Malignant Pleural Effusion
Malignant pleural effusion complicates the care of approximately 150,000 people in the United States each year. The pleural effusion is usually caused by a disturbance of the normal Starling forces regulating reabsorption of fluid in the pleural space, secondary to obstruction of mediastinal lymph nodes draining the parietal pleura. Tumors that metastasize frequently to these nodes (eg, lung cancer, breast cancer, and lymphoma) cause most malignant effusions. It is, therefore, puzzling that small-cell lung cancer infrequently causes effusions. Primary effusion lymphomas caused by human herpesvirus 8 and perhaps Epstein-Barr virus (EBV) are seen in patients with acquired immune deficiency syndrome (AIDS).
Sidebar: Stathopoulos et al from Athens, Greece have provided a model to explain why only some cancers result in malignant effusions. They suggest that expression of transcriptional programs leading to higher levels of signaling molecules intrapleurally result in increased permeability. Further interaction with other host cells results in angiogenesis and vascular leakage (Stathopoulos GT, et al: Am J Respir Crit Care Med 186:487–492, 2012). Investigators from Tel Hashomer, Israel provide microstructural support for this theory in a study of pleural biopsies from patients with pleural effusion with and without adenocarcinoma. They demonstrate a striking increase in microvessel density. Capillaries and lymphatics are abnormal, displaying changes in normal antigen expression on endothelial cells and pericytes; these changes correspond to disturbed vessel wall integrity that is consistent with hyperpermeability (Damianovich M, et al: Clin Lung Cancer 14:688–698, 2013). The role of vascular endothelial growth factor in these processes is discussed in this chapter.
Pleural effusion restricts ventilation and causes progressive shortness of breath by compression of lung tissue as well as paradoxical movement of the inverted diaphragm. Pleural deposits of tumor cause pleuritic pain.
Pleural effusions occur more commonly in patients with advanced-stage tumors, who frequently have metastases to the brain, bone, and other organs; physiologic deficits; malnutrition; debilitation; and other comorbidities. Because of these numerous clinical and pathologic variables, it is difficult to perform prospective trials in patients with pleural effusions. For the same reason, it is often difficult to predict a potential treatment outcome or anticipated duration of survival for the specific patient with multiple interrelated clinical problems.
William et al generated survival curves for more than 8,000 patients with non–small-cell lung cancer (NSCLC) with pleural effusion (ie, stage IIIB) from the SEER database and showed that long-term survival is uncommon in this group. The median survival time is approximately 3 months.
Sidebar: Investigators in São Paulo, Brazil studied 22 patients with unilateral malignant pleural effusions following thoracentesis with electrical impedance tomography and described heterogeneous re-ventilation responses. They noted that pleural effusion causes ventilatory asynchrony—sometimes “so extreme that one lung was inflating while the other was deflating,” ie, paradoxical ventilation, immediately reversible with thoracentesis. The authors reported that after thoracentesis, “ipsilateral and contralateral lungs re-aerated immediately and without further re-aeration over the next hour”(Alves SH et al: Ann Am Thorac Soc 11:186–191, 2014).
Morgensztern et al, from Yale University, used Surveillance, Epidemiology, and End Results (SEER) data to identify 57,000 patients with NSCLC; among this group, 9,170 (15.9%) had malignant pleural effusions, including 5,226 with distant metastases and 3,944 without distant metastases. Malignant pleural effusions were associated with larger primary tumors, mediastinal nodal metastasis, and adenocarcinoma. Median survival was better in patients without distant metastasis compared with those who had distant metastasis (5 months vs 3 months, respectively), as were 1- and 2-year survival rates (24.8% vs 12.6% and 11.3 vs 5.4%, respectively).
The new onset of pleural effusion may herald the presence of a previously undiagnosed malignancy or, more typically, complicate the course of a known tumor. Malignant pleural effusions can lead to an initial diagnosis of cancer in patients. In Nantes, France, pleural effusion was the first symptom of cancer in 41% of 209 patients with malignant pleural effusion; lung cancer in men (42%) and ovarian cancer in women (27%) were most common. It is important to bear in mind that many cancer patients have comorbid illness and that pleural effusion may have another etiology.
Sidebar: A group in Bristol, England did CT pulmonary angiograms on consecutive new patients presenting with unilateral pleural effusion in instances in which there was not an immediately obvious cause. Pulmonary embolism was detected in 9 of 141 patients (6.4%); 8 of these 9 patients also had malignant pleural effusion (Hooper C, et al: Respiration 87:26–31, 2014).
Thoracentesis is the first step in management of almost all cases of malignant pleural effusion. Ultrasonography facilitates thoracentesis, reduces the rate of complications such as pneumothorax, and can identify pleural nodules and/or thickening, suggesting malignant etiology, as well as targeting known lesions for pleural biopsy. An adequate specimen should be obtained and sent for lab studies designed to separate benign and malignant effusions, including cell count; determination of glucose, protein, lactate dehydrogenase (LDH), and pH; and appropriate cultures and cytology. Chest pressure and pain during thoracentesis can occur when lung elastance is reduced and pleural pressures are markedly negative. Such pain suggests a “trapped” lung and signals an increased risk of postthoracentesis pulmonary edema.
