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Current Controversies in the Management of Malignant Pleural Effusions Maree Azzopardi, MBBS1 José M. Porcel, MD, FCCP, FACP, FAPSR2 Coenraad F. N. Koegelenberg, MBChB, FCP (SA), FRCP, PhD3 Y. C. Gary Lee, MBChB, PhD, FRCP, FACP, FRACP4,5 Edward T. H. Fysh, MBBS, BSc4,5
Vilanova University Hospital, Biomedical Research Institute of Lleida, Lleida, Spain 3 Division of Pulmonology, Department of Medicine, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa 4 Centre for Asthma, Allergy & Respiratory Research, School of Medicine & Pharmacology, University of Western Australia, Perth, Australia 5 Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Australia
Address for correspondence Edward T. H. Fysh, MBBS, BSc, Pleural Medicine Unit, Lung Institute of Western Australia, E Block, Sir Charles Gairdner Hospital, Perth, WA 6009, Australia (e-mail: [email protected]).
Semin Respir Crit Care Med 2014;35:723–731.
Abstract
Keywords
► ► ► ►
malignant effusion pleural pleurodesis indwelling pleural catheter ► talc ► cancer
Malignant pleural effusion (MPE) can complicate most malignancies and is a common clinical problem presenting to respiratory and cancer care physicians. Despite its frequent occurrence, current knowledge of MPE remains limited and controversy surrounds almost every aspect in its diagnosis and management. A lack of robust data has led to significant practice variations worldwide, inefficiencies in healthcare provision, and threats to patient safety. Recent studies have highlighted evolving concepts in MPE care that challenge traditional beliefs. Advancing laboratory techniques have improved the diagnostic yield from pleural fluid cytology, minimizing the need for invasive tissue biopsies, even in many cases of mesothelioma. Imaging-guided biopsy is comparable to thoracoscopy in suitable patients, if cytological examination was noncontributory. Cumulating evidence for the benefits of indwelling pleural catheters (IPCs) has led some centers to adopt this approach as first-line definitive management for MPE over conventional talc pleurodesis. The optimal technique of talc pleurodesis is still debated despite its use for many decades. Strategies combining pleurodesis and IPC are being studied. MPE consists of a heterogenous group of diseases and careful phenotyping of malignant effusion patients can provide important clinical information that will advance the field and allow better stratification of patients and planning of therapy accordingly. This review addresses the controversies in MPE diagnosis and management and exposes the deficits in knowledge of MPE that should be the focus of future research.
Malignant pleural effusions (MPEs) are common and represent one of the most common causes of exudative effusions. MPEs can complicate most cancers and the incidence of MPE is expected to rise, given the aging population and longer survival of cancer patients.
Issue Theme Interventional Pulmonology; Guest Editors: David Feller-Kopman, MD, and Lonny Yarmus, DO, FCCP
MPE has attracted little research interest relative to its high incidence, and disturbingly few advances have been made in the past 80 years. Talc pleurodesis (first published in 1935)1 remains the mainstay of treatment worldwide. Such a striking lack of progress is rarely seen in other common respiratory diseases.
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1395795. ISSN 1069-3424.
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1 Thoracic Medicine Program, The Prince Charles Hospital, Brisbane, Australia 2 Pleural Diseases Unit, Department of Internal Medicine, Arnau de
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The paucity of high-quality data results in heterogeneity of practice worldwide, as was highlighted in a previous International Survey of Pleurodesis Practice (ISPP).2 Controversies surround almost all steps of the diagnosis and treatment of MPEs; clinical care is generally based on “conventional teaching” that has never been subjected to vigorous scientific scrutiny. This article discusses some of these controversies and reviews the latest evidence that may guide practice.
Diagnosis of Malignant Pleural Effusion Confirming a MPE often heralds incurable cancer and significantly impacts treatment plans. A prompt and accurate diagnosis is paramount. However, pleural effusions can arise from no fewer than 60 causes3 and the workup toward a diagnosis of MPE can be lengthy. In up to 25% of patients with MPE, the effusion is the first presentation of their cancer. Along with establishing a diagnosis of MPE, determining the cancer subtype and, where relevant, its mutational status, is equally important in modern-day oncological practice.
Role and Value of Cytological Examination of the Pleural Fluid Ideally, the diagnosis of MPE should be established using the least invasive approach, such as pleural fluid cytological analyses. To identify free-floating malignant cells among the vast range and number of cells arguably requires a higher level of expertise than demonstrating histologic tumor invasion which necessitates pleural tissue biopsies. The role and value of fluid cytology has been debated. For example, in a recent teaching case published in the Clinico-pathological Conference section of the New England Journal of Medicine,4 the patient was subjected to “definitive” surgical biopsy without prior sampling of the fluid, as the discussants felt that fluid cytology was unlikely to provide a diagnosis. This controversy, or myth, warrants clarification. The cytological yield depends on many factors, including sample handling, the volume and number of submitted specimens, the techniques of immunocytochemistry employed, the tumor type, and the experience of the cytopathologist.5 Collected specimens should ideally be processed within 2 hours, although cellular integrity can be preserved for up to 72 hours with appropriate refrigeration at 2 to 8°C.6 Controversy exists concerning the minimum volume of pleural fluid required to diagnose a malignant effusion. Many clinicians propagate the conventional belief that the more fluid sent to the laboratory, the higher the likelihood of having a positive cytological diagnosis. Recent studies have, however, revealed that moderate volumes of pleural fluid, for example, >507 or >150 mL,8 are adequate; others concluded that even smaller quantities, such as 6 mL,9 25 to 50 mL,10 or 50 mL,11 suffice. The latest clinical guidelines recommend that 50 mL of pleural fluid be sent for diagnostic purposes.12 Therefore, a diagnostic thoracentesis can be performed with a small needle and syringe, and negates the need for large volume drainage, for example, via thoracostomy, and the associated risks. Seminars in Respiratory and Critical Care Medicine
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Another controversy surrounds the optimal number of diagnostic aspirations to be performed prior to thoracoscopic or imaging-guided pleural biopsies. The overall sensitivity of pleural fluid cytology is approximately 60%.5,12 In a recent study, the first specimen was positive in 51% of 831 patients with MPEs.13 Further aspirations provide limited benefits. A second sample identified only an additional 7%, and a third sample identified a further 2%. The yield of pleural fluid cytology depends importantly on sample processing. Preparation of cell blocks by centrifuging the fluid sample and obtaining a cell block for hematoxylin and eosin stains14 and immunocytochemistry should routinely be performed. This approach can help (1) confirm malignancy when cytomorphology alone is equivocal; (2) distinguish between reactive mesothelial cells, mesothelioma, and adenocarcinoma; (3) establish the origin of metastatic cancers; and (4) select patients for targeted therapies (e.g., lung cancer patients whose tumors exhibit suitable epidermal growth factor receptor mutations). Immunostaining substantially improves the diagnostic accuracy of conventional cytology (from 57 to 93%) as was illustrated in a study of 603 carcinomatous effusions.15 There is, however, no agreement on the ideal combination of immune markers used. A reasonable choice is a restricted panel of antibodies that combines one marker of malignancy (e.g., epithelial membrane antigen), two mesothelial cell markers (e.g., calretinin, cytokeratin 5/6), and carcinoma markers (e.g., carcinoembryonic antigen, and thyroid transcription factor-1).16 The panel can be expanded if the results are inconclusive or if specific tumors are being considered (e.g., estrogen receptors for breast carcinomas). The role of cytology in diagnosing mesothelioma has been controversial. Fluid cytology is not accepted by many mesothelioma tumor boards, clinical trials, and medicolegal settings as a concrete diagnosis of mesothelioma, which will only be considered with histological proof. Separating benign, reactive, and malignant mesothelial cells require particular expertise. Western Australia has one of the world’s highest incidences of mesothelioma and a recent study from their mesothelioma referral center confirms that the diagnosis of mesothelioma can be reliably made using fluid cytology by specialist cytopathologists. A correct diagnosis of mesothelioma was made from fluid cytology (with immunocytochemistry) in 73% of 517 autopsy-confirmed mesothelioma cases,17 with a specificity of 99.9%. Only two false-positive diagnoses were made and these were eventually found to be metastatic carcinoma; in both cases, the conclusions were made before the availability of specific mesothelial markers.17
Diagnostic Biopsies of the Pleura in Malignant Pleural Effusion Repeated aspirations and biopsies can lead to immediate and delayed complications and should be minimized where possible (►Fig. 1). However, the most efficient and cost-effective approach to obtain a diagnosis for pleural exudates that remain undiagnosed despite pleural fluid analysis is controversial.18,19 Thoracoscopy and imaging-guided biopsies are the two modalities most commonly employed.
