h-1), talc mediastinal shift on perioperative radiographs or
instillation, at the same dose used initially, should be may be seen only at surgery. A shunt should be
repeated. readily available when undertaking such treatment
[156]. Shunt complications, chiefly occlusion, will
occur in 12% of patients, and such occlusion is treated
Treatment of pleurodesis failure by shunt replacement [158], unless infection is
confirmed. In that case, long-term drainage with a
Initial failure of pleurodesis can occur as a result of chest tube is indicated. The possibility of inducing
suboptimal techniques or inappropriate patient selec- peritoneal seeding with a pleuroperitoneal shunt is a
tion (e.g. a patient with a trapped lung or mainstem potential risk but has not been convincingly docu-
bronchial occlusion). Recurrence after pleurodesis is mented, and in this group of patients, there is no
unusual with talc but does occur occasionally, usually established alternative treatment.
soon after attempted pleurodesis.
When initial pleurodesis for malignant pleural Intrapleural therapy. When the malignancy is localized
effusion fails, several alternatives may be considered. in the pleural cavity, intrapleural chemotherapy may
treat the underlying neoplasm in addition to con- cancer and paramalignant effusion is comparable to
trolling the effusion [159, 160]. To obtain maximal that for those in the same stage without pleural
anticancer activity with minimal systemic side effects, effusion [87, 169]. This is also true for small-cell lung
however, a high intrapleural concentration with cancers where there is limited disease, with or without
minimal systemic spread of the antineoplastic agent pleural effusion. Pleural effusions with positive
is required. To meet these requirements, several cytology for small-cell lung carcinoma constitute a
authors have proposed including cytostatic drugs in worse prognosis for patients with otherwise limited
poly-L-lactic acid microspheres [161]. disease without malignant effusion [171]. In nonsmall
Active cytokines may be instilled directly into the cell lung cancer at an advanced, inoperable stage, talc
pleural space. Interleukin-2 (IL-2), interferon-b, and pleurodesis should be considered [172, 173]. With a
interferon-c (IFN-c) have been tried, with variable large pleural effusion and suspicion of tumour
success, in the treatment of malignant pleural effusion obstruction of the central bronchi, suggested by
and mesothelioma [162–167]. It is not clear whether absence of contralateral mediastinal shift and sup-
the observed responses are due to intrinsic sclerosing ported by CT findings, bronchoscopy should be
activity or, instead, to an immunological effect such as performed first and the obstruction removed (e.g. by
an increased natural killer cell population. Thus, the laser), permitting lung re-expansion after fluid
results of phase II intrapleural therapy studies to date removal.
have been inconclusive, because most of these evalua- Systemic chemotherapy is the treatment of choice in
tions have been based on radiographic findings or small-cell lung cancer, where the pleural effusion often
cytological examination of the pleural fluid. There are resolves without the need for local treatment [171].
few studies using endoscopic staging for malignancy Pleurodesis is indicated only when chemotherapy is
involving the pleura [164]. contraindicated or ineffective.
Other potential candidates for intrapleural therapy
include patients with malignant effusion and an
unknown primary tumour. Many of these tumours Mesothelioma
probably originate from small subpleural carcinomas
[168], a condition sometimes termed "pseudomesothe- Median survival of patients with mesothelioma is
liomatous carcinoma of the lung." Such carcinomas 6–18 months. Unfortunately, the clinical course is
demonstrate a characteristic growth pattern of peri- not significantly affected by current therapeutic man-
pheral adenocarcinoma of the lung with extensive oeuvres. Most commonly, the cause of death is local
pleural growth and little peripheral parenchymal extension and/or respiratory failure. Distant meta-
involvement and, therefore, may be ideal targets for static disease resulting from haematogenous spread
attempts at local therapy. may also be present, typically at the end stage
[174–176].
A poor prognosis is indicated by histological type
Malignant pleural effusions in specific diseases (i.e. sarcomatous or mixed histology), thrombocyto-
sis, fever of unknown origin, age w65 yrs, and poor
Lung carcinoma Karnofsky index. A more favourable prognosis is
associated with epithelial histology, stage I disease
Lung carcinoma is the leading cause of malignant (particularly if the disease is localized to the parietal
pleural effusions. Malignant effusions are observed pleura), absence of chest pain, and the presence of
in 7–15% of all bronchogenic carcinomas at some symptoms for v6 months before diagnosis [90, 177].
time during the course of the illness [2, 3, 13, 169]. Single-modality therapy for mesothelioma has been
Effusions occur with all histological types, most disappointing. High-dose external beam irradiation,
frequently with adenocarcinoma [12, 87]. The pub- intrapleural administration of radioactive isotopes,
lished occurrences have been obtained by evaluation and various chemotherapeutic regimens have shown
of standard chest radiographs and would undoubtedly no significant effect on overall survival. Nor is there
be more numerous if ultrasound and CT were used to proof that a surgical approach alone improves patient
define the presence of effusions. survival. To be curative, resection must include the
The presence of pleural effusion typically signals an pleura (in stage Ia), lung (in stage Ib, II, III) and,
advanced stage of disease and is therefore associated often, the diaphragm, the pericardium, and a portion
with poor prognosis. In some cases, however, the of the chest wall (extrapleural pneumonectomy). In
pleura itself is not involved in tumour growth. These spite of careful selection (age v60 yrs, early-stage
