Malignant pleural effusions are a common complication

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1 Management of Malignant Pleural Effusions* 11wmas]. Lynch, Jr., M.D. Malignant pleural effusions (MPEs) are a common complication of advaucecl maligoaucies, particularly lung and breast caocer. They are caused by a variety of mechanisms including tumor obstruction of lymphatic ftow, spread oc malignant ceus via the systemic circulation, and tumor invasion of the pulmonary arterioles. Therapy is determined by tumor histology, stage of malignancy, and a careful assessment of a patient's performance status and comorbid diseases. A number of approaches have been used to treat patients with MPE ranging from thoracentesis to pleurectomy. Tube thoracostomy drainage followed by application of a sclerosing agent is the most common strategy. Efl'ective sclerosing agents include quinacrine, talc, bleomycin, tetracycline and Corynebacterium paroum. Results from a recent multicenter randomized trial suggest that bleomycin may be superior in terms of control of effusion at 30 days. Further randomized studies are ongoing to determine the optimal method oc draining the pleural space and the most efl'ective sclerosing agent. Thoracoscopy using video-assisted techniques is a promising new approach to MPEs both for diagnosis and treatment. The application oc biological agents such as interleuldn-2, the interferons, and novel chemotherapeutic agents are experimental approaches that are under investigation. (Clam 1993; 103:385S-89S) Malignant pleural effusions are a common complication of advanced malignancy. Lung cancer and breast cancer account for approximately 75% of malignant pleural effusions with the remaining 25% representing the cross section of neoplastic disease. In the United States it is estimated that in 1992, there will be close to 100,000 cases ofmpe. While MPE is often a sign of advanced, progressive cancer, many patients with MPE survive in excess of six months. Furthermore, some patients with MPE (lymphoma, germ cell tumors) can be cured of their malignancy. Thus, control of malignant pleural effusions in a manner which promptly relieves symptoms and maintains quality of life is an important part of the overall management of patients with advanced cancer. MAUGNANT EFFUSIONS: PATHOPHYSIOLOGY N()I'TI'JQ/, Pleural Fluid Rmnation The pleural space is a 10 to 20 J.Lm space between the visceral and parietal pleura. In considering the formation of pleural fluid, it is essential to note that the visceral pleural blood supply is primarily bronchial and that the parietal pleural blood supply is systemic arterial. It is also important to recognize that the parietal pleura is the "business end" of the pleural space. The parietal pleura is distinguished by the presence of stomata, 2 to 12 J.Lm openings between *From the Division of Clinical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston. mesothelial cells.. These stomata are essential for the exit of pleural fluid, protein, and cells from the pleural space. From the pleural space, the stomata communicate directly with lymphatic channels and drain to mediastinal nodes. Contrary to prior views regarding pleural fluid formation in man, only 100 to 200 ml of pleural fluid is produced each day in man. Older views contended that several liters of pleural fluid progressed across the pleural space in 1 day, when in fact pleural fluid is formed and removed slowly. Pleural fluid is a filtrate from the parietal pleura, enters the pleural space, and is then resorbed via the parietal pleural stomata. The protein content of normal pleural fluid is lower than the protein concentration in lung and peripheral lymph. The visceral pleura contributes little to the formation or resorbtion of pleural fluid in the normal state. In the normal state, the lymphatic drainage of the pleural space can accommodate a large volume of pleural fluid. Since the rate of entry into the pleural space is equal to the rate of exit of fluid, no net fluid accumulates. Factors that influence the rate of pleural fluid formation and that can play a role in the development and progression of MPE are intrapleural pressure, and plasma and lymphatic oncotic pressure. lbthophysiology of Malignant Pleural Fluid Accumula«on Impaired lymphatic drainage is the primary mechanism for malignant pleural fluid formation. Lymphatic channels can become obstructed directly by tumor occlusion of stomata on the parietal pleura. Mediastinal nodes can become enlarged due to tumor and can lead to lymphatic backup. In addition, tumor can obstruct lymph channels between the stomata and the draining mediastinal nodes. Some tumors may produce an MPE by causing lymphatic obstruction in all these areas. In most patients with MPE, both the visceral and parietal pleura are involved with cancer.' The seeding of the pleural fluid with cancer cells can also increase pleural fluid formation by creating an inflammatory response in