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Current Respiratory Medicine Reviews, 2012, 8, 314-321 314 Malignant Pleural Effusion Evaluation and Management Jed A. Gorden* and Joelle Thirsk Fathi Swedish Cancer Institute, 1101 Madison Ave, Seattle, WA 98104, USA Abstract: Malignant pleural effusion represents advanced disease. Management is determined by the patient’s performance status, symptoms and degree of lung re expansion after pleural fluid drainage. The goal of management is control of patient symptoms, with minimum morbidity and maximum patient independence. Pleural fluid evacuation and long term palliation can be achieved by either chemical pleurodesis or patient controlled drainage with a tunneled pleural catheter. Thoughtful patient evaluation is critical to choosing the appropriate palliative option for each individual with malignant pleural effusion. Keywords: Malignant effusions, pleurodesis, thoracoscopy, tunneled pleural catheter. INTRODUCTION (A) A pleural effusion is defined as a malignant pleural effusion by the presence of malignant cells in the pleural fluid and an increase in the volume of pleural fluid [1] (Fig. 1). Malignant pleural effusions (MPE) occur in patients with advanced malignancies and are most commonly associated with lung, breast, gastric, and ovarian cancers, as well as lymphoma. Breast and lung primaries are associated with nearly 75% of MPE [2] (lung cancers accounting for 35%45% and metastatic breast cancers for 25% of all malignant pleural effusions) [3]. Malignant pleural effusions represent 22% of all pleural effusions, and in 20% of these patients MPE is the first clinical presentation of their malignancy [4]. Malignant pleural effusions are an immense contribution to the morbidity experienced by cancer patients, and their management often requires repeated interventions and repeated hospital admissions. Over the years, the annual incidence of MPE has grown as the number of cancer survivors has increased, with at least 150,000 annual cases seen in the US [5-7]. Women constitute a larger portion of this MPE population due to the prevalence of breast cancer and secondary risk of MPE in breast cancer victims. (B) A malignant pleural effusion is an ominous clinical indicator and represents advanced stage neoplasm. The prognosis of patients affected with MPE is usually poor with a reported median survival of 6 months [8]. Patient survival is influenced by the type of neoplasm, the functional status of the patient at time of diagnosis, and the responsiveness of the underlying neoplasm to treatment [9-13]. ANATOMY AND PHYSIOLOGY OF THE PLEURAL LINING AND SPACE The pleural space (or cavity) is a self-contained space that is defined by the visceral and parietal pleural membranes, with the visceral membrane lining each lung and fissures and the parietal membrane lining the chest wall, diaphragm, pericardium and mediastinum [14]. The pleural space is a potential space between the two surfaces and *Address correspondence to this author at the Swedish Cancer Institute, 1101 Madison Ave, Seattle, WA 98104, USA; Tel: (206) 215-6800; Fax: (206)215-6801; E-mail: [email protected] 1875-6387/12 $58.00+.00 Fig. (1). (A) Normal pleural space with normal visceral and parietal pleural surfaces. (B) Malignant pleural space with tumor studding the visceral pleura, the parietal pleura and pleural effusion present. usually contains less than 1 ml of lubricating fluid [15, 16]. These smooth membranes facilitate the movement of the lung within the pleural space through secretion and absorption of pleural fluid. The lubricated pleural membranes are divided into five cellular layers: a single mesothelial cellular layer, the subendothelial connective tissue and basal lamina, a thin superficial sub-elastic layer, a sub-connective tissue layer and a deep fibro-elastic layer [15]. © 2012 Bentham Science Publishers Malignant Pleural Effusion Evaluation and Management The mesothelial layer has secretory and absorption capabilities; this layer synthesizes glycosaminoglycans and surfactant that deliver lubrication for the parietal and visceral pleural membranes [15]. The primary function of the mesothelial cells is to reduce the friction between the mobile organs including the lung and the chest wall; it is also integral to membrane transport [17]. The sub-endothelial connective tissue layer of the pleura is a complex structure that lies beneath the mesothelial cellular layer and functions as an anchoring structure. This lining is a strong contributor to the low oncotic pressure of the pleural space and the resulting negative pleural pressure that allows the lung to expand [17]. The fourth layer, known as the loose connective