Download Cancer Management Chapter 41: Fluid complications

Cancer Management Chapter 41: Fluid complications
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Cancer Management Chapter 41: Fluid complications
March 15, 2010
By Frederic W. Grannis, Jr, MD [1], Carey A. Cullinane, MD [2], Lily Lai, MD [3], Casandra Anderson,
MD [4], and Minia Hellan, MD [5]
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.
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 AIDS.
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 more commonly occur 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 trials in patients with pleural effusions. For the same reason, it is often difficult to predict a
potential treatment outcome for the specific patient with multiple interrelated clinical problems.
William generated survival curves for more than 8,000 patients with non–small-cell lung cancer
(NSCLC) from the SEER (Surveillance, Epidemiology, and End Results) database with pleural effusion
(ie, stage IIIB) and showed that long-term survival is uncommon in this group. The median survival is
approximately 3 months.
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%). Sarkar et al have introduced a simple bedside test that allows identification
of exudative effusion at the time of thoracentesis. They added 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 (Sarkar S et al: Clin Chim Acta 405:83–86, 2009).
Thoracentesis The first step in management in almost all cases is thoracentesis. An adequate
specimen should be obtained and sent for 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.
The Light criteria (LDH > 200 U/L; pleural-serum LDH ratio > 0.6; and pleural-serum protein ratio >
0.5) help 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 (LDH) in the fluid. Brain natriuretic protein levels are markedly elevated in effusions
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secondary to congestive heart failure.
Because it is sometimes difficult to prove the malignant nature of an effusion, 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, but to date, no test or panel of tests can reliably
diagnose malignant effusions.
Investigators in Cambridge, England, report that thickening of the pleura > 1 cm, pleural nodularity,
and diaphragmatic thickening > 7 mm on either CT or ultrasonography suggest malignant effusion.
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.
PET scan may be positive with malignant pleural effusion; a high SUV (standard uptake value) is an
adverse prognosticator. Kwek et al, from Massachusetts General Hospital, reported that PET scans
performed on nine patients, an average of 22 months following talc pleurodesis, showed focal
nodular fluorodeoxyglucose uptake in the pleura (mean standard error of mean 5.4; range: 1.2–16.
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. There was no incidence of later development of a malignant pleural effusion
following a benign thoracoscopic study in 25 patients at the Lahey Clinic. Furthermore, this
technique permits the diagnosis and staging of malignant mesothelioma if it is the cause of the
effusion. Thoracoscopy also offers the opportunity for simultaneous treatment.
Gaspari et al of Milan, Italy, report an 89% success rate following video-assisted thoracic surgery
(VATS) talc pleurodesis in breast cancer patients with malignant pleural effusion. Biopsies taken
during VATS showed that receptor status and c-erbB2 status changed from negative to positive in
15% of patients.
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 for 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).
Treatment
Initial treatment
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 many different
methods available for the 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 the clinician decides to administer 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 and to treat such recurrences
immediately. There are few published data to document the chance of success in clearance of
malignant pleural effusions with systemic chemotherapy.
If a malignant pleural effusion is left untreated, the underlying collapsed lung will become encased
by tumor and fibrous tissue in as many as 10% to 30% of cases. Once this 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
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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 chest tube or small pleural catheter drainage.
Intrapleural alteplase (in doses between 10 and 100 mg diluted in 50 to 150 mL of saline) has been
used with success in some patients with gelatinous or loculated effusions without systemic bleeding
complications.
Physical techniques
To avoid encasement atelectasis, pleural effusion should be treated definitively at the time of initial
diagnosis. Multiple physical techniques of producing adhesions between the parietal and visceral
pleurae, obliterating the space, and preventing recurrence have been used. 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 can easily be 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 in those with normal pleural fluid pH and superior in patients with
a low pH. In Thessaloniki, Greece, 34 patients with symptomatic recurrent malignant pleural
effusions had a chest tube placed followed by pleurodesis with erythromycin. Success was evaluated
after 90 days. A complete response (ie, no reaccumulation of pleural fluid after 90 days) was seen in
79.4%, and a partial response (ie, reaccumulation but without symptoms and not requiring drainage)
was seen in another 8.8%. Recurrence with necessity for re-intervention was seen in 11.8%. All
patients experienced pleurodynia during administration. Sinus tachycardia and mild hypertension
were also observed. They concluded that erythromycin is effective and safe as a sclerosing agent for
pleurodesis in patients with malignant pleural effusions (Balassoulis G et al: Am J Clin Oncol
31:384-389, 2008).
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 are probably equivalent in efficacy to tetracycline.
Bleomycin Intrapleural bleomycin, in 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 the
use of either drug singly.
Talc pleurodesis was first introduced by 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.
Talc has also been shown to cause decreases in forced vital capacity (FVC), forced expiratory volume
in one second (FEV1), and diffusing capacity 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.
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Pleurodesis technique With talc pleurodesis, 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.
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 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.