In circumstances in which it is thought desirable to provide continuing drainage of fluid, Seldinger wire–guided placement of small-bore catheters have largely replaced larger chest tubes. Cafarotti et al described the use of 12-F small-bore catheter placements in more than 1,000 patients, with successful drainage in 93.8% of 324 cases of malignant pleural effusion.
The Light criteria (lactate dehydrogenase [LDH] > 200 U/L; pleural-serum LDH ratio > 0.6; and pleural–serum protein ratio > 0.5) help to categorize pleural effusions as exudates.
The majority of undiagnosed exudates are eventually diagnosed as malignant, whereas < 5% of transudates are shown to be caused by cancer. Transudates may be misclassified as exudates following dehydration or diuresis and if there are erythrocytes (and LDH) in the fluid. Brain natriuretic protein levels are markedly elevated in effusions secondary to congestive heart failure.
Sarkar et al have introduced a simple bedside test that allows identification of exudative effusion at the time of thoracentesis. They add 10 mL of 30% hydrogen peroxide to 200 mL of pleural effusion. When catalase is present (exudates), the effusion foams. None of 32 transudates produced foam, whereas all 52 exudates produced profuse bubbles. The test is not accurate if blood contaminates the fluid.
A negative cytology result is not uncommon and does not rule out a malignant etiology. If cytology is negative in an exudative effusion, approximately 25% will have a positive cytology on a second thoracentesis; blind pleural biopsy may increase the yield to nearly 50%. This low diagnostic yield can be improved by CT or ultrasonographic guidance of needle biopsy.
Investigators in Cambridge, England, report that thickening of the pleura > 1 cm, pleural nodularity, and diaphragmatic thickening > 7 mm on either CT (computed tomography) or ultrasonography suggest malignant effusion. On positron emission tomography (PET) scan, a high SUV (standard uptake value) may indicate a malignant pleural effusion. It is important to note that high SUV values may persist for long periods following talc pleurodesis (TP).
Metintas et al reported results of a randomized, controlled trial of medical thoracoscopy vs CT-guided Abrams pleural needle biopsy for diagnosis in patients with malignant pleural effusions. They studied 124 patients with exudative pleural effusions that were not diagnosed by cytologic analysis. Patients were randomized after CT scan to either thoracoscopy and biopsy or CT-guided needle biopsy. CT-guided needle biopsy yielded diagnostic sensitivity of 87.5%, compared with 94.1% in the thoracoscopy group (not statistically significant). Complication rates were low and acceptable with both methods. The authors recommend use of CT-guided needle biopsy for pleural biopsy as the primary method of diagnosis in patients with pleural thickening or lesions observed by CT scan. In patients with pleural fluid without pleural thickening on CT scan and in those who may have benign pleural pathologies other than tuberculosis, the primary method of diagnosis recommended is thoracoscopy. Letovanec et al, from Lausanne, Switzerland, reported on 47 patients with pleural effusion studied with PET/CT, noting that SUV in malignant effusions is higher than in benign effusions (3.7 vs 1.7 g/mL), showing a correlation between malignant effusion and SUV. They conclude that PET/CT may assist in differentiation between malignant vs benign origin of pleural effusion with high specificity in patients with known cancer, specifically NSCLC.
Because it is sometimes difficult to prove the malignant nature of an effusion cytologically, and because thousands of proteins (secretome) and many other nucleic acids, volatile compounds, etc, have been identified in pleural fluid, many molecular tests on pleural fluid have been investigated. Multiple reports measure pleural tumor marker proteins, glycosaminoglycans, cadherins, matrix metalloproteins, cytokines, telomerase, mRNA, exosomes, and serum and pleural DNA methylation patterns, fluorescence in situ hybridization (FISH), proteomics, and many other methods of pleural fluid testing are described. A number of meta-analyses of diagnostic testing have been published, but to date we are unaware of any test or panel of tests that can reliably diagnose malignant effusions with sufficient confidence to allow clinicians to prescribe treatment with cytotoxic agents in the absence of a pathological diagnosis of cancer. Accordingly, biomarker tests and panels have limited utility at present, except perhaps to guide further diagnostic efforts.
Bhattacharya et al, from Kolkata, India, reported on 66 patients with malignant pleural effusion who underwent closed pleural biopsy routinely with diagnostic thoracentesis. Overall, there was 69% positive cytology: 52% on the first examination, 15% on the second, and 1.5% on the third. Closed pleural biopsy identified malignant pleural effusion in 10 additional patients not diagnosed by fluid cytology. There were no major complications.
Thoracoscopic examination performed with the patient under either general or local anesthesia and using rigid or partly flexible thoracoscopes offers a very high sensitivity, specificity, and diagnostic accuracy with a low complication rate. It allows comprehensive visualization of one pleural cavity, coupled with the opportunity to biopsy areas of disease. This method provides a definitive diagnosis and allows the pathologist to suggest possible sites of primary disease based on the histopathology.
Galbis et al from Valencia, Spain prospectively investigated 110 patients who had thoracoscopy for undiagnosed pleural effusions with negative cytologic examination of fluid obtained by thoracentesis. Following thoracoscopy and biopsy, 30% were diagnosed with nonspecific pleuritis, 17% with malignant pleural mesothelioma, 1.8% with pleural tuberculosis, and 48% with pleural carcinoma.