tissue layer, contains adipose tissue, fibroblasts, mast cells, blood vessels, nerves and lymphatics; the fifth layer, known as the deep fibroelastic layer, is typically an adherent layer to the presiding structures including the lung, mediastinum, diaphragm, ribs or intercostals muscles [15]. The parietal pleura also possess stomata that communicate directly with the lymphatic system. These stomata are openings in the mesothelial cells that aid in the absorption (i.e. egress and removal) of pleural fluid, protein, and cells [18]. PHYSIOLOGY OF PLEURAL FLUID Pleural fluid is a low protein interstitial fluid that promotes the lung mechanics of respiration. As the lung expands and contracts during respiration, pleural fluid is the lubricant that allows the lung to slide, reducing friction. Pleural fluid is normally produced and absorbed at a relatively slow rate of 0.01ml/kg/h. This amounts to the presence of less than 1ml in the pleural space at any given time, and a total production of approximately 17 ml/day [4, 18, 19]. The maximal absorptive capacity of the pleura is 0.2-0.3 ml/kg/h, and once absorbed, the fluid is then drained into the lymphatic system [4]. Fluid volume is kept constant by a combination of Starling forces, the oncotic pressure in the circulation, and the negative pressure in the lymphatics of the lungs [15, 20]. A sub-atmospheric pressure exists in the pleural space as compared to the sub-pleural space creating a negative pressure gradient from the pleural interstitium to the pleural space. This pressure gradient coupled with the porous qualities of the mesothelium facilitates the continual production of pleural fluid, absorption of concentrated pleural fluid through the mesothelium, passage through the parietal stomata, and ultimate drainage into the lymphatic system [15, 18]. LUNG AND PLEURAL LYMPHATIC SYSTEM The lymphatic drainage system for the lungs and pleura is an expansive network of endothelium lined lymphatic vessels within the loose sub-pleural connective tissue. This lymphatic network runs the surface of the lungs and penetrates them while communicating with the inter-lobar septa [17, 21, 22]. Current Respiratory Medicine Reviews, 2012, Vol. 8, No. 4 315 The pleural space thus resides between the pulmonary (visceral) and the parietal pleura lymphatic circulations [17, 23]. The visceral and parietal pleura possess their own groups of lymph nodes, but here we will consider only those nodal groups of the parietal pleura. The sternal, intercostal, mediastinal and diaphragmatic nodes comprise the parietal pleural lymph node groups. These nodal groups are large contributors to the pleural lymphatic system, and play a significant role in the drainage of pleural fluid into the interstitial space, in both healthy and diseased states [17, 23]. The pleural lymphatics directly drain the pleura via the mesothelium at the parietal stomata. The direct anatomical connections between the pleural space to the parietal stomata, the lumen to the lymphatics, and the negative pressure within the lymphatic drainage system are vital in successful space drainage, and are responsible for the majority of the pleural fluid drainage [17, 18, 22]. Due to a greater thickness and lower water and solute permeability, there is limited drainage via the visceral pleura. The visceral pleural drainage that does occur is noted to be greatest at the lower lobes where the visceral pleural lymphatics are the most abundant [22, 24]. The negative pressure within the pulmonary lymphatics facilitates fluid drainage through the parietal pleura. The lymphatic drainage system can increase absorption to accommodate up to a 28-fold increase in pleural fluid volume [18, 22, 24]. PROPERTIES OF MALIGNANT PLEURAL EFFUSION Malignant pleural effusions are most often characterized chemically as exudative pleural effusions [25]. There are numerous mechanisms in which a malignancy can contribute to the formation of an MPE. In many cases, the malignancy causes inflammation, subsequent increased pleural permeability, and enhanced production of pleural fluid and resulting accumulation of an effusion. Malignancy can also impair the pleura via direct pleural invasion resulting in an increased pleural effusion. If the mediastinal lymph nodes are involved, the pleural lymphatic drainage system will be impaired, decreasing outflow and resulting in increased fluid accumulation. Cases where the thoracic duct is interrupted by malignancy can be the most challenging to manage as chyle is continuously produced and floods the pleural space resulting in a rapidly reoccurring large volume chylothorax [7, 26, 27]. Lymphatic drainage disruption also occurs when there is fibrosis