Fluid Complications
By Frederic W. Grannis, Jr., MD , Lily Lai, MD 1 Section of Thoracic Surgery, City of Hope National Medical Center Division of General and Oncologic Surgery, City of Hope National Medical Center MALIGNANT PLEURAL EFFUSION
Malignant pleural effusion complicates the care of approximately 150,000 Malignant Pleural
people in the United States each year. The pleural effusion is usually caused Effusion
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 Pericardial Effusion
malignant effusions. It is, therefore, puzzling that small-cell lung cancer Malignant Ascites
infrequently causes effusions. Primary effusion lymphomas caused byhuman herpesvirus 8 and perhaps Epstein-Barr virus (EBV) are seen inpatients with AIDS.
Pleural effusion restricts ventilation and causes progressive shortness of breath by compression of lungtissue as well as paradoxical movement of the inverted diaphragm. Pleural deposits of tumor causepleuritic pain.
Pleural effusions more commonly occur in patients with advanced-stage tumors, who frequently havemetastases to the brain, bone, and other organs, physiologic deficits, malnutrition, debilitation, and othercomorbidities. Because of these numerous clinical and pathologic variables, it is difficult to performtrials in patients with pleural effusions. For the same reason, it is often difficult to predict a potentialtreatment 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) with pleural effusion (ie, stage IIIB) from the SEER database and showed that long-termsurvival is uncommon in this group. The median survival time is approximately 3 months.
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 http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 initial diagnosis of cancer in patients. In Nantes, France, pleural effusion was the first symptom ofcancer in 41% of 209 patients with malignant pleural effusion; lung cancer in men (42%) and ovariancancer in women (27%).
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 eventuallydiagnosed as malignant, whereas < 5% of transudates are shown to be caused by cancer. Transudatesmay 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 secondary to congestiveheart failure.
Because it is sometimes difficult to prove the malignant nature of an effusion, many molecular tests onpleural fluid have been investigated. Multiple reports measure pleural tumor marker proteins,glycosaminoglycans, cadherins, matrix metalloproteins, cytokines, telomerase, mRNA, exosomes, andserum and pleural DNA methylation patterns, but to date, no test or panel of tests can reliably diagnosemalignant effusions.
Investigators in Cambridge, England, report that thickening of the pleura > 1 cm, pleural nodularity, anddiaphragmatic 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 isnegative in an exudative effusion, approximately 25% will have a positive cytology on a secondthoracentesis; blind pleural biopsy may increase the yield to nearly 50%. This low diagnostic yield canbe 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 anadverse prognosticator. Kwek et al, from Massachusetts General Hospital, reported that PET scansperformed on nine patients, an average of 22 months following talc pleurodesis, showed focal nodularfluorodeoxyglucose uptake in the pleura (mean standard error of mean 5.4; range: 1.2–16).
Sarkar et al have introduced a simple bedside test that allows identification of exudative effusion at thetime 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 thefluid (Sarkar S et al: Clin Chim Acta 405:83–86, 2009).
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
http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 malignant mesothelioma if it is the cause of the effusion. Thoracoscopy also offers the opportunity forsimultaneous 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 duringVATS showed that receptor status and c-erbB2 status changed from negative to positive in 15% ofpatients.
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 of patients with malignant pleural effusion varies by primary tumor. For example, mediansurvival for patients with lung cancer is 3 months, whereas it is 10 months for patients with breastcancer. Median survival is also shorter in patients with encasement atelectasis (3 months).
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 bytumor and fibrous tissue in as many as 10% to 30% of cases. Once this encasement atelectasis hasoccurred, the underlying lung is "trapped" and will no longer reexpand after thoracentesis or tubethoracostomy. Characteristically, the chest x-ray in such cases shows resolution of the pleural effusionafter thoracentesis, but the underlying lung remains partially collapsed. This finding is oftenmisinterpreted 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 pulmonaryphysiotherapy. Allowing the chest tube to remain in place can worsen the situation, resulting inbronchopleural fistulization and empyema. In some cases, a trapped lung on an initial chest x-ray willhave 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 usedwith success in some patients with gelatinous or loculated effusions without systemic bleedingcomplications.
http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 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.