There was no incidence of later development of a malignant pleural effusion following a benign thoracoscopic study in 25 patients at the Lahey Clinic, but Davies et al from the Oxford Pleural Unit report on longer-term follow-up of patients with a diagnosis of nonspecific pleuritis/fibrosis on thoracoscopic pleural biopsy. They retrospectively reviewed 142 patients with a prior medical thoracoscopy and biopsy. Patients were followed until death or for a mean of 21 months. A total of 44 patients were diagnosed with nonspecific pleuritis/fibrosis and 98 patients (69%) had a definitive histological diagnosis. The authors reported that five (12%) patients with nonspecific pleuritis/fibrosis subsequently had a diagnosis of malignant pleural mesothelioma after a mean interval of 9.8 months. Accordingly the false-negative rate of thoracoscopic biopsy for the detection of pleural malignancy was 5%, with a diagnostic sensitivity of 95% and a negative predictive value of 90%. They conclude that “patients with nonspecific pleuritis/fibrosis require careful follow-up.”
Furthermore, thoracoscopic pleural biopsy permits the diagnosis and staging of malignant mesothelioma if it is the cause of the effusion. Thoracoscopy also offers the opportunity for simultaneous treatment. Both talc pleurodesis and intrapleural catheter drainage have shown sustained benefit in palliative management of both malignant pleural effusion and malignant pleural mesothelioma.
Occult malignancy can exist even in the case of a grossly normal pleura at the time of thoracotomy for resection of lung cancer. Multiple studies, particularly in Japan, have investigated the prognostic value of intraoperative pleural lavage specimen cytologic examination. This would appear to be an area in which productive research could be conducted to answer the question of whether prognosis might be improved in these patients through prospective adjuvant interventional trials.
Kaneda et al, from the Mie Chuo Medical Center in Japan, have reported on the value of pleural lavage cytology examined during surgery for primary lung cancer. They studied 3,231 patients retrospectively who had had thoracic washing cytology at the time of surgical resection of lung cancer, and noted that cytology was positive in 4.58% of cases. These patients had significantly worse survival (P = .001) and a higher incidence of recurrent pleural carcinoma. The investigators comment that positive cytologic findings should be treated as “supplemental…to the precise diagnosis of TNM staging.” They suggest scoring positive pleural cytology findings as a new T3 sub-category (PL3).
This would appear to be an area in which productive research could be conducted to answer the question of whether prognosis might be improved in these patients through prospective adjuvant interventional trials.
Sidebar: What should be done when a small malignant effusion or limited pleural metastases are found at the time of thoracotomy for otherwise resectable lung cancer? The presence of even small pleural effusions has been shown to correlate with reduced survival. Small series have described aggressive surgical interventions—including lobectomy or even pneumonectomy combined with pleurectomy and intrapleural chemotherapy—in lung cancer patients who have metastatic pleural nodules, with and without small pleural effusions. Fiorelli conducted a literature review on this subject and concluded that “no current guidelines support surgery over conservative therapy even when combined with postoperative adjuvant chemotherapy or radiation therapy.” (Fiorelli A, Santini M: Interact Cardiovasc Thorac Surg 17:407-412, 2013).
Bronchoscopy 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, median survival of patients with lung cancer is 3 months, whereas it is 10 months for patients with breast cancer. Median survival is also shorter in patients with encasement atelectasis (3 months).
Sakr retrospectively reviewed prognostic indicators among 421 patients with malignant pleural effusion who underwent medical thoracoscopy. The median survival of patients with malignant pleural effusion was 9.4 months. In univariate analysis, melanoma, age < 60, bloody effusion, extensive pleural adhesions, and widespread pleural nodules correlated with reduced survival, but extent of pleural tumor did not correlate with reduced survival on multivariate analysis. Survival can be predicted with some precision using a LENT prognostic score.
Initial treatment: Palliation
Because malignant pleural effusion causes distress and disability and is associated with brief survival, initial management has chiefly been palliative with either drainage of fluid serially over time or obliteration of the pleural space by pleurodesis. Because the specific clinical circumstances may vary markedly in different patients, treatment must be individualized to provide the best palliation for each patient. Generally, there are a variety of methods available for palliative treatment of malignant effusions, and there is little compelling evidence to guide clinicians in the choice of the best methods. Accordingly, treatment decisions must be made with careful reference to the status of the patient and the skills and equipment available in the local community. In general, malignant pleural effusion should be treated aggressively as soon as it is diagnosed. In most cases, effusion will rapidly recur after treatment by thoracentesis or tube thoracostomy alone.