induced by chemotherapy or radiation therapy; fibrosis results in decreased absorption and increased accumulation of pleural fluid [7, 26-28]. CLINICAL PRESENTATION PLEURAL EFFUSION OF MALIGNANT Symptoms of pleural fluid accumulation are associated with patient physiology and not fluid volume. Pleural fluid can cause changes in chest wall mechanics, restrictive lung disease and mediastinal shift. Patients with compromised pulmonary or cardiac function can be symptomatic with small volumes of fluid in the pleural space, other patients 316 Current Respiratory Medicine Reviews, 2012, Vol. 8, No. 4 can tolerate larger volumes before symptoms are detected [7, 29, 30]. Dyspnea is the most common symptom of MPE: symptoms can be positional with patients complaining of increased symptoms when they lie down or bend over to tie their shoes. Dyspnea is often worsened with exertion. Malignant pleural effusion can also be accompanied by fever, pleuritic chest pain, non–productive cough, or chest pressure [7, 31]. First time symptoms in association with a physical exam suspicious for an effusion, including decreased breath sounds or dullness to percussion, warrant a work up including radiographic imaging (CXR; often followed by CT or ultrasound). PLEURAL SPACE EVALUATION The full work-up of MPE begins with an ultrasound guided thoracentesis and drainage of the pleural fluid collection. The pleural space should be analyzed by ultrasound. This allows for assessment of pleural anatomy including pleural or diaphragmatic masses, pleural space septations, and for the most accurate localization of the pleural fluid allowing for a safe thoracentesis [32, 33]. EVACUATION OF THE PLEURAL SPACE Pleural fluid should be drained completely or to the extent tolerated. Indications for stopping pleural fluid drainage include chest pain or pressure and difficulty breathing experienced by the patient as fluid is being removed. Pleural manometry has been studied as a tool to diagnose lung entrapment and to determine the safest fluid volume to extract [34, 35]. Evacuation of the pleural space allows for the assessment of lung entrapment vs trapped lung. Entrapped lung describes a lung that fails to expand due to visceral pleural thickening, endobronchial blockage or increase in lung elastic recoil from interstitial disease; this is pathophysiologically different from trapped lung, which is a restrictive visceral pleural peel that prevents re-expansion [36, 37]. Entrapped or trapped lung will not fully re-expand after evacuation of the effusion (Fig. 2) and will need to be accounted for in any long-term palliative management strategy. Gorden and Fathi EVALUATION OF THE PLEURAL FLUID The pleural fluid should be sent for laboratory evaluation including: glucose, LDH, total protein, cell count and differential as well as cytology. A malignant pleural effusion is often exudative and lymphocyte predominant. The diagnostic yield of pleural fluid cytology ranges from 20-80% depending on the cancer type, with breast being the highest yield and sarcoma the lowest [15]; additional maneuvers may be required to confirm the diagnosis of a malignant pleural effusion. If the malignant nature of the pleural effusion cannot be confirmed by fluid evaluation alone, a pleural biopsy can be obtained by either VideoAssisted Thoracic Surgery (VATS) or single port semi-rigid thoracoscopy, often termed medical thoracoscopy [38]. Both tools allow for the visual inspection of the pleural surfaces and for pleural biopsy, allowing for generous tissue samples, which can be used to prove the diagnosis, identify the underlying malignancy type and even possibly assess for mutation analysis for possible tailored systemic therapy. Pleural biopsies should only be considered if it has been determined that the findings will impact the treatment plan. A patient with a known advanced malignancy and a recurrent symptomatic effusion may require palliation only, and an invasive diagnostic procedure may not be necessary to guide therapy. TREATMENT STRATEGY Malignant pleural effusion represents an advanced disease state and treatment should be tailored to the individual patient and must take into account their condition, prognosis, performance status, and future expectations and goals of treatment. Any therapeutic intervention should conform to the principles of palliative care: 1. The intervention should be rapid and effective at controlling the symptoms. 2. It should have low associated morbidity and mortality. 