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 Table of Contents  
Year : 2015  |  Volume : 1  |  Issue : 4  |  Page : 131-136

Palliative Treatment of Malignant Pleural Effusion

1 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Southern Medical University, Nanjing, Jiangsu, China
2 Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu, China

Date of Submission13-Jul-2015
Date of Acceptance10-Aug-2015
Date of Web Publication27-Aug-2015

Correspondence Address:
Dr. Wenkui Sun
Department of Respiratory and Critical Care Medicine, Jinling Hospital, No. 305, Zhongshan Road, Nanjing 210002, Jiangsu
Yi Shi
Department of Respiratory and Critical Care Medicine, Jinling Hospital, No. 305, Zhongshan Road, Nanjing 210002, Jiangsu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2395-3977.163804

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Malignant pleural effusion (MPE) is a common clinical problem caused by cancers. Pleural effusion can be the first sign of cancer in more than 25% of patients. Lung cancer and breast cancer are the most common cancers that metastasize to the pleura in men and women, respectively. Other cancers, including, but not limited to, lymphomas, ovarian cancer, stomach cancer, and several unknown primary cancers can also lead to MPE. Dyspnea and chest pain are the most common symptoms of MPE along with other symptoms such as a cough, weight loss, anorexia, fatigue, and weakness. Aggravation of these symptoms is closely related to the rate of accumulation of pleural effusion. Treatment options to MPE are determined by the type and extent of the underlying malignancy. The major goals of the treatment are to relieve symptoms, restore functions, improve the quality of life, and minimize the duration of hospital stay and costs. Although some patients can be treated with systemic therapies, most of these treatments are temporary, and MPE would recur soon. Hence, further palliative treatments to effectively control pleural effusions and relieve symptoms are necessary. This review addresses the pathophysiology of MPE and the treatment options for patients with MPE.

Keywords: Cancer, malignant pleural effusion, palliative treatment, pathophysiology

How to cite this article:
Liu C, Qian Q, Geng S, Sun W, Shi Y. Palliative Treatment of Malignant Pleural Effusion. Cancer Transl Med 2015;1:131-6

How to cite this URL:
Liu C, Qian Q, Geng S, Sun W, Shi Y. Palliative Treatment of Malignant Pleural Effusion. Cancer Transl Med [serial online] 2015 [cited 2021 Mar 1];1:131-6. Available from: http://www.cancertm.com/text.asp?2015/1/4/131/163804

Chenyang Liu and Qian Qian have contributed equally to this article and were co-first authors

  Introduction Top

Malignant pleural effusion (MPE) presenting with neoplastic cells in the pleural fluid is a common problem. Lung cancer is the most common etiology for MPE, followed by breast cancer. Malignant mesothelioma is the most common primary malignancy associated with pleural effusion. [1] The presence of MPE indicates an advanced stage of the disease with a median life expectancy of 3 and 12 months depending on the stage and type of underlying malignancy. [2] Management of MPE relies on tumor type, pulmonary reexpansion, performance status, symptoms and life expectancy. [3] British Thoracic Society (BTS) recommends keeping the patient under observation, if he/she is asymptomatic with a known tumor type and responding well to systemic therapies. [4] Some cancers such as small cell lung cancer, lymphoma, breast cancer, prostate, and ovary cancer may respond well to chemotherapy. [1],[4],[5] However, systemic therapies cannot always be effective due to the barrier function of the pleura. Patients with life expectancy more than 3 months or resistant to chemotherapy should be treated with palliative treatments, [6] such as observation, thoracentesis, indwelling pleural catheters (IPCs), pleurodesis, intrapleural therapies, radiation therapy, and pleuroperitoneal shunting (PPS). [3],[4],[6],[7] This systematic review focuses on the pathophysiology and different treatment options for MPE.