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The early utilization of thoracoscopy, either medical or surgical, has conventionally been advocated.12 It has a diagnostic yield of 91 to 95% for pleural malignancy12,20 and allows breakdown of loculations and talc insufflation to achieve pleurodesis in patients with malignancy.12,20,21 The choice between medical and surgical thoracoscopy remains debated. Medical thoracoscopy (pleuroscopy) is currently considered standard practice in some parts of the world (e.g., United Kingdom), but in other parts (e.g., United States), surgical thoracoscopy is often favored. Pleuroscopy can be performed via rigid scopes or flexi-rigid ones; many interventionalists have polarized views which we have summarized elsewhere.22 Pleuroscopy can be performed under conscious sedation in an endoscopy suite, potentially as a daycase.19 Surgical or video-assisted thoracoscopy (VAT) is significantly more invasive and expensive than pleuroscopy, and requires general anesthesia, intubation with a double-lumen endotracheal tube, and more than one port of entry. However, the latter permits complete deflation of a lung, hence superior visualization and access for interventions.18,21 Image-guided closed biopsy offers a rapid, more accessible and cheaper alternative to thoracoscopy, albeit at the cost of a marginally lower yield.19 The choice between ultrasonography and computed tomography (CT) as the preferred imaging modality may be dictated by local expertise and the need to perform the biopsies outside of the radiology unit.19 In some countries, positron emission tomography (PET) scans can be performed rapidly, potentially increasing the yield of CT biopsy without any additional delay. Nevertheless, it must be remembered that benign pleural disease can masquerade as PET-avid pleural malignancy (►Fig. 2) and that pleural drainage sites may remain avid on PET scans for many weeks. Pleural abnormalities and small fluid collections can be accurately identified by means of transthoracic ultrasonography. The appearance of the pleura itself, rather than the echogenicity of effusions, often suggests a neoplastic etiology
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Fig. 2 PET/CT scan in a patient with asbestos exposure depicts unilateral pleural thickening which was FDG-avid (arrow). Although the imaging appearances were suspicious of malignant pleural mesothelioma, subsequent guided biopsy revealed rheumatoid pleuritis that resolved completely with steroid treatment. This highlights the importance of histocytologic confirmation as mimics of pleural malignancy are not uncommon. CT, computed tomography; PET, positron emission tomography.
(►Fig. 3). Evidence suggests that both radiologists and experienced clinicians can categorize effusions as malignant with a sensitivity and specificity of 80 and 84 to 100%, respectively.23,24 Ultrasonographic guidance allows for the biopsy of overtly abnormal pleura, or for the use of other devices (e.g., cutting needles) to biopsy “dry” mesothelioma (►Fig. 4) while decreasing the risk of visceral lacerations.19 Ultrasound guidance has also been shown to increase the likelihood of obtaining pleural tissue and diagnostic yield independent of pleural thickening.25 Moreover, pleural biopsy close to the diaphragm can safely be performed under image guidance, which is important as malignant deposits are more frequently located near the midline and diaphragm.26
Fig. 3 This low-frequency ultrasound image was obtained from a female patient with metastatic breast cancer who presented with a large pleural effusion (E). Note the multiple malignant nodules (N) visible on the diaphragm, and the thickened parietal pleura (P, best seen on high-frequency scanning). Other signs suggestive of malignancy (not seen in this case) include visceral pleural thickening and nodularity as well as hepatic metastases. Seminars in Respiratory and Critical Care Medicine
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Fig. 1 Patients with malignant pleural mesothelioma often have to undergo multiple diagnostic and/or therapeutic pleural interventions with cumulative risks of developing needle tract metastases. This patient with mesothelioma underwent several pleural procedures before an IPC was placed for definitive fluid control (black arrow). The axial CT images showed a significant tract metastasis (white arrow) from a prior diagnostic procedure via a posterior approach several months before, and distant from his IPC insertion sites. CT, computed tomography; IPC, indwelling pleural catheter.
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Azzopardi et al. Metintas et al reported an overall diagnostic sensitivity of 88% for the former, compared with 94% for the latter (p ¼ 0.25).35 In cases with pleural thickening 1 cm, CT-guided Abrams needle biopsy had a sensitivity of 95%, which was equivalent to thoracoscopy (96%). Thoracoscopy was nonsignificantly superior in cases with 3 cm.27–31 In general, contrast-enhanced thoracic CT scan is still the preferred modality to diagnose pleural malignancy.12 Features that are helpful in distinguishing malignant from benign pleural disease are circumferential pleural thickening, nodular pleural thickening, parietal pleural thickening >1 cm, and mediastinal pleural involvement32 (►Fig. 5). CT guidance significantly increases the diagnostic yield in the setting of pleural thickening.33 Maskell et al found that CT-guided cutting needle biopsy had a sensitivity of 87%, while unguided needle biopsy had a sensitivity of 44% (p ¼ 0.02).33 An earlier study found that CT-guided biopsies had a sensitivity of 93% for malignant mesothelioma.34 In the only randomized study comparing Abrams needle biopsy guided by CT scan findings to medical thoracoscopy,
Management of Malignant Pleural Effusion Heterogeneity of care continues after the diagnosis of MPE is made. What treatment to offer and when remains controversial. Physicians must always be mindful that MPE usually heralds an incurable stage of cancer. However, patients with MPEs are highly variable in both prognosis and symptomatology and treatment must be tailored to individual needs.36 The treatment options available are (i) observation while awaiting treatment response to underlying malignancy; (ii) repeated thoracentesis; (iii) pleurodesis; (iv) indwelling pleural catheter (IPC) placement; or (v) palliation of symptoms with opioids and oxygen in terminal patients. The therapeutic goals that mean most to patients are not simply fluid removal, but also symptom relief (especially from breathlessness), improvement in quality-of-life (QoL), and maximizing time outside of hospital.36 All pleural drainage procedures are associated with risks of complications, most commonly pain, pneumothorax, and infection.37 Thoracentesis has a slightly lower complication rate when compared with chest tube insertion; however, if repeated it exposes patients to cumulative risks each time a new procedure is performed. A strategy of repeated thoracenteses also means recurrence of symptoms and ongoing presentations to hospital. Pleurodesis and IPC placement are effective treatments for recurrent MPE, with two recent studies showing improvements in dyspnea and QoL with both treatments in the majority of the 171 patients treated.38,39 Definitive control of the MPE with pleurodesis or IPC placement should therefore be undertaken in all patients who are likely to require ongoing and frequent drainages.
Timing of Pleurodesis for Malignant Pleural Effusions
Fig. 5 This axial computed tomographic image of a patient with mesothelioma shows the cardinal signs of malignant pleural disease: circumferential pleural thickening, pleural thickening >1 cm, pleural nodularity, and mediastinal pleural involvement. In addition, in this patient, there was direct invasion of the chest wall, resulting in erosion of the third rib (arrow). Seminars in Respiratory and Critical Care Medicine
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Some pulmonologists argue that almost all MPEs will recur if not dealt definitively. Therefore, they recommend that all patients with symptoms and a confirmed MPE should be treated with a pleurodesis procedure or IPC placement at their first presentation.40,41 This strategy could reduce the number of procedures endured by patients and the burden of their symptoms over the course of their disease. However, there are drawbacks to this approach. First, breathlessness in MPE patients42 is not always attributable
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to the effusion; only those whose symptoms can be improved by fluid removal should be subjected to pleurodesis or IPC placement. In a series of 902 patients from six different centers in Western Australia, the United Kingdom, Spain, and the Netherlands, only 51.3% were deemed to require definitive treatment over the course of their disease.43 In one study comparing IPC and pleurodesis where clinicians and patients were allowed to choose treatments, only 65 out 160 patients (40.6%) with MPE opted for, or were considered suitable for, definitive treatment.38 Subjecting all MPE patients to pleurodesis/IPC may be inappropriate in a significant portion of this population. In a large series of 390 mesothelioma patients, only 42% received/required pleurodesis.44 Second, patients who respond to chemotherapy may have no or slow reaccumulation of their effusion, negating the need of pleurodesis/IPC. Third, accurate prognosis is notoriously difficult in these patients and fewer drainage procedures may be required in patients with shorter survival, tipping the balance in favor of simple thoracentesis or observation alone.45,46 Studies are urgently needed to identify prognosis of patients with MPE to guide treatment. A recent study has identified the LENT score as a useful algorithm; LENT scores comprise the pleural fluid LDH, ECOG performance status, neutrophil-to-lymphocyte ratio in peripheral blood, and tumor type.46 Likewise, predictors for recurrence of fluid and their associated symptoms are paramount in selecting patients for early definitive treatment.
