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 frekquently 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 et al generated survival curves for more than 8,000 patients with non–small-cell lung cancer (NSCLC) with pleural effusion (ie, stage IIIB) from the SEER database and showed that long-term survival is uncommon in this group. The median survival time is approximately 3 months.
Diagnosis
The new onset of pleural effusion may herald the presence of a previously undiagnosed malignancy or, more typically, complicate the course of a known tumor. Malignant pleural effusions can lead to an initial diagnosis of cancer in patients. In Nantes, France, pleural effusion was the first symptom of cancer in 41% of 209 patients with malignant pleural effusion; lung cancer in men (42%) and ovarian cancer in women (27%) were most common.
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 (lactate dehydrogenase [LDH] > 200 U/L; pleural-serum LDH ratio > 0.6; and pleural-serum protein ratio > 0.5) help to categorize pleural effusions as exudates.
The majority of undiagnosed exudates are eventually diagnosed as malignant, whereas < 5% of transudates are shown to be caused by cancer. Transudates may be misclassified as exudates following dehydration or diuresis and if there are erythrocytes (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 we are unaware of any test or panel of tests that can reliably diagnose malignant effusions.
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(Drug information on 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.
Investigators in Cambridge, England, report that thickening of the pleura > 1 cm, pleural nodularity, and diaphragmatic thickening > 7 mm on either CT (computed tomography) or ultrasonography suggest malignant effusion.
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, thoracoscopic pleural biopsy permits the diagnosis and staging of malignant mesothelioma if it is the cause of the effusion. Thoracoscopy also offers the opportunity for simultaneous treatment.
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
Bronchoscopy may be helpful when an underlying lung cancer is suspected, especially if there is associated hemoptysis, a lung mass, atelectasis, or a massive effusion. It may also be useful when there is a cytologically positive effusion with no obvious primary tumor.
Prognosis
Prognosis of patients with malignant pleural effusion varies by primary tumor. For example, median survival of patients with lung cancer is 3 months, whereas it is 10 months for patients with breast cancer. Median survival is also shorter in patients with encasement atelectasis (3 months).
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 a variety of methods available for 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, a multiloculated effusion may develop or the underlying collapsed lung will become encased by tumor and fibrous tissue in as many as 10% to 30% of cases. Multiloculated effusions are difficult to drain by thoracentesis or chest tube placement. Once encasement atelectasis has occurred, the underlying lung is "trapped" and will no longer reexpand after thoracentesis or tube thoracostomy. Characteristically, the chest x-ray in such cases shows resolution of the pleural effusion after thoracentesis, but the underlying lung remains partially collapsed. This finding is often misinterpreted by the inexperienced clinician as evidence of a pneumothorax, and a chest tube is placed. The air space persists and the lung remains unexpanded, even with high suction and pulmonary physiotherapy. Allowing the chest tube to remain in place can worsen the situation, resulting in bronchopleural fistulization and empyema. In some cases, a trapped lung on an initial chest x-ray will have delayed reexpansion following chest tube or small pleural catheter drainage.
Intrapleural alteplase(Drug information on 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 be easily employed when unresectable lung cancer with associated effusion is found at the time of thoracotomy.
In 2008, Balassoulis et al reported a study of 34 patients In Thessaloniki, Greece,with symptomatic recurrent malignant pleural effusions who had a chest tube placed followed by pleurodesis with erythromycin(Drug information on erythromycin). The patients were evaluated over a 2-year period. Success of the treatment in each patient 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. The investigators concluded that erythromycin is effective and safe as a sclerosing agent for pleurodesis in patients with malignant pleural effusions.
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.
Chemical agents
Multiple chemical agents have been used.
Tetracycline Tetracycline(Drug information on 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(Drug information on minocycline) are probably equivalent in efficacy to tetracycline.
Bleomycin Intrapleural bleomycin(Drug information on 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 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 over the long term.
Talc can be insufflated in a dry state at the time of thoracoscopy or instilled as a slurry through a chest tube. The dose should be restricted to no more than 5 g. A prospective phase III Intergroup trial of 501 patients randomized to receive thoracoscopic talc vs talc slurry pleurodesis showed similar efficacy in each arm, with increased respiratory complications (14% vs 6%) but less fatigue and higher patient ratings in the insufflation group.
Multiloculated effusions may follow talc use. It is important to ensure that talc does not solidify and form a concretion in the chest tube, thus preventing the drainage of pleural fluid and complete reexpansion of the lung following pleurodesis. Such an event is more likely when small-bore chest tubes are used.
Pleurodesis technique With 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(Drug information on doxycycline) or talc is to be used, the patient should be premedicated with narcotics. Intrapleural instillation of 20 mL of 1% lidocaine(Drug information on lidocaine) before administration of the chemical agent may help to reduce pain.
Following instillation of the chemical agent, the chest tube should remain clamped for at least 2 hours. If high-volume drainage persists, the treatment can be repeated. The chest tube can be removed after 2 or 3 days if drainage is < 300 mL/d.
Follow-up x-rays at monthly intervals assess the adequacy of treatment and allow early retreatment in case of recurrence.
