Malignant Pleural Effusion
Malignant pleural effusions are a common complication of malignancy, and malignancy is a common cause of pleural effusions in general. Malignancy accounts for roughly 40% of symptomatic pleural effusions, with congestive heart failure and infection being the other leading causes. Lung cancer, breast cancer, lymphoma, and leukemia account for approximately 75% of all malignancy-associated effusions. Significant use of health care resources is attributable to malignant effusions, with approximately 100,000 cases per year being diagnosed in the United States and 43 cases being detected per 100,000 hospital admissions.
The normal pleural fluid space is occupied with approximately 10 cc of fluid with 2 g/dL protein. A pleural effusion is an accumulation of an abnormal amount of fluid between the visceral and parietal pleura of the chest. Normally, pleural fluid is absorbed by pulmonary venous capillaries (80%–90%), with some of it also absorbed by pleural lymphatics. Malignant effusions are usually exudative rather than transudative. Exudative effusions exhibit any one of the following characteristics:
- Pleural fluid to serum protein ratio greater than 0.5.
- Pleural fluid to serum lactate dehydrogenase (LDH) ratio greater than 0.6.
- Pleural fluid LDH greater than two-thirds of the upper limit of serum LDH.
These exudative malignant effusions are generally caused by pleural metastases, disruption of pulmonary capillary endothelium, or malignant obstruction of pleural lymphatics. Paramalignant effusions may result from chemotherapy, radiation therapy, atelectasis, or lymph node involvement.
Common symptoms associated with malignant pleural effusions include dyspnea, cough, and chest discomfort. About 20% of patients may experience weight loss and malaise. A chest x-ray is most commonly used for radiographic assessment. About 175 cc of pleural fluid will cause a blunted costophrenic angle discernible on chest radiography. A chest computerized tomography scan is more sensitive than a simple chest x-ray and is often used for assessment of loculated effusions because, in some instances, up to 500 cc of loculated fluid can be obscured behind the dome of the diaphragm.
Not all pleural effusions detected in cancer patients will turn out to be malignant effusions. Cancer patients are prone to developing conditions such as congestive heart failure, pneumonia, pulmonary embolism, malnutrition, and associated low serum albumin, each of which may cause a symptomatic effusion for which the clinical management would substantially differ from the management of a malignant effusion. For this reason, cytologic assessment is important. Pleural fluid cytology requires a minimum sample of 250 cc. The morphology of cells obtained from the pleural space can be difficult to assess because of mesothelial and macrophage abnormalities. The diagnostic sensitivity of pleural fluid cytology is approximately 65%, with a specificity of 97%. Flow cytometry can be applied to these specimens and is often useful, especially for assessment of lymphomas. Thoracoscopy and pleural biopsy are rarely needed for definitive diagnosis, but these techniques may be useful when routine pleural fluid collection and assessment are difficult because of loculation of the effusion. Thoracoscopy-guided biopsy is generally performed under local anesthesia and has a yield of more than 80%, with a lower risk of complications than thoracotomy.
Management of Malignant Pleural Effusions
To treat or not to treat
Pleural effusions are generally markers of advanced, unresectable disease or disease progression. The median survival for patients with malignant pleural effusions is around 3 to 4 months.[4,5] Because a paramalignant effusion resulting from pneumonia or atelectasis may be present, the cytology should be confirmed before major treatment decisions are made. Once the cytology has been confirmed, the management strategy depends on the underlying primary malignancy and the number and type of previous therapies. For example, patients with newly diagnosed small cell carcinoma or malignant lymphoma are very likely to respond to systemic chemotherapy; however, patients who have already failed several lines of chemotherapy for gastric or ovarian cancer are unlikely to obtain significant palliation with systemic therapy.
About three-quarters of patients exhibit symptoms such as cough, dyspnea, and chest discomfort. Such patients may benefit from efforts to reduce the fluid burden, depending on their performance status, expected survival, and preference for risks versus benefits. The literature on the efficacy of treatment for pleural effusions is difficult to interpret because of the paucity of randomized trials, and the wide variability in the response criteria and the timing and duration of follow-up in uncontrolled trials.[6,7] Generally, the goal of therapy is palliation of symptoms. Measures of success may include complete drainage of the effusion, lung re-expansion, lack of fluid reaccumulation (i.e., duration of response), and subjective report of symptom relief. The choice of treatment depends on patient prognosis, functional status, and goals of care.
Thoracentesis involves percutaneous insertion of a needle for drainage of the effusion. Thoracentesis is not expected to permanently resolve the problem but rather to alleviate symptoms that are acute and severe. The use of thoracentesis is also appropriate as a therapeutic trial to determine whether fluid drainage is beneficial when the relationship between symptoms and effusion is unclear.
