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Fluid Complications
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Fluid Complications
November 01, 2015 | Cancer Management [1]
By Frederic W. Grannis, Jr, MD [2], Jae Y. Kim, MD [3], and Lily Lai, MD [4]
Malignant pleural effusion complicates the care of approximately 150,000 people in the United
States each year.
Malignant Pleural Effusion
Malignant pleural effusion complicates the care of approximately 150,000 people in the United
States each year. The pleural effusion is usually caused by a disturbance of the normal Starling
forces regulating reabsorption of fluid in the pleural space, secondary to obstruction of mediastinal
lymph nodes draining the parietal pleura. Tumors that metastasize frequently to these nodes (eg,
lung cancer, breast cancer, and lymphoma) cause most malignant effusions. It is, therefore, puzzling
that small-cell lung cancer infrequently causes effusions. Primary effusion lymphomas caused by
human herpesvirus 8 and perhaps Epstein-Barr virus (EBV) are seen in patients with acquired
immune deficiency syndrome (AIDS).
Sidebar: Stathopoulos et al from Athens, Greece have provided a model to explain why only some
cancers result in malignant effusions. They suggest that expression of transcriptional programs
leading to higher levels of signaling molecules intrapleurally result in increased permeability. Further
interaction with other host cells results in angiogenesis and vascular leakage (Stathopoulos GT, et
al: Am J Respir Crit Care Med 186:487–492, 2012). Investigators from Tel Hashomer, Israel provide
microstructural support for this theory in a study of pleural biopsies from patients with pleural
effusion with and without adenocarcinoma. They demonstrate a striking increase in microvessel
density. Capillaries and lymphatics are abnormal, displaying changes in normal antigen expression
on endothelial cells and pericytes; these changes correspond to disturbed vessel wall integrity that is
consistent with hyperpermeability (Damianovich M, et al: Clin Lung Cancer 14:688–698, 2013). The
role of vascular endothelial growth factor in these processes is discussed in this chapter.
Pleural effusion restricts ventilation and causes progressive shortness of breath by compression of
lung tissue as well as paradoxical movement of the inverted diaphragm. Pleural deposits of tumor
cause pleuritic pain.
Pleural effusions occur more commonly in patients with advanced-stage tumors, who frequently
have metastases to the brain, bone, and other organs; physiologic deficits; malnutrition; debilitation;
and other comorbidities. Because of these numerous clinical and pathologic variables, it is difficult to
perform prospective trials in patients with pleural effusions. For the same reason, it is often difficult
to predict a potential treatment outcome or anticipated duration of survival for the specific patient
with multiple interrelated clinical problems.
William et al generated survival curves for more than 8,000 patients with non–small-cell lung cancer
(NSCLC) with pleural effusion (ie, stage IIIB) from the SEER database and showed that long-term
survival is uncommon in this group. The median survival time is approximately 3 months.
Sidebar: Investigators in São Paulo, Brazil studied 22 patients with unilateral malignant pleural
effusions following thoracentesis with electrical impedance tomography and described
heterogeneous re-ventilation responses. They noted that pleural effusion causes ventilatory
asynchrony—sometimes “so extreme that one lung was inflating while the other was deflating,” ie,
paradoxical ventilation, immediately reversible with thoracentesis. The authors reported that after
thoracentesis, “ipsilateral and contralateral lungs re-aerated immediately and without further
re-aeration over the next hour”(Alves SH et al: Ann Am Thorac Soc 11:186–191, 2014).
Morgensztern et al, from Yale University, used Surveillance, Epidemiology, and End Results (SEER)
data to identify 57,000 patients with NSCLC; among this group, 9,170 (15.9%) had malignant pleural
effusions, including 5,226 with distant metastases and 3,944 without distant metastases. Malignant
pleural effusions were associated with larger primary tumors, mediastinal nodal metastasis, and
adenocarcinoma. Median survival was better in patients without distant metastasis compared with
those who had distant metastasis (5 months vs 3 months, respectively), as were 1- and 2-year
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survival rates (24.8% vs 12.6% and 11.3 vs 5.4%, respectively).
Diagnosis
The new onset of pleural effusion may herald the presence of a previously undiagnosed malignancy
or, more typically, complicate the course of a known tumor. Malignant pleural effusions can lead to
an initial diagnosis of cancer in patients. In Nantes, France, pleural effusion was the first symptom of
cancer in 41% of 209 patients with malignant pleural effusion; lung cancer in men (42%) and ovarian
cancer in women (27%) were most common. It is important to bear in mind that many cancer
patients have comorbid illness and that pleural effusion may have another etiology.
Sidebar: A group in Bristol, England did CT pulmonary angiograms on consecutive new patients
presenting with unilateral pleural effusion in instances in which there was not an immediately
obvious cause. Pulmonary embolism was detected in 9 of 141 patients (6.4%); 8 of these 9 patients
also had malignant pleural effusion (Hooper C, et al: Respiration 87:26–31, 2014).
Thoracentesis
Thoracentesis is the first step in management of almost all cases of malignant pleural effusion.
Ultrasonography facilitates thoracentesis, reduces the rate of complications such as pneumothorax,
and can identify pleural nodules and/or thickening, suggesting malignant etiology, as well as
targeting known lesions for pleural biopsy. An adequate specimen should be obtained and sent for
lab studies designed to separate benign and malignant effusions, including cell count; determination
of glucose, protein, lactate dehydrogenase (LDH), and pH; and appropriate cultures and cytology.
Chest pressure and pain during thoracentesis can occur when lung elastance is reduced and pleural
pressures are markedly negative. Such pain suggests a “trapped” lung and signals an increased risk
of postthoracentesis pulmonary edema.
In circumstances in which it is thought desirable to provide continuing drainage of fluid, Seldinger
wire–guided placement of small-bore catheters have largely replaced larger chest tubes. Cafarotti et
al described the use of 12-F small-bore catheter placements in more than 1,000 patients, with
successful drainage in 93.8% of 324 cases of malignant pleural effusion.
The Light criteria (lactate dehydrogenase [LDH] > 200 U/L; pleural-serum LDH ratio > 0.6; and
pleural–serum protein ratio > 0.5) help to categorize pleural effusions as exudates.
The majority of undiagnosed exudates are eventually diagnosed as malignant, whereas < 5% of
transudates are shown to be caused by cancer. Transudates may be misclassified as exudates
following dehydration or diuresis and if there are erythrocytes (and LDH) in the fluid. Brain natriuretic
protein levels are markedly elevated in effusions secondary to congestive heart failure.
Sarkar et al have introduced a simple bedside test that allows identification of exudative effusion at
the time of thoracentesis. They add 10 mL of 30% hydrogen peroxide to 200 mL of pleural effusion.
When catalase is present (exudates), the effusion foams. None of 32 transudates produced foam,
whereas all 52 exudates produced profuse bubbles. The test is not accurate if blood contaminates
the fluid.
A negative cytology result is not uncommon and does not rule out a malignant etiology. If cytology is
negative in an exudative effusion, approximately 25% will have a positive cytology on a second
thoracentesis; blind pleural biopsy may increase the yield to nearly 50%. This low diagnostic yield
can be improved by CT or ultrasonographic guidance of needle biopsy.
Investigators in Cambridge, England, report that thickening of the pleura > 1 cm, pleural nodularity,
and diaphragmatic thickening > 7 mm on either CT (computed tomography) or ultrasonography
suggest malignant effusion. On positron emission tomography (PET) scan, a high SUV (standard
uptake value) may indicate a malignant pleural effusion. It is important to note that high SUV values
may persist for long periods following talc pleurodesis (TP).
Metintas et al reported results of a randomized, controlled trial of medical thoracoscopy vs
CT-guided Abrams pleural needle biopsy for diagnosis in patients with malignant pleural effusions.
They studied 124 patients with exudative pleural effusions that were not diagnosed by cytologic
analysis. Patients were randomized after CT scan to either thoracoscopy and biopsy or CT-guided
needle biopsy. CT-guided needle biopsy yielded diagnostic sensitivity of 87.5%, compared with
94.1% in the thoracoscopy group (not statistically significant). Complication rates were low and
acceptable with both methods. The authors recommend use of CT-guided needle biopsy for pleural
biopsy as the primary method of diagnosis in patients with pleural thickening or lesions observed by
CT scan. In patients with pleural fluid without pleural thickening on CT scan and in those who may
have benign pleural pathologies other than tuberculosis, the primary method of diagnosis
recommended is thoracoscopy. Letovanec et al, from Lausanne, Switzerland, reported on 47 patients
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with pleural effusion studied with PET/CT, noting that SUV in malignant effusions is higher than in
benign effusions (3.7 vs 1.7 g/mL), showing a correlation between malignant effusion and SUV. They
conclude that PET/CT may assist in differentiation between malignant vs benign origin of pleural
effusion with high specificity in patients with known cancer, specifically NSCLC.
Because it is sometimes difficult to prove the malignant nature of an effusion cytologically, and
because thousands of proteins (secretome) and many other nucleic acids, volatile compounds, etc,
have been identified in pleural fluid, many molecular tests on pleural fluid have been investigated.
Multiple reports measure pleural tumor marker proteins, glycosaminoglycans, cadherins, matrix
metalloproteins, cytokines, telomerase, mRNA, exosomes, and serum and pleural DNA methylation
patterns, fluorescence in situ hybridization (FISH), proteomics, and many other methods of pleural
fluid testing are described. A number of meta-analyses of diagnostic testing have been published,
but to date we are unaware of any test or panel of tests that can reliably diagnose malignant
effusions with sufficient confidence to allow clinicians to prescribe treatment with cytotoxic agents in
the absence of a pathological diagnosis of cancer. Accordingly, biomarker tests and panels have
limited utility at present, except perhaps to guide further diagnostic efforts.
Bhattacharya et al, from Kolkata, India, reported on 66 patients with malignant pleural effusion who
underwent closed pleural biopsy routinely with diagnostic thoracentesis. Overall, there was 69%
positive cytology: 52% on the first examination, 15% on the second, and 1.5% on the third. Closed
pleural biopsy identified malignant pleural effusion in 10 additional patients not diagnosed by fluid
cytology. There were no major complications.
Thoracoscopy
Thoracoscopic examination performed with the patient under either general or local anesthesia and
using rigid or partly flexible thoracoscopes offers a very high sensitivity, specificity, and diagnostic
accuracy with a low complication rate. It allows comprehensive visualization of one pleural cavity,
coupled with the opportunity to biopsy areas of disease. This method provides a definitive diagnosis
and allows the pathologist to suggest possible sites of primary disease based on the histopathology.
Galbis et al from Valencia, Spain prospectively investigated 110 patients who had thoracoscopy for
undiagnosed pleural effusions with negative cytologic examination of fluid obtained by
thoracentesis. Following thoracoscopy and biopsy, 30% were diagnosed with nonspecific pleuritis,
17% with malignant pleural mesothelioma, 1.8% with pleural tuberculosis, and 48% with pleural
carcinoma.
There was no incidence of later development of a malignant pleural effusion following a benign
thoracoscopic study in 25 patients at the Lahey Clinic, but Davies et al from the Oxford Pleural Unit
report on longer-term follow-up of patients with a diagnosis of nonspecific pleuritis/fibrosis on
thoracoscopic pleural biopsy. They retrospectively reviewed 142 patients with a prior medical
thoracoscopy and biopsy. Patients were followed until death or for a mean of 21 months. A total of
44 patients were diagnosed with nonspecific pleuritis/fibrosis and 98 patients (69%) had a definitive
histological diagnosis. The authors reported that five (12%) patients with nonspecific pleuritis/fibrosis
subsequently had a diagnosis of malignant pleural mesothelioma after a mean interval of 9.8
months. Accordingly the false-negative rate of thoracoscopic biopsy for the detection of pleural
malignancy was 5%, with a diagnostic sensitivity of 95% and a negative predictive value of 90%.