If a malignant pleural effusion is left untreated, a multiloculated effusion may develop or the underlying collapsed lung will become encased by tumor and fibrous tissue in as many as 10% to 30% of cases. Multiloculated effusions are difficult to drain by thoracentesis or chest tube placement. Once encasement atelectasis has occurred, the underlying lung is “trapped” and will no longer reexpand after thoracentesis or tube thoracostomy. Characteristically, the chest x-ray in such cases shows resolution of the pleural effusion after thoracentesis, but the underlying lung remains partially collapsed. This finding is often misinterpreted by the inexperienced clinician as evidence of a pneumothorax, and a chest tube is placed. The air space persists and the lung remains unexpanded, even with high suction and pulmonary physiotherapy. Allowing the chest tube to remain in place can worsen the situation, resulting in bronchopleural fistulization and empyema. In some cases, a trapped lung on an initial chest x-ray will have delayed reexpansion following drainage with a chest tube or small pleural catheter.
Intrapleural alteplase (10–20 mg diluted in 50 to 150 mL of saline) has been used with success in some patients with gelatinous or loculated effusions, with a low incidence of bleeding complications.
Physical techniques. To avoid encasement atelectasis, pleural effusion should be treated definitively at the time of initial diagnosis. Multiple physical techniques have been used to produce adhesions between the parietal and visceral pleurae, obliterate the space, and prevent recurrence. They include open or thoracoscopic pleurectomy, gauze abrasion, or laser pleurodesis. Surgical methods have not been demonstrated to have any advantage over simpler chemical pleurodesis techniques in the treatment of malignant effusions. Gauze abrasion pleurodesis can be easily employed when unresectable lung cancer with associated effusion is found at the time of thoracotomy.
A randomized, prospective study from Ljubljanska, Slovenia, of 87 patients with malignant pleural effusion secondary to breast cancer showed that the thoracoscopic mechanical abrasion pleurodesis was equivalent to talc pleurodesis (TP) in those with normal pleural fluid pH and superior in patients with a low pH.
Chemical agents. Multiple chemical agents have been used.
• Tetracycline—Tetracycline pleurodesis results in a lower incidence of recurrence when compared with tube thoracostomy alone but often causes severe pain. Tetracycline is no longer commercially available in the United States.
• Doxycycline and minocycline—Doxycycline and minocycline are probably equivalent to tetracycline in terms of their efficacy and associated patient discomfort.
• Erythromycin—Erythromycin also causes pleural pain on administration, and in a small series produced a complete response in 79% of patients at 90 days. Recurrence with necessity for re-intervention was seen in 11.8%.
• Bleomycin—Intrapleural bleomycin, at a dose of 60 U, has been shown to be more effective than tetracycline and is not painful, but it is costly. Absorption of the drug can result in systemic toxicity. Combined use of tetracycline and bleomycin has been demonstrated to be more efficacious than use of either drug singly.
• Talc—Talc pleurodesis was first introduced by Norman Bethune in the 1930s. The first use of talc in malignant pleural effusion was by John Chambers in 1958. Talc powder (Sclerosol Intrapleural Aerosol) has demonstrated efficacy in numerous large studies, preventing recurrent effusion in 70% to 92% of cases. Talc is less painful than tetracycline. Cost is minimal, but special sterilization techniques must be mastered by the hospital pharmacy. Talc formulations may have significant differences in the size of particles. Smaller particles may be absorbed and disseminated systemically and may contribute to the increased incidence of adult respiratory distress syndrome (ARDS) or substantial hypoxemia. Gonzalez et al studied the incidence of lung injury following TP with a median dose of talc (Sclerosol) of 6 g. Cases with new infiltrates on a chest x-ray, increased oxygen requirement, and no identifiable trigger other than talc exposure were considered to represent a talc-related lung injury. A total of 12 of 138 patients experienced increased oxygen requirements within 72 hours of the treatment. Four patients (2.8%) had talc-related lung injury.
Talc has also been shown to cause decreases in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and diffusing capacity over the long term.
Talc can be insufflated in a dry state at the time of thoracoscopy or instilled as a slurry through a chest tube. The dose should be restricted to no more than 5 g. A prospective phase III Intergroup trial of 501 patients randomized to receive thoracoscopic talc vs talc slurry pleurodesis showed similar efficacy in each arm, with increased respiratory complications (14% vs 6%) but less fatigue and higher patient ratings in the insufflation group.
Multiloculated effusions may follow talc use. It is important to ensure that talc does not solidify and form a concretion in the chest tube, thus preventing the drainage of pleural fluid and complete reexpansion of the lung following pleurodesis. Such an event is more likely when small-bore chest tubes are used.
• Pleurodesis technique—With TP, a 24- to 32-French tube has customarily been inserted through a lower intercostal space and placed on underwater seal suction drainage until all fluid is drained and the lung has completely reexpanded. Because severe lung damage can be produced by improper chest tube placement, it is imperative to prove the presence of free fluid by a preliminary needle tap and to enter the pleural space gently with a blunt clamp technique, rather than by blind trocar insertion. If there is any question about the presence of loculated effusion or underlying adhesions, the use of CT or sonography may enhance the safety of the procedure. In the case of large effusions, especially those that have been present for some time, the fluid should be drained slowly to avoid reexpansion pulmonary edema.
Significant complications can occur with both thoracentesis and chest tube thoracostomy. These procedures should not be performed by inexperienced practitioners without training and supervision. Ultrasound guidance is recommended.
Premedications: If doxycycline or talc is to be used, the patient should be premedicated with narcotics. Intrapleural instillation of 20 mL of 1% lidocaine before administration of the chemical agent may help to reduce pain.