the pleural space. In patients with lung cancer, most MPEs are caused by pulmonary arterial invasion and embolization of tumor cells to the visceral pleura. Tumor cells can then transgress the pleural space. Some peripheral tumors, primarily adenocarcinomas, may directly seed the pleural space. Malignant pleural effusions from breast cancer can arise from either direct spread of cancer through the chest wall or from seeding via the systemic circulation. A prominent site of entrance of malignant cells into the systemic circulation is the liver. Breast cancer cells that have metastasized to the liver can reach the pleural space via the inferior vena cava, right side of the heart, and pulmonary artery. This explains the development of bilateral pleural effusions in some patients. CHEST I 103 I 4 I APRIL I Supplement 385S

2 lbramalignant Effusions Sahn 8 bas described the phenomena of the paramalignant effusion. These are pleural effusions which in most instances are caused by malignancy but do not result from direct tumor spread to the pleural surface. Distinguishing a malignant pleural effusion from a paramalignant effusion has importance in patients with non-small-cell lung cancer (NSCLC). Patients with lung cancer and a paramalignant effusion may be eligible for resection for cure or may be candidates for aggressive multimodality therapy protocols. Paramalignant effusions can be caused by a variety of mechanisms and can be either exudative or transudative. Bronchial obstruction with tumor can lead to atelectasis and pleural fluid formation. Pulmonary embolism can lead to small pleural effusions. Mediastinal node involvement with tumor can lead to a paramalignant effusion. Superior vena cava (SVC) obstruction can lead to pleural effusion. Finally radiation therapy can be associated with a small effusion. In all of these cases, the effusion is clearly related to tumor, but it does not result from direct spread of tumor to the pleural space. DIAGNOSTIC APPROACH DWgnostic Evaluation of Suspected MPE The diagnosis of MPEs is usually straightforward. The only difficulty exists when a patient without a known primary malignancy presents with an exudate. The advent of video thoracoscopic evaluation of the pleural space has made this process more definitive. 10 The MPEs are almost always exudates unless they result from a paramalignant etiology. A simple thoracentesis is the most important step in diagnosing an MPE. Pleural fluid should always be sent for LDH and protein analysis." Cell counts and cultures (including AFB) can be helpful if infection is suspected and no primary malignancy is obvious. A sample of fluid for cytologic examination is the gold standard for diagnosing MPE. Cytology is positive or suspicious in 70% to 80% of patients with MPEs.tJ. 13 An exudative pleural effusion with a negative cytologic examination can now be approached in a straightforward fashion with the advent of video thoracoscopy. In the setting of a recognized advanced malignancy, the MPE can be treated as malignant if an infectious cause is ruled out. An exudative effusion with a negative cytology without a known primary requires a diagnostic procedure. In the past, this has been pleural biopsy or a thoracotomy. Developments in video thoracoscopy make this the preferred procedure for establishing a diagnosis." Thoracoscopy can also be therapeutic in that it allows the instillation of a sclerosing agent such as talc directly on the pleural surfaces. APPROACH TO THE PATIENT WITH MPE Getwwal Considerations The overall approach to MPEs is determined by the performance status of the patient and the histology of the tumor. It is paramount to define whether therapy is given with palliative or curative intent. Patients with small-cell lung cancer (SCLC), lymphoma, and germ cell tumors can be cured with combination chemotherapy and radiotherapy. In these patients, an MPE does not necessarily rule out a curative approach. However, MPE can be a negative prognostic factor. 15 Most patients with MPE will be treated with palliative intent. Not all MPEs need immediate therapy. If the effusion is asymptomatic, and the patient shows evidence of advancing cancer elsewhere, deferring therapy for the MPE is appropriate. Before any therapy is selected, the degree of palliation a given therapy can achieve must be balanced against the clinical course, tumor histology, and performance status of the patient. Treatment choices for a man with critical aortic stenosis and triple vessel coronary artery disease who has an MPE secondary to metastatic NSCLC will be different from those for a young woman with newly diagnosed metastatic breast cancer. Lung Cancer Lung cancer is the most frequent histology producing MPEs that require therapy. The approach to MPE in patients with lung cancer is guided by the exact histology of the tunior, fe, SCLC vs NSCLC. Patients with SCLC are highly lilcely to respond to chemotherapy (80% or greater). In this setting, it is