They conclude that “patients with nonspecific pleuritis/fibrosis require careful follow-up.”
Furthermore, thoracoscopic pleural biopsy permits the diagnosis and staging of malignant
mesothelioma if it is the cause of the effusion. Thoracoscopy also offers the opportunity for
simultaneous treatment. Both talc pleurodesis and intrapleural catheter drainage have shown
sustained benefit in palliative management of both malignant pleural effusion and malignant pleural
mesothelioma.
Occult malignancy can exist even in the case of a grossly normal pleura at the time of thoracotomy
for resection of lung cancer. Multiple studies, particularly in Japan, have investigated the prognostic
value of intraoperative pleural lavage specimen cytologic examination. This would appear to be an
area in which productive research could be conducted to answer the question of whether prognosis
might be improved in these patients through prospective adjuvant interventional trials.
Kaneda et al, from the Mie Chuo Medical Center in Japan, have reported on the value of pleural
lavage cytology examined during surgery for primary lung cancer. They studied 3,231 patients
retrospectively who had had thoracic washing cytology at the time of surgical resection of lung
cancer, and noted that cytology was positive in 4.58% of cases. These patients had significantly
worse survival (P = .001) and a higher incidence of recurrent pleural carcinoma. The investigators
comment that positive cytologic findings should be treated as “supplemental…to the precise
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diagnosis of TNM staging.” They suggest scoring positive pleural cytology findings as a new T3
sub-category (PL3).
This would appear to be an area in which productive research could be conducted to answer the
question of whether prognosis might be improved in these patients through prospective adjuvant
interventional trials.
Sidebar: What should be done when a small malignant effusion or limited pleural metastases are
found at the time of thoracotomy for otherwise resectable lung cancer? The presence of even small
pleural effusions has been shown to correlate with reduced survival. Small series have described
aggressive surgical interventions—including lobectomy or even pneumonectomy combined with
pleurectomy and intrapleural chemotherapy—in lung cancer patients who have metastatic pleural
nodules, with and without small pleural effusions. Fiorelli conducted a literature review on this
subject and concluded that “no current guidelines support surgery over conservative therapy even
when combined with postoperative adjuvant chemotherapy or radiation therapy.” (Fiorelli A, Santini
M: Interact Cardiovasc Thorac Surg 17:407-412, 2013).
Bronchoscopy
Bronchoscopy may be helpful when an underlying lung cancer is suspected, especially if there is
associated hemoptysis, a lung mass, atelectasis, or a massive effusion. It may also be useful when
there is a cytologically positive effusion with no obvious primary tumor.
Prognosis
Prognosis of patients with malignant pleural effusion varies by primary tumor. For example, median
survival of patients with lung cancer is 3 months, whereas it is 10 months for patients with breast
cancer. Median survival is also shorter in patients with encasement atelectasis (3 months).
Sakr retrospectively reviewed prognostic indicators among 421 patients with malignant pleural
effusion who underwent medical thoracoscopy. The median survival of patients with malignant
pleural effusion was 9.4 months. In univariate analysis, melanoma, age < 60, bloody effusion,
extensive pleural adhesions, and widespread pleural nodules correlated with reduced survival, but
extent of pleural tumor did not correlate with reduced survival on multivariate analysis. Survival can
be predicted with some precision using a LENT prognostic score.
Treatment
Initial treatment: Palliation
Because malignant pleural effusion causes distress and disability and is associated with brief
survival, initial management has chiefly been palliative with either drainage of fluid serially over time
or obliteration of the pleural space by pleurodesis. Because the specific clinical circumstances may
vary markedly in different patients, treatment must be individualized to provide the best palliation
for each patient. Generally, there are a variety of methods available for palliative treatment of
malignant effusions, and there is little compelling evidence to guide clinicians in the choice of the
best methods. Accordingly, treatment decisions must be made with careful reference to the status of
the patient and the skills and equipment available in the local community. In general, malignant
pleural effusion should be treated aggressively as soon as it is diagnosed. In most cases, effusion will
rapidly recur after treatment by thoracentesis or tube thoracostomy alone.
If a malignant pleural effusion is left untreated, a multiloculated effusion may develop or the
underlying collapsed lung will become encased by tumor and fibrous tissue in as many as 10% to
30% of cases. Multiloculated effusions are difficult to drain by thoracentesis or chest tube placement.
Once encasement atelectasis has occurred, the underlying lung is “trapped” and will no longer
reexpand after thoracentesis or tube thoracostomy. Characteristically, the chest x-ray in such cases
shows resolution of the pleural effusion after thoracentesis, but the underlying lung remains partially
collapsed. This finding is often misinterpreted by the inexperienced clinician as evidence of a
pneumothorax, and a chest tube is placed. The air space persists and the lung remains unexpanded,
even with high suction and pulmonary physiotherapy. Allowing the chest tube to remain in place can
worsen the situation, resulting in bronchopleural fistulization and empyema. In some cases, a
trapped lung on an initial chest x-ray will have delayed reexpansion following drainage with a chest
tube or small pleural catheter.
Intrapleural alteplase (10–20 mg diluted in 50 to 150 mL of saline) has been used with success in
some patients with gelatinous or loculated effusions, with a low incidence of bleeding complications.
Physical techniques. To avoid encasement atelectasis, pleural effusion should be treated
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definitively at the time of initial diagnosis. Multiple physical techniques have been used to produce
adhesions between the parietal and visceral pleurae, obliterate the space, and prevent recurrence.
They include open or thoracoscopic pleurectomy, gauze abrasion, or laser pleurodesis. Surgical
methods have not been demonstrated to have any advantage over simpler chemical pleurodesis
techniques in the treatment of malignant effusions. Gauze abrasion pleurodesis can be easily
employed when unresectable lung cancer with associated effusion is found at the time of
thoracotomy.
A randomized, prospective study from Ljubljanska, Slovenia, of 87 patients with malignant pleural
effusion secondary to breast cancer showed that the thoracoscopic mechanical abrasion pleurodesis
was equivalent to talc pleurodesis (TP) in those with normal pleural fluid pH and superior in patients
with a low pH.
Chemical agents. Multiple chemical agents have been used.
• Tetracycline—Tetracycline pleurodesis results in a lower incidence of recurrence when compared
with tube thoracostomy alone but often causes severe pain. Tetracycline is no longer commercially
available in the United States.
• Doxycycline and minocycline—Doxycycline and minocycline are probably equivalent to tetracycline
in terms of their efficacy and associated patient discomfort.
• Erythromycin—Erythromycin also causes pleural pain on administration, and in a small series
produced a complete response in 79% of patients at 90 days. Recurrence with necessity for
re-intervention was seen in 11.8%.
• Bleomycin—Intrapleural bleomycin, at a dose of 60 U, has been shown to be more effective than
tetracycline and is not painful, but it is costly. Absorption of the drug can result in systemic toxicity.
Combined use of tetracycline and bleomycin has been demonstrated to be more efficacious than use
of either drug singly.
• Talc—Talc pleurodesis was first introduced by Norman Bethune in the 1930s. The first use of talc in
malignant pleural effusion was by John Chambers in 1958. Talc powder (Sclerosol Intrapleural
Aerosol) has demonstrated efficacy in numerous large studies, preventing recurrent effusion in 70%
to 92% of cases. Talc is less painful than tetracycline. Cost is minimal, but special sterilization
techniques must be mastered by the hospital pharmacy. Talc formulations may have significant
differences in the size of particles. Smaller particles may be absorbed and disseminated systemically
and may contribute to the increased incidence of adult respiratory distress syndrome (ARDS) or
substantial hypoxemia. Gonzalez et al studied the incidence of lung injury following TP with a median
dose of talc (Sclerosol) of 6 g. Cases with new infiltrates on a chest x-ray, increased oxygen
requirement, and no identifiable trigger other than talc exposure were considered to represent a
talc-related lung injury. A total of 12 of 138 patients experienced increased oxygen requirements
within 72 hours of the treatment. Four patients (2.8%) had talc-related lung injury.
Talc has also been shown to cause decreases in forced vital capacity (FVC), forced expiratory volume
in one second (FEV1), and diffusing capacity over the long term.
Talc can be insufflated in a dry state at the time of thoracoscopy or instilled as a slurry through a
chest tube. The dose should be restricted to no more than 5 g. A prospective phase III Intergroup
trial of 501 patients randomized to receive thoracoscopic talc vs talc slurry pleurodesis showed
similar efficacy in each arm, with increased respiratory complications (14% vs 6%) but less fatigue
and higher patient ratings in the insufflation group.
Multiloculated effusions may follow talc use. It is important to ensure that talc does not solidify and
form a concretion in the chest tube, thus preventing the drainage of pleural fluid and complete
reexpansion of the lung following pleurodesis. Such an event is more likely when small-bore chest
tubes are used.
• Pleurodesis technique—With TP, a 24- to 32-French tube has customarily been inserted through a
lower intercostal space and placed on underwater seal suction drainage until all fluid is drained and
the lung has completely reexpanded. Because severe lung damage can be produced by improper
chest tube placement, it is imperative to prove the presence of free fluid by a preliminary needle tap
and to enter the pleural space gently with a blunt clamp technique, rather than by blind trocar
insertion. If there is any question about the presence of loculated effusion or underlying adhesions,
the use of CT or sonography may enhance the safety of the procedure. In the case of large effusions,
especially those that have been present for some time, the fluid should be drained slowly to avoid
reexpansion pulmonary edema.
Significant complications can occur with both thoracentesis and chest tube thoracostomy. These
procedures should not be performed by inexperienced practitioners without training and supervision.
Ultrasound guidance is recommended.
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Premedications: If doxycycline or talc is to be used, the patient should be premedicated with
narcotics. Intrapleural instillation of 20 mL of 1% lidocaine before administration of the chemical
agent may help to reduce pain.
Following instillation of the chemical agent, the chest tube should remain clamped for at least 2
hours. If high-volume drainage persists, the treatment can be repeated. The chest tube can be
removed after 2 or 3 days if drainage is < 300 mL/d.
Follow-up x-rays at monthly intervals assess the adequacy of treatment and allow early retreatment
in case of recurrence.
Sidebar: Arellano-Orden et al, from Sevilla, Spain, studied 227 patients with malignant pleural
effusions treated with large particle (50% of particles > 10 nm) vs small particle (< 20% of particles
> 10 nm) talc pleurodesis. Death within 7 days occurred in 8 of 107 patients with small-talc
pleurodesis vs 1/127 using large-talc pleurodesis. Levels of interleukin, tumor necrosis factor alpha,
vascular endothelial growth factor, and thrombin-antithrombin complex were higher in patients with
small-talc pleurodesis, and proinflammatory cytokines were higher in patients with greater tumor
burden. The authors concluded that small talc particles provoke a strong inflammatory reaction in
both the pleural space and serum, associated with a higher rate of early deaths (Arellano-Orden E, et
al: Respiration 86:201–209, 2013).
• Alternative approaches—Use of fluid-sclerosing agents and outpatient pleurodesis has been
advocated by some investigators and has the potential for reducing hospital stay and treatment
cost. Patz performed a prospective, randomized trial of bleomycin vs doxycycline (72% bleomycin vs
79% doxycycline) pleurodesis via a 14-French catheter and found no difference in efficacy. Aglayan,
in Istanbul, Turkey, evaluated iodopovidone via either chest tube or a small-bore catheter in 41
patients. Complete and partial successes were observed in 60% and 27%, respectively. Results did
not differ by diameter of the tube. (Because of the risk of iodine toxicity with renal failure and
seizures, such use of iodopovidone should be limited to 2% solutions and should not be used in
patients taking amiodarone or with prolonged use of topical iodine wound treatments.)