Following instillation of the chemical agent, the chest tube should remain clamped for at least 2 hours. If high-volume drainage persists, the treatment can be repeated. The chest tube can be removed after 2 or 3 days if drainage is < 300 mL/d.
Follow-up x-rays at monthly intervals assess the adequacy of treatment and allow early retreatment in case of recurrence.
Sidebar: Arellano-Orden et al, from Sevilla, Spain, studied 227 patients with malignant pleural effusions treated with large particle (50% of particles > 10 nm) vs small particle (< 20% of particles > 10 nm) talc pleurodesis. Death within 7 days occurred in 8 of 107 patients with small-talc pleurodesis vs 1/127 using large-talc pleurodesis. Levels of interleukin, tumor necrosis factor alpha, vascular endothelial growth factor, and thrombin-antithrombin complex were higher in patients with small-talc pleurodesis, and proinflammatory cytokines were higher in patients with greater tumor burden. The authors concluded that small talc particles provoke a strong inflammatory reaction in both the pleural space and serum, associated with a higher rate of early deaths (Arellano-Orden E, et al: Respiration 86:201–209, 2013).
• Alternative approaches—Use of fluid-sclerosing agents and outpatient pleurodesis has been advocated by some investigators and has the potential for reducing hospital stay and treatment cost. Patz performed a prospective, randomized trial of bleomycin vs doxycycline (72% bleomycin vs 79% doxycycline) pleurodesis via a 14-French catheter and found no difference in efficacy. Aglayan, in Istanbul, Turkey, evaluated iodopovidone via either chest tube or a small-bore catheter in 41 patients. Complete and partial successes were observed in 60% and 27%, respectively. Results did not differ by diameter of the tube. (Because of the risk of iodine toxicity with renal failure and seizures, such use of iodopovidone should be limited to 2% solutions and should not be used in patients taking amiodarone or with prolonged use of topical iodine wound treatments.)
Schneider et al reported on 100 patients with tunneled pleural catheters. The mean residence time of the catheter was 70 days. Spontaneous pleurodesis was achieved in 29 patients. The rate of empyema was 4%. The investigators identified three groups that seemed to benefit: (1) patients with the intraoperative finding of a trapped lung in diagnostic video-assisted thoracic surgery (VATS) procedures; (2) patients after repeated thoracentesis or previously failed attempts at pleurodesis; and (3) patients with a limited life span due to underlying disease.
Other approaches that have been utilized include quinacrine, silver nitrate, powdered collagen, and distilled water, as well as various biologic agents, including Corynebacterium parvum, OK-432, tumor necrosis factor, interleukin-2, interferon-α, interferon-β, and interferon-gamma (Actimmune).
Treatment of encasement atelectasis
If encasement atelectasis is found at thoracentesis or thoracoscopy, tube thoracostomy and pleurodesis are futile and contraindicated.
Surgical decortication. Surgical decortication has been advocated for this problem. This potentially dangerous procedure may result in severe complications, however, such as bronchopleural fistula and empyema. In carefully selected cases with early multiloculated malignant effusion, gentle thoracoscopic debridement can restore a single cavity and allow effective pleural drainage or TP.
Pleuroperitoneal shunts. The Royal Brompton Hospital, London, group reported experience with pleuroperitoneal shunts in 160 patients with malignant pleural effusion and a trapped lung. Effective palliation was achieved in 95% of patients; 15% of patients required shunt revisions for complications.
Intermittent thoracentesis. Intermittent thoracentesis, as needed to relieve symptoms, may be the best option in patients with a short anticipated survival time.
Catheter drainage. Another option is to insert a tunneled, small-bore, cuffed, silicone catheter (PleurX pleural catheter, Denver Biomaterials, Inc., Denver, Colorado) into the pleural cavity. The patient or family members may then drain fluid, using vacuum bottles, whenever recurrent effusion causes symptoms. Bard manufactures an indwelling catheter gravity drainage system under the trade name Aspira.
Kakuda reported on placement of 61 PleurX pleural catheters in 50 patients with malignant pleural effusions at City of Hope; 34% had lung cancer and 24% had breast cancer. There were no operative deaths. In cases in which the catheter was placed under thoracoscopic control, 27 of 38 patients (68%) had encasement atelectasis visualized. A total of 81% had a good result with control of effusion, with subsequent catheter removal (19%) or intermittent drainage for more than 1 month or until death (62%). A total of 5% of patients had major complications, including empyema and tumor implant. Thoracoscopic techniques are useful in the presence of multiloculated effusion. These catheters can also be inserted using the Seldinger technique with the patient under local anesthesia. Tremblay et al placed 250 PleurX pleural catheters by percutaneous technique in patients under local anesthesia. No further pleural intervention was required during the lives of 90% of the patients. The median overall survival was 144 days, and spontaneous pleurodesis occurred in 43%. Subsequent studies showed that 70% of patients who had full lung expansion had spontaneous pleurodesis, with lifetime control of pleural effusion in 92%. They also reported good results in patients with mesothelioma effusions.