  Pathophysiology Top

The pleural space is a potential space between the visceral and parietal pleural layers that normally contains a small amount, typically 10-20 mL, of pleural fluid. [7] The parietal pleura is more important to pleural fluid exchange than the visceral pleura because it is adjacent to microvessels and lymphatic openings. The presence of malignant cells in the pleural fluid indicates the obliteration of pleural defense mechanisms. [8] The accurate mechanism of MPE development remains unclear. Traditionally, it is believed that it develops in different manners, including loss of adhesion and dislodgement of tumor cells from the primary site, adherence and penetration of the blood vessel wall, migration to the pleura, production of growth factors, and blocking the lymphatic evacuation tracts. [8],[9],[10]

In recent studies, immunocompetent mouse models of tumor-induced MPE revealed another pathway to MPE formation. [10] The vicious interactions between tumor cells and host vascular and immune systems contribute to MPE development. [11] The pleural levels of vasoactive mediators, including vascular endothelial growth factor, tumor necrosis factor,  chemokine ligand 2, osteopontin and possible protective molecules (e.g., endostatin) dictate the occurrence of vasoactive events and, ultimately, the MPE development. Also, it has been shown previously that myeloid cells such as macrophages, neutrophils, and eosinophils can induce MPE pathophysiology. [10] A recent study revealed the role of two lymphocyte subset, Th1 and Th17, in tumor-caused MPE pathophysiology. They discovered that interferon gamma (IFN-g) inhibited Th17-cell differentiation and promoted MPE formation, whereas interleukin (IL)-17A inhibited Th1-cell differentiation and inhibited the formation of MPE. [12] Pathophysiology of MPE is an intricate signaling network. We still have a long way to go to better understand interactions between tumor cells and host vascular and immune systems in the MPE development.

  Management Options Top

MPE is a common clinical problem in cancer patients presenting to respiratory and cancer care physicians. It always signifies incurable diseases associated with high morbidity and mortality, and can cause many symptoms such as shortness of breath, chest pain, dry cough, weight loss, etc. Hence, important points that mean most to patients are not only effusion removal, but also the relief of symptoms (especially breathlessness and chest pain), improvement in quality of life and minimizing their hospital stay. If the patient is asymptomatic, and the tumor type is known, clinical observation is recommended. Thoracentesis is the most efficient approach to relieve symptoms. However, almost all MPEs treated by thoracentesis alone would recur within 1-month. Pleurodesis and IPC placement are two effective treatments recommended for recurrent MPE, both of which can effectively improve dyspnea and quality of life of patients. Other options such as intrapleural therapies, radiation therapy, and PPSs are alternative treatments. Management options depend on the tumor type, pulmonary reexpansion, performance status, symptoms, life expectancy, and economic status of patients.

  Thoracentesis Top

Thoracentesis, guided by ultrasound (US) with experienced physicians, is a diagnostic and therapeutic option for MPE. [13] For patients with advanced disease and a short life expectancy (1-3 months), or slow pleural fluid reaccumulation, or poor performance status that prevents the patient from other interventional therapies, thoracentesis or repeated therapeutic thoracentesis is a good choice. [3],[14] US helps physicians to determine an accurate needle insertion site and thus reduce risks associated with thoracentesis. Pneumothorax is one of the most common complication associated with thoracentesis, with an incidence rate as high as 20-39%. [15] A retrospective study, including 445 patients with MPE, found that pneumothorax occurred in 0.97% of cases with thoracentesis procedure performed with US guidance and in 8.89% without it (P < 0.0001). Also, 3 patients with pneumothorax required tube thoracostomy among all patients performed without US guidance. [16] An observational cohort study, analyzed 61,261 thoracenteses, indicated that US guidance reduced the risk of pneumothorax by 19% (odds ratio, 0.81; 95% of confidence interval [CI], 0.74-0.90). Pneumothorax significantly increased the total cost of hospitalization and length of stay by 1.5 days. [17]

Thorough removal of MPE will be helpful to relieve overall symptoms, identify underlying trapped lung, estimate the rate of fluid reaccumulation and guide future treatment options. [18] The volume of fluid drained should be strictly guided by symptoms, and if a cough or chest discomfort is observed, thoracentesis must be stopped immediately. Reexpansion pulmonary edema occurs rapidly if the removed fluid is more than 1.5 L. [19],[20] Notably, thoracentesis is generally safe and can effectively relieve symptoms, but almost all patients experience recurrence of symptoms and effusions within 1-month. [4],[21]