reasonable to initiate chemotherapy unless the effusion is massive and causing hemodynamic or respiratory compromise. In either of these settings, a simple thoracentesis will relieve symptoms prior to the initiation of chemotherapy. In cases of refractory SCLCs that have failed chemotherapy and radiation, it is usually necessary to place a chest tube and proceed to sclerosis if the overall clinical situation warrants this. Non-small-cell lung cancer is much less lilcely than SCLC to respond to combination chemotherapy. Thus, the initial approach to management of effusions in patients with NSCLC will more often rely on local control of effusion with chest tube drainage and sclerosis. In patients with apparently localized NSCLC (stages I to IliA) it is essential to perform a cytologic examination to determine the presence or absence of malignant cells in the pleural fluid. Patients with a paramalignant effusion are candidates for curative resection depending upon their stage. It would be wrong to deny a patient a potentially curative approach because of the finding of pleural fluid that may arise because of atelectasis, mediastinal node involvement, or postobstructive pneumonia. Alternatively, the finding of malignant cells in the pleural space is an absolute contraindication for surgical resection. Thus, a diagnostic thoracentesis is essential in all of these patients. If an MPE is documented, a tube thoracostomy followed by sclerosis is the standard of care. Systemic therapy can then follow depending on the patients performance status. Breast Cancer In patients with breast cancer, an MPE is a frequent initial site of relapse following definitive local therapy. Breast cancer patients can often have prolonged survival after finding an MPE, with many patients living longer than 1 year. If the MPE is documented early in the course of disease (fe, no prior hormonal therapy, chemotherapy, or more than 2 years from adjuvant therapy), then a simple thoracentesis followed by systemic therapy can be done. If the patient is more advanced in the course of her disease, then chest tube drainage followed by sclerosis is appropriate.

3 I..ymphoma Malignant lymphoma is the leading noniatrogenic cause of chylothorax. The finding of a lipid-laden chylous effusion should alert the treating physician to the possibility that lymphomatous involvement of the mediastinum is possible. Systemic treatment of lymphoma is the rule. Patients with refractory end-stage lymphoma may benefit from aggressive local therapy followed by an attempt at salvage systemic therapy. Supportive Can? THERAPEUTIC 0PJ10NS For patients with widely metastatic end-stage cancer, adequate palliation can be achieved with morphine and oxygen. This is particularly appropriate for patients who are in the last 2 to 3 weeks of life and are being cared for in the hospice setting. Any potential improvement in respiratory status is offset by the negative impact on quality of life of a 6- to 7 -day hospitalization. Pleun?ctomy Surgical resection of the parietal and visceral pleura is effective in controlling MPE fluid accumulation in nearly 100% of cases. The chief limitation of this approach is that it is rarely indicated as a palliative procedure and carries the morbidity of an extensive operation. Since the majority of patients with MPE survive 6 months or less, it is difficult to widely advocate the use of such extensive surgery. Pleurectomy is appropriate for use in the setting of a relapsed pleural effusion in patients who have a significant expectation of survival from their underlying tumor. Thoracentem Thoracentesis is an essential step in diagnosing and managing MPE. However, the wisdom of repeated therapeutic thoracentesis can and should be questioned. At the time of the initial diagnostic tap, removing an additional liter of pleural fluid with resultant relief of symptoms can predict response to further local therapies. Repeated weekly thoracentesis rarely provides benefit beyond a week in patients with NSCLC. Anderson et al 18 found that thoracentesis alone was associated with a mean time of effusion recurrence of 4.2 days with the majority recurring in 1 to 3 days. Repeated thoracentesis increases the risks of pneumothorax, empyema, and pleural fluid loculation. Therapeutic thoracentesis should thus be reserved for patients who have a highly responsive underlying malignancy and will be undergoing chemotherapy (SCLC, germ ceu tumor, lymphoma} or for patients who are severely dyspneic with life expectancy ofless than 1 month. 'lube Thoracostomy Tube thoracostomy is an important step prior to instillation of a sclerosing agent. The principal goal is to drain the pleural effusion to allow apposition of the visceral and parietal pleura. Chest tube drainage is routinely performed until pleural fluid production is less than 150 ml/day. As therapy alone, tube thoracostomy is usually not sufficient. Reported 30-day success rates range from 11% to 40%, and chest tube drainage alone rarely leads to long-term control of effusion. The principal role of tube thoracostomy is to drain the pleural space prior to the instillation of a sclerosing agent. 