In Thessaloniki, Greece, 34 patients with symptomatic recurrent malignant pleural effusions had achest tube placed followed by pleurodesis with erythromycin. Success was evaluated after 90 days. Acomplete response (ie, no reaccumulation of pleural fluid after 90 days) was seen in 79.4%, and apartial response (ie, reaccumulation but without symptoms and not requiring drainage) was seen inanother 8.8%. Recurrence with necessity for re-intervention was seen in 11.8%. All patientsexperienced pleurodynia during administration. Sinus tachycardia and mild hypertension were alsoobserved. The investigators concluded that erythromycin is effective and safe as a sclerosing agent forpleurodesis in patients with malignant pleural effusions (Balassoulis G et al: Am J Clin Oncol31:384–389, 2008).
A randomized, prospective study from Ljubljanska, Slovenia, of 87 patients with malignant pleuraleffusion secondary to breast cancer showed that the thoracoscopic mechanical abrasion pleurodesis wasequivalent to talc pleurodesis in those with normal pleural fluid pH and superior in patients with a lowpH.
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 (FEV ), and
Talc can be insufflated in a dry state at the time of thoracoscopy or instilled as a slurry through a chesttube. The dose should be restricted to no more than 5 g. A prospective phase III intergroup trial of 501patients randomized to receive thoracoscopic talc vs talc slurry pleurodesis showed similar efficacy in http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 each arm, with increased respiratory complications (14% vs 6%) but less fatigue and higher patientratings in the insufflation group.
Multiloculated effusions may follow talc use. It is important to ensure that talc does not solidify andform a concretion in the chest tube, thus preventing the drainage of pleural fluid and completereexpansion of the lung following pleurodesis. Such an event is more likely when small-bore chest tubesare used.
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. Theseprocedures 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 helpreduce 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 2or 3 days if drainage is < 300 mL/d.
Follow-up x-rays at monthly intervals assess the adequacy of treatment and allow early retreatment incase 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.)
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 29patients. The rate of empyema was 4%. The investigators identified three groups that seemed tobenefit: (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) patientswith a limited life span due to underlying disease (Schneider T et al: Thorac Cardiovasc Surg57:42–46, 2009).
http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 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 Corynebacteriumparvum, OK-432, tumor necrosis factor, interleukin-2 (Proleukin), interferon- (Intron A, Roferon-A),interferon- (Betaseron), 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 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 pleuraleffusions at City of Hope; 34% had lung cancer and 24% had breast cancer. There were no operativedeaths. In cases where the catheter was placed under thoracoscopic control, 27 of 38 patients (68%) hadencasement atelectasis visualized. A total of 81% had a good result with control of effusion, withsubsequent catheter removal (19%) or intermittent drainage for > 1 month or until death (62%). A totalof 5% of patients had major complications, including empyema and tumor implant. These catheters canalso be inserted using the Seldinger technique with the patient under local anesthesia. Tremblay et alplaced 250 PleurX pleural catheters by percutaneous technique in patients under local anesthesia. Nofurther pleural intervention was required during the lives of 90% of the patients. The median overallsurvival was 144 days, and spontaneous pleurodesis occurred in 43%. Subsequent studies showed that70% of patients who had full lung expansion had spontaneous pleurodesis, with lifetime control ofpleural 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 systemicchemotherapy was given to 71 patients who initially presented with malignant pleural/pericardialeffusions. New studies in this area are much needed.
In Taiwan, Su et al treated 27 patients with NSCLC presenting with a malignant pleural effusion using aregimen of intrapleural cisplatin and gemcitabine (Gemzar), followed by radiotherapy (7,020 cGy in 39 http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 fractions), and completed treatment with IV docetaxel (Taxotere). Only two patients experiencedrecurrent 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, from the National Kyushu Cancer Center, Fukuoka, Japan, reported a single-arm series of 80patients with previously untreated malignant pleural effusions from NSCLC. The patients had a chesttube placed and were given 25 mg of cisplatin in 500 mL of distilled water intrapleurally. Toxicity wasacceptable. Median time of drainage was 4 days. A total of 34% had a complete response and 49% had apartial response, for an overall response rate of 83%. A striking finding in this study was that the mediansurvival time of all patients was 239 days, a longer survival than seen in comparable patients treatedwith 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.