  Indwelling Pleural Catheters Top

IPCs have become widely used for the palliative treatment of recurrent MPE. It involves the insertion of a small soft pleural catheter into the pleural cavity that allows intermittent drainage with a vacuum bottle. IPC insertion can be performed in the outpatient setting, and can be useful for patients with a trapped lung or failed pleurodesis or wish to avoid hospitalization. [22] It has been shown that IPC, as a first-line treatment for MPE, is at least as effective as pleurodesis. Both of them can effectively improve dyspnea and quality of life, whereas there was no significant difference in success rate or complications. [23],[24],[25],[26] However, IPC has an advantage of avoiding further pleural interventions, which in turn reduces the duration of hospitalization and associated risks and costs. [18] A TIME2 randomized controlled trial indicated that median length of hospitalization was significantly shorter in the IPC group than talc group (0 vs. 4 days; P < 0.001). Fewer patients with IPCs required further pleural procedures than talc group (6% vs. 22%, P = 0.03). [24] Another prospective multicenter study achieved the same results. [27]

IPC can stimulate an inflammatory reaction and promote spontaneous pleurodesis. Spontaneous pleurodesis can be achieved in 40-70% of patients after IPC, allowing for pleural catheter removal. [24],[28],[29] Several studies have shown that serious adverse events are uncommon with the use of IPC, but are still a noteworthy concern to clinicians and patients. [28],[30],[31],[32],[33] A multicenter, retrospective study, including 1,021 patients with IPCs showed that IPC-related pleural infection was low (4.9%) and most of them (94%) were successfully managed with antibiotics. The overall mortality due to pleural infection associated with IPC was only 0.29%. It also confirmed that 54% of these infections can be treated effectively without catheter removal, and postinfection pleurodesis was common (especially those infected with staphylococci), often leading to removal of IPC. [34] Chemotherapy is a routine procedure for patients with advanced malignancies. A retrospective study showed that chemotherapy does not increase the rate of IPC-related infection. [35] Whereas, the use of IPC can potentially increase the risk of tumor seeding along the catheter tract. [36] One study on catheter tract metastasis (CTM), including 107 patients with IPCs, indicated that IPC-related CTM developed in 10% of patients mainly with mesothelioma and metastatic carcinomas. Radiotherapy was well tolerated, which can be carried out safely without catheter removal. [37]

  Pleurodesis Top

Pleurodesis refers to the process of chemically or mechanically inducing pleural inflammation to the visceral and parietal pleura to obliterate the area and prevent the accumulation of air or liquid into the pleural space. The exact mechanism of pleurodesis remains unknown; however, several studies claimed that it was associated with diffuse inflammation of pleura, fibrinolysis imbalance, recruitment and proliferation of fibroblasts, and release of inflammatory factors like IL-8 and transforming growth factor beta. [7],[38] Thus, more serious the injury is, more likelihood of its success, but at the expense of more adverse effects. [18]

Pleurodesis is a better option for recurrent MPE than thoracocentesis unless the patient has a very poor performance status, or a short life expectancy, or a trapped lung. [19] A variety of sclerosing agents have been used to treat MPE such as talc, tetracycline, doxycycline, bleomycin, cisplatin, silver nitrate (SN), iodopovidone and biological agents such as IL-2 and IFN. [21] Talc is the most effective sclerosant available for pleurodesis, especially graded talc, which can be delivered as slurry via an intercostal catheter or by dry-powder poudrage during a thoracoscopy. [4] A prospective, randomized trial found that talc poudrage and talc slurry are similar in efficacy and there was no difference in the percentage of patients with successful 30-day outcomes between talc delivery (78% for poudrage vs. 71% for slurry, P = 0.169). However, there was a significant difference in the rate of successful pleurodesis at 30 days among patients with breast and lung cancers compared to other cancers. [39] A recent meta-analysis showed that thoracoscopic talc poudrage was more effective than bedside talc slurry (relative risk, 1.12; 95% of CI, 1.01-1.23; P = 0.026), with similar adverse events. Hence, the study recommends that if patient presents with MPE with life expectancy more than 1-month, then talc pleurodesis, especially thoracoscopic talc poudrage pleurodesis, is preferred. [40]