Pleurodesis versus Indwelling Pleural Catheter Once a decision has been made that a patient is likely to benefit from definitive therapy, a choice has to be made as to which treatment option will offer the best chance of achieving the goals of fluid control with relief of symptoms, improvement in QoL, and independence from health care. Pleurodesis is the traditional approach and is recommended by current guidelines as first-line therapy for patients without trapped lung47 (►Fig. 6). Talc is the pleurodesing agent most commonly used by pulmonologists in English-speaking countries and its superiority over alternative compounds has been suggested in a Cochrane review of small comparative trials.2,48,49 Talc is inexpensive and readily available worldwide. Talc can be delivered intrapleurally as slurry via an intercostal catheter or by dry-powder poudrage during thoracoscopy. IPC has, in recent years, become the first choice of MPE management in some centers. There are no data to guide the choice of pleurodesis or IPC in individual patients and the treatment used is largely dependent on clinicians’ preference.50 We summarize the key data that may influence decisions. Fluid and symptom control: In the largest randomized study on MPE of over 450 patients, the success rate of talc pleurodesis was approximately 75% at 1 month but progressively reduced to approximately 50% at 6 months.51 The longer the patient lives, the more likely pleurodesis will fail. On the other hand, IPC can be inserted as an outpatient52 to facilitate ambulatory drainage of the MPE for the remaining lifespan of the patient. Spontaneous pleurodesis without
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Fig. 6 A typical chest radiograph of a patient with a trapped lung from malignant pleural disease: the lung failed to expand fully following drainage of the pleural fluid. This patient would not be a suitable candidate for pleurodesis; indwelling pleural catheter should be considered.
chemical instillation occurs in approximately 50% of IPC patients.38,39,53 Four studies comparing talc pleurodesis and IPC38,39,53,54 found that patients undergoing pleurodesis were more likely to need subsequent pleural drainage procedures with a pooled failure rate of 22.1% (36/163), compared with 8.9% in IPC patients (21/236).38,39,53,54 Both pleurodesis and IPC improve shortness of breath in the majority of patients. In three studies that reported dyspnea scores, there were trends to less breathlessness in IPC-treated patients.38,39,53 Some results reached significance at 30 days53 and 6 months after therapy.39 Quality of life: In a randomized trial of talc slurry pleurodesis versus IPC as first-line therapy for MPE, Davies et al39 found no significant difference in the overall QoL measures, though a trend favoring the IPC group was noted at the 6week time point. Similarly, in another nonrandomized patient-choice study, more IPC patients reported improvement in early QoL scores (93 vs 50% in the talc group, p ¼ 0.02).38 Hospital stay: Patients undergoing talc slurry pleurodesis spend longer times in hospital during the initial procedure (median 4 vs. 0 days in one study and 6.5 vs. 1.0 days in another).39,53 There are suggestions that patients treated with IPC spent fewer days in hospital in their remaining lifespan both in pleural-related and all-cause hospital stay38,39,54 compared with those treated with talc pleurodesis. In one study, the pleurodesis group spent 11.2% of their remaining life in hospital as opposed to 8.0% with IPC (p < 0.001). This result is being tested in a multicenter randomized trial. Complications: Pleurodesis, regardless of methods, aims to obliterate the pleural space by inducing a diffuse inflammatory reaction and subsequent fibrosis to prevent fluid accumulation.55 Pain and fever are therefore common. Talc pleurodesis has been associated with respiratory failure and acute respiratory distress syndrome (ARDS) as a result Seminars in Respiratory and Critical Care Medicine
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of systemic absorption of small size talc particle.56 Using only talc preparations of large particle size, an observational study of 550 patients undergoing thoracoscopic talc poudrage found no cases of ARDS; nonetheless, oxygenation deteriorated in the first few days after pleurodesis.57 IPC has a different profile of complications. Pleural infection with IPC is often a deterring factor in the uptake of this therapy, although it has actually proven to be relatively uncommon. In the largest systematic review of IPC use thus far, empyema occurred in 2.8% and cellulitis in 3.4% of patients.58 A large, international series of over 1,000 IPC patients showed that pleural infections occurred in 4.8% of patients, but most were mild and easily treated with antibiotics. The mortality from IPC-pleural infection was only 0.3% and removal of the catheter was not always necessary to achieve a favorable outcome.59 Others have confirmed that some infections can be treated effectively without catheter removal, although further clarification of the best treatment strategy is required.60 Concerns regarding the effects of chemotherapy on the frequency of infections should be alleviated by two studies that found no differences in infection rates in IPC-treated patients on chemotherapy compared with those who were not.61,62 Tumor metastasis along the catheter tract complicates up to 10% of cases, especially in mesothelioma patients, but these are easily controlled with local irradiation.63–65 Symptomatic loculation, cellulitis, and mechanical failures (e.g., catheter dislodgment or blockage) are uncommon but can occur.66 Cost-Effectiveness: Comparing cost-effectiveness of IPC and pleurodesis is difficult.50 The major problems have been the wide variation in both the cost of the IPC and drainage equipments around the world and the marked differences in the frequency and location of drainage. Some centers prefer to perform the majority of drainages in an outpatient clinic, others by the patients’ caregivers at home; some advocate routine daily drainages, others only when the patient is symptomatic. These differences in practice impact significantly on costs. Heterogeneity in survival time, fluid accumulation rate, and time to spontaneous pleurodesis considerably influence the number of drainages (and associated costs) required. These variables probably explain why a Dutch study found that costs differed significantly between the underlying tumor types, with the highest in mesothelioma and least with lung cancer67—a direct reflection of median survival times. Prognosis was also shown to be a significant determinant of cost in two studies from the United States. One concluded that IPCs were more effective and less costly than pleurodesis if the survival was less than 3 months, but the reverse was true with survival greater than 12 months.68 The other study combined data from a literature review and extrapolated costs based on their own practice. It determined a difference in cost/benefit between the therapies at 6 weeks.69 This again highlights the need for studies that enable better prediction of survival and need for definitive fluid control.70 Current data provide no clear conclusion of superiority between pleurodesis and IPC. Further studies are underway to provide better guidance on the use of each procedure in Seminars in Respiratory and Critical Care Medicine
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different subsets of patients. In the meantime, several lines of investigation are in progress to combine the advantages of pleurodesis and IPC. Placement of IPC at the time of pleuroscopic talc insufflation has been shown useful in a pilot study.40 A multicenter study is assessing the usefulness of IPC placement followed by intrapleural talc instillation via the catheter when the lung fully expands. Sclerosant-eluting IPCs have been shown to induce effective pleurodesis in different animal models and awaits clinical evaluation.71
Talc Pleurodesis: Controversy on Route of Delivery Optimal methods for talc pleurodesis in MPE continue to be debated. Randomized trials have challenged traditional beliefs that thoracoscopic talc poudrage (dry powder insufflation) is superior to talc slurry pleurodesis performed via bedside tube thoracostomy.51,72 Dresler et al, however, showed in the largest randomized trial of MPE (n ¼ 482) that both methods of talc delivery had similar efficacy in fluid control at 30 days (poudrage 78 vs. slurry 71%).51 Two other smaller randomized studies also showed no significant difference in recurrence rates, drainage time, hospitalizations, or QoL.72,73 Terra et al observed a significant benefit of poudrage in immediate lung expansion, but this did not correlate with clinical outcomes.73 VAT talc poudrage is more invasive and resource consuming. Complications such as postoperative pneumonia and respiratory failure were found to be more common after talc poudrage (9.3 versus 3.6% and 8.1 versus 4.0%, respectively), although poudrage was reported to be more comfortable (p ¼ 0.019).51 VAT-related complications such as bleeding and prolonged air leak have been reported in up to 15% of patients and persistent pain or discomfort at 3 months for over a third of patients.74,75
Talc Pleurodesis: Optimal Procedure Details Although talc slurry pleurodesis is performed everyday around the world, significant practice variations occur because of the lack of data on essentially every step of the pleurodesis process.2 The optimal timing for talc instillation after chest tube insertion is not known. Traditional practice is to defer instillation until daily pleural fluid output falls, usually less than 150 mL/day, correlating with radiological evidence of lung expansion.2 This prolongs hospitalization and its value has not been formally assessed in quality clinical studies. Large bore catheters were conventionally used for pleurodesis, however studies of drain size, predominantly with the use of tetracycline as the sclerosing agent, have shown that smallbore catheters (12–14F) may be as effective and safer.76,77 This is now being evaluated in a multicenter clinical trial. Chest tube clamping time, rotation of patients during clamping, and the timing for drain removal are other controversial areas. Guidelines suggest clamping for 1 hour (without any evidence support) while other centers clamp for up to 4 hours.2,47 Rotating patients in the attempt to improve the dispersion of the sclerosant is time consuming, can cause patient discomfort or tube dislodgement, and is no longer thought to be necessary.12,48,78–80 Scintigraphic imaging studies of radiolabeled talc and tetracycline showed no effect
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6 Antonangelo L, Vargas FS, Acencio MM, et al. Effect of temperature
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Looking into the Future There is increasing realization that current knowledge of MPE is extremely limited and management practice is significantly behind the times.83 Controversies exist and persist because of the ongoing lack of quality data to address key clinical questions. Studies in recent years have revealed major deficits in knowledge that permit harmful practice. Only three-quarters of a century after talc pleurodesis started did we uncover the frequent occurrence (1 in 50 cases)51 of fatal ARDS associated with small particle talc preparations. Multicenter efforts have started to disperse myths from conventional teaching, such as the perceived advantage of talc poudrage over slurry. There are still numerous important questions that demand urgent answers from proper clinical trials to guide patient care. Novel concepts continue to evolve and will challenge conventional perceptions. MPE consists of a heterogenous group of diseases and careful phenotyping of malignant effusion patients can provide important clinical information that will advance the field. International collaborative efforts are required to provide the large cohorts to cover the diverse spectrum of patients with MPE.