accompanying paramalignant effusions are due to disease, favourable epithelial type), the 5-yr survival
postobstructive pneumonia or atelectasis, venous rate is only 11% [175, 178, 179].
obstruction by tumour compression, or lymphatic In light of this outlook, there has been ongoing
obstruction by mediastinal lymph nodes, and are not focus on multimodality therapy [180, 181]. A combi-
associated with direct pleural involvement. Such nation of parietal pleurectomy with postoperative
patients are few in number, but if pleural cytology is intrapleural therapy and/or external beam irradiation
negative, the clinician should explore additional resulted in median survival of 22.5 months and a 2-yr
diagnostic avenues, including CT, pleural biopsy, medi- survival rate of 41% in a selected group of 27 patients,
cal thoracoscopy, or surgical procedures (VATS/open predominantly with the epithelial subtype [181].
biopsy) [170]. Early-stage disease appears to be the key factor in
The prognosis of patients with nonsmall cell lung treatment success. In stage I, and especially in stage Ia
(without involvement of the visceral pleura), the other tumour types. Chemotherapy with cytotoxic
disease is still intrapleural and thus can be treated agents and/or hormones may be effective [137, 187,
by intrapleural therapy. Although they are still not 188]. If those approaches do not relieve symptoms,
available on the market, there have been promising local treatment options must be considered.
results with interferon and IL-2 intrapleural injections Median survival after the appearance of metastatic
made via an implantable port [165, 166, 182]. The best pleural effusions in one series of 105 patients was 13
indication for intrapleural treatment is stage Ia (or Ib) months (range, 0–72 months), without taking into
in epithelial-type mesothelioma, with nodules or consideration the different treatment modalities and
thickening ¡5 mm, in patients whose general status other factors [137]. RAJU and KARDINAL [184], in their
is still good. study of 122 patients, observed a median survival of
In patients with stage II and III mesothelioma, only 6 months after the onset of pleural effusion.
there is no randomized study showing the superiority Survival times are undoubtedly strongly related to the
of any one treatment compared with another; the presence of additional metastatic manifestations; in
practitioner has a choice between two alternatives. another study, median survival of patients whose
One is a multimodality treatment, including radical pleural effusions were the only evidence of recurrent
surgery, radiation therapy, and chemotherapy. The malignancy (n=10) was 48 months, whereas median
result of this approach is largely related to the survival of those with other evident sites of dissemi-
expertize and experience of the involved surgeons, so nated disease (n=35) was only 12 months [188].
that a surgical mortality rate as low as possible (range,
4–8%) is maintained. The second is medical treatment:
talc pleurodesis if necessary, preventive radiation the- Lymphoma, leukaemia, and multiple myeloma
rapy, and combined chemotherapy [183]. In patients
with stage IV disease, only conservative, palliative Approximately 10% of malignant pleural effusions
treatment to control pain is indicated. are due to lymphoma. According to reports in the
early 1940s, in Hodgkin9s disease, pleural effusions
develop in 16% of patients and pleural thickening in
Breast carcinoma 7%; the figures were, 15% and 11% in non-Hodgkin9s
lymphoma and 2% and 4% in leukaemia, respectively
Breast carcinoma is the second-ranking cause of [11]. Later observations have differed. Of 4,500 Mayo
malignant pleural effusion. About 7–11% of patients Clinic patients with lymphoma, only 7% had pleural
with breast carcinoma develop a malignant pleural effusions [7]. In other studies, the incidence of effusion
effusion during the course of the disease [4–6]. In 43% in Hodgkin9s disease has been variously reported as
of those patients, the effusion is the first symptom of 5% [189], 28%, or 33% [190].
metastatic disease [6]; the time from initial diagnosis Pleural effusion usually develops in the later stages
until the development of pleural effusion averages of the disease, with dyspnoea the chief symptom in
41.5 months (range, 0–246 months) [137]. In a review 63% [9], and occasionally it may be the only symptom
of seven autopsy series, the pleura was affected in [191]. The main cause of effusion, which may be
about one-half of 2,050 cases (range, 36–65%) [10]. unilateral or bilateral, is obstruction of the lymphatic
Higher tumour stages at the time of initial diagnosis drainage by enlarged mediastinal lymph nodes in
[136], as well as chest wall recurrences [6], were Hodgkin9s disease and by direct tumour infiltration of
associated more often with pleural effusion. the parietal or visceral pleura in non-Hodgkin9s
Besides the rare direct invasion through the chest lymphoma [11, 192–194]. The effusion is usually an
wall, the pathogenesis of pleural involvement in breast exudate but may occasionally have transudative
carcinoma is through either lymphatic or haemato- characteristics. Effusions may be serous, haemorrha-
genic spread. FENTIMAN et al. [137] found, in 99 gic, or chylous [194, 195]; non-Hodgkin9s lymphoma
patients with unilateral breast tumours and pleural is the most common cause of chylothorax [195, 196].
effusions, that 50% of the effusions were ipsilateral, The cytological yield lies between 31–55% [197],
40% were contralateral, and 10% were bilateral; RAJU with the lowest yield reported in Hodgkin9s disease
and KARDINAL [184], however, observed ipsilateral [193, 194]. Chromosome analysis has high sensitivity,
effusions in 85 of 122 patients. about 85% [198]; results obtained by medical thoraco-
The yield from cytological examination of the scopy are superior [58, 191]. Clonality can also be
effusion is usually higher than with other tumours demonstrated via flow cytometry. Effusions can also
[185], so that pleural biopsy or medical thoracoscopy result from radiation of the mediastinum or from
is rarely indicated. Determination of hormone recep- obstruction of lymphatic drainage of the pleural space