Dresler CM, Olak J, Herndon JE 2nd, et al: Phase III intergroup study of talc poudrage vs talc slurry
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2):ii1–ii76, 2010.
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of pleural effusions. Chest 135:201–209, 2009.
Gasparri R, Leo F, Veronesi G, et al: Video-assisted management of malignant pleural effusion in
breast carcinoma. Cancer 106:271–276, 2006.
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,
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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in patients fit for pleurodesis. Eur Respir J 30:759–762, 2007.
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Pericardial effusion develops in 5% to 15% of patients with cancer and is Malignant Pleural
sometimes the initial manifestation of malignancy. Most pericardial Effusion
effusions in cancer patients result from obstruction of the lymphatic Pericardial Effusion
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.
Malignant Ascites
The most common malignant causes of pericardial effusions are lung andbreast cancers, leukemias (specifically acute myelogenous, lymphoblastic, and chronic myelogenousleukemia [blast crisis]), and lymphomas. At Boston City Hospital, 39% of children with moderate tolarge pericardial effusions had malignant effusions.
Not all pericardial effusions associated with cancer are malignant, and cases with negative cytology mayrepresent as many as half of cancer-associated pericardial effusions. Such effusions are more common inpatients with mediastinal lymphoma, Hodgkin lymphoma, or breast cancer. Other nonmalignant causesinclude drug-induced (eg, sirolimus [Rapamune] or docetaxel) or postirradiation pericarditis,tuberculosis, collagen diseases, uremia, and congestive heart failure. Many effusions that initially havenegative cytology will become positive over time.
Tamponade occurs when fluid accumulates faster than the pericardium can stretch. Compression of allfour heart chambers ensues, with tachycardia and diminishing cardiac output. Fluid loading cancounteract intrapericardial pressure temporarily. Reciprocal filling of right- and left-sided chambers withinspiration and expiration, secondary to paradoxical movement of the ventricular septum, is a finalmechanism to maintain blood flow before death.
A high index of suspicion is required to make the diagnosis of pericardial effusion.
http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 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.
Electrocardiogram (ECG)
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 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
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. 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.
http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 Pericardioscopy
This allows visualization and biopsy at the time of subxiphoid or thoracoscopic pericardiotomy and can
improve the diagnostic yield.
In general, cancer patients who develop a significant pericardial effusion have a high mortality, with amean time to death of 2.2 to 4.7 months. However, about 25% of selected patients treated surgically forcardiac tamponade enjoy a 1-year survival.
Investigators in Barcelona, Spain, studied the effects of volume expansion in patients with largepericardial effusions and pericardial tamponade. They administered 500 mL of normal saline over 10minutes and measured hemodynamic and echocardiographic parameters. A total of 57% hadtamponade on physical exam, and 20% were hypotensive. Volume expansion resulted in increases inmean arterial, intrapericardial, right atrial, and left ventricular end-diastolic pressures. The cardiacindex increased by > 10% in 47% of patients, remained unchanged in 22%, and decreased in 31%. Nopatient had clinical complications. Predictors of improved hemodynamics were a pressure below 100mm Hg and a low cardiac index. The authors concluded that in approximately half of patients withcardiac tamponade, particularly those with low blood pressure, cardiac output will increase aftervolume overload (Sagrista-Sauleda J et al: Circulation 117:1545–1549, 2008).
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 bedismissed summarily as having an untreatable and/or terminal problem.
• Ultimately, both the management and natural course of the effusion depend on (1) the underlyingcondition 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, therapyshould be aimed at relieving symptoms and preventing recurrence of tamponade or constrictivepericardial disease. Patients with tumors responsive to chemotherapy or radiation therapy may attainlonger remissions with appropriate therapy.
http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 There are two theoretical mechanisms for control of pericardial effusion: (1) creation of a persistentdefect 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 thepericardial cavity.