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Acknowledgments Prof. Lee is a National Health & Medical Research Council (NHMRC) Career Development Fellow and receives project grant funding from the NHMRC, New South Wales Dust Disease Board, Sir Charles Gairdner Research Advisory Committee, LIWA Westcare Grants and the Cancer Council of Western Australia.
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and storage time on cellular analysis of fresh pleural fluid samples. Cytopathology 2012;23(2):103–107 Lim MH, Garrettc J, Mowlem L, Yap E. Diagnosing malignant pleural effusions: how do we compare? N Z Med J 2013;126(1381):42–48 Swiderek J, Morcos S, Donthireddy V, et al. Prospective study to determine the volume of pleural fluid required to diagnose malignancy. Chest 2010;137(1):68–73 Sallach SM, Sallach JA, Vasquez E, Schultz L, Kvale P. Volume of pleural fluid required for diagnosis of pleural malignancy. Chest 2002;122(6):1913–1917 Thomas SC, Davidson LR, McKean ME. An investigation of adequate volume for the diagnosis of malignancy in pleural fluids. Cytopathology 2011;22(3):179–183 Abouzgheib W, Bartter T, Dagher H, Pratter M, Klump W. A prospective study of the volume of pleural fluid required for accurate diagnosis of malignant pleural effusion. Chest 2009; 135(4):999–1001 Hooper C, Lee YC, Maskell N; BTS Pleural Guideline Group. Investigation of a unilateral pleural effusion in adults: British Thoracic Society Pleural Disease Guideline 2010. Thorax 2010; 65(Suppl 2):ii4–ii17 Porcel JM, Esquerda A, Vives M, Bielsa S. Etiology of pleural effusions: analysis of more than 3,000 consecutive thoracenteses. Arch Bronconeumol 2014;50(5):161–165 Bhanvadia MV, Santwani PM, Vachhani JH. Analysis of diagnostic value of cytological smear method versus cell block method in body fluid cytology: study of 150 cases. Ethiop J Health Sci 2014; 24(2):125–131 Metzgeroth G, Kuhn C, Schultheis B, Hehlmann R, Hastka J. Diagnostic accuracy of cytology and immunocytology in carcinomatous effusions. Cytopathology 2008;19(4):205–211 Porcel JM. Pleural fluid biomarkers: beyond the Light criteria. Clin Chest Med 2013;34(1):27–37 Segal A, Sterrett GF, Frost FA, et al. A diagnosis of malignant pleural mesothelioma can be made by effusion cytology: results of a 20. year audit. Pathology 2013;45(1):44–48 Koegelenberg CF, Diacon AH. Image-guided pleural biopsy. Curr Opin Pulm Med 2013;19(4):368–373 Koegelenberg CF, Diacon AH. Pleural controversy: close needle pleural biopsy or thoracoscopy-which first? Respirology 2011; 16(5):738–746 Froudarakis ME. New challenges in medical thoracoscopy. Respiration 2011;82(2):197–200 Loddenkemper R. Thoracoscopy—state of the art. Eur Respir J 1998;11(1):213–221 Yap KH, Phillips MJ, Lee YC. Medical thoracoscopy: rigid thoracoscopy or flexi-rigid pleuroscopy? Curr Opin Pulm Med 2014;20(4): 358–365 Qureshi NR, Rahman NM, Gleeson FV. Thoracic ultrasound in the diagnosis of malignant pleural effusion. Thorax 2009;64(2): 139–143 Bugalho A, Ferreira D, Dias SS, et al. The diagnostic value of transthoracic ultrasonographic features in predicting malignancy in undiagnosed pleural effusions: a prospective observational study. Respiration 2014;87(4):270–278 Botana-Rial M, Leiro-Fernández V, Represas-Represas C, GonzálezPiñeiro A, Tilve-Gómez A, Fernández-Villar A. Thoracic ultrasound-assisted selection for pleural biopsy with Abrams needle. Respir Care 2013;58(11):1949–1954 Canto A, Rivas J, Saumench J, Morera R, Moya J. Points to consider when choosing a biopsy method in cases of pleurisy of unknown origin. Chest 1983;84(2):176–179 Koegelenberg C, Groote-Bidlingmaier FV, Bruwer JW, et al. An image-guided diagnostic pathway for undiagnosed pleural exudates. Eur Respir J 2013;42(Suppl 57):652s Koegelenberg CF, Bolliger CT, Theron J, et al. Direct comparison of the diagnostic yield of ultrasound-assisted Abrams and Tru-Cut Seminars in Respiratory and Critical Care Medicine
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on the intrapleural dispersion of the sclerosant and a small randomized study showed no significant benefit to the pleurodesis success rate.78–80 Two small randomized trials, one involving talc pleurodesis and other doxycyline, have assessed the duration of chest drainage following pleurodesis with similar results.81,82 Goodman and Davies showed that earlier drain removal at 24 hours following talc pleurodesis (with the benefit of shorter hospitalization) did not lead to greater recurrence rates compared with drain removal at 72 hours post–talc pleurodesis.81 The study was small, and the results not widely adopted. However, if verified in larger studies, this will save many inpatient days.