Thornton et al, from Memorial-Sloan Kettering Cancer Center, report on the use of tunneled pleural catheters for treatment of recurrent, symptomatic malignant pleural effusions following failed pleurodesis in 63 patients. Following placement of tunneled catheters, 60 of 63 patients had clinical improvement in dyspnea. After a median of 3 days in the hospital, 90% were discharged with the catheter in place. About one-third (31%) needed intrapleural fibrinolytic therapy for optimum evacuation.
Davies et al, from University Hospital of Wales in Cardiff, reported follow-up at 1 year in an unblinded study of 106 patients from seven hospitals in the United Kingdom who had previously untreated malignant pleural effusions. Patients were randomized to either intrapleural catheters (IPCs) placed on an outpatient basis or chest tube insertion and talc slurry pleurodesis (TP). Dyspnea improved on a visual analog scale in both groups with no significant difference in mean dyspnea (24.7 mm in the intrapleural catheter group; 24.4 mm in the talc group). After 6 months the IPC group had a statistically significant mean difference of 14 mm in the dyspnea score over the talc group. Hospitalization was minimized in the IPC group (median, 0 days compared with 4 days for the talc arm). There was no significant difference in quality of life. Twenty-two percent of patients in the TP arm required further pleural procedures compared with 6% in the IPC group. Adverse events occurred in 21 of 52 patients in the IPC group compared with 7 of 54 in the talc group.
Freeman et al, from Indianapolis, Indiana, performed a propensity-matched comparison of talc poudrage pleurodesis versus tunneled pleural catheters in patients undergoing diagnostic thoracoscopy for malignancy. The group treated with pleural catheters had a significantly shorter hospital stay and interval to initiation of systemic therapy for their malignancy, as well as a lower rate of operative morbidity compared with patients undergoing pleurodesis. The authors also noted that “the rate of freedom from re-intervention equaled that of talc pleurodesis.”
A Point/Counterpoint article in Chest between Pyng Lee, MD, and Richard Light, MD, on the question, “Should thoracoscopic talc pleurodesis be the first choice management for malignant effusion?”serves as a good review of published literature on management of malignant pleural effusions and a spirited debate on the relative risks and benefits of treatment options.
IPCs have been used safely in pediatric patients in two small series. Although there is a small risk of infection in patients with IPCs, it has been shown that such infection is not increased in patients undergoing chemotherapy following catheter placement. There is a small incidence of tumor implantation at the site of the catheter.
Sidebar: Although this chapter does not deal directly with the subject of management of malignant pleural mesothelioma (MPM), the question arises as to what the clinician should do when MPM is identified at the time of diagnostic thoracoscopy and no immediate plan for surgical resection is in place. A review of cases in the Western Australia Mesothelioma registry showed that either talc poudrage or postoperative talc slurry pleurodesis prevented reaccumulation of malignant effusion in approximately 70% of cases. A prospective randomized trial of 175 patients with MPM showed no survival advantage of VATS (video-assisted thoracic surgery) pleurectomy over talc poudrage.
Chemotherapy. If the clinician decides to precede palliative intervention with administration of systemic chemotherapy for the underlying primary malignancy, in tumors such as breast cancer, lymphoma, and small-cell lung cancer, it is important to monitor the patient carefully for recurrent effusion after thoracentesis and to treat such recurrences immediately. A recent spate of published data document the chance of success in clearance of malignant pleural effusions with systemic and intrapleural chemotherapy and/or targeted molecular therapies. Chemotherapy options depend on the cell type of the tumor and the general condition of the patient. Although intrapleural chemotherapy offers the possibility of high-dose local therapy with limited systemic effects, only a few small pilot studies utilizing mitoxantrone, doxorubicin, and hyperthermic cisplatin have been published.
Ang reported longer mean survival (12 months vs 5 months) when systemic chemotherapy was given to 71 patients who initially presented with malignant pleural/pericardial effusions.
Su et al treated 27 patients with NSCLC presenting with a malignant pleural effusion using a regimen of intrapleural cisplatin and gemcitabine (Gemzar) followed by radiotherapy (7,020 cGy in 39 fractions), and completed treatment with IV docetaxel. Only two patients experienced recurrent pleural effusion. The median disease-free and overall survival times were 8 and 16 months, respectively, and 63% of patients were alive at 1 year.
Seto et al reported a single-arm series of 80 patients with previously untreated malignant pleural effusions from NSCLC. The patients had chest tubes placed and were given 25 mg of cisplatin in 500 mL of distilled water intrapleurally. Toxicity was acceptable. Median time of drainage was 4 days. A total of 34% had a complete response and 49% had a partial response, for an overall response rate of 83%. An interesting finding in this study was that the median survival time of all patients was 239 days, longer than typically seen in other series of comparable patients treated with pleurodesis. The authors recommend a phase III study.
Chen et al, in Wenzhou, China, performed a prospective randomized study to evaluate the safety and efficacy of combined intrapleural cisplatin and OK-432 with or without hyperthermic therapy in patients with malignant pleural effusion. A total of 358 patients were randomized. The investigators reported a significantly higher overall response (93% vs 79%) in patients treated with hyperthermic therapy. Median survival time of patients was 8.9 months and 6.2 months, respectively, with versus without hyperthermic therapy, with only mild toxicity reported.