tor status in the pleural tissue may be helpful in due to mediastinal fibrosis, constrictive pericarditis, or
guiding hormonal therapy [94]. superior vena caval obstruction. This may occur a
In differential diagnosis, it is important to exclude year or two after radiotherapy [199] and may also
pleural effusions caused by postoperative radiother- result in a chylous effusion [200]. Average survival
apy, which usually occur during the first 6 months and time after the first thoracentesis is short, 6 or 7
are commonly accompanied by radiation pneumoni- months, but there may be a wide range [7, 41]. The
tis; they usually resolve spontaneously over several presence of malignant cells in the effusion is associated
months [186]. with a poor prognosis.
Recommended treatment of metastatic pleural The treatment of choice is systemic chemothe-
effusion with breast carcinoma differs from that for rapy. Pleurodesis by talc poudrage combined with
parenteral alimentation, in order to reduce chyle pro- Partially successful pleurodesis. Diminution of dyspnoea
duction, may be necessary when chemotherapy fails related to the effusion, with only partial reaccumula-
[201]. Mediastinal radiation may be useful when there tion of fluid (v50% of the initial radiographic evidence
is mediastinal node involvement and may be effective of fluid), with no further therapeutic thoracenteses
in chylothorax [195]. In patients with chylothorax, required for the remainder of the patient9s life.
pleuroperitoneal shunt may be a good approach in
failed therapy, as it can recirculate the chyle [202]. Failed pleurodesis: Lack of success (as defined
Multiple myeloma is an infrequent cause of earlier). Comparative studies of different pleurodesis
malignant pleural effusion, which occurs in y6% of techniques should evaluate outcomes using time-to-
cases [189, 203]. High pleural protein values, in the event analyses censoring patients who are lost to
range of 8–9 g?L-1, are suggestive of this diagnosis. follow-up. Data should be reported with and without
Electrophoresis and immunoelectrophoresis of pleural inclusion of patients who die within 1 month of
fluid may be diagnostically characteristic [204]. pleurodesis.
Infiltration of the chest wall is usually present, due
to invasion from adjacent skeletal lesions (ribs, Prospects for clinical studies
sternum, and vertebrae), but pleuropulmonary infil-
tration may also originate from soft tissue plasmocy- There are few data on which the clinician can
toma of the chest wall or from direct involvement. confidently rely on, making important therapeutic
With pleural immunocytoma from Waldenström9s decisions in the management of malignant pleural
macroglobulinemia, pleural effusion is a rare mani- effusions. Most urgently needed are well-designed
festation [205]. prospective studies that will: 1) Determine the course
of small, asymptomatic malignant pleural effusions
with and without treatment. Because late pleurodesis
Factors affecting prognosis
attempts are more likely to fail than earlier interven-
tions, it might be suggested that pleurodesis simply be
According to several studies, the best correlation
performed at an early stage, once the malignant
for pleurodesis outcome and overall survival are
nature of the effusion is known. Many of these
pleural fluid pH and glucose [41–45]. However, a
patients, however, have few symptoms attributable to
meta-analysis of w400 patients found a poor pre-
the effusion itself and are not likely to seek relief or
dictive value for success of pleurodesis [52]. The
treatment for it. Prospective studies are therefore
patient9s general health status and tumour type should
needed to provide reliable management guidelines. 2)
be considered in deciding appropriateness for pleuro-
Assess talc slurry pleurodesis versus talc poudrage via
desis. Because pleural fluid glucose is usually more
thoracoscopy, with particular attention to optimal
sensitive to fluctuations in serum than pH, the
dosage, the use of intrapleural analgesics such as
predictive value of glucose is lower than that of pH.
lidocaine, and patient positioning during talc slurry
In one prospective study, measurement of the
procedures. 3) Explain the systemic complications and
elastance of the pleural space was associated with
side effects of talc pleurodesis, especially potential
pleurodesis outcome [107].
triggering of coagulation in the systemic circulation.
Quality of life of patients with malignant effusions
Because it is likely that this untoward event occurs
should be evaluated with regard to those symptoms
with other sclerosing agents as well, such information
that are related to the effusion itself. Relief of
would be useful in developing preventive measures. 4)
dyspnoea remains the primary objective for most
Explore and clarify the potential role of intrapleural
patients. Ideally, therapy should minimize discomfort,
therapeutic interventions, including not only chemo-
as well as limit hospitalization time, in these patients
therapeutic agents but also such immune modulators
with an often limited life span. However, an important
as cytokines and interferon. As observed in the earlier
aspect in any treatment is prevention of reoccurrence
discussion of this topic, employment of this modality
of the symptomatic effusion. Finally, pain relief is
has been largely hit-and-miss; randomized studies are
another important quality-of-life issue, which must be
needed to determine optimal application of agents,
addressed. This is particularly true for patients with
both singly and in combination, and the effect of
mesothelioma, whose primary complaint is often pain
various approaches on survival. 5) Identify depend-
instead of dyspnoea.
able tumour-related markers of malignant pleural
effusion. Markers that would help the clinician
Future directions for research differentiate, for example, between reactive mesothe-
lial cells, mesotheliomas, and metastatic adenocarci-
Definitions of success or failure of pleurodesis nomas would be especially valuable.
Uniform criteria for evaluating the results of Gene therapy

