Cancer Management Chapter 41: Fluid complications

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 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 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.

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 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 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.

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, 200

8).

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 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 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 therapyChemotherapy 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 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, 200

7).

Repeated paracentesis, probably the most frequently employed treatment modality, provides significant symptomatic relief in the majority of cases. The procedure is minimally invasive and can be combined with abdominal ultrasonography to better localize fluid collections. High-volume paracentesis has been performed without inducing significant hemodynamic instability and with good patient tolerance.

After paracentesis, 78% of all patients reported relief of their symptoms, especially in the areas of abdominal bloating, anorexia, dyspnea, insomnia, and fatigue. In addition, overall quality of life improved after paracentesis.

Significant morbidity occurs with repeated taps and becomes more severe with each tap necessary to alleviate symptoms. Ascitic fluid contains a high concentration of proteins. Routine removal of ascites further depletes protein stores. The removal of large volumes of fluid also can result in electrolyte abnormalities and hypovolemia. In addition, complications can result from the procedure itself. They include hemorrhage, injury to intra-abdominal structures, peritonitis, and bowel obstruction. Contraindications to repeated paracentesis are viscous loculated fluid and hemorrhagic fluid.

With the placement of an intraperitoneal port, used also for the instillation of intraperitoneal chemotherapy, removal of ascitic fluid is possible without the need for repeated paracentesis. Other possible catheters for use in repeated paracentesis include PleurX and Tenckoff catheters (used for intraperitoneal dialysis). Placement of a semipermanent catheter minimizes the risk of injury to intra-abdominal structures. However, the benefits are tempered by increased infectious risks as well as the possibility of a nonfunctioning catheter requiring removal and replacement.

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.

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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On pericardial effusion

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On malignant ascites

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