Postmortem studies have demonstrated that both of these mechanisms are operative. The fact thateffusions can recur implies that there is either insufficient damage to the mesothelial layer or that rapidrecurrence of effusion prevents coaptation of visceral and parietal pericardium and prevents theformation of adhesions. This, in turn, would suggest that early closure of the pericardial defect can resultin 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
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, 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 controlledtrial in 80 patients who had undergone pericardial drainage for malignant pericardial effusion. Thesepatients were then randomized to receive either observation alone (A) after drainage or intraperi-cardial bleomycin instillation (15 mg followed by 10 mg every 48 hours [B]). Drainage tubes wereremoved when daily drainage was 20 mL or less. Survival with control of malignant pleural effusion at2 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 (15mg on days 1, 3, and 5) following placement of a pericardial drainage catheter in 33 patients withmalignant pericardial effusion. There were three recurrent effusions (9.1%). The medial survival was115 days. They concluded that this protocol is safe, well tolerated, and improves the quality andduration 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.
http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 At the National Taiwan University, cardiologists performed percutaneous double-balloonpericardiotomy in 50 patients with cancer and pericardial effusion and followed their course using serialechocardiograms. Success without recurrence was achieved in 88%. Fifty percent of patients died within4 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 a surgicalpericardial window created for management of pericardial effusion. Windows were created eitherthoracoscopically (32) or by subxiphoid (12) or limited thoracotomy (18) approaches. Primary tumorsincluded 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 surgicalprocedure. The median survival was much shorter for patients with NSCLC (2.6 months) than forpatients with breast cancer (11 months) or hematologic malignancy (10 months). The surgicalpericardial window is a safe and durable operative procedure that may provide extended survival incertain 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
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.
http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 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 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.
on pericardial effusion
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.
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.
Restrepo CS, Lemos DF, Lemos JA, et al: Imaging findings in cardiac tamponade with emphasis on
CT. Radiographics 27:1595–1610, 2007.
Sagristá-Sauleda J, Angel J, Sambola A, et al: Hemodynamic effects of volume expansion in patients
with cardiac tamponade. Circulation 117:1545–1549, 2008.
Swanson N, Mirza I, Wijesinghe N, et al: Primary percutaneous balloon pericardiotomy for malignant
pericardial effusion. Catheter Cardiovasc Interv 71:508–509, 2008.
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.
Malignant ascites results when there is an imbalance in the secretion of Malignant Pleural
proteins and cells into the peritoneal cavity and absorption of fluids via the Effusion
http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 Pericardial Effusion
lymphatic system. Greater capillary permeability as a result of the release of Malignant Ascites
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, andimmobility. Complaints of abdominal bloating, heaviness, and ill-fitting clothes are common. Weightgain despite muscle wasting is a prominent sign.
A malignant etiology accounts for only 10% of all cases of ascites. Nonmalignant diseases causingascites include liver failure, congestive heart failure, and occlusion of the inferior vena cava or hepaticvein. About one-third of all patients with malignancies will develop ascites. Malignant ascites has beendescribed with many tumor types but is most commonly seen with gynecologic neoplasms (~50%), GImalignancies (20% to 25%), and breast cancer (10% to 18%). In 15% to 30% of patients, the ascites isassociated 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
Radiologic studies
Ascites can be inferred from plain radiographs of the abdomen. Signs include a ground-glass pattern and
centralization of the intestines and abdominal contents.
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, asdemonstrated in a randomized trial. Ultrasonography improved the physician's ability to aspirate ascitesfrom 67% (27 of 44 patients) to 95% (40 of 42 patients).
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.
After the diagnosis of peritoneal ascites has been made on the basis of the physical examination and
http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 imaging, paracentesis should be performed to characterize the fluid. The color and nature of the fluidoften suggest the diagnosis. Malignant ascites can be bloody, opaque, chylous, or serous. Benign ascitesis usually serous and clear.
Analysis of the fluid should include cell count, cytology, LDH level, proteins, and appropriateevaluation for infectious etiologies. In addition, the fluid can be sent for the determination of tumormarkers, such as CEA, CA-125, p53, and human chorionic gonadotropin- (hCG-). The hCG- level isfrequently elevated in malignancy-related ascites and has been combined with cytology to yield an89.5% 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 malignantascites.
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.
The presence of ascites in a patient with malignancy often portends end-stage disease. The mediansurvival after the diagnosis of malignant ascites ranges from 7 to 13 weeks. Patients with gynecologicand breast malignancies have a better overall prognosis than patients with GI malignancies.