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for management of malignant pleural effusions: the advantages. Curr Respir Care Rep. 2013;2:93–99 Dresler CM, Olak J, Herndon JE II, et al; Cooperative Groups Cancer and Leukemia Group B; Eastern Cooperative Oncology Group; North Central Cooperative Oncology Group; Radiation Therapy Oncology Group. Phase III intergroup study of talc poudrage vs talc slurry sclerosis for malignant pleural effusion. Chest 2005;127(3): 909–915 Putnam JB Jr, Walsh GL, Swisher SG, et al. Outpatient management of malignant pleural effusion by a chronic indwelling pleural catheter. Ann Thorac Surg 2000;69(2):369–375 Putnam JB Jr, Light RW, Rodriguez RM, et al. A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions. Cancer 1999;86(10):1992–1999 Hunt BM, Farivar AS, Vallières E, et al. Thoracoscopic talc versus tunneled pleural catheters for palliation of malignant pleural effusions. Ann Thorac Surg 2012;94(4):1053–1057, discussion 1057–1059 Davies HE, Lee YC, Davies RJO. Pleurodesis for malignant pleural effusion: talc, toxicity and where next? [Editorial]Thorax 2008; 63(7):572–574 Campos JR, Werebe EC, Vargas FS, Jatene FB, Light RW. Respiratory failure due to insufflated talc. Lancet 1997;349(9047): 251–252 Janssen JP, Collier G, Astoul P, et al. Safety of pleurodesis with talc poudrage in malignant pleural effusion: a prospective cohort study. Lancet 2007;369(9572):1535–1539 Van Meter ME, McKee KY, Kohlwes RJ. Efficacy and safety of tunneled pleural catheters in adults with malignant pleural effusions: a systematic review. J Gen Intern Med 2011;26(1): 70–76 Fysh ETH, Tremblay A, Feller-Kopman D, et al. Clinical outcomes of indwelling pleural catheter-related pleural infections: an international multicenter study. Chest 2013;144(5):1597–1602 Mahmood K, Bower C. Treatment of infection associated with tunneled pleural catheters. J Bronchology Interv Pulmonol 2010; 17(1):69–72 Mekhaiel E, Kashyap R, Mullon JJ, Maldonado F. Infections associated with tunnelled indwelling pleural catheters in patients undergoing chemotherapy. J Bronchology Interv Pulmonol 2013; 20(4):299–303 Morel A, Mishra E, Medley L, et al. Chemotherapy should not be withheld from patients with an indwelling pleural catheter for malignant pleural effusion. Thorax 2011;66(5):448–449 Thomas R, Budgeon CA, Kuok YJ, et al. Catheter tract metastasis associated with indwelling pleural catheters. Chest 2014;146(3): 557–562 Davies HE, Musk AW, Lee YCG. Prophylactic radiotherapy for pleural puncture sites in mesothelioma: the controversy continues. Curr Opin Pulm Med 2008;14(4):326–330 Janes SM, Rahman NM, Davies RJO, Lee YCG. Catheter-tract metastases associated with chronic indwelling pleural catheters. Chest 2007;131(4):1232–1234 Fysh ET, Smith NA, Lee YC. Optimal chest drain size: the rise of the small-bore pleural catheter. Semin Respir Crit Care Med 2010; 31(6):760–768 Boshuizen RC, Onderwater S, Burgers SJA, van den Heuvel MM. The use of indwelling pleural catheters for the management of malignant pleural effusion—direct costs in a Dutch hospital. Respiration 2013;86(3):224–228 Puri V, Pyrdeck TL, Crabtree TD, et al. Treatment of malignant pleural effusion: a cost-effectiveness analysis. Ann Thorac Surg 2012;94(2):374–379, discussion 379–380 Olden AM, Holloway R. Treatment of malignant pleural effusion: PleuRx catheter or talc pleurodesis? A cost-effectiveness analysis. J Palliat Med 2010;13(1):59–65
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tory out-patient care: a price worth paying? Respiration 2013; 86(3):181–182 Tremblay A, Dumitriu S, Stather DR, Maceachern P, Illanes O, Kelly MM. Use of a drug eluting pleural catheter for pleurodesis. Exp Lung Res 2012;38(9-10):475–482 Yim AP, Chan AT, Lee TW, Wan IY, Ho JK. Thoracoscopic talc insufflation versus talc slurry for symptomatic malignant pleural effusion. Ann Thorac Surg 1996;62(6): 1655–1658 Terra RM, Junqueira JJ, Teixeira LR, Vargas FS, Pêgo-Fernandes PM, Jatene FB. Is full postpleurodesis lung expansion a determinant of a successful outcome after talc pleurodesis? Chest 2009;136(2): 361–368 Harris RJ, Kavuru MS, Mehta AC, et al. The impact of thoracoscopy on the management of pleural disease. Chest 1995;107(3): 845–852 Furrer M, Rechsteiner R, Eigenmann V, Signer C, Althaus U, Ris HB. Thoracotomy and thoracoscopy: postoperative pulmonary function, pain and chest wall complaints. Eur J Cardiothorac Surg 1997; 12(1):82–87 Parulekar W, Di Primio G, Matzinger F, Dennie C, Bociek G. Use of small-bore vs large-bore chest tubes for treatment of malignant pleural effusions. Chest 2001;120(1):19–25
Faurschou P. Treatment of malignant pleural effusion: pleurodesis using a small percutaneous catheter. A prospective randomized study. Respir Med 1998;92(3):593–596 Mager HJ, Maesen B, Verzijlbergen F, Schramel F. Distribution of talc suspension during treatment of malignant pleural effusion with talc pleurodesis. Lung Cancer 2002;36(1):77–81 Lorch DG, Gordon L, Wooten S, Cooper JF, Strange C, Sahn SA. Effect of patient positioning on distribution of tetracycline in the pleural space during pleurodesis. Chest 1988;93(3):527–529 Dryzer SR, Allen ML, Strange C, Sahn SA. A comparison of rotation and nonrotation in tetracycline pleurodesis. Chest 1993;104(6): 1763–1766 Goodman A, Davies CW. Efficacy of short-term versus long-term chest tube drainage following talc slurry pleurodesis in patients with malignant pleural effusions: a randomised trial. Lung Cancer 2006;54(1):51–55 Villanueva AG, Gray AW Jr, Shahian DM, Williamson WA, Beamis JF Jr. Efficacy of short term versus long term tube thoracostomy drainage before tetracycline pleurodesis in the treatment of malignant pleural effusions. Thorax 1994;49(1):23–25 Thomas R, Francis R, Davies HE, Lee YC. Interventional therapies for malignant pleural effusions: the present and the future. Respirology 2014;19(6):809–822
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Controversies in Malignant Pleural Effusions
Current Controversies in the Management of Malignant Pleural Effusions Maree Azzopardi, MBBS1 José M. Porcel, MD, FCCP, FACP, FAPSR2 Coenraad F. N. Koegelenberg, MBChB, FCP (SA), FRCP, PhD3 Y. C. Gary Lee, MBChB, PhD, FRCP, FACP, FRACP4,5 Edward T. H. Fysh, MBBS, BSc4,5
Vilanova University Hospital, Biomedical Research Institute of Lleida, Lleida, Spain 3 Division of Pulmonology, Department of Medicine, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa 4 Centre for Asthma, Allergy & Respiratory Research, School of Medicine & Pharmacology, University of Western Australia, Perth, Australia 5 Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Australia
Address for correspondence Edward T. H. Fysh, MBBS, BSc, Pleural Medicine Unit, Lung Institute of Western Australia, E Block, Sir Charles Gairdner Hospital, Perth, WA 6009, Australia (e-mail: [email protected]).
Semin Respir Crit Care Med 2014;35:723–731.
Abstract
Keywords
► ► ► ►
malignant effusion pleural pleurodesis indwelling pleural catheter ► talc ► cancer
Malignant pleural effusion (MPE) can complicate most malignancies and is a common clinical problem presenting to respiratory and cancer care physicians. Despite its frequent occurrence, current knowledge of MPE remains limited and controversy surrounds almost every aspect in its diagnosis and management. A lack of robust data has led to significant practice variations worldwide, inefficiencies in healthcare provision, and threats to patient safety. Recent studies have highlighted evolving concepts in MPE care that challenge traditional beliefs. Advancing laboratory techniques have improved the diagnostic yield from pleural fluid cytology, minimizing the need for invasive tissue biopsies, even in many cases of mesothelioma. Imaging-guided biopsy is comparable to thoracoscopy in suitable patients, if cytological examination was noncontributory. Cumulating evidence for the benefits of indwelling pleural catheters (IPCs) has led some centers to adopt this approach as first-line definitive management for MPE over conventional talc pleurodesis. The optimal technique of talc pleurodesis is still debated despite its use for many decades. Strategies combining pleurodesis and IPC are being studied. MPE consists of a heterogenous group of diseases and careful phenotyping of malignant effusion patients can provide important clinical information that will advance the field and allow better stratification of patients and planning of therapy accordingly. This review addresses the controversies in MPE diagnosis and management and exposes the deficits in knowledge of MPE that should be the focus of future research.