Two important recent studies suggest that tissue obtained from malignant effusions may be useful in implementation of a personalized approach to cancer treatment. Molecular methods can be deployed in situations in which cellular tissue is unavailable or would require risky biopsy techniques. Tsai et al, from the National Taiwan University Hospital, have observed that tumor tissue is often not obtainable or suitable for molecular-based epidermal growth factor receptor (EGFR) mutational analysis in NSCLC. They performed a retrospective evaluation of the role of effusion immunocytochemistry using EGFR mutant–specific antibodies to detect relevant mutations in NSCLC on the cell blocks of malignant pleural effusion from 78 patients with lung adenocarcinoma. They report that their method exhibited a high sensitivity and specificity for mutations and comment that effusion immunocytochemistry provides better prediction of tumor response and progression-free survival with first-line EGFR tyrosine kinase inhibitors (TKIs) than clinical characteristics like sex and smoking status. Patients whose effusion immunocytochemistry showed a reaction to either of the two antibodies had a TKI response rate comparable to those with EGFR mutations assessed by direct sequencing from cell-derived RNA. The investigators suggest that effusion immunocytochemistry could be introduced into clinical practice to help identify NSCLC patients likely to benefit from first-line TKI treatment, especially among those with inadequate tissue for molecular-based EGFR analysis.
Guo et al, from Shandong China, studied the therapeutic effects of and adverse reactions from treatment with erlotinib (Tarceva) for malignant pleural effusions caused by metastatic adenocarcinoma. A total of 128 patients who had failed first-line chemotherapy were divided into mutation and nonmutation groups according to the presence or absence of EGFR mutations. The patients were treated with thoracoscopic TP and oral erlotinib. Short-term and long-term clinical therapeutic effects of erlotinib were evaluated. The EGFR mutation rate of lung adenocarcinoma in pleural metastasis tissue acquired through VATS was higher than that in surgical resection specimens. The authors report a higher complete remission rate in the mutation group compared with the nonmutation group. Overall survival time after erlotinib treatment in patients with EGFR mutations was longer than that in patients without EGFR mutations. The authors comment that “EGFR mutations predict a favorable outcome for malignant pleural effusion of lung carcinoma with Tarceva therapy.” Japanese investigators demonstrated that a multiplex molecular profile identifies genetic abnormalities in cells from approximately 40% of pleural effusions from patients with lung cancer, including EGFR, EML4-ALK, KRAS and EGFR amplification, with a high concordance rate with tissue samples.
Fluid from pleural effusions can also be studied in an attempt to identify mechanisms of acquired resistance to targeted therapies, for example crizotinib for ALK-rearranged lung cancer.
Lombardi et al, from Padova, Italy, treated 18 patients with malignant pleural effusion secondary to ovarian (11) and breast (7) cancers. Following pleural drainage, 120 mg/m2 paclitaxel in normal saline was infused and the pleural catheter clamped and drained 24 hours later. Paclitaxel was measured in blood and pleural fluid at 1, 4, and 24 hours. Chest radiographic surveillance at 1 and 2 months showed an overall response rate of 78%; median overall survival was 8.9 months. Patients with CR had longer survival. Intrapleural paclitaxel concentration was very high (478 mg/L) and declined slowly over 24 hours. Plasma levels were low in most patients (.045 mg/L). The authors concluded that intrapleural paclitaxel is safe and effective.
Sidebar: The role of VEGF and other angiogenic molecules are under active investigation as modulators of pleural hyperpermeability and malignant pleural effusion. A number of studies have demonstrated striking increases in VEGF levels in both blood and pleural fluid. This observation has served as the basis for a number of anecdotal observations and small, early trials of the VEGF antagonist bevacizumab, a humanized monoclonal antibody that binds to VEGF receptors and blocks biological effects of VEGF, given systemically or intrapleurally. VEGF levels in blood and pleural fluid fall in response to treatment and there has been gratifying control of MPE in a substantial percentage of cases treated.
Tamiya et al, in Osaka, Japan, reported on a phase II study of bevacizumab with carboplatin/paclitaxel in 23 patients with nonsquamous, non–small-cell lung cancer with malignant pleural effusion (without prior pleurodesis). Carboplatin/paclitaxel was given only in the first cycle. This was followed by 2 to 6 cycles of chemotherapy with bevacizumab, followed by continued bevacizumab in responding patients. The overall response rate was 60%, and the disease control rate was 87%. The median progression-free survival and overall survival times were 7.1 and 11.7 months, respectively. Plasma vascular endothelial growth factor (VEGF) levels in the effusion were very high at 1,800 pg/mL, and decreased significantly after chemotherapy.
Du et al from Beijing, China conducted a randomized trial in 72 patients with NSCLC and malignant pleural effusion with half of patients treated with intrapleural cisplatin (30 mg) vs intrapleural cisplatin plus bevacizumab (300 mg) at 2-week intervals in addition to 3 cycles of conventional chemotherapy. Control of pleural effusion was greater—83% vs 50%—in the bevacizumab arm. Levels of VEGF messenger RNA were lower in pleural fluid of patients treated with bevacizumab.
Radiation. Radiation therapy may be indicated in some patients with lymphoma but has limited effectiveness in other tumor types, particularly if mediastinal adenopathy is absent.