Schneider et al reported on 100 patients with tunneled pleural catheters. The mean residence time
of the catheter was 70 days. Spontaneous pleurodesis was achieved in 29 patients. The rate of
empyema was 4%. The investigators identified three groups that seemed to benefit: (1) patients with
the intraoperative finding of a trapped lung in diagnostic video-assisted thoracic surgery (VATS)
procedures; (2) patients after repeated thoracentesis or previously failed attempts at pleurodesis;
and (3) patients with a limited life span due to underlying disease.
Other approaches that have been utilized include quinacrine, silver nitrate, powdered collagen, and
distilled water, as well as various biologic agents, including Corynebacterium parvum, OK-432, tumor
necrosis factor, interleukin-2, interferon-α, interferon-β, and interferon-gamma (Actimmune).
Treatment of encasement atelectasis
If encasement atelectasis is found at thoracentesis or thoracoscopy, tube thoracostomy and
pleurodesis are futile and contraindicated.
Management options
Surgical decortication. Surgical decortication has been advocated for this problem. This
potentially dangerous procedure may result in severe complications, however, such as
bronchopleural fistula and empyema. In carefully selected cases with early multiloculated malignant
effusion, gentle thoracoscopic debridement can restore a single cavity and allow effective pleural
drainage or TP.
Pleuroperitoneal shunts. The Royal Brompton Hospital, London, group reported experience with
pleuroperitoneal shunts in 160 patients with malignant pleural effusion and a trapped lung. Effective
palliation was achieved in 95% of patients; 15% of patients required shunt revisions for
complications.
Intermittent thoracentesis. Intermittent thoracentesis, as needed to relieve symptoms, may be
the best option in patients with a short anticipated survival time.
Catheter drainage. Another option is to insert a tunneled, small-bore, cuffed, silicone catheter
(PleurX pleural catheter, Denver Biomaterials, Inc., Denver, Colorado) into the pleural cavity. The
patient or family members may then drain fluid, using vacuum bottles, whenever recurrent effusion
causes symptoms. Bard manufactures an indwelling catheter gravity drainage system under the
trade name Aspira.
Kakuda reported on placement of 61 PleurX pleural catheters in 50 patients with malignant pleural
effusions at City of Hope; 34% had lung cancer and 24% had breast cancer. There were no operative
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deaths. In cases in which the catheter was placed under thoracoscopic control, 27 of 38 patients
(68%) had encasement atelectasis visualized. A total of 81% had a good result with control of
effusion, with subsequent catheter removal (19%) or intermittent drainage for more than 1 month or
until death (62%). A total of 5% of patients had major complications, including empyema and tumor
implant. Thoracoscopic techniques are useful in the presence of multiloculated effusion. These
catheters can also be inserted using the Seldinger technique with the patient under local anesthesia.
Tremblay et al placed 250 PleurX pleural catheters by percutaneous technique in patients under
local anesthesia. No further pleural intervention was required during the lives of 90% of the patients.
The median overall survival was 144 days, and spontaneous pleurodesis occurred in 43%.
Subsequent studies showed that 70% of patients who had full lung expansion had spontaneous
pleurodesis, with lifetime control of pleural effusion in 92%. They also reported good results in
patients with mesothelioma effusions.
Thornton et al, from Memorial-Sloan Kettering Cancer Center, report on the use of tunneled pleural
catheters for treatment of recurrent, symptomatic malignant pleural effusions following failed
pleurodesis in 63 patients. Following placement of tunneled catheters, 60 of 63 patients had clinical
improvement in dyspnea. After a median of 3 days in the hospital, 90% were discharged with the
catheter in place. About one-third (31%) needed intrapleural fibrinolytic therapy for optimum
evacuation.
Davies et al, from University Hospital of Wales in Cardiff, reported follow-up at 1 year in an unblinded
study of 106 patients from seven hospitals in the United Kingdom who had previously untreated
malignant pleural effusions. Patients were randomized to either intrapleural catheters (IPCs) placed
on an outpatient basis or chest tube insertion and talc slurry pleurodesis (TP). Dyspnea improved on
a visual analog scale in both groups with no significant difference in mean dyspnea (24.7 mm in the
intrapleural catheter group; 24.4 mm in the talc group). After 6 months the IPC group had a
statistically significant mean difference of 14 mm in the dyspnea score over the talc group.
Hospitalization was minimized in the IPC group (median, 0 days compared with 4 days for the talc
arm). There was no significant difference in quality of life. Twenty-two percent of patients in the TP
arm required further pleural procedures compared with 6% in the IPC group. Adverse events
occurred in 21 of 52 patients in the IPC group compared with 7 of 54 in the talc group.
Freeman et al, from Indianapolis, Indiana, performed a propensity-matched comparison of talc
poudrage pleurodesis versus tunneled pleural catheters in patients undergoing diagnostic
thoracoscopy for malignancy. The group treated with pleural catheters had a significantly shorter
hospital stay and interval to initiation of systemic therapy for their malignancy, as well as a lower
rate of operative morbidity compared with patients undergoing pleurodesis. The authors also noted
that “the rate of freedom from re-intervention equaled that of talc pleurodesis.”
A Point/Counterpoint article in Chest between Pyng Lee, MD, and Richard Light, MD, on the question,
“Should thoracoscopic talc pleurodesis be the first choice management for malignant
effusion?”serves as a good review of published literature on management of malignant pleural
effusions and a spirited debate on the relative risks and benefits of treatment options.
IPCs have been used safely in pediatric patients in two small series. Although there is a small risk of
infection in patients with IPCs, it has been shown that such infection is not increased in patients
undergoing chemotherapy following catheter placement. There is a small incidence of tumor
implantation at the site of the catheter.
Sidebar: Although this chapter does not deal directly with the subject of management of malignant
pleural mesothelioma (MPM), the question arises as to what the clinician should do when MPM is
identified at the time of diagnostic thoracoscopy and no immediate plan for surgical resection is in
place. A review of cases in the Western Australia Mesothelioma registry showed that either talc
poudrage or postoperative talc slurry pleurodesis prevented reaccumulation of malignant effusion in
approximately 70% of cases. A prospective randomized trial of 175 patients with MPM showed no
survival advantage of VATS (video-assisted thoracic surgery) pleurectomy over talc poudrage.
Chemotherapy. If the clinician decides to precede palliative intervention with administration of
systemic chemotherapy for the underlying primary malignancy, in tumors such as breast cancer,
lymphoma, and small-cell lung cancer, it is important to monitor the patient carefully for recurrent
effusion after thoracentesis and to treat such recurrences immediately. A recent spate of published
data document the chance of success in clearance of malignant pleural effusions with systemic and
intrapleural chemotherapy and/or targeted molecular therapies. Chemotherapy options depend on
the cell type of the tumor and the general condition of the patient. Although intrapleural
chemotherapy offers the possibility of high-dose local therapy with limited systemic effects, only a
few small pilot studies utilizing mitoxantrone, doxorubicin, and hyperthermic cisplatin have been
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published.
Ang reported longer mean survival (12 months vs 5 months) when systemic chemotherapy was
given to 71 patients who initially presented with malignant pleural/pericardial effusions.
Su et al treated 27 patients with NSCLC presenting with a malignant pleural effusion using a regimen
of intrapleural cisplatin and gemcitabine (Gemzar) followed by radiotherapy (7,020 cGy in 39
fractions), and completed treatment with IV docetaxel. Only two patients experienced recurrent
pleural effusion. The median disease-free and overall survival times were 8 and 16 months,
respectively, and 63% of patients were alive at 1 year.
Seto et al reported a single-arm series of 80 patients with previously untreated malignant pleural
effusions from NSCLC. The patients had chest tubes placed and were given 25 mg of cisplatin in 500
mL of distilled water intrapleurally. Toxicity was acceptable. Median time of drainage was 4 days. A
total of 34% had a complete response and 49% had a partial response, for an overall response rate
of 83%. An interesting finding in this study was that the median survival time of all patients was 239
days, longer than typically seen in other series of comparable patients treated with pleurodesis. The
authors recommend a phase III study.
Chen et al, in Wenzhou, China, performed a prospective randomized study to evaluate the safety and
efficacy of combined intrapleural cisplatin and OK-432 with or without hyperthermic therapy in
patients with malignant pleural effusion. A total of 358 patients were randomized. The investigators
reported a significantly higher overall response (93% vs 79%) in patients treated with hyperthermic
therapy. Median survival time of patients was 8.9 months and 6.2 months, respectively, with versus
without hyperthermic therapy, with only mild toxicity reported.
Two important recent studies suggest that tissue obtained from malignant effusions may be useful in
implementation of a personalized approach to cancer treatment. Molecular methods can be
deployed in situations in which cellular tissue is unavailable or would require risky biopsy techniques.
Tsai et al, from the National Taiwan University Hospital, have observed that tumor tissue is often not
obtainable or suitable for molecular-based epidermal growth factor receptor (EGFR) mutational
analysis in NSCLC. They performed a retrospective evaluation of the role of effusion
immunocytochemistry using EGFR mutant–specific antibodies to detect relevant mutations in NSCLC
on the cell blocks of malignant pleural effusion from 78 patients with lung adenocarcinoma. They
report that their method exhibited a high sensitivity and specificity for mutations and comment that
effusion immunocytochemistry provides better prediction of tumor response and progression-free
survival with first-line EGFR tyrosine kinase inhibitors (TKIs) than clinical characteristics like sex and
smoking status. Patients whose effusion immunocytochemistry showed a reaction to either of the
two antibodies had a TKI response rate comparable to those with EGFR mutations assessed by direct
sequencing from cell-derived RNA. The investigators suggest that effusion immunocytochemistry
could be introduced into clinical practice to help identify NSCLC patients likely to benefit from
first-line TKI treatment, especially among those with inadequate tissue for molecular-based EGFR
analysis.
Guo et al, from Shandong China, studied the therapeutic effects of and adverse reactions from
treatment with erlotinib (Tarceva) for malignant pleural effusions caused by metastatic
adenocarcinoma. A total of 128 patients who had failed first-line chemotherapy were divided into
mutation and nonmutation groups according to the presence or absence of EGFR mutations. The
patients were treated with thoracoscopic TP and oral erlotinib. Short-term and long-term clinical
therapeutic effects of erlotinib were evaluated. The EGFR mutation rate of lung adenocarcinoma in
pleural metastasis tissue acquired through VATS was higher than that in surgical resection
specimens. The authors report a higher complete remission rate in the mutation group compared
with the nonmutation group. Overall survival time after erlotinib treatment in patients with EGFR
mutations was longer than that in patients without EGFR mutations. The authors comment that
“EGFR mutations predict a favorable outcome for malignant pleural effusion of lung carcinoma with
Tarceva therapy.” Japanese investigators demonstrated that a multiplex molecular profile identifies
genetic abnormalities in cells from approximately 40% of pleural effusions from patients with lung
cancer, including EGFR, EML4-ALK, KRAS and EGFR amplification, with a high concordance rate with
tissue samples.
Fluid from pleural effusions can also be studied in an attempt to identify mechanisms of acquired
resistance to targeted therapies, for example crizotinib for ALK-rearranged lung cancer.
Lombardi et al, from Padova, Italy, treated 18 patients with malignant pleural effusion secondary to
ovarian (11) and breast (7) cancers. Following pleural drainage, 120 mg/m2 paclitaxel in normal
saline was infused and the pleural catheter clamped and drained 24 hours later. Paclitaxel was
measured in blood and pleural fluid at 1, 4, and 24 hours. Chest radiographic surveillance at 1 and 2
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months showed an overall response rate of 78%; median overall survival was 8.9 months. Patients
with CR had longer survival. Intrapleural paclitaxel concentration was very high (478 mg/L) and
declined slowly over 24 hours. Plasma levels were low in most patients (.045 mg/L). The authors
concluded that intrapleural paclitaxel is safe and effective.