'lube Thoracostomy with Sclerodng Agent The principle behind this approach is that the chest tube drains the pleural space, and the sclerosing agent creates a pleuritis that joins the visceral and parietal pleura and prevents fluid re-accumulation. There are several mechanical considerations that can prevent a successful pleurodesis. If pleural fluid is loculated, the sclerosing agent will not evenly distribute in the pleural space. If the lung is "trapped" and does not re-expand to allow apposition of the pleural surfaces, the sclerosis will not be successful. Agents that are effective sclerosing agents share the property of causing a chemical pleuritis. Although many antitumor agents have been used successfully as sclerosing agents, it appears that the mechanism of control of effusion is related to their ability to induce a pleuritis rather than their antitumor activity. Tetracycline controls effusion in between 33% and 84% of patients treated. 11 The standard dose of tetracycline used is 1 g intrapleurauy. Tetracycline distributes well throughout the pleural space. 13 The frequent practice of rotating positions to distribute sclerosing agents bas been called into question by studies that show that radio-labeled tetracycline spreads well throughout the chest cavity. There does not appear to be any benefit to repeated instillations of tetracycline... The chief side effects of tetracycline sclerosis are fever (33%} and pain (41 %}. The use of intrapleural lidocaine may substantially reduce local pain following instillation of tetracycline. Tetracycline is a low-cost, effective therapy that is well tolerated. Unfortunately, the parenteral formulation is no longer available in the United States. Doxycycline, prepared as 500 mg30 ml of saline solution, bas been reported to be effective in 15 out of 18 patients (83%}, but this experience bas yet to be confirmed in larger studies. Cooperative group trials are now being planned comparing doxycycline with other sclerosing agents. Bleomycin is an antitumor antibiotic whose efficacy is related to sclerosing action rather than antineoplastic effects. The standard dose of bleomycin is 60 U intrapleurally; higher doses may be associated with increased toxicity, especiauy in the elderly. When used in this manner, effectiveness ranges from 60% to 80% at 1 month. Side effects of intrapleural bleomycin include fever and pain, which in a recent randomized trial were similar to tetracycline. The major drawback of this agent is cost (pharmacy cost of approximately $850, patient cost $2,000 to $3,000 in 1993}. A number of compounds have historically shown effectiveness as sclerosing agents but are no longer widely in use. The antimalarial, quinacrine is highly effective as a sclerosing agent (64% to 100%). However, most trials have used multiple instillations. The reported toxicities include fever (95%) and pain (40%}. Corynebacterium paroum extract given weekly in a dose of 4 mg has controlled 90% to 100% of MPE at 4 weeks. Randomized trials have shown that C paroum has activity that is at least as good as, if not superior to, tetracycline and bleomycin However, fever and pain were significantly more common with C paroum, and the agent is not widely available in the United States. What is the optimal sclerosing agent to use following chest CHEST I 103 I 4 I APRIL, 1993 I Supplement 3878

4 tube drainage? Trials of various approaches to MPE suffer from several difficulties in design. They lack consistent end points. Most studies are very small and do not have sufficient power to detect a significant treatment effect. Often, there is no stratification for tumor type or disease status. Finally, in many series a high percentage of randomized patients are unevaluable because of progression of systemic disease. We can derive some guidelines from the multicenter study reported by Ruckdeschel et al in This study compared bleomycin (60 U) to tetracycline (1 g) following chest tube drainage. There were 55 evaluable patients despite an initial registration of 100 patients. The low ratio of evaluable to entered patients shows how difficult clinical research can be in a group of patients with rapidly advancing systemic malignancy. The principal end point was control of effusion at 30 days and strongly favored bleomycin 64% vs 33% over tetracycline, p= Median time of effusion recurrence was also significantly prolonged for bleomycin, 46 days vs 32 days for tetracycline, p= Notably, toxicities such as pain and fever, were similar between the groups. 'Ihoracoscopy with Talc Poudrage Thlc produces an intense reactive pleuritis that is highly effective in producing a chemical pleurodesis. When instilled directly onto the pleural surface via poudrage, talc is effective in close to 100% of cases. 