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(Drug information on 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(Drug information on 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 29 patients. The rate of empyema was 4%. The investigators identified three groups that seemed to benefit: (1) patients with the intraoperative finding of a trapped lung in diagnostic VATS procedures; (2) patients after repeated thoracentesis or previously failed attempts at pleurodesis; and (3) patients with a limited life span due to underlying disease.
Other approaches that must be considered experimental at this time include quinacrine, silver nitrate(Drug information on silver nitrate), powdered collagen(Drug information on collagen), and distilled water, as well as various biologic agents, including Corynebacterium parvum, OK-432, tumor necrosis factor, interleukin-2, interferon-α, interferon-β, and interferon-gamma (Actimmune).
Treatment of encasement atelectasis
If encasement atelectasis is found at thoracentesis or thoracoscopy, tube thoracostomy and pleurodesis are futile and contraindicated.
Management options
Surgical decortication 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% 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. A total of 81% had a good result with control of effusion, with subsequent catheter removal (19%) or intermittent drainage for > 1 month or until death (62%). A total of 5% of patients had major complications, including empyema and tumor implant. Thoracoscopic techniques are useful in the presence of multiloculated effusion. These catheters can also be inserted using the Seldinger technique with the patient under local anesthesia. Tremblay et al placed 250 PleurX pleural catheters by percutaneous technique in patients under local anesthesia. No further pleural intervention was required during the lives of 90% of the patients. The median overall survival was 144 days, and spontaneous pleurodesis occurred in 43%. Subsequent studies showed that 70% of patients who had full lung expansion had spontaneous pleurodesis, with lifetime control of pleural effusion in 92%. They also reported good results in patients with mesothelioma effusions.
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(Drug information on mitoxantrone), doxorubicin(Drug information on doxorubicin), and hyperthermic cisplatin(Drug information on 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 using a regimen of intrapleural cisplatin and gemcitabine(Drug information on gemcitabine) (Gemzar), followed by radiotherapy (7,020 cGy in 39 fractions), and completed treatment with IV docetaxel(Drug information on docetaxel). Only two patients experienced recurrent pleural effusion. The median disease-free and overall survival times were 8 and 16 months, respectively, and 63% of patients were alive at 1 year.
Seto et al, from the National Kyushu Cancer Center, Fukuoka, Japan 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. Initial treatment is with chest tube drainage and a medium chain triglyceride diet. If chylous drainage persists then consideration of strict NPO status and hyperalimentation may be needed. Although thoracic duct ligation is frequently successful in benign chylothorax there are few reports of its use for malignant effusions. Chylothorax secondary to lymphoma is usually of low volume and responds to 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. Cost-effectiveness analysis comparing long-term catheter drainage vs talc pleurodesis has not found one approach to be significantly better than the other.
Suggested reading
On malignant pleural effusion
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Dresler CM, Olak J, Herndon JE 2nd, et al: Phase III intergroup study of talc poudrage vs talc slurry sclerosis for malignant pleural effusion. Chest 127:909–915, 2005.
Du Rand I, Maskell N, eds: British Thoracic Society Pleural Disease Guideline 2010. Thorax 65(Suppl 2):ii1–ii76, 2010.
Feller-Kopman D, Parker MJ, Schwartzstein RM: Assessment of pleural pressure in the evaluation 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(Drug information on urokinase) for the treatment of loculated malignant pleural effusions and trapped lungs in medically inoperable cancer patients. J Thorac Oncol 1:460–467, 2006.
Paschoalini Mda S, Vargas FS, Marchi E, et al: Prospective randomized trial of silver nitrate vs talc slurry in pleurodesis for symptomatic malignant pleural effusions. Chest 128:684–689, 2005.
Sarkar S, Bhattacharya G, Bhattacharjee S, Banerjee D: A drop of hydrogen peroxide can differentiate exudative pleural effusion from transudate--development of a bedside screening test. Clin Chim Acta 405:83–86, 2009.
Schneider T, Reimer P, Storz K, et al: Recurrent pleural effusion: who benefits from a tunneled pleural catheter? Thorac Cardiovasc Surg 57:42–46, 2009.
Steger V, Mika U, Toomes H, et al: Who gains most? A 10-year experience with 611 thoracoscopic talc pleurodeses. Ann Thorac Surg 83:1940–1945, 2007.
Tan C, Sedrakyan A, Browne J, et al: The evidence on the effectiveness of management for malignant pleural effusion: A systematic review. Eur J Cardiothorac Surg 29: 829–838, 2006.
Tremblay A, Mason C, Michaud G: Use of tunnelled pleural catheters for malignant pleural effusions in patients fit for pleurodesis. Eur Respir J 30:759–762, 2007.
Vignon P, Dugard A, Abraham J, et al: Focused training for goal-oriented hand-held echocardiography performed by noncardiologist residents in the intensive care unit. Intensive Care Med 33:1795–1799, 2007.
Warren WH, Kalimi R, Khodadadian LM, et al: Management of malignant pleural effusions using the Pleur (x) catheter. Ann Thorac Surg 85:1049–1055, 2008.
William WN Jr, Lin HY, Lee JJ, et al: Revisiting stage IIIB and IV non-small cell lung cancer: Analysis of the surveillance, epidemiology, and end results data. Chest 136:701–709, 2009.