Sidebar: The role of VEGF and other angiogenic molecules are under active investigation as
modulators of pleural hyperpermeability and malignant pleural effusion. A number of studies have
demonstrated striking increases in VEGF levels in both blood and pleural fluid. This observation has
served as the basis for a number of anecdotal observations and small, early trials of the VEGF
antagonist bevacizumab, a humanized monoclonal antibody that binds to VEGF receptors and blocks
biological effects of VEGF, given systemically or intrapleurally. VEGF levels in blood and pleural fluid
fall in response to treatment and there has been gratifying control of MPE in a substantial
percentage of cases treated.
Tamiya et al, in Osaka, Japan, reported on a phase II study of bevacizumab with
carboplatin/paclitaxel in 23 patients with nonsquamous, non–small-cell lung cancer with malignant
pleural effusion (without prior pleurodesis). Carboplatin/paclitaxel was given only in the first cycle.
This was followed by 2 to 6 cycles of chemotherapy with bevacizumab, followed by continued
bevacizumab in responding patients. The overall response rate was 60%, and the disease control
rate was 87%. The median progression-free survival and overall survival times were 7.1 and 11.7
months, respectively. Plasma vascular endothelial growth factor (VEGF) levels in the effusion were
very high at 1,800 pg/mL, and decreased significantly after chemotherapy.
Du et al from Beijing, China conducted a randomized trial in 72 patients with NSCLC and malignant
pleural effusion with half of patients treated with intrapleural cisplatin (30 mg) vs intrapleural
cisplatin plus bevacizumab (300 mg) at 2-week intervals in addition to 3 cycles of conventional
chemotherapy. Control of pleural effusion was greater—83% vs 50%—in the bevacizumab arm.
Levels of VEGF messenger RNA were lower in pleural fluid of patients treated with bevacizumab.
Radiation. Radiation therapy may be indicated in some patients with lymphoma but has limited
effectiveness in other tumor types, particularly if mediastinal adenopathy is absent.
Chylothorax. Chylothorax (in the absence of trauma) is usually secondary to cancer, most
frequently lymphoma. An added element of morbidity is conferred by the loss of protein, calories,
and lymphocytes in the draining fluid. Initial treatment is with chest tube drainage and a medium
chain triglyceride diet. If chylous drainage persists then consideration of strict nothing-by-mouth
status and hyperalimentation may be needed. Although thoracic duct ligation is frequently
successful in benign chylothorax, there are few reports of its use for malignant effusions.
Chylothorax secondary to lymphoma is usually of low volume and responds to TP in combination with
radiotherapy or chemotherapy.
Gross et al, from Sao Paulo, Brazil, reported an overall survival rate of 5.6 months for patients with
simultaneous ascites and malignant pleural effusions vs 7.8 months in patients without ascites. They
observed that success rates for TP were equal and concluded that concomitant ascites did not
influence the effectiveness of palliative surgical management of pleural effusion in patients with
malignancies.
Research into quality of life and cost-effectiveness research has advanced in the last few years.
Cost-effectiveness analysis comparing long-term catheter drainage vs TP has not found one
approach to be significantly better than the other.
Puri et al, from Washington University at St. Louis, performed a decision analysis to compare
repeated thoracentesis, tunneled pleural catheter (TPC), bedside pleurodesis (BP), and thoracoscopic
pleurodesis (TP). They studied two scenarios: expected survival of 3 months and 12 months. The
incremental cost-effectiveness ratio (ICER) was estimated as least expensive with repeat
thoracentesis, in the case of 3-month survival. In comparison, the ICER with intrapleural catheter was
$6,450 vs $4,946, with expected survivals of 3 months and 12 months, respectively. Bedside TP
(about $11,000) and operative TP (a little over $18,000) were more expensive. The ICER for tunneled
pleural catheter over repeat thoracentesis was nearly $50,000. In the case of 12 month–long
survival, bedside TP was least expensive (about $13,000) and provided 0.59 quality-adjusted
life-years. IPC was approximately $150 more expensive, whereas TP cost $19,000 and repeat
thoracentesis was $21,000. They noted that thoracoscopic TP was more effective than bedside TP
but that ICER was greater than $250,000. They conclude that IPC treatment is preferable for patients
with malignant pleural effusion who have limited survival. Penz et al studied costs in Britain using
data from a clinical trial, and found no significant difference in cost between IPC and talc pleurodesis.
IPC treatment was slightly less expensive in patients with short survival.
In a study from Kiel, Germany, Schniewind et al reported on 45 of 123 patients with malignant
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pleural effusions treated with TP who completed quality of life EORTC (European Organisation for
Research and Treatment of Cancer) QLC C-30 questionnaires before and after treatment. The
authors reported that patients experienced statistically and clinically significant improvements in
functional scales throughout the study period, and noted that global health values increased after
surgery throughout the entire study period. They also noted “a clear decline in dyspnea upon
discharge, followed by a continuous remote increase throughout subsequent months.” The authors
conclude that pleurodesis reduces respiratory symptoms. Median survival in the patients who
completed the questionnaire was 10.2 months vs 7.5 months in patients who did not participate.
Basso et al, from Pordenone, Italy, studied 46 patients with malignant pleural effusion treated with
thoracoscopic TP (56% secondary to lung cancer). Chest tube drainage time averaged 9 days.
In-hospital mortality was 8%. Following pleurodesis, there was improvement in both Karnofsky scores
(4.2 to 2.7) and MRC (Medical Research Council, UK) scores (62 to 71). The authors concluded that
quality of life improved following thoracoscopic TP.
Sabur et al, from Calgary, Alberta, reported upon utilization of tunneled pleural catheters in 82
patients with malignant pleural effusions studied using EORTC QLQ-C30 and LC13 quality of life
scores at baseline, then at 2 and 14 weeks after catheter placement. Dyspnea improved at 2 weeks
(LC13, 64 to 44; C30, 79 to 47; MRC scores, 4.2 to 3) and improvement was maintained at 14 weeks
in survivors (55%).
Boshuizen, from Amsterdam, The Netherlands, did a cost analysis based upon direct analysis of data
from a prospectively collected database. They report that mean costs for intrapleural catheter use
were €2,173, which they noted is acceptable when compared with estimated hospitalization costs for
pleurodesis.
Summary
Treatment of malignant pleural effusion with either talc pleurodesis or indwelling pleural catheters
produces approximately equal results in terms of survival, control of recurrent effusion, improvement
in quality of life, and cost-effectiveness. The major advantage of tunneled pleural catheters is a
shorter time of hospitalization, which is counterbalanced by patient inconvenience in draining
effusions. Although there may be a small cost-effectiveness benefit for pleurodesis in patients with
prolonged survival, prediction of survival is not accurate enough to select a treatment method based
upon this consideration. Choice of treatment method should take patient preferences into careful
consideration.
Review of a number of small, early trials of intrapleural and systemic treatment following palliative
management of malignant pleural effusions with chemotherapy and/or targeted agents suggests to
us that there may be improved survival in patients with malignant pleural effusions treated with
systemic and/or intrapleural therapy with chemotherapeutic or targeted molecular agents. Further
investigations in this area are needed to confirm this impression.
Pericardial Effusion
Pericardial effusion develops in 5% to 15% of patients with cancer and is sometimes the initial
manifestation of malignancy. Most pericardial effusions in cancer patients result from obstruction of
the lymphatic drainage of the heart secondary to metastases. The typical presentation is that of a
patient with known cancer who is found to have a large pericardial effusion without signs of
inflammation. Bloody pericardial fluid is not a reliable sign of malignant effusion.
The most common malignant causes of pericardial effusions are lung and breast cancers, leukemias
(specifically acute myelogenous, lymphoblastic, and chronic myelogenous leukemia [blast crisis]),
and lymphomas. In one report from Kühn et al, at Children’s Hospital Boston, 39% of children with
moderate to large pericardial effusions had malignant effusions.
Not all pericardial effusions associated with cancer are malignant, and cases with negative cytology
may represent as many as half of cancer-associated pericardial effusions. Many effusions that
initially have negative cytology will become positive over time. Such effusions are more common in
patients with mediastinal lymphoma, Hodgkin lymphoma, or breast cancer. Other nonmalignant
causes include drug-induced (eg, sirolimus [Rapamune] or docetaxel) or postirradiation pericarditis,
tuberculosis, collagen diseases, uremia, and congestive heart failure. As reported by Fukada and
colleagues, pericardial effusions can be seen in up to 35% of patients after chemoradiotherapy for
esophageal cancer, but only 8% of patients will develop symptoms.
Tamponade occurs when fluid accumulates faster than the pericardium can stretch. Compression of
all four heart chambers ensues, with tachycardia and diminishing cardiac output. Fluid loading can
counteract intrapericardial pressure temporarily. Reciprocal filling of right- and left-sided chambers
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with inspiration and expiration, secondary to paradoxical movement of the ventricular septum, is a
final mechanism to maintain blood flow before death.
Diagnosis
A high index of suspicion is required to make the diagnosis of pericardial effusion.
Signs and symptoms
Dyspnea is the most common symptom, but it is very nonspecific. Patients may also complain of
chest pain or discomfort, easy fatigability, cough, and orthopnea, or they may be completely
asymptomatic. Signs include distant heart sounds, and pericardial friction rub. With cardiac
tamponade, progressive heart failure occurs, with increased shortness of breath, cold sweats,
confusion, hypotension, jugular venous distention, and pulsus paradoxus. Pulsus paradoxus is often
misunderstood as a “paradoxical” decrease in systolic blood pressure with inspiration. In fact,
decrease in systolic blood pressure is a normal physiologic phenomenon with inspiration but is
typically less than 10 mm Hg. If pulsus paradoxus is greater than 13 mm Hg, pericardial effusion
should be suspected.
Chest x-ray
Chest radiographic evidence of pericardial effusion includes cardiomegaly with a “water bottle”
heart; an irregular, nodular contour of the cardiac shadow; and mediastinal widening.
Electrocardiogram
ECG shows nonspecific ST- and T-wave changes, tachycardia, low QRS voltage, electrical alternans,
and atrial dysrhythmia.
Pericardiocentesis and echocardiography
An echocardiogram not only can confirm a suspected pericardial effusion but also can document the
size of the effusion and its effect on ventricular function. Vignon reported on the accuracy of
echocardiography performed by noncardiologist residents with limited training in an ICU and
concluded that brief and limited training of noncardiologist ICU residents with no prior training in
ultrasound methods appears “feasible and efficient” to address simple clinical questions about using
echocardiography and was specifically useful in the diagnosis of pleural and pericardial effusions. A
pericardial tap with cytologic examination (positive in 50% to 85% of cases with associated
malignancy) will confirm the diagnosis of malignant effusion or differentiate it from other causes of
pericardial effusion. Serious complications, including cardiac perforation and death, can occur during
pericardiocentesis, even when performed with echocardiographic guidance by experienced
clinicians.
Tumor markers/staining and cytogenetics
Tumor markers or special staining and cytogenetic techniques may improve the diagnostic yield, but
ultimately an open pericardial biopsy may be necessary. Szturmowicz et al, from Warsaw, Poland,
studied pericardial fluid carcinoembryonic antigen (CEA) and cytokeratin fragment (CYFRA) 21-1
levels in 84 patients with pericardial effusion. There were significant differences in patients with
malignant vs benign effusions with both tests. With cutoff points of > 100 ng/mL for CYFRA 21-1 and
> 5 ng/mL for CEA, 14 of 15 patients who had malignant pericardial effusion with negative cytologic
results had a positive result on one or both tests.
CT and MRI
CT and MRI as diagnostic adjuncts may provide additional information about the presence and
location of loculations or mass lesions within the pericardium and adjacent structures. Restrepo et al
have published a comprehensive, well-illustrated description of CT features of pericardial
tamponade.