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.)
Other approaches that must be considered experimental at this time 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 (Proleukin), interferon-α
(Intron A, Roferon-A), interferon-β (Betaseron), and interferon-γ (Actimmune). Schneider et al, from
Heidelberg, Germany, 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%. They identified three groups that seemed to benefit: 1) patients with the
intraoperative finding of a trapped lung in diagnostic 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 (Schneider T et al: Thorac Cardiovasc Surg 57:42-46, 2009).
Treatment of encasement atelectasis
If encasement atelectasis is found at thoracentesis or thoracoscopy, tube thoracostomy and
pleurodesis are futile and contraindicated.
Surgical decortication has been advocated for this problem. This potentially dangerous procedure
may result in severe complications, however, such as bronchopleural fistula and empyema.
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, as needed to relieve symptoms, may be the best option in patients
with a short anticipated survival.
Catheter drainage Another new 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.
Kakuda reported on placement of 61 PleurX pleural catheters in 50 patients with malignant pleural
effusions at City of Hope. 34% percent had lung cancer and 24% had breast cancer. There were no
operative deaths. In cases where the catheter was placed under thoracoscopic control, 27 of 38
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patients (68%) had encasement atelectasis visualized. 81% had a good result with control of
effusion, with subsequent catheter removal (19%) or intermittent drainage for > 1 month or until
death (62%). 5% of patients had major complications, including empyema and tumor implant. 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.
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
minimal systemic effects, only a few, small pilot studies utilizing mitoxantrone, doxorubicin, and
hyperthermic cisplatin have been published.
Ang and colleagues from Singapore reported longer mean survival (12 vs 5 months) when systemic
chemotherapy was given to 71 patients who initially presented with malignant pleural/pericardial
effusions. New studies in this area are much needed.
In Taiwan, Su et al treated 27 patients with NSCLC presenting with a malignant pleural effusion with
a regimen of intrapleural cisplatin and gemcitabine (Gemzar), followed by radiotherapy (7,020 cGy in
39 fractions), and completed with IV docetaxel (Taxotere). Only two patients experienced recurrent
pleural effusion. The median disease-free and overall survival rates were 8 and 16 months,
respectively, and 63% of patients were alive at 1 year.
Seto et al, from the Kyushu Cancer Center, reported a single-arm series of 80 patients with
previously untreated malignant pleural effusions from NSCLC. The patients had a chest tube 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%. A striking finding in this study was that the median
survival time of all patients was 239 days, a longer survival than seen in comparable patients treated
with pleurodesis. The authors recommend a phase III study.
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 (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. Chylothorax secondary to lymphoma is usually of low volume and responds to talc
pleurodesis 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 talc
pleurodesis were equal and concluded that concomitant ascites did not influence the effectiveness of
palliative surgical management of pleural effusion in patients with malignancies.
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. At Boston City Hospital, 39% of children with moderate to large pericardial effusions
had malignant effusions. To determine whether clinical recognition of cardiac tamponade had
changed over 20 years, Gandhi et al compared physicians' awareness of cardiac tamponade at the
Tufts New England Medical Center in cohorts of patients with tamponade in 1988 and 2002. They
concluded that the diagnosis of cardiac tamponade remains delayed and that results emphasize a
need for a heightened index of suspicion (Gandhi S et al: Echocardiography 25:237-241, 2008).
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. Such effusions are more
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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.
Many effusions that initially have negative cytology will become positive over time.
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
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. Patients may also complain of chest
pain or discomfort, easy fatigability, cough, and orthopnea or 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, pulsus paradoxus
> 13 mm Hg, jugular venous distention, and hypotension.
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. Vignon
et al, from Limoges, Cedex-France, reported on the accuracy of echocardiography performed by
noncardiologist residents with limited training in an ICU. They 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 using echocardiography and was
specifically useful in the diagnosis of pleural and pericardial effusions (Vignon P et al: Intensive Care
Med 33:1684-1686, 2007).
ECG The 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. 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. A retrospective study of 273 patients with Hodgkin's lymphoma from the
University of Tennessee Health Science Center in Memphis revealed a rate of pericardial disease of
5%. All had nodular sclerosing tumor, and most had a large mediastinal mass. Two patients required
pericardial drainage. In the 11 cases that did not have drainage, the effusion resolved rapidly after
starting chemotherapy. Disease-free survival is 100%, with a median follow-up of 9.7 years (Bashir H
et al: Pediatr Blood Cancer 49:666-671, 2007).
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 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 with malignant pericardial effusion with negative cytologic results had a
positive result on one or both tests.
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 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. In experimental animals, pericardial
fluid has been aspirated by femoral vein catheterization and needle puncture of the right atrial
appendage from within. This technique has not been used in humans.
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Pericardioscopy 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.