Although some other sclerosing agents (e.g., tetracycline, bleomycin, iodopovidone, SN, and others) have been used for chemical pleurodesis, there are few head-to-head randomized control trials to help us decide, which agent to choose. [7] A prospective randomized trial compared the safety, efficacy, and outcome of povidone-iodine pleurodesis with talc pleurodesis. The results showed that there was no difference in the symptomatic relief, hospital stay and the rate of recurrence. Povidone-iodine may be a good alternative to talc used for pleurodesis. [41] However, larger randomized control trials are needed to confirm its safety and efficacy. SN can be used for pleurodesis and its effectiveness, compared to talc, has been shown both in animal and human studies. [42],[43] A recent study evaluated adverse events of SN treatment at three different doses (30 mL 0.3%, 30 mL 0.5%, or 60 mL 0.3%) for pleurodesis, which revealed that hypoxia was most significant and mild metabolic events were common. Notably, systemic inflammatory responses, reflected by the significant increase in serum C-reactive protein levels, were dose-dependent. It suggests that patients' general status must be assessed before treatment with SN. [44]

Chest pain and fever are the most common complications of chemical pleurodesis. Other complications include a cough, empyema, local site infection, trapped lung, and acute respiratory distress syndrome. [21] Failure of pleurodesis is related to pleural fibrinolytic activity, extensive pleural disease, pleural fluid pH and systemic use of corticosteroids. [19] If pleurodesis fails, there is no evidence for the most effective secondary procedure, but second pleurodesis or IPC can be considered. [4]

  Intrapleural Therapies Top

Intrapleural chemotherapy

Intrapleural chemotherapeutic agents (e.g., 5-fluorouracil [5-FU], cisplatin, etoposide, paclitaxel, carboplatin, cytarabine, and docetaxel) have been demonstrated safe by several Phase I and II studies. [7] Cisplatin is the widely used intrapleural chemotherapeutic drug and most effective agent for controlling lung cancer or other pleural-disseminated lesions. Hyperthermotherapy can increase the effect of many chemotherapeutic agents in human cell culture models and animal models. [45] A recent study compared survival benefit of intrapleural hyperthermic perfusion chemotherapy (HIPEC) after surgical interventions (pleurectomy, decortication and/or lung resection) with talc pleurodesis or pleurectomy/decortication and found that median survival of HIPEC was 15.4 months that was longer than pleurodesis or pleurectomy/decortications alone (6 months and 8 months, respectively). It seems that HIPEC combined with cytoreductive surgery is a promising treatment for patients with metastatic MPE. [46] Another similar prospective study achieved the same results that cytoreductive surgery and hyperthermic intrapleural chemotherapy were good options in the treatment of malignant pleural diseases. [47] Although these results seem promising, the general condition of MPE patients is usually very poor that they cannot tolerate the adverse effects (e.g., renal toxicity and bone marrow suppression) of cisplatin. [48] Larger studies are needed for the optimization of these methods, the dosage and the type of chemotherapeutic drugs.

Intrapleural gene therapy

Gene therapy is a promising option for local intrapleural therapy, which includes inserting a therapeutic gene into tumor cells via viral and nonviral gene transfer vectors, thus modifying a noncytotoxic drug into a cytotoxic and arresting uncontrolled cell proliferation. [49],[50] Many Phase I trials have shown the promising role of intrapleural gene therapy for patients with MPEs, including the delivery of IFN-β, bevacizumab, IFN-α2b and tumor suppressor p53 via adenoviral vectors. [51],[52],[53],[54],[55],[56] A Phase III trial goes further than the others, which enrolled two patients with MPEs due to lung cancer and showed that intrapleural Ad-cytosine deaminase transferred into tumor cells can convert the antifungal drug 5-fluorocytosine to antimetabolite 5-FU. It kills not only the transfected tumor cells, but also their neighbors by so-called bystander effects. [57] Although these options achieve some promising results, larger studies are needed to compare the safety and efficacy of intrapleural gene therapy with the standard pleurodesis or drainage methods for MPEs.