Cardiac catheterization
This may occasionally be of value to rule out superior vena caval obstruction, diagnose
microvascular tumor spread in the lungs with secondary pulmonary hypertension, and document
constrictive pericarditis before surgical intervention. Right atrial and pulmonary capillary wedge
pressures may also be measured. In most cases of effusion, catheterization does not yield
information beyond the echocardiogram.
Pericardioscopy
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This allows visualization and biopsy at the time of subxiphoid or thoracoscopic pericardiotomy and
can improve the diagnostic yield.
Prognosis
In general, cancer patients who develop a significant pericardial effusion have a high mortality, with
a mean time to death of 2.2 to 4.7 months. However, about 25% of selected patients treated
surgically for cardiac tamponade enjoy a 1-year survival.
Investigators in Barcelona, Spain studied the effects of volume expansion in patients with large
pericardial effusions and pericardial tamponade. They administered 500 mL of normal saline over 10
minutes and measured hemodynamic and echocardiographic parameters. A total of 57% had
tamponade on physical examination, and 20% were hypotensive. Volume expansion resulted in
increases in mean arterial, intrapericardial, right atrial, and left ventricular end-diastolic pressures.
The cardiac index increased by > 10% in 47% of patients and remained unchanged in 22%, but
actually decreased in 31%. No patient had clinical complications. Predictors of improved
hemodynamics were a pressure below 100 mm Hg and a low cardiac index. Sagrista-Sauleda et al
reported in 2008 that in approximately half of patients with cardiac tamponade, particularly those
with low blood pressure, cardiac output will increase after volume overload. Therefore, the
administration of fluids should be guided by the patient’s clinical status rather than used routinely in
patients with suspected tamponade.
Treatment
General concepts
As is the case with malignant pleural effusion, it is difficult to evaluate treatments for pericardial
effusion because of the many variables. Because malignant pericardial effusion is less common than
malignant pleural effusion, it is more difficult to collect data in a prospective manner. Certain
generalizations can, however, be derived from available data:
• All cancer patients with pericardial effusion require a systematic evaluation and should not be
dismissed summarily as having an untreatable and/or terminal problem.
• Ultimately, both the management and natural course of the effusion depend on (1) the underlying
condition of the patient, (2) the extent of clinical symptoms associated with the cardiac compression,
and (3) the type and extent of the underlying malignant disease.
General treatment approaches
Asymptomatic, small effusions may be managed with careful follow-up and treatment directed
against the underlying malignancy. On the other hand, cardiac tamponade is a true oncologic
emergency. Immediate pericardiocentesis, under echocardiographic guidance, may be performed to
relieve the patient’s symptoms. A high failure rate is anticipated because the effusion rapidly recurs
unless steps are taken to prevent it. Therefore, a more definitive treatment plan should be made
following the initial diagnostic/therapeutic tap.
In patients with symptomatic, moderate-to-large effusions who do not present as an emergency,
therapy should be aimed at relieving symptoms and preventing recurrence of tamponade or
constrictive pericardial disease. Patients with tumors responsive to chemotherapy or radiation
therapy may attain longer remissions with appropriate therapy.
There are two theoretical mechanisms for control of pericardial effusion: (1) creation of a persistent
defect in the pericardium, allowing fluid to drain out and be reabsorbed by surrounding tissues; or
(2) sclerosis of the mesothelium, resulting in the formation of fibrous adhesions that obliterate the
pericardial cavity.
Postmortem studies have demonstrated that both of these mechanisms are operative. The fact that
effusions can recur implies that there is either insufficient damage to the mesothelial layer or that
rapid recurrence of effusion prevents coaptation of visceral and parietal pericardium and prevents
the formation of adhesions. This, in turn, would suggest that early closure of the pericardial defect
can result in recurrence.
Treatment methods. Various methods can be used to treat malignant pericardial effusion.
• Observation—Observation alone may be reasonable in the presence of small asymptomatic
effusions.
• Pericardiocentesis—Pericardiocentesis is useful in relieving tamponade and obtaining a diagnosis.
Echocardiographic guidance considerably enhances the safety of this procedure. About 90% of
pericardial effusions will recur within 3 months after pericardiocentesis alone.
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• Pericardiocentesis and percutaneous tube drainage—Pericardiocentesis and percutaneous tube
drainage can now be performed with low risk and are recommended by some clinical groups. Marcy
et al, of Nice, France, reviewed multiple, well-illustrated percutaneous methods for management of
malignant pericardial effusions. Problems that may occur include occlusion or displacement of the
small-bore tubes, dysrhythmia, recurrent effusion, and infections. Mayo Clinic cardiologists
recommend initial percutaneous pericardiocentesis with extended catheter drainage as their
technique of choice.
Kunitoh et al, from the National Cancer Center Hospital in Tokyo, performed a randomized controlled
trial in 80 patients who had undergone pericardial drainage for malignant pericardial effusion. These
patients were then randomized to either observation alone (A) after drainage or intrapericardial
bleomycin instillation (15 mg followed by 10 mg every 48 hours [B]). Drainage tubes were removed
when daily drainage was 20 mL or less. The results, published in 2009, showed that survival with
control of malignant pleural effusion at 2 months was 29% in arm A and 46% in arm B (P = .08); the
median survival was 79 days vs 119 days.
• Intrapericardial sclerotherapy and chemotherapy—Intrapericardial sclerotherapy and
chemotherapy following percutaneous or open drainage have been reported to be effective
treatments by some groups. Problems include pain during sclerosing agent treatments and
recurrence of effusions. Good results have been reported with instillation of a number of agents,
including bleomycin (10 mg), cisplatin (30 mg), mitomycin (2 mg), thiotepa (1.5 mg), and
mitoxantrone (10 to 20 mg). Agents are selected based on their antitumor or sclerosing effect.
Martinoni et al, from Milan, Italy, reported on the use of intrapericardial administration of thiotepa
(15 mg on days 1, 3, and 5) following placement of a pericardial drainage catheter in 33 patients
with malignant pericardial effusion. There were three recurrent effusions (9.1%). The median survival
time was 115 days. They concluded that this protocol is safe, well tolerated, and improves the
quality and duration of life.
• Pericardiocentesis and prolonged catheter drainage—Simple pericardiocentesis alone has
unacceptable recurrence rates of up to 90%. However, using a guidewire, a pigtail catheter may be
inserted into the pericardial space and left in place until the drainage becomes minimal.
Percutaneous catheter drainage has a low complication rate, but higher rates of recurrence than
pericardial window. In their experience with 246 patients, McDonald and colleagues reported a 16.5
% rate of recurrent symptomatic effusion after percutaneous catheter drainage vs 5% after
pericardial window. However, for patients with malignant effusions and limited life expectancy,
results may be comparable, as recently reported by Patel and others.
• Balloon pericardial window—After percutaneous placement of a guidewire following
pericardiocentesis, a balloon-dilating catheter can be placed across the pericardium under
fluoroscopic guidance and a window created by balloon inflation.
At the National Taiwan University, cardiologists performed percutaneous double-balloon
pericardiotomy in 50 patients with cancer and pericardial effusion and followed their course using
serial echocardiograms. Success without recurrence was achieved in 88%. Fifty percent of patients
died within 4 months, and 25% survived to 11 months.
Sidebar: Ruiz-García et al, from Madrid, Spain, treated 16 patients with malignant pericardial
effusions, using percutaneous balloon pericardiotomy as the initial and definitive treatment. All
patients had been hemodynamically compromised on echocardiography. There were no acute
complications and all cases were initially successful. There were three later failures, requiring two
pericardial window surgeries and one repeat percutaneous balloon pericardiotomy. The authors
consider percutaneous balloon pericardiotomy to be a simple, safe technique that can be effective in
preventing recurrence in many patients with severe malignant pericardial effusion (Ruiz-García J et
al: Rev Esp Cardiol 66:357–363, 2013).
• Subtotal pericardial resection—Subtotal pericardial resection is seldom performed today. Although
it is the definitive treatment, in that there is almost no chance of recurrence or constriction, higher
morbidity and longer recovery time render this operation undesirable in patients who have a short
anticipated survival time. Its use is restricted to patients with good prognosis and constrictive
pericarditis rather than pericardial effusion.
• Limited pericardial resection—Limited pericardial resection (pericardial window) via anterior
thoracotomy, thoracoscopic, or subxiphoid approach has a low morbidity. There is a low risk of
recurrence. Cardiac herniation is possible if the size of the opening in the pericardium is not carefully
controlled. A pericardial drain is typically placed at the time of the procedure. If necessary, a
sclerosing agent may also be administered. Subxiphoid pericardial window may be performed with
the under local anesthesia or combined with endoscopic instrumentation.
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At City of Hope, Cullinane et al reported on 62 patients with malignant disease who had a surgical
pericardial window created for management of pericardial effusion. Windows were created either
thoracoscopically (32) or by subxiphoid (12) or limited thoracotomy (18) approaches. Primary tumors
included NSCLC, breast, hematologic, and other solid-organ malignancies. Three recurrent effusions
(4.8%) required reoperations. Eight patients (13%) died during the same admission as their surgical
procedure. The median survival was much shorter for patients with NSCLC (2.6 months) than for
patients with breast cancer (11 months) or hematologic malignancy (10 months). The surgical
pericardial window is a safe and durable operative procedure that may provide extended survival in
certain subgroups of cancer patients.
• Development of a subxiphoid pericardioperitoneal window—Development of a subxiphoid
pericardioperitoneal window through the fused portion of the diaphragm and pericardium allows
continued drainage of pericardial fluid into the peritoneum. This may be done laparoscopically in
stable patients, but we advise caution. As described in a case series by Romano and Glass, carbon
dioxide pneumoperitoneum may adversely affect the cardiopulmonary hemodynamics due to
increased intra-abdominal pressure, caval compression, and decreased venous return. There will also
be increased afterload. In addition, there is the potential for prolonged hypercarbia, acidosis, and
hypoxemia.
Toth et al, from Miskolc, Hungary, reported in 2012 on a new technical method using a Chamberlain,
parasternal mediastinoscopic approach to create a pericardial window in 22 patients with malignant
pericardial effusions. There were no operative deaths, and one patient (4.5%) experienced
recurrence of a pericardial effusion.
• Technical factors—Prior pleurodesis for malignant pleural effusion makes an ipsilateral transpleural
operation difficult or impossible. In lung cancer patients, major airway obstruction may preclude
single-lung anesthesia and, thus, thoracoscopic pericardiectomy. Prior median sternotomy may
prohibit the use of a subxiphoid approach.
• Complications—A 30-day mortality rate of 10% or higher has been reported for all of these
modalities but is related more to the gravity of the underlying tumor and its sequelae. A small
percentage of patients will develop severe problems with pulmonary edema or cardiogenic shock
following pericardial decompression. The mechanisms of these problems are poorly understood.
Wagner et al, from Memorial Sloan-Kettering Cancer Center, retrospectively studied 179 consecutive
pericardial windows for malignant effusions over a 5-year period. These included lung (44%), breast
(20%), hematologic (10%), and gastrointestinal cancers (7%). The overall survival of the whole group
was poor, with a median of 5 months survival. They defined paradoxical hemodynamic instability
(PHI) as hypotension and shock in the immediate postoperative period. PHI occurred in 19 (11%) of
patients. Patients most likely to have PHI showed evidence of tamponade on echocardiogram (89%
vs 56% without tamponade; P = .005), had a positive cytology or pathology (68% vs 41%; P = .03),
and had larger volumes drained. Most important, 58% of patients with paradoxical hemodynamic
instability did not survive the initial hospitalization.
Late neoplastic pericardial constriction can occur following initially successful partial
pericardiectomy. Patients with combined malignant pericardial and pleural effusions will often have
relief of recurrent pleural effusion following control of pericardial effusion, perhaps because reducing
systemic venous pressure results in reduced production of pleural fluid. Simultaneous pleurodesis in
the left side of the chest following a pericardial window procedure might increase the incidence of
recurrent pericardial effusion and should be avoided.