3. It should require minimal follow-up. 4. The intervention should maximize independence, comfort and quality of life. CLINICAL OPTIONS FOR THE MANAGEMENT OF MALIGNANT PLEURAL EFFUSION There are three fundamental mechanisms for controlling recurrent malignant pleural effusions: repeat thoracentesis, evacuation and pleurodesis, or placement of a tunneled pleural catheter (TPC). THORACENTESIS Fig. (2). Lung entrapment: Failure of the lung to re expand following lung insufflation at the time of VATS. A thoracentesis is a proven safe and effective tool for removing pleural fluid and eliminating symptoms. It is best reserved for rapid symptom palliation and assessment of lung re-expansion after drainage. Thoracentesis provide no lasting protection from pleural fluid re-accumulation and may need to be repeated every time symptoms recur as the pleural fluid re-accumulates; this often translates into patients needing repeated visits to the ER or clinic for drainage while tethering them to the medical community and Malignant Pleural Effusion Evaluation and Management diminishing their independence. For most patients, thoracentesis does not provide long-term palliation for recurrent MPE. There are also theoretical concerns that repeated thoracentesis can lead to loculations and potential lung entrapment. POTENTIAL COMPLICATIONS OF THORACENTESIS Thoracentesis can be safely performed in the outpatient setting. Principle risks include bleeding and pneumothorax. In some centers it is not required to stop patient anticoagulation prior to thoracentesis. The risk of pneumothorax is small and was decreased by the use of ultrasound. The incidence of pneumothorax is about 10% and drops to 4% when ultrasound guidance is used [29, 39, 40]. After uneventful thoracentesis, when the clinician does not identify a complication, a post procedure X-ray is not required [28]. If the symptoms of MPE are relieved after thoracentesis and the symptomatic MPE recurs, then a long-term management strategy must be considered. Thoracentesis as a primary palliative tool should probably be reserved only for the most end-stage patients when dyspnea interferes with the palliative goals of a comfortable and dignified end of life. Thoracentesis can also be used to identify patients whose symptoms will not be relieved by pleural space evacuation and in whom a more definitive and often invasive procedure will not be required. PLEURODESIS Pleurodesis is established by fusing the visceral and parietal pleural surfaces and thus eliminating the very space in which pleural fluid may accumulate. To consider pleurodesis the lung must re-expand after pleural fluid evacuation, thereby placing the two pleural surfaces in contact. Pleurodesis can be cautiously considered if the lung fails to completely re-expand after drainage. A significant reexpansion though incomplete may at times suffice to attempt pleurodesis as long as enough visceral-parietal pleural contact is achieved. In such a scenario, re-accumulation of a smaller but hopefully asymptomatic effusion is the target. Unfortunately no guidelines exist for what constitutes “enough” lung re-expansion. If after pleural fluid evacuation an isolated space persists, one could consider this strategy in the fit, well informed patient. Fusion of the visceral and parietal surfaces is achieved by introducing a chemical irritant into the pleural space and promoting an inflammatory response to ensue. Many agents have been used to fuse the pleural space, including talc, povidone-iodine, doxycycline, hypertonic dextrose, and other sclerosants [7, 31, 41]; talc is clearly favored over other sclerosing agents in multiple trials [26]. Sclerosants can be introduced in the pleural space via large or small-bore chest tubes or by VATS or medical thoracoscopy [27, 42-44]. Contrary to popular belief, following intrapleural chemical instillation, patients do not require side-to-side rotation to disperse the sclerosant as natural respiratory movements will disperse it throughout the pleural surface [45]. The manner with which sclerosants are Current Respiratory Medicine Reviews, 2012, Vol. 8, No. 4 317 introduced in the pleural space does not appear critical as shown in a large randomized phase III CALGB trial where no difference in overall pleurodesis rates was seen between VATS talc and bedside talc slurry via chest tube [42]. Pleurodesis is very effective at achieving fusion, with successful pleurodesis rates reported at 67-84%, but the need for re-intervention is not insignificant at 16% [30]. The major limitation of pleurodesis relates to periprocedure pain and the requirements for hospitalization. Following sclerosant instillation, pleurodesis requires chest tube drainage of the space to keep the two pleural surfaces in apposition and to allow optimal adhesion to occur. Hospital length-of-stay varies anywhere from 3-10 days, following pleurodesis [30, 44, 46]. POTENTIAL