Malignant pleural effusions (MPEs) are common and represent one of the most common causes of exudative effusions. MPEs can complicate most cancers and the incidence of MPE is expected to rise, given the aging population and longer survival of cancer patients.
Issue Theme Interventional Pulmonology; Guest Editors: David Feller-Kopman, MD, and Lonny Yarmus, DO, FCCP
MPE has attracted little research interest relative to its high incidence, and disturbingly few advances have been made in the past 80 years. Talc pleurodesis (first published in 1935)1 remains the mainstay of treatment worldwide. Such a striking lack of progress is rarely seen in other common respiratory diseases.
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1395795. ISSN 1069-3424.
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1 Thoracic Medicine Program, The Prince Charles Hospital, Brisbane, Australia 2 Pleural Diseases Unit, Department of Internal Medicine, Arnau de
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The paucity of high-quality data results in heterogeneity of practice worldwide, as was highlighted in a previous International Survey of Pleurodesis Practice (ISPP).2 Controversies surround almost all steps of the diagnosis and treatment of MPEs; clinical care is generally based on “conventional teaching” that has never been subjected to vigorous scientific scrutiny. This article discusses some of these controversies and reviews the latest evidence that may guide practice.
Diagnosis of Malignant Pleural Effusion Confirming a MPE often heralds incurable cancer and significantly impacts treatment plans. A prompt and accurate diagnosis is paramount. However, pleural effusions can arise from no fewer than 60 causes3 and the workup toward a diagnosis of MPE can be lengthy. In up to 25% of patients with MPE, the effusion is the first presentation of their cancer. Along with establishing a diagnosis of MPE, determining the cancer subtype and, where relevant, its mutational status, is equally important in modern-day oncological practice.
Role and Value of Cytological Examination of the Pleural Fluid Ideally, the diagnosis of MPE should be established using the least invasive approach, such as pleural fluid cytological analyses. To identify free-floating malignant cells among the vast range and number of cells arguably requires a higher level of expertise than demonstrating histologic tumor invasion which necessitates pleural tissue biopsies. The role and value of fluid cytology has been debated. For example, in a recent teaching case published in the Clinico-pathological Conference section of the New England Journal of Medicine,4 the patient was subjected to “definitive” surgical biopsy without prior sampling of the fluid, as the discussants felt that fluid cytology was unlikely to provide a diagnosis. This controversy, or myth, warrants clarification. The cytological yield depends on many factors, including sample handling, the volume and number of submitted specimens, the techniques of immunocytochemistry employed, the tumor type, and the experience of the cytopathologist.5 Collected specimens should ideally be processed within 2 hours, although cellular integrity can be preserved for up to 72 hours with appropriate refrigeration at 2 to 8°C.6 Controversy exists concerning the minimum volume of pleural fluid required to diagnose a malignant effusion. Many clinicians propagate the conventional belief that the more fluid sent to the laboratory, the higher the likelihood of having a positive cytological diagnosis. Recent studies have, however, revealed that moderate volumes of pleural fluid, for example, >507 or >150 mL,8 are adequate; others concluded that even smaller quantities, such as 6 mL,9 25 to 50 mL,10 or 50 mL,11 suffice. The latest clinical guidelines recommend that 50 mL of pleural fluid be sent for diagnostic purposes.12 Therefore, a diagnostic thoracentesis can be performed with a small needle and syringe, and negates the need for large volume drainage, for example, via thoracostomy, and the associated risks. Seminars in Respiratory and Critical Care Medicine
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Another controversy surrounds the optimal number of diagnostic aspirations to be performed prior to thoracoscopic or imaging-guided pleural biopsies. The overall sensitivity of pleural fluid cytology is approximately 60%.5,12 In a recent study, the first specimen was positive in 51% of 831 patients with MPEs.13 Further aspirations provide limited benefits. A second sample identified only an additional 7%, and a third sample identified a further 2%. The yield of pleural fluid cytology depends importantly on sample processing. Preparation of cell blocks by centrifuging the fluid sample and obtaining a cell block for hematoxylin and eosin stains14 and immunocytochemistry should routinely be performed. This approach can help (1) confirm malignancy when cytomorphology alone is equivocal; (2) distinguish between reactive mesothelial cells, mesothelioma, and adenocarcinoma; (3) establish the origin of metastatic cancers; and (4) select patients for targeted therapies (e.g., lung cancer patients whose tumors exhibit suitable epidermal growth factor receptor mutations). Immunostaining substantially improves the diagnostic accuracy of conventional cytology (from 57 to 93%) as was illustrated in a study of 603 carcinomatous effusions.15 There is, however, no agreement on the ideal combination of immune markers used. A reasonable choice is a restricted panel of antibodies that combines one marker of malignancy (e.g., epithelial membrane antigen), two mesothelial cell markers (e.g., calretinin, cytokeratin 5/6), and carcinoma markers (e.g., carcinoembryonic antigen, and thyroid transcription factor-1).16 The panel can be expanded if the results are inconclusive or if specific tumors are being considered (e.g., estrogen receptors for breast carcinomas). The role of cytology in diagnosing mesothelioma has been controversial. Fluid cytology is not accepted by many mesothelioma tumor boards, clinical trials, and medicolegal settings as a concrete diagnosis of mesothelioma, which will only be considered with histological proof. Separating benign, reactive, and malignant mesothelial cells require particular expertise. Western Australia has one of the world’s highest incidences of mesothelioma and a recent study from their mesothelioma referral center confirms that the diagnosis of mesothelioma can be reliably made using fluid cytology by specialist cytopathologists. A correct diagnosis of mesothelioma was made from fluid cytology (with immunocytochemistry) in 73% of 517 autopsy-confirmed mesothelioma cases,17 with a specificity of 99.9%. Only two false-positive diagnoses were made and these were eventually found to be metastatic carcinoma; in both cases, the conclusions were made before the availability of specific mesothelial markers.17
Diagnostic Biopsies of the Pleura in Malignant Pleural Effusion Repeated aspirations and biopsies can lead to immediate and delayed complications and should be minimized where possible (►Fig. 1). However, the most efficient and cost-effective approach to obtain a diagnosis for pleural exudates that remain undiagnosed despite pleural fluid analysis is controversial.18,19 Thoracoscopy and imaging-guided biopsies are the two modalities most commonly employed.
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The early utilization of thoracoscopy, either medical or surgical, has conventionally been advocated.12 It has a diagnostic yield of 91 to 95% for pleural malignancy12,20 and allows breakdown of loculations and talc insufflation to achieve pleurodesis in patients with malignancy.12,20,21 The choice between medical and surgical thoracoscopy remains debated. Medical thoracoscopy (pleuroscopy) is currently considered standard practice in some parts of the world (e.g., United Kingdom), but in other parts (e.g., United States), surgical thoracoscopy is often favored. Pleuroscopy can be performed via rigid scopes or flexi-rigid ones; many interventionalists have polarized views which we have summarized elsewhere.22 Pleuroscopy can be performed under conscious sedation in an endoscopy suite, potentially as a daycase.19 Surgical or video-assisted thoracoscopy (VAT) is significantly more invasive and expensive than pleuroscopy, and requires general anesthesia, intubation with a double-lumen endotracheal tube, and more than one port of entry. However, the latter permits complete deflation of a lung, hence superior visualization and access for interventions.18,21 Image-guided closed biopsy offers a rapid, more accessible and cheaper alternative to thoracoscopy, albeit at the cost of a marginally lower yield.19 The choice between ultrasonography and computed tomography (CT) as the preferred imaging modality may be dictated by local expertise and the need to perform the biopsies outside of the radiology unit.19 In some countries, positron emission tomography (PET) scans can be performed rapidly, potentially increasing the yield of CT biopsy without any additional delay. Nevertheless, it must be remembered that benign pleural disease can masquerade as PET-avid pleural malignancy (►Fig. 2) and that pleural drainage sites may remain avid on PET scans for many weeks. Pleural abnormalities and small fluid collections can be accurately identified by means of transthoracic ultrasonography. The appearance of the pleura itself, rather than the echogenicity of effusions, often suggests a neoplastic etiology
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Fig. 2 PET/CT scan in a patient with asbestos exposure depicts unilateral pleural thickening which was FDG-avid (arrow). Although the imaging appearances were suspicious of malignant pleural mesothelioma, subsequent guided biopsy revealed rheumatoid pleuritis that resolved completely with steroid treatment. This highlights the importance of histocytologic confirmation as mimics of pleural malignancy are not uncommon. CT, computed tomography; PET, positron emission tomography.