• Radiotherapy—External-beam irradiation is utilized infrequently in this clinical setting but may be
an important option in specialized circumstances, especially in patients with radiosensitive tumors
who have not received prior radiation therapy. Responses ranging from 66% to 93% have been
reported with this form of treatment, depending on the type of associated tumor.
• Chemotherapy—Systemic chemotherapy is effective in treating pericardial effusions in patients
with lymphomas, hematologic malignancies, or breast cancer. Long-term survival can be attained in
these patients. If the pericardial effusion is small and/or asymptomatic, invasive treatment may be
omitted in some of these cases. Data are limited regarding the effectiveness of systemic
chemotherapy or chemotherapy delivered locally in prevention of recurrent pericardial and pleural
effusion. Several studies have reported on the effectiveness of intrapericardial instillation of
chemotherapy (most commonly cisplatin) for the treatment of malignant effusion. It is unclear
whether the results are due to cytotoxic effect on malignant cells or the sclerosing effect of the
drugs.
Biologic therapy with various agents is in the early stages of investigation.
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Malignant Ascites
Malignant ascites results when there is an imbalance in the secretion of proteins and cells into the
peritoneal cavity and absorption of fluids via the lymphatic system. Greater capillary permeability as
a result of the release of cytokines by malignant cells increases the protein concentration in the
peritoneal fluid. Recently, several studies have demonstrated higher levels of VEGF, a cytokine
known to cause capillary leak, in the sera and effusions of patients with malignancies.
Signs and Symptoms
Patients with malignant ascites usually present with anorexia, nausea, respiratory compromise, and
immobility. Complaints of abdominal bloating, heaviness, and ill-fitting clothes are common. Weight
gain despite muscle wasting is a prominent sign.
Diagnosis
A malignant etiology accounts for only 10% of all cases of ascites. Nonmalignant diseases causing
ascites include liver failure, congestive heart failure, and occlusion of the inferior vena cava or
hepatic vein. About one-third of all patients with malignancies will develop ascites. Malignant ascites
has been described with many tumor types but is most commonly seen with gynecologic neoplasms
(~50%), gastrointestinal malignancies (20% to 25%), and breast cancer (10% to 18%). In 15% to
30% of patients, the ascites is associated with diffuse carcinomatosis of the peritoneal cavity.
Physical examination
Physical examination does not distinguish whether ascites is due to malignant or benign conditions.
Patients may have abdominal fullness with fluid wave, anterior distribution of the normal abdominal
tympany, and pedal edema. Occasionally, the hepatic metastases or tumor nodules studding the
peritoneal surface can be palpated through the abdominal wall, which has been altered by ascitic
distention.
Radiologic studies
Radiographs. Ascites can be inferred from plain radiographs of the abdomen. Signs include a
ground-glass pattern and centralization of the intestines and abdominal contents.
Ultrasonography. Abdominal ultrasonography has been shown to be the most sensitive, most
specific method for detecting and quantifying ascites. It also permits delineation of areas of
loculation.
Success at removing peritoneal fluid in patients was markedly better with ultrasonographic
assistance, as demonstrated in a randomized trial by Nazeer et al. Ultrasonography improved the
physicians’ ability to aspirate ascites from 67% (27 of 44 patients) to 95% (40 of 42 patients).
CT. Abdominal and pelvic CT is effective in detecting ascites. In addition, CT scans may demonstrate
masses, mesenteric stranding, omental studding, and diffuse carcinomatosis. Use of IV and oral
contrast agents is necessary, thus increasing the degree of invasiveness of this modality.
Paracentesis. After the diagnosis of peritoneal ascites has been made on the basis of the physical
examination and imaging, paracentesis should be performed to characterize the fluid. The color and
nature of the fluid often suggest the diagnosis. Malignant ascites can be bloody, opaque, chylous, or
serous. Benign ascites is usually serous and clear.
Analysis of the fluid should include cell count, cytology, LDH level, proteins, and appropriate
evaluation for infectious etiologies. In addition, the fluid can be sent for the determination of tumor
markers, such as CEA, CA-125, p53, and human chorionic gonadotropin-β (hCG-β). The hCG-β level is
frequently elevated in malignancy-related ascites and has been combined with cytology to yield an
89.5% efficiency in diagnosis. The use of DNA ploidy indices, Decker et al found, allowed a 98.5%
sensitivity and a 100% sensitivity in the identification of malignant cells within ascitic fluid. The use
of the telomerase assay, along with cytologic evaluation of the ascitic fluid contents, Li et al
reported, has a 77% sensitivity in detecting malignant ascites.
Laparoscopy. Several studies have utilized minimally invasive laparoscopy as the diagnostic tool of
choice. The fluid can be drained under direct visualization, the peritoneal cavity can be evaluated
carefully, and any suspicious masses can be biopsied at the time of the laparoscopy.
Prognosis
The presence of ascites in a patient with malignancy often portends end-stage disease. The median
survival after the diagnosis of malignant ascites ranges from 7 to 13 weeks. Patients with
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gynecologic and breast malignancies have a better overall prognosis than patients with
gastrointestinal malignancies.
Treatment
Medical therapy
Traditionally, the first line of treatment is medical management. Medical therapies include repeated
paracentesis, fluid restriction, diuretics, chemotherapy, and intraperitoneal sclerosis.
Repeated paracentesis
Repeated paracentesis, probably the most frequently employed treatment modality, provides
significant symptomatic relief in the majority of cases. The procedure is minimally invasive and can
be combined with abdominal ultrasonography to better localize fluid collections. High-volume
paracentesis has been performed without inducing significant hemodynamic instability and with
good patient tolerance.
After paracentesis, 78% of all patients reported relief of their symptoms, especially in the areas of
abdominal bloating, anorexia, dyspnea, insomnia, and fatigue. In addition, overall quality of life
improved after paracentesis.
Significant morbidity occurs with repeated taps and becomes more severe with each tap necessary
to alleviate symptoms. Ascitic fluid contains a high concentration of proteins. Routine removal of
ascites further depletes protein stores. The removal of large volumes of fluid also can result in
electrolyte abnormalities and hypovolemia. In addition, complications can result from the procedure
itself. They include hemorrhage, injury to intra-abdominal structures, peritonitis, and bowel
obstruction. Contraindications to repeated paracentesis are viscous loculated fluid and hemorrhagic
fluid.
With the placement of an intraperitoneal port, used also for the instillation of intraperitoneal
chemotherapy, removal of ascitic fluid is possible without the need for repeated paracentesis. Other
possible catheters for use in repeated paracentesis include PleurX and Tenckoff catheters (used for
intraperitoneal dialysis). Placement of a semipermanent catheter minimizes the risk of injury to
intra-abdominal structures. However, the benefits are tempered by increased infectious risks as well
as the possibility of a nonfunctioning catheter requiring removal and replacement.
An analysis of the efficacy and cost-effectiveness of PleurX catheter drainage in treatment-resistant,
recurrent malignant ascites was performed in the United Kingdom for the National Institute for
Health and Care Excellence. The study, reported in 2012 by White and Carolan-Rees, concluded that
use of the PleurX catheter in this population was clinically effective, with low complication rates. In
addition, the use of PleurX was associated with improved quality of life and decreased overall cost
when compared with serial paracentesis.
Diuretics and restriction of fluid and salt. Unlike ascites from benign causes such as cirrhosis
and congestive heart failure, malignant ascites responds poorly to fluid restriction, decreased salt
intake, and diuretic therapy. The most commonly used diuretics (in patients who may have some
response to diuretic treatment) are spironolactone (Aldactone) and amiloride (Midamor). Patients
with massive hepatic metastases are most likely to benefit from spironolactone.
The onset of action for spironolactone is delayed (3–4 days), whereas the effects of amiloride are
seen after 24 hours. The most common complications associated with these diuretics are painful
gynecomastia, renal tubular acidosis, and hyperkalemia.
Chemotherapy. Chemotherapy, both systemic and intraperitoneal, has had some success in the
treatment of malignant ascites. The most commonly used agents are cisplatin and mitomycin.
Intraperitoneal hyperthermic chemotherapy has been used with some efficacy in gastrointestinal
malignancies to decrease recurrence of ascites as well as to prevent the formation of ascites in
patients with peritoneal carcinomatosis.
Sclerotherapy. Sclerosing agents include bleomycin (60 mg/50 mL of normal saline) and talc (5
g/50 mL of normal saline). Responses are seen in ~30% of patients treated with these agents.
Theoretically, intraperitoneal chemotherapy and sclerosis obliterate the peritoneal space and
prevent future fluid accumulation. If sclerosis is unsuccessful, it may produce loculations and make
subsequent paracentesis difficult.
Other therapies. Approved for use to treat malignant ascites in the European Union since 2009,
catumaxomab (Removab) is a trifunctional antibody specific for epithelial cell adhesion molecule
(EPCAM) on tumor cells, CD3 antigen on T cells, and the Fc regions on accessory cells such as
macrophages, dendritic cells, and natural killer cells. A phase II/III clinical trial demonstrated efficacy
of the antibody, given as intraperitoneal infusions, in decreasing the number of and timing between
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paracentesis sessions needed to control the volume and symptoms of malignant ascites.
Catumaxomab is being studied in a randomized phase IIIb trial to improve on the dosing regimen of
the antibody in patients with EPCAM+ epithelial carcinomas. The study is ongoing and results are
pending.
Experimental models and early clinical trials have shown that an intraperitoneal bolus of tumor
necrosis factor (45–350 μg/m2) given weekly may be effective in resolving malignant ascites. Other
cytokines, including interferon-α, have had various degrees of success. A randomized, prospective
trial definitively addressing the role of cytokines and other biologic treatments in the management of
malignant ascites has yet to be completed. Intraperitoneal injection of antibodies directed at VEGF
has shown promise in decreasing ascites in early-phase clinical trials, but further studies are needed.
Aflibercept (Zaltrap) has demonstrated the ability to reduce formation of ascites in preclinical models
of epithelial ovarian cancer (EOC), as well as in patients with advanced EOC. Aflibercept, a potent
angiogenesis inhibitor fusion protein, comprises portions of human VEGF receptor R1+R2 (Flt-1, KDR)
extracellular domains fused to the Fc-portion of human IgG. Aflibercept binds VEGF-A and neutralizes
all VEGF-A isoforms plus placental growth factor.
A randomized, phase II study by Gotlieb et al determined the efficacy of intravenous aflibercept in
the management of symptomatic malignant ascites from ovarian cancer. A total of 26 patients
received placebo and 29 patients were treated. Mean time to paracentesis was longer in the
aflibercept arm (55.1 days) than in the placebo arm (23.3 days). Side effects included dypsnea,
fatigue, dehydration, and bowel perforation.
Surgical techniques
Limited surgical options are available to treat patients who have refractory ascites after maximal
medical management, demonstrate a significant decrease in quality of life as a result of ascites, and
have a life expectancy of > 3 months.
Peritoneovenous shunts. These have been used since 1974 for the relief of ascites associated
with benign conditions. In the 1980s, shunting was applied to the treatment of malignant ascites.
The LeVeen shunt contains a disc valve in a firm polypropylene casing, whereas the Denver shunt
has a valve that lies within a fluid-filled, compressible silicone chamber. Both valves provide a
connection between the peritoneal cavity and venous system that permits the free flow of fluid from
the peritoneal cavity when a 2- to 4-cm water pressure gradient exists.
Success rates vary with shunting, depending on the nature of the ascites and the pathology of the
primary tumor. Patients with ovarian cancer, for example, do very well, with palliation achieved in ≥
50% of cases. However, ascites arising from gastrointestinal malignancies is associated with a poorer
response rate (10% to 15%).