Most effusions will reaccumulate a few days after thoracentesis. The reaccumulation rate is approximately 98% by day 30. Repeated thoracenteses carry the potential risks of bleeding, infection, and pneumothorax. Other potential complications of thoracentesis include noncardiogenic pulmonary edema from rapid lung re-expansion (usually with the rapid removal of >1,500 cc) and pleural shock caused by an excessive vagal response to penetration of the parietal pleura. Any of these complications may be lethal, especially for the cancer patient with poor cardiopulmonary reserve.
Chronic long-term indwelling tunneled pleural catheters
Indwelling pleural catheters (IPCs) represent an alternative to pleurodesis for patients with malignant pleural effusion whose dyspnea has responded to thoracentesis. IPCs are relatively contraindicated in patients with a short life expectancy, pleural infections, multiloculated collections, and chylothorax. The insertion of chronic long-term indwelling tunneled pleural catheters is useful against recurrent and symptomatic malignant pleural effusions, including for patients with trapped lung. These tunneled pleural catheters allow up to 96% of patients to achieve symptom improvement, with spontaneous pleurodesis occurring in up to 44% of patients. Published results indicate significantly shorter hospital stays (1 day) for patients with IPCs versus the doxycycline pleurodesis group (6 days). In the IPC group, spontaneous pleurodesis was achieved in 42 of 91 patients. Both the IPC group and doxycycline pleurodesis group reported modest improvement in quality of life and dyspnea. A randomized controlled trial comparing IPC and talc pleurodesis showed similar reduction of dyspnea (24 mm of 100 mm) and similar quality of life. IPC use was associated with a shorter initial hospitalization and lower rates of re-treatment, with a spontaneous pleurodesis rate of 51%. However, there were also higher rates of adverse effects, such as infections and catheter blockage. The choice between IPC and pleurodesis should be based on patient preference and local resource availability.
Use of pleural sclerosing agents after chest tube drainage
Chemical sclerosants may be administered through a chest tube to create inflammation and subsequent fusion of the parietal and visceral pleura so that fluid cannot reaccumulate in this potential space. This kind of fusion is called pleurodesis. Numerous chemical agents can cause the irritation necessary to produce pleurodesis. The ideal agent would produce effective pleurodesis with minimal cost and minimal side effects. Agents that have been studied include chemotherapeutic agents (bleomycin, cisplatin, etoposide, doxorubicin, mitomycin-C, fluorouracil), antibiotics (doxycycline, minocycline, tetracycline), infectious agents (Corynebacterium parvum), biological agents (interferon beta, interleukin-2), bovine dermal collagen,[Level of evidence: II] and other agents (talc, methylprednisolone). Several uncontrolled trials and case series report the efficacy of pleurodesis,;[14,15][Level of evidence: II];[16,17] as do numerous randomized trials.[18-24][Level of evidence: I] A meta-analysis of pleurodesis studies that were reported between 1966 and 1992 indicates that about two-thirds of patients respond to pleurodesis and that tetracyclines (or tetracycline replacement agents, such as doxycycline and minocycline), bleomycin, and talc appear to be the most effective agents. A prospective, randomized study of video-assisted thoracoscopic pleurodesis with talc versus doxycycline in 33 patients with malignant pleural effusion suggests that talc provides superior short-term and long-term results.[Level of evidence: I] Talc appears to be the least expensive agent, at least when given as a slurry rather than by video-assisted thoracoscopic talc insufflation.[Level of evidence: I] Bleomycin, however, is the only agent approved by the U.S. Food and Drug Administration for the prevention of recurrent pleural effusions. An observational cohort study investigated the use of intrapleural urokinase in 48 patients with loculated pleural effusions or trapped lungs. Lung reexpansion and resolution of dyspnea occurred in approximately 60% of patients, suggesting that intrapleural urokinase may be useful in treating loculated pleural effusions or trapped lungs in medically inoperable cancer patients. Most responders successfully maintained pleurodesis when urokinase was followed by minocycline pleurodesis.[Level of evidence: II]
For rare patients, standard management of the malignant effusion is unsuccessful and aggressive treatment remains appropriate. Pleuroperitoneal shunting can be considered for these patients. This procedure involves implantation of a shunt with one-way valves that allow the transfer of fluid from the pleural space to the peritoneal space, in which the fluid creates less hazard and is more easily removed. Another option is surgical pleurectomy, but this procedure requires general anesthesia. The risks of significant acute and chronic pain as well as other morbidity approaches 20% to 25%, and the risk of 1-month mortality is 5% to 10%.
Current Clinical Trials
Check NCI’s list of cancer clinical trials for U.S. supportive and palliative care trials about malignant pleural effusion that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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