Chylothorax. Chylothorax (in the absence of trauma) is usually secondary to cancer, most frequently lymphoma. An added element of morbidity is conferred by the loss of protein, calories, and lymphocytes in the draining fluid. Initial treatment is with chest tube drainage and a medium chain triglyceride diet. If chylous drainage persists then consideration of strict nothing-by-mouth status and hyperalimentation may be needed. Although thoracic duct ligation is frequently successful in benign chylothorax, there are few reports of its use for malignant effusions. Chylothorax secondary to lymphoma is usually of low volume and responds to TP in combination with radiotherapy or chemotherapy.
Gross et al, from Sao Paulo, Brazil, reported an overall survival rate of 5.6 months for patients with simultaneous ascites and malignant pleural effusions vs 7.8 months in patients without ascites. They observed that success rates for TP were equal and concluded that concomitant ascites did not influence the effectiveness of palliative surgical management of pleural effusion in patients with malignancies.
Research into quality of life and cost-effectiveness research has advanced in the last few years.
Cost-effectiveness analysis comparing long-term catheter drainage vs TP has not found one approach to be significantly better than the other.
Puri et al, from Washington University at St. Louis, performed a decision analysis to compare repeated thoracentesis, tunneled pleural catheter (TPC), bedside pleurodesis (BP), and thoracoscopic pleurodesis (TP). They studied two scenarios: expected survival of 3 months and 12 months. The incremental cost-effectiveness ratio (ICER) was estimated as least expensive with repeat thoracentesis, in the case of 3-month survival. In comparison, the ICER with intrapleural catheter was $6,450 vs $4,946, with expected survivals of 3 months and 12 months, respectively. Bedside TP (about $11,000) and operative TP (a little over $18,000) were more expensive. The ICER for tunneled pleural catheter over repeat thoracentesis was nearly $50,000. In the case of 12 month–long survival, bedside TP was least expensive (about $13,000) and provided 0.59 quality-adjusted life-years. IPC was approximately $150 more expensive, whereas TP cost $19,000 and repeat thoracentesis was $21,000. They noted that thoracoscopic TP was more effective than bedside TP but that ICER was greater than $250,000. They conclude that IPC treatment is preferable for patients with malignant pleural effusion who have limited survival. Penz et al studied costs in Britain using data from a clinical trial, and found no significant difference in cost between IPC and talc pleurodesis. IPC treatment was slightly less expensive in patients with short survival.
In a study from Kiel, Germany, Schniewind et al reported on 45 of 123 patients with malignant pleural effusions treated with TP who completed quality of life EORTC (European Organisation for Research and Treatment of Cancer) QLC C-30 questionnaires before and after treatment. The authors reported that patients experienced statistically and clinically significant improvements in functional scales throughout the study period, and noted that global health values increased after surgery throughout the entire study period. They also noted “a clear decline in dyspnea upon discharge, followed by a continuous remote increase throughout subsequent months.” The authors conclude that pleurodesis reduces respiratory symptoms. Median survival in the patients who completed the questionnaire was 10.2 months vs 7.5 months in patients who did not participate. Basso et al, from Pordenone, Italy, studied 46 patients with malignant pleural effusion treated with thoracoscopic TP (56% secondary to lung cancer). Chest tube drainage time averaged 9 days. In-hospital mortality was 8%. Following pleurodesis, there was improvement in both Karnofsky scores (4.2 to 2.7) and MRC (Medical Research Council, UK) scores (62 to 71). The authors concluded that quality of life improved following thoracoscopic TP.
Sabur et al, from Calgary, Alberta, reported upon utilization of tunneled pleural catheters in 82 patients with malignant pleural effusions studied using EORTC QLQ-C30 and LC13 quality of life scores at baseline, then at 2 and 14 weeks after catheter placement. Dyspnea improved at 2 weeks (LC13, 64 to 44; C30, 79 to 47; MRC scores, 4.2 to 3) and improvement was maintained at 14 weeks in survivors (55%).
Boshuizen, from Amsterdam, The Netherlands, did a cost analysis based upon direct analysis of data from a prospectively collected database. They report that mean costs for intrapleural catheter use were €2,173, which they noted is acceptable when compared with estimated hospitalization costs for pleurodesis.
Treatment of malignant pleural effusion with either talc pleurodesis or indwelling pleural catheters produces approximately equal results in terms of survival, control of recurrent effusion, improvement in quality of life, and cost-effectiveness. The major advantage of tunneled pleural catheters is a shorter time of hospitalization, which is counterbalanced by patient inconvenience in draining effusions. Although there may be a small cost-effectiveness benefit for pleurodesis in patients with prolonged survival, prediction of survival is not accurate enough to select a treatment method based upon this consideration. Choice of treatment method should take patient preferences into careful consideration.
Review of a number of small, early trials of intrapleural and systemic treatment following palliative management of malignant pleural effusions with chemotherapy and/or targeted agents suggests to us that there may be improved survival in patients with malignant pleural effusions treated with systemic and/or intrapleural therapy with chemotherapeutic or targeted molecular agents. Further investigations in this area are needed to confirm this impression.