Intrapleural fibrinolysis

More than 13.5% of patients can present with loculated and symptomatic MPEs after IPC. [18],[34] Intrapleural fibrinolytics can break the locules and improve pleural fluid drainage. Thus it is recommended for patients with multiloculated malignant effusion. [4],[19] Several studies have shown its safety and efficacy in the treatment of loculated MPE. [25],[34],[58],[59],[60],[61] An observational study, including 66 patients with symptomatic loculations, first described intrapleural fibrinolytic therapy for IPC-related symptomatic loculations. It revealed that intrapleural fibrinolytics (tissue-plasminogen activator, urokinase, and streptokinase) increased pleural fluid drainage in 93% of patients and improved dyspnea in 83% following therapy. However, there may be a small risk of nonfatal pleural bleeding (3%). [60] In another study, 40 patients with multiloculated MPEs were randomly divided into two groups: fibrinolytic group (250,000 IU of streptokinase in 50 mL saline) and control group (50 mL saline solution alone). There was a significant difference in the improvement of dyspnea symptoms in the fibrinolytic group compared to the control group (90% vs. 55%, respectively, P = 0.03). Recurrence rate was 11% in fibrinolytic group and 45% in control group (P = 0.07). [61] It seems that an intrapleural fibrinolysis is a promising option for patients with multiloculated malignant effusions. Further studies are needed to confirm the patient selection and optimal dosing regimen, and to define its safety profile.

  Radiotherapy Top

Up to 40% of patients with mesothelioma can develop needle tract metastasis (NTM) after pleural interventions, especially tube thoracostomy and thoracoscopy. [37] However, it can be prevented by local radiation at the access sites within 2 weeks. [3] Prophylactic radiotherapy was recommended by the BTS that should be performed on the site of thoracoscopy, surgery or large-bore chest drain insertion. However, there is little evidence to support this operation for pleural aspirations or pleural biopsy. [4] A study described that prophylactic irradiation is effective in preventing NTMs from mesothelioma following pleural procedures (e.g., thoracostomy or thoracoscopy) instead of long-term IPC. [36] A recent study reported that the largest series of IPC-related CTMs, found that IPC-related CTM was uncommon and mostly complicated with mesothelioma or metastatic carcinomas. Its symptoms were mild, and radiotherapy appeared effective, which can be administered safely without removal of the catheter. [37]

  Pleuroperitoneal Shunting (PPS) Top

PPS will be an alternative approach to control MPEs for patients with a trapped lung that cannot undergo pleurodesis, or failed pleurodesis, or patients with large loculated effusions. [62],[63] Another study indicated that the option was safe and effective, and more than 95% of properly selected patients could achieve effective palliation. [64] However, PPS has some specific complications, including occlusion of the catheter that often need catheter revision, removal and/or replacement, shunt infections, and pain. [18] In addition, PPS is expensive, and some patients complained of the need to activate the pump hundreds of times a day. [3] All of these disadvantages limit its usefulness in patients with MPEs, and the popularity of IPC and other interventions have diminished the use of PPS.

MPE usually associates with incurable diseases. There are no standard management options for patients with MPE. Individualized treatment strategy should be established depending on patients' symptoms, functional status, life expectancy, socio-economic status. [Table 1] summarizes the appropriate candidates, advantages and disadvantages of these mentioned management options. Thoracentesis is the best choice for patients with poor performance status and short life expectancy. However, pleural effusion and associated symptoms recur soon. Pleurodesis and IPC are appropriate for patients with recurrent MPE and a longer life expectancy. Radiotherapy can reduce tumor-related seeding or tract metastasis after pleural interventions, especially in malignant effusion with mesothelioma. Intrapleural therapy seems promising, whereas large, randomized controlled trials are needed to confirm its efficacy and safety.
Table 1: Management options of MPE

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Financial support and sponsorship

This study was supported by National Natural Science Foundation of China (Grant Numbers. 81270064 and 81200063).

Conflicts of interest

There are no conflicts of interest.

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