(►Fig. 3). Evidence suggests that both radiologists and experienced clinicians can categorize effusions as malignant with a sensitivity and specificity of 80 and 84 to 100%, respectively.23,24 Ultrasonographic guidance allows for the biopsy of overtly abnormal pleura, or for the use of other devices (e.g., cutting needles) to biopsy “dry” mesothelioma (►Fig. 4) while decreasing the risk of visceral lacerations.19 Ultrasound guidance has also been shown to increase the likelihood of obtaining pleural tissue and diagnostic yield independent of pleural thickening.25 Moreover, pleural biopsy close to the diaphragm can safely be performed under image guidance, which is important as malignant deposits are more frequently located near the midline and diaphragm.26
Fig. 3 This low-frequency ultrasound image was obtained from a female patient with metastatic breast cancer who presented with a large pleural effusion (E). Note the multiple malignant nodules (N) visible on the diaphragm, and the thickened parietal pleura (P, best seen on high-frequency scanning). Other signs suggestive of malignancy (not seen in this case) include visceral pleural thickening and nodularity as well as hepatic metastases. Seminars in Respiratory and Critical Care Medicine
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Fig. 1 Patients with malignant pleural mesothelioma often have to undergo multiple diagnostic and/or therapeutic pleural interventions with cumulative risks of developing needle tract metastases. This patient with mesothelioma underwent several pleural procedures before an IPC was placed for definitive fluid control (black arrow). The axial CT images showed a significant tract metastasis (white arrow) from a prior diagnostic procedure via a posterior approach several months before, and distant from his IPC insertion sites. CT, computed tomography; IPC, indwelling pleural catheter.
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Azzopardi et al. Metintas et al reported an overall diagnostic sensitivity of 88% for the former, compared with 94% for the latter (p ¼ 0.25).35 In cases with pleural thickening 1 cm, CT-guided Abrams needle biopsy had a sensitivity of 95%, which was equivalent to thoracoscopy (96%). Thoracoscopy was nonsignificantly superior in cases with 3 cm.27–31 In general, contrast-enhanced thoracic CT scan is still the preferred modality to diagnose pleural malignancy.12 Features that are helpful in distinguishing malignant from benign pleural disease are circumferential pleural thickening, nodular pleural thickening, parietal pleural thickening >1 cm, and mediastinal pleural involvement32 (►Fig. 5). CT guidance significantly increases the diagnostic yield in the setting of pleural thickening.33 Maskell et al found that CT-guided cutting needle biopsy had a sensitivity of 87%, while unguided needle biopsy had a sensitivity of 44% (p ¼ 0.02).33 An earlier study found that CT-guided biopsies had a sensitivity of 93% for malignant mesothelioma.34 In the only randomized study comparing Abrams needle biopsy guided by CT scan findings to medical thoracoscopy,
Management of Malignant Pleural Effusion Heterogeneity of care continues after the diagnosis of MPE is made. What treatment to offer and when remains controversial. Physicians must always be mindful that MPE usually heralds an incurable stage of cancer. However, patients with MPEs are highly variable in both prognosis and symptomatology and treatment must be tailored to individual needs.36 The treatment options available are (i) observation while awaiting treatment response to underlying malignancy; (ii) repeated thoracentesis; (iii) pleurodesis; (iv) indwelling pleural catheter (IPC) placement; or (v) palliation of symptoms with opioids and oxygen in terminal patients. The therapeutic goals that mean most to patients are not simply fluid removal, but also symptom relief (especially from breathlessness), improvement in quality-of-life (QoL), and maximizing time outside of hospital.36 All pleural drainage procedures are associated with risks of complications, most commonly pain, pneumothorax, and infection.37 Thoracentesis has a slightly lower complication rate when compared with chest tube insertion; however, if repeated it exposes patients to cumulative risks each time a new procedure is performed. A strategy of repeated thoracenteses also means recurrence of symptoms and ongoing presentations to hospital. Pleurodesis and IPC placement are effective treatments for recurrent MPE, with two recent studies showing improvements in dyspnea and QoL with both treatments in the majority of the 171 patients treated.38,39 Definitive control of the MPE with pleurodesis or IPC placement should therefore be undertaken in all patients who are likely to require ongoing and frequent drainages.
Timing of Pleurodesis for Malignant Pleural Effusions
Fig. 5 This axial computed tomographic image of a patient with mesothelioma shows the cardinal signs of malignant pleural disease: circumferential pleural thickening, pleural thickening >1 cm, pleural nodularity, and mediastinal pleural involvement. In addition, in this patient, there was direct invasion of the chest wall, resulting in erosion of the third rib (arrow). Seminars in Respiratory and Critical Care Medicine
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Some pulmonologists argue that almost all MPEs will recur if not dealt definitively. Therefore, they recommend that all patients with symptoms and a confirmed MPE should be treated with a pleurodesis procedure or IPC placement at their first presentation.40,41 This strategy could reduce the number of procedures endured by patients and the burden of their symptoms over the course of their disease. However, there are drawbacks to this approach. First, breathlessness in MPE patients42 is not always attributable
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to the effusion; only those whose symptoms can be improved by fluid removal should be subjected to pleurodesis or IPC placement. In a series of 902 patients from six different centers in Western Australia, the United Kingdom, Spain, and the Netherlands, only 51.3% were deemed to require definitive treatment over the course of their disease.43 In one study comparing IPC and pleurodesis where clinicians and patients were allowed to choose treatments, only 65 out 160 patients (40.6%) with MPE opted for, or were considered suitable for, definitive treatment.38 Subjecting all MPE patients to pleurodesis/IPC may be inappropriate in a significant portion of this population. In a large series of 390 mesothelioma patients, only 42% received/required pleurodesis.44 Second, patients who respond to chemotherapy may have no or slow reaccumulation of their effusion, negating the need of pleurodesis/IPC. Third, accurate prognosis is notoriously difficult in these patients and fewer drainage procedures may be required in patients with shorter survival, tipping the balance in favor of simple thoracentesis or observation alone.45,46 Studies are urgently needed to identify prognosis of patients with MPE to guide treatment. A recent study has identified the LENT score as a useful algorithm; LENT scores comprise the pleural fluid LDH, ECOG performance status, neutrophil-to-lymphocyte ratio in peripheral blood, and tumor type.46 Likewise, predictors for recurrence of fluid and their associated symptoms are paramount in selecting patients for early definitive treatment.
Pleurodesis versus Indwelling Pleural Catheter Once a decision has been made that a patient is likely to benefit from definitive therapy, a choice has to be made as to which treatment option will offer the best chance of achieving the goals of fluid control with relief of symptoms, improvement in QoL, and independence from health care. Pleurodesis is the traditional approach and is recommended by current guidelines as first-line therapy for patients without trapped lung47 (►Fig. 6). Talc is the pleurodesing agent most commonly used by pulmonologists in English-speaking countries and its superiority over alternative compounds has been suggested in a Cochrane review of small comparative trials.2,48,49 Talc is inexpensive and readily available worldwide. Talc can be delivered intrapleurally as slurry via an intercostal catheter or by dry-powder poudrage during thoracoscopy. IPC has, in recent years, become the first choice of MPE management in some centers. There are no data to guide the choice of pleurodesis or IPC in individual patients and the treatment used is largely dependent on clinicians’ preference.50 We summarize the key data that may influence decisions. Fluid and symptom control: In the largest randomized study on MPE of over 450 patients, the success rate of talc pleurodesis was approximately 75% at 1 month but progressively reduced to approximately 50% at 6 months.51 The longer the patient lives, the more likely pleurodesis will fail. On the other hand, IPC can be inserted as an outpatient52 to facilitate ambulatory drainage of the MPE for the remaining lifespan of the patient. Spontaneous pleurodesis without
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Fig. 6 A typical chest radiograph of a patient with a trapped lung from malignant pleural disease: the lung failed to expand fully following drainage of the pleural fluid. This patient would not be a suitable candidate for pleurodesis; indwelling pleural catheter should be considered.