Candidates for shunt placement should be carefully selected. Cardiac and respiratory evaluations
should be performed prior to the procedure. Shunt placement is contraindicated in the presence of
the following:
• a moribund patient whose death is anticipated within weeks
• peritonitis
• major organ failure
• adhesive loculation
• thick, tenacious fluid.
Complications of shunting. Initial concerns about the use of a shunt in the treatment of malignant
ascites centered on intravascular dissemination of tumor. In practice, there has been little difference
in overall mortality in patients with and without shunts.
Disseminated intravascular coagulation. During the early experience with shunting, particularly
in cirrhotic patients, symptomatic clinical disseminated intravascular coagulation (DIC) developed
rapidly and was a major source of morbidity and mortality. However, overwhelming DIC occurs
infrequently in the oncologic population.
The pathophysiology of DIC has been studied extensively and is thought to be multifactorial. The
reinfusion of large volumes of ascitic fluid may cause a deficiency in endogenous circulating
coagulation factors by dilution. Secondarily, a fibrinolytic state is initiated by the introduction of
soluble collagen (contained within the ascitic fluid) into the bloodstream, leading to a DIC state.
Infrequently, full-blown DIC is the result and requires ligation of the shunt or even shunt removal.
Discarding 50% to 70% of the ascitic fluid before establishing the peritoneovenous connection may
prevent this complication but may increase the risk of early failure due to a reduced initial flow rate.
Commonly, coagulation parameters are abnormal without signs or symptoms. In some institutions,
these laboratory values are so consistently abnormal that they are used to monitor shunt patency.
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Abnormalities most commonly seen include decreased platelets and fibrinogen and elevated
prothrombin time, partial thromboplastin time, and fibrin split products.
Other common complications include shunt occlusion (10%–20%), heart failure (6%), ascitic leak
from the insertion site (4%), infection (< 5%), and perioperative death (10% to 20% when all
operative candidates are included).
Shunt patency may be indirectly correlated with the presence of malignant cells. One study found
that patients with positive cytology results had a 26-day shunt survival, as compared with 140 days
in patients with negative cytology results. Other studies have failed to demonstrate a correlation
between ascites with malignant cells and decreased survival.
Clearly, shunting is not a benign procedure, but in carefully selected patients who have not
responded to other treatment modalities and who are experiencing symptoms from ascites, it may
provide needed palliation. Because of the limited effectiveness of peritoneovenous shunts, patients
should be carefully selected prior to shunt placement.
Radical peritonectomy. Other surgical procedures used to treat malignant ascites have been
proposed. They include radical peritonectomy combined with intraperitoneal chemotherapy. This is
an extensive operation with significant morbidity, although initial results appear to demonstrate that
it decreases the production of ascites. To date, no randomized trial has demonstrated that radical
peritonectomy increases efficacy or survival. However, there is an emerging body of literature
supporting use of intraperitoneal chemotherapy in the management of malignant ascites. Although
different chemotherapeutic agents have been studied for intraperitoneal use, Mitomycin-C is most
often used.
Combined fluid complications. Combinations of pleural and pericardial effusion, ascites and
pleural effusion, or even ascites combined with pleural and bilateral pleural effusion are not
uncommon. Management is complex in these cases, and in the authors’ experience, survival is more
limited.
Management of patients with ovarian cancer, ascites, and pleural effusion is particularly challenging.
Two reports published in 2010 are illustrative.
Kim et al, from Seoul National University College of Medicine, Korea, studied 38 patients with ovarian
cancer with pleural effusion on CT scan who had undergone thoracentesis before treatment. The
investigators assessed the amount of ascites and pleural effusion, as well as lymph node
enlargement and presence of pleural nodules or thickening. A total of 16 patients (42%) had a
malignant pleural effusion. In patients with malignant pleural effusion, the volumes of pleural
effusions were larger than in those with nonmalignant effusions. Pleural nodules were found more
frequently in the malignant group (50% vs 0%). Supradiaphragmatic lymph node enlargement also
was more frequent in the malignant group (25% vs 9%). The investigators concluded that the
probability of malignant pleural effusion was correlated with the volume of pleural effusion, the
presence of pleural nodules, and supradiaphragmatic lymph node enlargement on CT.
Diaz et al, from Memorial Sloan Kettering Cancer Center, performed VATS of pleural effusions in
patients with advanced ovarian cancer. They studied 42 patients with a median age of 58 years and
a median CEA-125 of 1,747 units/mL. Effusions were right-sided in 30 patients (71%). Macroscopic
pleural disease was found in 29 (69%) of patients. Of 11 patients with negative cytology,
macroscopic pleural disease was found in 4 (36%). Six of 18 patients had intrathoracic cytoreductive
surgery after VATS. A total of 29 of 42 patients (69%) underwent attempted primary abdominal
surgical debulking. VATS investigation prompted changes in management in 43% of cases.
Suggested Reading
On Malignant Pleural Effusion
Akamatsu H, Koh Y, Kenmotsu H, et al: Multiplex molecular profiling of lung cancer using pleural
effusion. J Thorac Oncol 9:1048–1052, 2014.
Balassoulis G, Sichletidis L, Spyratos D, et al: Efficacy and safety of erythromycin as sclerosing
agent in patients with recurrent malignant pleural effusion. Am J Clin Oncol 31:384–389, 2008.
Basso SM, Mazza F, Marzano B, et al: Improved quality of life in patients with malignant pleural
effusion following videoassisted thoracoscopic talc pleurodesis. Preliminary results. Anticancer Res
32:5131–5134, 2012.
Bhattacharya S, Bairagya TD, Das A, et al: Closed pleural biopsy is still useful in the evaluation
of malignant pleural effusion. J Lab Physicians 4:35–38, 2012.
Boshuizen RC, Onderwater S, Burgers SJ, et al: The use of indwelling pleural catheters for the
management of malignant pleural effusion - direct costs in a Dutch hospital. Respiration 86:224–228,
Page 18 of 22
Fluid Complications
Published on Cancer Network (http://www.cancernetwork.com)
2013.
Boshuizen RC, Sinaasappel M, Vincent AD, et al: Pleural pressure swing and lung expansion
after malignant pleural effusion drainage: the benefits of high-temporal resolution pleural
manometry. J Bronchology Interv Pulmonol 20:200–205, 2013.
Bradshaw M, Mansfield A, Peikert T: The role of vascular endothelial growth factor in the
pathogenesis, diagnsosis and treatment of malignant pleural effusion. Curr Oncol Rep 15:207–216,
2013.
Bugalho A, Ferreira D, Dias SS, et al: The diagnostic value of transthoracic ultrasonographic
features in predicting malignancy in undiagnosed pleural effusions: A prospective observational
study. Respiration 87:270–278, 2014.
Cavanna L, Mordenti P, Berte R, et al: Ultrasound guideance reduces pneumothorax rate and
improves safety of thoracentesis in malignant pleural effusion: Report on 445 consecutive patients
with advanced cancer. World J Surg Oncol 12:139, 2014.
Chen WJ, Yuan SF, Yan QY, et al: Intrapleural chemo- and hyperthermotherapies for malignant
pleural effusion: A randomized prospective study. Cancer Invest 30:126–130, 2012.
Clive AO, Kahan BC, Hooper CE, et al: Predicting survival in malignant pleural effusion:
Development and validation of the LENT prognostic score. Thorax 69:1098–1104, 2014.
Damianovich M, Siloni GH, Barshack I, et al: Structural basis for hyperpermeability of tumor
vessels in advanced lung adenocarcinoma complicated by pleural effusion. Clin Lung Cancer
14:688–698, 2013.
Davies HE, Mishra EK, Kahan BC, et al: Effect of an indwelling pleural catheter vs chest tube and
talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: The TIME2
randomized controlled trial. JAMA 307:2383–2389, 2012.
Davies HE, Nicholson JE, Rahman NM, et al: Outcome of patients with nonspecific
pleuritis/fibrosis on thoracoscopic pleural biopsies. Eur J Cardiothorac Surg 38:472–477, 2010.
Dresler CM, Olak J, Herndon JE 2nd, et al: Phase III intergroup study of talc poudrage vs talc
slurry sclerosis for malignant pleural effusion. Chest 127:909–915, 2005.
Du N, Li X, Li F, et al: Intrapleural combination therapy with bevacizumab and cisplatin for
non-small cell lung cancer-mediated malignant pleural effusion. Oncol Rep 29:2332–2340, 2013.
Du Rand I, Maskell N, eds: British Thoracic Society Pleural Disease Guideline 2010. Thorax
65(Suppl 2):ii1–ii76, 2010.
Fiorelli A, Santini M: In lung cancer patients where a malignant pleural effusion is found at
operation could resection ever still be justified? Interact Cardiovasc Thorac Surg 17:407–412, 2013.
Freeman RK, Ascioti AJ, Mahidhara RS: A propensity-matched comparison of pleurodesis or
tunneled pleural catheter in patients undergoing diagnostic thoracoscopy for malignancy. Ann
Thorac Surg 96:259–263, 2013.
Fysh ET, Tan SK, Read CA, et al: Pleurodesis outcome in malignant pleural mesothelioma. Thorax
68:594–596, 2013.
Galbis JM, Mata M, Guijarro R, et al: Clinical-therapeutic management of thoracoscopy in pleural
effusion: A groundbreaking technique in the twenty-first century. Clin Transl Oncol 13:57–60, 2011.
Gonzalez AV, Bedwada V, Beamis JF Jr, et al: Lung injury following thoracoscopic talc
insufflation: Experience of a single North American center. Chest 137:1375–1381, 2010.
Guo H, Wan Y, Tian G, et al: EGFR mutations predict a favorable outcome for malignant pleural
effusion of lung adenocarcinoma with Tarceva therapy. Oncol Rep 27:880–890, 2012.
Gross JL, Disanzio TG, Younes RN, et al: Do concomitant ascites influence the effectiveness of
palliative surgical management of pleural effusion in patients with malignancies? World J Surg
33:266–271, 2009.
Hooper C, Laurence I, Harvey J, et al: The role of CT pulmonary angiography in the investigation
of unilateral pleural effusions. Respiration 87:26-31, 2014.
Hsu LH, Soong TC, Feng AC, et al: Intrapleural urokinase for the treatment of loculated malignant
pleural effusions and trapped lungs in medically inoperable cancer patients. J Thorac Oncol
1:460–467, 2006.
Kakuda JT, Karamanoukian R, Grannis FW Jr: The utility and safety of an indwelling catheter
system (PleurX) to manage malignant pleural effusions. Chest 122:165s, 2002.
Kaneda M, Yokoi K, Ito S, et al: The value of pleural lavage cytology examined during surgery for
primary lung cancer. Eur J Cardiothorac Surg 41:1335–1341, 2012.
Kim S, Kim TM, Kim DW, et al: Heterogeneity of genetic changes associated with acquired
crizotinib resistance in ALK-arranged lung cancer. J Thorac Oncol 8:415–422, 2013.
Lee P, Light R: Point/Counterpoint Editorials. Should thoracoscopic talc pleurodesis be the first
Page 19 of 22
Fluid Complications
Published on Cancer Network (http://www.cancernetwork.com)
choice management for malignant effusion? Chest 142:15–21, 2012.
Letovanec I, Allenbach G, Mihaescu A, et al: 18F-fluorodeoxyglucose PET/CT findings in pleural
effusions of patients with known cancer. A cytopathological correlation. Nuklearmedizin 51:186–193,
2012.
Lombardi G, Nicoletto MO, Gusella M, et al: Intrapleural paclitaxel for malignant pleural effusion
from ovarian and breast cancer: A phase II study with pharmacokinetic analysis. Cancer Chemother
Pharmacol 69:781–787, 2012.
