Malignant Pleural Effusions: Management Options

David J. McCracken, MRCP; Jose M. Porcel, MD; Najib M. Rahman, DPhil

Disclosures

Semin Respir Crit Care Med. 2018;39(6):704-712. 

In This Article

Future Directions

Current methods to identify patients who are not suitable for consideration of talc pleurodesis due to unexpandable lung include detection via simple chest radiography following therapeutic aspiration or the use of pleural manometry. The role of manometry in clinical practice remains unclear. It is advocated by some proponents, but the cumbersome, complicated equipment, and prolonged procedure times have prevented its widespread acceptance.[30] Several prospective techniques have therefore been suggested that may assist with the identification of these patients, allowing them to proceed directly to a more appropriate intervention, such as an IPC, avoiding unnecessary procedures.

  1. Sonographic Pleurodesis: Prediction unexpandable lung may be identified prior to aspiration by measuring cardiac pulsation-induced lung movement using M-mode ultrasound. Although an appropriate cutoff value has yet to be fully defined and validated, it is suggested that movement detected using M-mode of more than 1.2 mm is predictive of fully expandable atelectatic lung. A value less than this is highly suggestive of unexpandable lung (Figure 3). A single center, retrospective observational study published recently in 2018 used an M-mode cut off of 2 mm and demonstrated a sensitivity of 91% and specificity of 88% using this technique to detect unexpandable lung. Further studies are required to adequately define and validate appropriate M-mode cutoff values.[25,31,32] The role of ultrasound to predict pleurodesis success in those patients with adequate pleural apposition also remains unclear. Sonographic echogenicity, which represents a higher complexity or density of fluid was associated with higher pleurodesis success in an animal study performed in rabbits. It is thought that this may reflect higher protein concentrations which increase fibrin activation and subsequently improve efficacy of the pleurodesis agent. Echogenicity is a nonspecific ultrasound finding, and therefore, the role in predicting pleurodesis success requires further investigation.[1,23,24,33]

  2. Biomarker pleurodesis prediction: The development of biomarkers has dramatically increased over recent times with advancement of the era of personalized medicine. In a respiratory context, progress has been mostly marked in asthma and airways disease with the emergence of the crucial role of biomarkers such as the fraction of exhaled nitric oxide.[34] Serum mesothelin is also thought to have an increasingly important role in the investigation and management of some pleural diseases such as malignant pleural mesothelioma.[35] The PROMISE study published by Psallidas et al in 2018 was a multicohort study using datasets from five randomized controlled trials and was designed to assess the role of biomarkers in predicting pleurodesis success and survival. Three biomarkers were identified as accurate predictors of survival. Unfortunately, all eight biomarkers examined in the prediction of pleurodesis outcomes were unsuccessful, including tumor necrosis factor (TNF) α, TNFβ, interleukin 6, and fibroblast growth factor 2.[3] Although unsuccessful in predicting pleurodesis outcome in this instance, potential has been shown with the development of a prognostic survival score using biomarkers and further investigation is warranted.

  3. Fibrinolytics for multiloculated malignant effusion: Management of multiloculated MPE presents a challenging dilemma as these effusions often cannot be adequately drained to relieve symptoms using conventional methods, with residual pleural effusion also preventing pleurodesis attempts. This leads to reduced symptom benefit, an increased frequency of pleural interventions, and generally inadequate palliation of symptoms. Local anesthetic thoracoscopy has been suggested as a potential solution by causing disruption of septations and clearance of the pleural space prior to either pleurodesis or IPC insertion. However, there are a number of impediments. This approach requires practitioners to have advanced skills and for patients to be relatively fit and have a good performance status to undergo the procedure. Also, in those patients with unexpandable lung, septations and loculations often recur with the effusion which in turn complicates ongoing management with an IPC. It has therefore been suggested that unification of the pleural space may be possible using fibrinolytic therapy to break down septations, particularly given the positive outcomes associated with its use in pleural infection.[36,37] The consideration of the role of fibrinolytics in MPE is not a new concept and multiple previous trials have been conducted with variable success. Two small randomized controlled trials demonstrated improvements in drainage and lung re-expansion, but no effect on pleurodesis success.[38–40] TIME3 was a randomized controlled trial of 71 patients published in 2018 and was designed with greater patient-centered outcomes in mind by assessing dyspnea and pleurodesis failure. No statistically significant differences were demonstrated, although radiographic appearances improved which was a finding in keeping with previous studies. The European Respiratory Society/European Association for Cardio-Thoracic Surgeons suggests that although no clinical benefits have been demonstrated, few alternatives are available.[41] It is thought that results from TIME3 may have been confounded by patient selection. Approximately 80% of patients enrolled had a performance status of 3 to 4 resulting in a relatively frail cohort in whom improvements in dyspnea may have been more difficult to detect or perceive. The results may therefore not be applicable to the wider population with MPE, and intrapleural fibrinolytics may still have a role in selected circumstances. Further studies may also be indicated with particular reference to the IPC population, as this is a group who may self-select as a fitter, more ambulatory cohort.[36]

Figure 3.

M-mode and B-mode images showing (a) reduced lung movement suggesting high likelihood of unexpandable lung and (b) normal or unrestricted lung movement in keeping with a high likelihood of adequate lung re-expansion.

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