COMPLICATIONS OF PLEURODESIS Pulmonary complications with talc pleurodesis have been reported including the development of Acute Respiratory Distress Syndrome [7, 26, 47, 48]. This risk is related to talc particle size and even when allowing the use of talc containing small particles, the risk has been mitigated by limiting talc instillation to no more than 4 grams. The most reported side effects from pleurodesis include: pain, dyspnea and fever [43]. Thirty day mortality rates vary; in the CALGB phase III trial, a 20% - 30 day mortality rate was seen, emphasizing the importance of patient selection and adherence to palliative principles [11, 42]. Various approaches have been tried to minimize the morbidity of pleurodesis [49], but the procedure still requires a hospital stay and may be painful. Pleurodesis is limited to the specific population where the lung re-expands and should not be considered for patients with lung entrapment regardless of their performance status except in limited circumstances. The main advantage of pleurodesis however, is that it is a onetime procedure and when successful, patients do not require persistent care of their effusion. Early cost effectiveness data suggests for patients with 12 month or greater survival, bedside pleurodesis is favorable over Tunneled Pleural Catheter (TPC) or VATS pleurodesis [50]. TUNNELED IN-DWELLING PLEURAL CATHETERS The tunneled pleural catheter was first approved for patient placement by the FDA in 1997. The catheter consists of an intra-pleural component, a tunneled subcutaneous portion, a fibrous subcutaneous cuff (which prevents migration), and an external access section. At the proximal end of the catheter is a one-way valve, which permits safe pleural space drainage (Fig. 3). Because the TPC allows for repeated patient controlled access and drainage of the pleural fluid, it can be used to palliate patients with lung entrapment as well as those with complete lung expansion. The TPC is usually placed in an outpatient or bedside procedure, by the Seldinger technique, but can be placed in adjunct to a diagnostic VATS or medical thoracoscopy. The minimally invasive nature of catheter placement allows it to be used to palliate a spectrum of patients with varying performance statuses, and is unique in that it can be offered to frail patients with diminished performance status. 318 Current Respiratory Medicine Reviews, 2012, Vol. 8, No. 4 (A) (B) Gorden and Fathi The TPC can be placed in the ambulatory setting and immediately managed by supportive caregivers, without requirement for hospitalization. In our experience, when placed in hospitalized patients the mean post procedure length of stay was 3 days, significantly less than the 6 days required after pleurodesis; most placed on an outpatient basis required no hospitalization [30, 46]. In multiple trials the TPC has been shown to palliate the clinical symptoms of MPE with improved dyspnea scores [51-53]. In published series, TPC achieve pleurodesis in approximately 50% of patients but this “bonus” effect cannot be determined apriori. The average time to auto pleurodesis after catheter placement exceeds 40 days [54, 55]. Successful pleurodesis does allow for removal of the TPC but this will not be achieved in all patients and should not be established as an expectation of placement. Tunneled pleural catheter provides durable palliation with limited need for reintervention. In our series, TPCs required significantly less need for ipsilateral re-intervention when compared to talc pleurodesis (2% vs 16% ) [30]. Tunneled pleural catheters require on-going management and active drainage for symptom palliation. Because TPCs require continued engagement, placement must be considered as part of a program and not as isolated procedures. A tunneled pleural catheter program requires a supportive team to ensure maximum palliation and to provide post-procedure support for the patient and caregiver. The education must begin before insertion and followed up for first drainage with the caregiver present. It requires participation of physicians, allied health professionals and/or nurses, a willing patient, and an able caregiver structure. TPC management also requires assistance for drainage and dressing changes: this can often be provided by a family member or visiting caregiver. Additionally, an important part of the TPC program staff is to secure insurance approval and initiate the supply chain for drainage equipment. (C) Fig. (3). (A) Tunneled pleural catheter with intra-thoracic portion, tunneled portion, fibrous cuff and external portion with one way valve and cap. Disposable pleural drainage bottle and tubing for tunneled pleural catheter. (B) Tunneled