33 In the past, this approach was used with a rigid thoracoscope under local or general anesthesia. The rapid evolution of techniques of video-assisted thoracoscopic surgery (VATS) have made this approach much easier to perform. There are several distinct advantages to thoracoscopic talc poudrage. Thoracoscopy allows visualization of pleural surfaces. Small adhesions can be broken with instruments allowing apposition of the pleural surfaces. Patients who have an extensive pleural rind that will never re-expand can be identified and spared a prolonged attempt at sclerosis. Finally, thoracoscopic techniques can significantly improve diagnostic accuracy in cases of erudate effusions without pathologic explanation. Thlc poudrage can be performed with thoracoscopy under local anesthesia, but general one-lung anesthesia is preferred. Major difficulties in using talc include the need to sterilize talc in a moisture-free environment and occasional reports of adult respiratory distress syndrome (ARDS) following talc administration As thoracic surgeons gain experience in VATS, it is anticipated that this approach will become increasingly attractive. EXPERIMENTAL APPROACHES TO MPE Intracavitary Chemotheraw Chemotherapeutic agents that have produced effective sclerosis of pleural effusions include anthracyclines, nitrogen mustard, and cisplatin. Intracavitary chemotherapy is appealing because the therapy directed at the MPE might be effective against the underlying malignancy. Rusch and coworkers"" recently reported the Lung Cancer Study Group (LCSG) experience with cisplatin and cytarabine given intrapleurally. Rusch found a 49% success rate with minimal hematologic toxicity. The duration of response was particularly encouraging (9 months for complete responders and 5.1 months for partial responders). Others have found a 39% success rate with doxorubicin 37 and a 41% effectiveness rate with mitomycin-c. 311 Pleuroperitoneal Shunting The placement of a pleuroperitoneal shunt is an alternative approach that has particular appeal in patients with refractory effusions In this approach, a catheter is placed subcutaneously into the pleural and peritoneal spaces. A pump is manually compressed to drain fluid from the pleura into the peritoneal cavity. This approach may also aid patients when the lung is "trapped" and unable to re-expand to allow effective sclerosis. The pump requires an alert, cooperative patient. Tumor seeding of the peritoneum is less likely to be a major issue in patients who have such advanced malignancy. Results with this approach are inconclusive and work is ongoing. Biologic Response Modifiers An appeal of the pleural space is the ability to place active substances such as cytokines or biologicals directly into the pleural space and to observe any potential cellular and inflammatory response. Interleukin-2, beta-interferon, and gamma-interferon have all been tried with varying degrees of success in the treatment of MPE... The streptococcal preparation OK432 has been shown to augment the activity of mitomycin-c in the pleural space (30-day success rate 41% vs 73%). It is not clear whether this effect is due to intrinsic sclerosing activity or rather to an immunologic effect such as increasing naturalldller cell populations..., In the future, more results of studies with biologic response modifiers in the approach to pleural malignancy should be available. CoNCLUSIONS Chest tube drainage with sclerosis remains the standard of care for the treatment of MPEs. Pleurodesis should be attempted when an MPE is documented in patients with cancers that are not highly responsive to systemic therapy. Multiple therapeutic thoracentesis procedures are unlikely to produce the desired palliation. In patients with cancers that are chemotherapy-responsive, a therapeutic thoracentesis may allow initiation of appropriate chemotherapy. There is evidence from a multicenter randomized trial that bleomycin is superior to tetracycline in terms of success of sclerosis at 30 days and time to effusion return. In patients who are appropriate candidates for chest tube drainage and sclerosis, bleomycin is a reasonable choice. However, there are many areas for improvement in this approach. Bleomycin is expensive. An agent of equal efficacy with lower cost would be preferred. Chest tube drainage is painful and requires a prolonged hospitalization (6 to 7 days in our experience). Techniques that would drain the pleural space, such as small bore catheter drainage, are being explored. Compounds that may be active without drainage are also being investigated. Clearly the most exciting development in the approach to MPE is the availability of video-assisted thoracoscopy. It may well be that a 2-day hospitalization for a surgical procedure that is highly effective (such as thoracoscopic talc poudrage) may greatly enhance quality of life. Cooperative group studies are being planned comparing thoracoscopic 3888

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