chemical instillation occurs in approximately 50% of IPC patients.38,39,53 Four studies comparing talc pleurodesis and IPC38,39,53,54 found that patients undergoing pleurodesis were more likely to need subsequent pleural drainage procedures with a pooled failure rate of 22.1% (36/163), compared with 8.9% in IPC patients (21/236).38,39,53,54 Both pleurodesis and IPC improve shortness of breath in the majority of patients. In three studies that reported dyspnea scores, there were trends to less breathlessness in IPC-treated patients.38,39,53 Some results reached significance at 30 days53 and 6 months after therapy.39 Quality of life: In a randomized trial of talc slurry pleurodesis versus IPC as first-line therapy for MPE, Davies et al39 found no significant difference in the overall QoL measures, though a trend favoring the IPC group was noted at the 6week time point. Similarly, in another nonrandomized patient-choice study, more IPC patients reported improvement in early QoL scores (93 vs 50% in the talc group, p ¼ 0.02).38 Hospital stay: Patients undergoing talc slurry pleurodesis spend longer times in hospital during the initial procedure (median 4 vs. 0 days in one study and 6.5 vs. 1.0 days in another).39,53 There are suggestions that patients treated with IPC spent fewer days in hospital in their remaining lifespan both in pleural-related and all-cause hospital stay38,39,54 compared with those treated with talc pleurodesis. In one study, the pleurodesis group spent 11.2% of their remaining life in hospital as opposed to 8.0% with IPC (p < 0.001). This result is being tested in a multicenter randomized trial. Complications: Pleurodesis, regardless of methods, aims to obliterate the pleural space by inducing a diffuse inflammatory reaction and subsequent fibrosis to prevent fluid accumulation.55 Pain and fever are therefore common. Talc pleurodesis has been associated with respiratory failure and acute respiratory distress syndrome (ARDS) as a result Seminars in Respiratory and Critical Care Medicine
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of systemic absorption of small size talc particle.56 Using only talc preparations of large particle size, an observational study of 550 patients undergoing thoracoscopic talc poudrage found no cases of ARDS; nonetheless, oxygenation deteriorated in the first few days after pleurodesis.57 IPC has a different profile of complications. Pleural infection with IPC is often a deterring factor in the uptake of this therapy, although it has actually proven to be relatively uncommon. In the largest systematic review of IPC use thus far, empyema occurred in 2.8% and cellulitis in 3.4% of patients.58 A large, international series of over 1,000 IPC patients showed that pleural infections occurred in 4.8% of patients, but most were mild and easily treated with antibiotics. The mortality from IPC-pleural infection was only 0.3% and removal of the catheter was not always necessary to achieve a favorable outcome.59 Others have confirmed that some infections can be treated effectively without catheter removal, although further clarification of the best treatment strategy is required.60 Concerns regarding the effects of chemotherapy on the frequency of infections should be alleviated by two studies that found no differences in infection rates in IPC-treated patients on chemotherapy compared with those who were not.61,62 Tumor metastasis along the catheter tract complicates up to 10% of cases, especially in mesothelioma patients, but these are easily controlled with local irradiation.63–65 Symptomatic loculation, cellulitis, and mechanical failures (e.g., catheter dislodgment or blockage) are uncommon but can occur.66 Cost-Effectiveness: Comparing cost-effectiveness of IPC and pleurodesis is difficult.50 The major problems have been the wide variation in both the cost of the IPC and drainage equipments around the world and the marked differences in the frequency and location of drainage. Some centers prefer to perform the majority of drainages in an outpatient clinic, others by the patients’ caregivers at home; some advocate routine daily drainages, others only when the patient is symptomatic. These differences in practice impact significantly on costs. Heterogeneity in survival time, fluid accumulation rate, and time to spontaneous pleurodesis considerably influence the number of drainages (and associated costs) required. These variables probably explain why a Dutch study found that costs differed significantly between the underlying tumor types, with the highest in mesothelioma and least with lung cancer67—a direct reflection of median survival times. Prognosis was also shown to be a significant determinant of cost in two studies from the United States. One concluded that IPCs were more effective and less costly than pleurodesis if the survival was less than 3 months, but the reverse was true with survival greater than 12 months.68 The other study combined data from a literature review and extrapolated costs based on their own practice. It determined a difference in cost/benefit between the therapies at 6 weeks.69 This again highlights the need for studies that enable better prediction of survival and need for definitive fluid control.70 Current data provide no clear conclusion of superiority between pleurodesis and IPC. Further studies are underway to provide better guidance on the use of each procedure in Seminars in Respiratory and Critical Care Medicine
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different subsets of patients. In the meantime, several lines of investigation are in progress to combine the advantages of pleurodesis and IPC. Placement of IPC at the time of pleuroscopic talc insufflation has been shown useful in a pilot study.40 A multicenter study is assessing the usefulness of IPC placement followed by intrapleural talc instillation via the catheter when the lung fully expands. Sclerosant-eluting IPCs have been shown to induce effective pleurodesis in different animal models and awaits clinical evaluation.71
Talc Pleurodesis: Controversy on Route of Delivery Optimal methods for talc pleurodesis in MPE continue to be debated. Randomized trials have challenged traditional beliefs that thoracoscopic talc poudrage (dry powder insufflation) is superior to talc slurry pleurodesis performed via bedside tube thoracostomy.51,72 Dresler et al, however, showed in the largest randomized trial of MPE (n ¼ 482) that both methods of talc delivery had similar efficacy in fluid control at 30 days (poudrage 78 vs. slurry 71%).51 Two other smaller randomized studies also showed no significant difference in recurrence rates, drainage time, hospitalizations, or QoL.72,73 Terra et al observed a significant benefit of poudrage in immediate lung expansion, but this did not correlate with clinical outcomes.73 VAT talc poudrage is more invasive and resource consuming. Complications such as postoperative pneumonia and respiratory failure were found to be more common after talc poudrage (9.3 versus 3.6% and 8.1 versus 4.0%, respectively), although poudrage was reported to be more comfortable (p ¼ 0.019).51 VAT-related complications such as bleeding and prolonged air leak have been reported in up to 15% of patients and persistent pain or discomfort at 3 months for over a third of patients.74,75
Talc Pleurodesis: Optimal Procedure Details Although talc slurry pleurodesis is performed everyday around the world, significant practice variations occur because of the lack of data on essentially every step of the pleurodesis process.2 The optimal timing for talc instillation after chest tube insertion is not known. Traditional practice is to defer instillation until daily pleural fluid output falls, usually less than 150 mL/day, correlating with radiological evidence of lung expansion.2 This prolongs hospitalization and its value has not been formally assessed in quality clinical studies. Large bore catheters were conventionally used for pleurodesis, however studies of drain size, predominantly with the use of tetracycline as the sclerosing agent, have shown that smallbore catheters (12–14F) may be as effective and safer.76,77 This is now being evaluated in a multicenter clinical trial. Chest tube clamping time, rotation of patients during clamping, and the timing for drain removal are other controversial areas. Guidelines suggest clamping for 1 hour (without any evidence support) while other centers clamp for up to 4 hours.2,47 Rotating patients in the attempt to improve the dispersion of the sclerosant is time consuming, can cause patient discomfort or tube dislodgement, and is no longer thought to be necessary.12,48,78–80 Scintigraphic imaging studies of radiolabeled talc and tetracycline showed no effect
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Looking into the Future There is increasing realization that current knowledge of MPE is extremely limited and management practice is significantly behind the times.83 Controversies exist and persist because of the ongoing lack of quality data to address key clinical questions. Studies in recent years have revealed major deficits in knowledge that permit harmful practice. Only three-quarters of a century after talc pleurodesis started did we uncover the frequent occurrence (1 in 50 cases)51 of fatal ARDS associated with small particle talc preparations. Multicenter efforts have started to disperse myths from conventional teaching, such as the perceived advantage of talc poudrage over slurry. There are still numerous important questions that demand urgent answers from proper clinical trials to guide patient care. Novel concepts continue to evolve and will challenge conventional perceptions. MPE consists of a heterogenous group of diseases and careful phenotyping of malignant effusion patients can provide important clinical information that will advance the field. International collaborative efforts are required to provide the large cohorts to cover the diverse spectrum of patients with MPE.
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Acknowledgments Prof. Lee is a National Health & Medical Research Council (NHMRC) Career Development Fellow and receives project grant funding from the NHMRC, New South Wales Dust Disease Board, Sir Charles Gairdner Research Advisory Committee, LIWA Westcare Grants and the Cancer Council of Western Australia.
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