pleural catheter with external thoracic portion and one way valve with cap showing. (C) CT Scout image of a tunneled pleural catheter in the pleural space. Patients with TPC should be given a drainage schedule: currently no established drainage schedules exist and it is unknown if drainage frequency impacts the pleurodesis rate. Patients should be drained frequently enough to preempt symptoms and should be taught to drain the maximum comfortable volume of fluid per session. Painful drainage is most commonly associated with lung entrapment, and drainage should be interrupted if pain results. Patients must be educated that the volume of fluid drained is not important, and that the palliative effect of fluid drainage is really what matters. Complications of TPC are rare, reported deep infection rates are less than 5% [51, 55]. Occlusion of the TPC is rare and can be potentially managed with the instillation of a small dose/volume of thrombolytic. Tunneled pleural catheter placement supports an active functional lifestyle. Patients should be encouraged to participate in all their usual activities including active sports, travel, work, and showering. The only specific activity limitations are those activities which result in submerging the catheter; swimming, scuba diving, snorkeling, hot tubs or baths. Early cost effective data supports the use of TPC for patients with more limited life expectancy, i.e. 3 months or less [50]. CONCLUSION Malignant pleural effusions represent an advanced state of malignancy and a significant barrier to a good quality of Malignant Pleural Effusion Evaluation and Management Current Respiratory Medicine Reviews, 2012, Vol. 8, No. 4 life. The development of a strategy for managing MPE requires education and engagement of the patient and their caregiver. Any strategy to control the symptoms of MPE must adhere to defined palliative goals: 1. The intervention should be rapid and effective at controlling dyspnea. 2. The intervention should have low - associated morbidity and mortality; 3. The intervention should require minimal followup; 4. The intervention should maximize independence and quality of life. presence of pleural fluid adds an increased symptom layer to their diminished baseline. Three strategies exist for managing MPE: thoracentesis, pleurodesis and tunneled pleural catheter placement. We propose an algorithm for the management of MPE, (Fig. 4) [30]. Thoracentesis is an excellent diagnostic tool to differentiate patients with lung entrapment from those whose lung will fully expand, and to identify patients whose symptoms will not improve despite pleural space evacuation. This is the first branch point in deciding on palliative options. Thoracentesis usually provides no durable symptom relief and in that regard is often a sub-optimal long-term palliative option. Tunneled pleural catheters can be placed in patients with full lung re-expansion post evacuation as well as in those with lung entrapment. The placement of TPC Palliation of MPE must be tailored to the individual patient; some patients remain active despite their diagnosis of malignancy and experience significant loss of function when pleural fluid is present, and become once again highly functional when it is evacuated. Other patients are significantly impaired by their diagnosis of cancer and the Symptomatic pleural effusion in a patient with cancer Thoracentesis Relief of symptoms, followed by recurrent symptomatic effusion? No No further intervention. Yes Was the tap diagnostic of cancer? No Pleural biopsy, if it will change management. Palliative therapy (TPC or pleurodesis) at the time of biopsy. Yes Does the lung fully reexpand on CXR? Yes TPC or pleurodesis. 319 No TPC Fig. (4). Proposed algorithm for evaluation and management of malignant pleural effusion [30]. 320 Current Respiratory Medicine Reviews, 2012, Vol. 8, No. 4 carries low morbidity risks, requires no or limited hospitalization and provides durable relief of symptoms. Tunneled pleural catheter requires on-going self-directed drainage to palliate symptoms and support from caregivers. Tunneled pleural catheter can be placed in both frail and active patients and supports a fully functional lifestyle. Pleurodesis is only compatible with patients who have complete lung expansion and requires hospitalization of 4-6 days with chest tube suction and drainage during this period. After successful pleurodesis patients do not require on-going maintenance or care giver support. For a frail population with MPE, both those with lung entrapment and complete lung expansion, we favor TPC due to its lower morbidity and durable palliation. 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