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. 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 exam, 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,
remained unchanged in 22%, and decreased in 31%. No patient had clinical complications. Predictors
of improved hemodynamics were a pressure below 100 mm Hg and a low cardiac index. The authors
concluded that in approximately half of patients with cardiac tamponade, particularly those with low
blood pressure, cardiac output will increase after volume overload (Sagrista-Sauleda J et al:
Circulation 117:1545-1549, 2008).
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: creation of a persistent
defect in the pericardium allowing fluid to drain out and be reabsorbed by surrounding tissues or
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 is useful in relieving tamponade and obtaining a diagnosis. Echocardiographic
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guidance considerably enhances the safety of this procedure. Ninety percent of pericardial effusions
will recur within 3 months after pericardiocentesis alone.
Pericardiocentesis and percutaneous tube drainage can now be performed with low risk and
are recommended by some clinical groups. Marcy et al, of Nice, Cedex- 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.
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. 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 receive 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. 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 (Kunitoh H et al: Br J Cancer 10:464-469, 2009).
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 medial survival
was 115 days. They concluded that this protocol is safe, well tolerated, and improves the quality and
duration of life.
Pericardiocentesis and 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.
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. Its use is
restricted to cancer patients with recurrent effusions who are in good overall condition and are
expected to survive for up to 1 year.
Limited pericardial resection (pericardial window) via anterior thoracotomy or a thoracoscopic
approach has a lower morbidity than less invasive techniques, but recovery is delayed. There is a
low risk of recurrence. Cardiac herniation is possible if the size of the opening in the pericardium is
not carefully controlled.
At City of Hope, Cullinane et al reported on 62 patients with malignant disease who had surgical
pericardial window 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). Surgical pericardial
window is a safe and durable operative procedure that may provide extended survival in certain
subgroups of cancer patients.
Subxiphoid pericardial resection can be performed with the patient under local anesthesia and
may be combined with endoscopic instrumentation, tube drainage, and/or pericardial sclerosis.
Subxiphoid pericardioperitoneal window through the fused portion of the diaphragm and
pericardium has been developed to allow continued drainage of pericardial fluid into the peritoneum.
Experience with this procedure is limited.
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
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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. 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 pericardial window 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.
Systemic therapy
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 regarding the effectiveness of systemic chemotherapy or
chemotherapy delivered locally in prevention of recurrent pericardial and pleural effusion are limited.
New studies in this area are badly needed.
Biologic therapy with various agents is in the early stages of investigation.
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 vascular endothelial
growth factor (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%), GI 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 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
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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. Ultrasonography improved the physician’s 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. IV and oral contrasts
are 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 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, 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
gynecologic and breast malignancies have a better overall prognosis than patients with GI
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. Intraperitoneal
anti-VEGF therapy may be efficacious in malignant ascites. Nine patients with end-stage disease and
malignant ascites were treated with intraperitoneal bevacizumab (Avastin). The instillation was
noted to be safe, and none of the nine patients had reaccumulation of ascites (El-Shami K et al: J Clin
Oncol 25[18S]: abstract 9043, 2007).
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
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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.
Diuretics, fluid and salt restriction 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 to 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, 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 GI malignancies to decrease
recurrence of ascites as well as to prevent the formation of ascites in patients with peritoneal
carcinomatosis. Antibodies directed at adhesion molecules given as intraperitoneal infusions have
been tested in a phase I/II trial to determine their safety and efficacy in patients with refractory
ascites. A trifunctional anti-EpCAM x anti-CD3 antibody was tested in 23 patients. Side effects were
well tolerated. Repeat paracentesis was required in only one patient. In addition, the antibody
induced a dramatic decrease in EpCAM-positive malignant cells in the ascites, suggesting that
antibodies directed at adhesion molecules may be useful in patients with malignant ascites (Burges
A et al: Clin Cancer Res 13:3899-3905, 2007).
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 Experimental models and early clinical trials have shown that an intraperitoneal
bolus of tumor necrosis factor (45 to 350 µg/m2) given weekly may be effective in resolving
malignant ascites. Other cytokines, including interferon-α, had varying 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.
Surgery
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 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 GI 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 around intravascular dissemination of tumor. In practice, there has been little
difference in overall mortality in patients with and without shunts.
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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 results 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.
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% to 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 peritoniectomy Other surgical procedures used to treat malignant ascites have been
proposed. They include radical peritoniectomy 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
peritoniectomy increases efficacy or survival.
References:
SUGGESTED READING
ON MALIGNANT PLEURAL EFFUSION
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pleural effusion caused by non-small cell lung cancer. Respirology 11:90–97, 2006.
Paschoalini Mda S, Vargas FS, Marchi E, et al: Prospective randomized trial of silver nitrate vs
talc slurry in pleurodesis for symptomatic malignant pleural effusions. Chest 128:684–689, 2005.
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Steger V, Mika U, Toomes H, et al: Who gains most? A 10-year experience with 611
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malignant pleural effusion: A systematic review. Eur J Cardiothorac Surg 29: 829–838, 2006.
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.
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.
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On malignant ascites
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Source URL:
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