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 ofabdominal bloating, anorexia, dyspnea, insomnia, and fatigue. In addition, overall quality of lifeimproved after paracentesis.
Significant morbidity occurs with repeated taps and becomes more severe with each tap necessary toalleviate symptoms. Ascitic fluid contains a high concentration of proteins. Routine removal of ascitesfurther depletes protein stores. The removal of large volumes of fluid also can result in electrolyteabnormalities and hypovolemia. In addition, complications can result from the procedure itself. Theyinclude 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 intraperitonealchemotherapy, removal of ascitic fluid is possible without the need for repeated paracentesis. Other http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 possible catheters for use in repeated paracentesis include PleurX and Tenckoff catheters (used forintraperitoneal dialysis). Placement of a semipermanent catheter minimizes the risk of injury tointra-abdominal structures. However, the benefits are tempered by increased infectious risks as well asthe 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 (3–4 days), whereas the effects of amiloride are seenafter 24 hours. The most common complications associated with these diuretics are painfulgynecomastia, 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.
A randomized phase II/III study evaluated the trifunctional antibody directed at adhesion molecules(catumaxomab) in 258 patients with refractory malignant ascites from epithelial cancers. The studydemonstrated improvements in puncture-free survival (a measure of decreased frequency ofparacentesis) as well as longer duration between paracentesis in the patients who received the antibody.
Treatment was well tolerated with moderate but manageable toxicities (Heiss MM et al: Int J Cancer127:2209–2221, 2010).
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 preventfuture fluid accumulation. If sclerosis is unsuccessful, it may produce loculations and make subsequentparacentesis difficult.
Other therapies
Experimental models and early clinical trials have shown that an intraperitoneal bolus of tumor necrosis
factor (45–350 g/m²) given weekly may be effective in resolving malignant ascites. Other cytokines,
including interferon-, have 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. Intraperitoneal injection of antibodies directed at VEGF has shown promise in decreasing
ascites in early-phase clinical trials but further studies are needed.
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.
http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 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 avalve that lies within a fluid-filled, compressible silicone chamber. Both valves provide a connectionbetween the peritoneal cavity and venous system that permits the free flow of fluid from the peritonealcavity 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 theprimary 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%–15%).
Candidates for shunt placement should be carefully selected. Cardiac and respiratory evaluations shouldbe performed prior to the procedure. Shunt placement is contraindicated in the presence of thefollowing: • a moribund patient whose death is anticipated within weeks 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. Thereinfusion of large volumes of ascitic fluid may cause a deficiency in endogenous circulatingcoagulation factors by dilution. Secondarily, a fibrinolytic state is initiated by the introduction of solublecollagen (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 butmay 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, theselaboratory values are so consistently abnormal that they are used to monitor shunt patency.
Abnormalities most commonly seen include decreased platelets and fibrinogen and elevatedprothrombin time, partial thromboplastin time, and fibrin split products.
http://www.cancernetwork.com/cancer-management/fluid-complications/article/10165/1802878 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 thatpatients with positive cytology results had a 26-day shunt survival, as compared with 140 days inpatients with negative cytology results. Other studies have failed to demonstrate a correlation betweenascites with malignant cells and decreased survival.
Clearly, shunting is not a benign procedure, but in carefully selected patients who have not responded toother treatment modalities and who are experiencing symptoms from ascites, it may provide neededpalliation. Because of the limited effectiveness of peritoneovenous shunts, patients should be carefullyselected 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
on malignant ascites
Ayantunde AA, Parsons SL: Pattern and prognostic factors in patients with malignant ascites: A
retrospective study. Ann Oncol 18:945–949, 2007.
Gushchin V, Demmy TL, Kane JM 3rd: Surgical management of metastatic peritoneal or pleural
disease. Semin Oncol 34:215–225, 2007.
Rosenberg SM: Palliation of malignant ascites. Gastroenterol Clin North Am 35:189–199, 2006.
Seike M, Maetani I, Sakai Y: Treatment of malignant ascites in patients with advanced cancer:
Peritoneal shunt versus paracentesis. J Gastroenterol Hepatol 22:2161–2166, 2007.
Abbreviations in this chapter
SEER = Surveillance, Epidemiology, and End Results

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