pleurodesis in future studies are badly needed. The
following definitions are proposed: In the absence of other effective, nontoxic thera-
pies for malignant mesothelioma, several groups of
Completely successful pleurodesis. Long-term relief of investigators have turned to the newly evolving tech-
symptoms related to the effusion, with absence of fluid nology of gene therapy for new treatment modalities
reaccumulation on chest radiographs until death. [206, 207].
One approach is the intrapleural administration of frequency and pathogenic mechanisms in a post-
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Copyright #ERS Journals Ltd 2001

Eur Respir J 2001; 18: 402–419 European Respiratory Journal

ERS ATS STATEMENT

Management of malignant pleural effusions

V.B. Antony, R. Loddenkemper#, P. Astoul}, C. Boutin}, P. Goldstrawz, J. Hott,

Aetiology and pathogenesis . . . . . . . . . . . . . . 402 Treatment of pleurodesis failure. . . . . . . . . . . 410

Table 1. – Incidence of malignant pleural effusions (MPEs)

Lung cancer 8–15 20–46 25–52 160,000 32,000–73,600§

Table 2. – Causes of paramalignant pleural effusions

Local effects of tumour

Medical thoracoscopy as compared with surgical 74 96

provide easier identification of primary tumour [80],

remain undiagnosed [80, 83, 96, 97]; whereas with

Therapeutic thoracentesis Chemical pleurodesis

Table 3. – Complete success rates of commonly used pleurodesis agents

Talc 165 153 93 2.5–10 g

Uniform criteria for evaluating the results of Gene therapy

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