Marshall MB, Choong CKC, eds: Management of benign and malignant pleural effusions
[monograph]. Thorac Surg Clin 23:1–101, 2013.
Metintas M, Ak G, Dundar E, et al: Medical thoracoscopy vs CT scan-guided Abrams pleural
needle biopsy for diagnosis of patients with pleural effusions: a randomized, controlled trial. Chest
137:1362–1368, 2010.
Morgensztern D, Waqar S, Subramanian J, et al: Prognostic impact of malignant pleural
effusion at presentation in patients with metastatic non-small-cell lung cancer. J Thorac Oncol
7:1485–1489, 2012.
Ost DE, Jiminez CA, Lei X, Cantor SB, et al: Quality-adjusted survival following treatment of
malignant pleural effusions with indwelling pleural catheters. Chest 2014;145:1347-56.
Penz ED, Mishra EK, Davies HE, Manns BJ, Miller RF, Rahman NM. Comparing cost of indwelling
catheter vs. talc pleurodesis for malignant effusion. Chest 2014; 146:991-1000.
Pichelmayer o, Gruenberger B, Zielinski C, Raderer M. Bevacizumab is active in malignant effusion.
Ann Oncol 2006, 17:1853.
Puri V, Pyrdeck TK, Crabtree TD, et al: Treatment of malignant pleural effusion: A
cost-effectiveness analysis. Ann Thorac Surg 94:374–380, 2012.
Rintoul RC, Ritchie AJ, Edwards JG, et al; MesoVATS Collaborators: Efficacy and cost of
video-assisted thoracoscopic partial pleurectomy versus talc pleurodesis in patients with malignant
pleural mesothelioma (MesoVATS): an open-label, randomised, controlled trial. Lancet 2014
;384:1118-27.
Ryu HJ, Lee SN, Memon A, Lee SK, et al: Prognostic impact of minimal pleural effusion in
non-small-cell lung cancer. J Clin Oncol 2014;32:960-7.
Sabur NF, Chee A, Stather DR, et al: The impact of tunneled pleural catheters on the quality of
life of patients with malignant pleural effusions. Respiration 85:36–42, 2013.
Sakr L, Maldonado F, Greillier L, et al: Thoracoscopic assessment of pleural tumor burden in
patients with malignant pleural effusion: prognostic and therapeutic implications. J Thorac Oncol
6:592–597, 2011.
Sarkar S, Bhattacharya G, Bhattacharjee S, et al: A drop of hydrogen peroxide can differentiate
exudative pleural effusion from transudate--development of a bedside screening test. Clin Chim Acta
405:83–86, 2009.
Schneider T, Reimer P, Storz K, et al: Recurrent pleural effusion: Who benefits from a tunneled
pleural catheter? Thorac Cardiovasc Surg 57:42–46, 2009.
Schniewind B, Rose T, Woltmann N, et al: Clinical outcomes and health-related quality of life
after thoracoscopic talc pleurodesis. J Palliat Med 15:37–42, 2012.
Stathopoulos GT, Kalomenidis I: Malignant pleural effusion: Tumor-host interactions unleashed.
Am J Respir Crit Care Med 186:487-492, 2012.
Steger V, Mika U, Toomes H, et al: Who gains most? A 10-year experience with 611
thoracoscopic talc pleurodeses. Ann Thorac Surg 83:1940–1945, 2007.
Tamiya M, Tamiya A, Yamadori T, et al: Phase 2 study of bevacizumab with
carboplatin-paclitaxel for non-small cell lung cancer with malignant pleural effusion. Med Oncol
30:676, 2013.
Tan C, Sedrakyan A, Browne J, et al: The evidence on the effectiveness of management for
malignant pleural effusion: A systematic review. Eur J Cardiothorac Surg 29: 829–838, 2006.
Thornton RH, Miller Z, Covey AM, et al: Tunneled pleural catheters for treatment of recurrent
malignant pleural effusion following failed pleurodesis. J Vasc Interv Radiol 21:696–700, 2010.
Tremblay A, Mason C, Michaud G: Use of tunnelled pleural catheters for malignant pleural
effusions in patients fit for pleurodesis. Eur Respir J 30:759–762, 2007.
Tsai TH, Wu SG, Chang YL, et al: Effusion immunocytochemistry as an alternative approach for
the selection of first-line targeted therapy in advanced lung adenocarcinoma. J Thorac Oncol
7:993–1000, 2012.
Vignon P, Dugard A, Abraham J, et al: Focused training for goal-oriented hand-held
echocardiography performed by noncardiologist residents in the intensive care unit. Intensive Care
Page 20 of 22
Fluid Complications
Published on Cancer Network (http://www.cancernetwork.com)
Med 33:1795–1799, 2007.
Warren WH, Kalimi R, Khodadadian LM, et al: Management of malignant pleural effusions using
the Pleur (x) catheter. Ann Thorac Surg 85:1049–1055, 2008.
William WN Jr, Lin HY, Lee JJ, et al: Revisiting stage IIIB and IV non-small cell lung cancer:
Analysis of the surveillance, epidemiology, and end results data. Chest 136:701–709, 2009.
On Pericardial Effusion
Cullinane CA, Paz IB, Smith D, et al: Prognostic factors in the surgical management of pericardial
effusion in the patient with concurrent malignancy. Chest 125:1328–1334, 2004.
Fukada J, Shigematsu N, Takeuchi H, et al: Symptomatic pericardial effusion after
chemoradiation therapy in esophageal cancer patients. Int J Rad Onc Biol Phys 87:487–493, 2013.
Kühn B, Peters J, Marx GR, et al: Etiology, management, and outcome of pediatric pericardial
effusions. Pediatr Cardiol 29:90–94, 2008.
Kunitoh H, Tamura T, Shibata T, et al: A randomised trial of intrapericardial bleomycin for
malignant pericardial effusion with lung cancer (JCOG9811). Br J Cancer 100:464–469, 2009.
Maisch B, Seferovic PM, Ristic AD, et al: Guidelines on the diagnosis and management of
pericardial diseases executive summary: The Task Force on the Diagnosis and Management of
Pericardial Diseases of the European Society of Cardiology. Eur Heart J 25:587–610, 2004.
Marcy PY, Bondiau PY, Brunner P: Percutaneous treatment in patients presenting with malignant
cardiac tamponade. Eur Radiol 15:2000–2009, 2005.
McDonald JM, Meyers BF, Guthrie TJ, et al: Comparison of open subxiphoid pericardial drainage
with percutaneous catheter drainage for symptomatic pericardial effusion. Ann Thorac Surg
76:811–816, 2003.
Neragi-Miandoab S, Linden PA, Ducko CT, et al: VATS pericardiotomy for patients with known
malignancy and pericardial effusion: Survival and prognosis of positive cytology and metastatic
involvement of the pericardium: A case control study. Int J Surg 6:110–114, 2008.
Patel N, Rafique AM, Eshaghian S, et al: Retrospective comparison of outcomes, diagnostic
value, and complications of percutaneous prolonged drainage versus surgical pericardiotomy of
pericardial effusion associated with malignancy. Am J Cardiol 112:1235–1239, 2013.
Restrepo CS, Lemos DF, Lemos JA, et al: Imaging findings in cardiac tamponade with emphasis
on CT. Radiographics 27:1595–1610, 2007.
Romano EJ, Glass PS: Laparoscopic pericardial window: Anesthetic implications. J Cardiothorac
Vasc Anesth 16:623–625, 2002.
Sagristà-Sauleda J, Angel J, Sambola A, et al: Hemodynamic effects of volume expansion in
patients with cardiac tamponade. Circulation 117:1545–1549, 2008.
Szturmowicz M, Tomkowski W, Fijalkowska A, et al: Diagnostic utility of CYFRA 21-1 and CEA
assays in pericardial fluid for the recognition of neoplastic pericarditis. Int J Biol Markers 20:43–49,
2005.
Swanson N, Mirza I, Wijesinghe N, et al: Primary percutaneous balloon pericardiotomy for
malignant pericardial effusion. Catheter Cardiovasc Interv 71:508–509, 2008.
Tomkowski WZ, Wisniewska J, Szturmowicz M, et al: Evaluation of intrapericardial cisplatin
administration in cases with recurrent malignant pericardial effusion and cardiac tamponade.
Support Care Cancer 12:53–57, 2004.
Toth I, Szucs G, Molnar TF: Mediastinoscope-controlled parasternal fenestration of the
pericardium: definitive surgical palliation of malignant pericardial effusion. J Cardiothorac Surg 7:56,
2012.
Tsang TS, Enrique-Sarano M, Freeman WK, et al: Consecutive 1,127 therapeutic
echocardiographically guided pericardiocenteses: Clinical profile, practice patterns, and outcomes
spanning 21 years. Mayo Clin Proc 77:429–436, 2002.
Wagner PL, McAleer E, Stillwell E, et al: Pericardial effusions in the cancer population:
Prognostic factors after pericardial window and the impact of paradoxical hemodynamic instability. J
Thorac Cardiovasc Surg 141:34–38, 2011.
On Malignant Ascites
Barni S, Cabiddu M, Ghilardi M, et al: A novel perspective for an orphan problem: Old and new
drugs for the medical management of malignant ascites. Crit Rev Oncol Hematol 79:144–153, 2011.
Cavazzoni E, Bugiantella W, Graziosi L, et al: Malignant ascites: Pathophysiology and
treatment. Int J Clin Oncol 18:1–9, 2013.
Diaz JP, Abu-Rustum NR, Sonoda Y, et al: Video-assisted thoracic surgery (VATS) evaluation of
Page 21 of 22
Fluid Complications
Published on Cancer Network (http://www.cancernetwork.com)
pleural effusions in patients with newly diagnosed advanced ovarian carcinoma can influence the
primary management choice for these patients. Gynecol Oncol 116:483–488, 2010.
Eskander RN, Tewari KS: Epithelial cell-adhesion molecule-directed trifunctional antibody
immunotherapy for symptom management of advanced ovarian cancer. Clin Pharmacol 5(Suppl
1):55–61, 2013.
Keen A, Fitzgerald D, Bryant A, et al: Management of drainage for malignant ascites in
gynaecological cancer. Cochrane Database Syst Rev 1:CD007794, 2010.
Kim KW, Choi HJ, Kang S, et al: The utility of multi-detector computed tomography in the
diagnosis of malignant pleural effusion in the patients with ovarian cancer. Eur J Radiol 75:230–235,
2010.
Li CP, Huang TS, Chao Y, et al: Advantages of assaying telomerase activity in ascites for
diagnosis of digestive tract malignancies. World J Gastroenterol 10:2468–2471, 2004.
Nazeer SR, Dewbre H, Miller AH: Ultrasound-assisted paracentesis performed by emergency
physicians vs the traditional technique: A prospective, randomized study. Am J Emerg Med
23:363–367, 2005.
Sangisetty SL, Miner TJ: Malignant ascites: A review of prognostic factors, pathophysiology and
therapeutic measures. World J Gastrointest Surg 4:87–95, 2012.
Seimetz D, Lindhofer H, Bokemeyer C: Development and approval of the trifunctional antibody
catumaxomab (anti-EpCAM × anti-CD3) as a targeted cancer immunotherapy. Cancer Treat Rev
36:458–467, 2010.
White J, Carolan-Rees G: PleurX peritoneal catheter drainage system for vacuum-assisted
drainage of treatment-resistant, recurrent malignant ascites: A NICE Medical Technology Guidance.
Appl Health Econ Health Policy 10:299–308, 2012.
Source URL: http://www.cancernetwork.com/cancer-management/fluid-complications
Links:
[1] http://www.cancernetwork.com/cancer-management
[2] http://www.cancernetwork.com/authors/frederic-w-grannis-jr-md
[3] http://www.cancernetwork.com/authors/jae-y-kim-md
[4] http://www.cancernetwork.com/authors/lily-lai-md
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