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Predicting Patient Outcome in the Evolving Field of Malignant Pleural Effusion

Gleeson, Laura E. MBChB, BAO, PhD*,†; Gary Lee, Y.C. MBChB, PhD, FCCP, FRCP, FRACP‡,§

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Journal of Bronchology & Interventional Pulmonology: January 2020 - Volume 27 - Issue 1 - p 1-3
doi: 10.1097/LBR.0000000000000630
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Malignant pleural effusions (MPEs) are present in up to 15% of patients with cancer.1 Traditional management of symptomatic MPE involves either pleurodesis (which fails in 30%) or repeated thoracentesis, especially for those with trapped lung.2 Recent landmark randomized controlled trials have demonstrated the advantages of employing an indwelling pleural catheter (IPC) as the first-choice definitive therapy for MPE. Patients treated with IPC spend fewer days in hospital (important in this palliative patient population) and need fewer additional invasive pleural procedures while enjoying similar improvement in breathlessness control and quality of life compared with those who received talc pleurodesis.2–5 This had led to a global surge in IPC use. Despite these advantages, long-term IPC use results in more adverse events than pleurodesis,2,4 and raises questions around the cost-effectiveness and burden on aftercare services, especially among patients with longer life expectancy.6,7

“Autopleurodesis” has been described in up to 45% of patients with IPC placed for MPE.8 Studies to date, such as Grosu et al,9 in this edition of the Journal, have referred to “autopleurodesis” as the cessation of fluid drainage via IPC without radiographic fluid accumulation. This usually allows catheter removal and thus reduces longer-term complications, ongoing care needs, and associated costs. Attention has unsurprisingly been directed, therefore, at factors that may enhance rates of autopleurodesis, such as increased frequency of drainage, early administration of talc via IPC, and coating of the IPC catheter with pleurodesing agents.10–12 Likewise, predictors of autopleurodesis are a topic of interest, and it may potentially influence decisions around the choice of IPC or talc pleurodesis as the preferred front-line definitive treatment in individual patients.

“Autopleurodesis,” however, is an ill-defined term. It can arise from the induction of fibrotic adhesions between the visceral and parietal pleura and obliteration of the pleural space (the definition of pleurodesis). However, it can also result from a range of causes without pleurodesis, such as chemotherapeutic response of the pleural malignancy that stops fluid production, or extensive loculation within the pleural space preventing further fluid accumulation, etc. The ability of bedside ultrasound assessment of lung gliding (the absence of which favors genuine pleurodesis over cessation of fluid formation) may help future studies to better define whether pleurodesis has indeed occurred.

This new era of IPC utilization provides a unique opportunity for repeated/serial sampling of MPE in the same individual, which was not previously feasible. Recent work by others on pleural fluid cytokines had found molecules of interests, such as monocyte chemotactic protein-1 and transforming growth factor (TGF)-β, which may reflect the biological activities of pleural fluid formation or fibrosis, respectively.13,14 In the study by Grosu et al,9 a longitudinal analysis of pleural fluid cytokines was conducted in 22 MPE patients after IPC placement to look for possible predictors of IPC removal. The cytokines examined include interleukin-8, vascular endothelial growth factor, basic fibroblast growth factor, and 3 isoforms of TGF-β, selected on the basis of their published links with pleural fibrosis and inflammation.15–18 Plot profiles were used to detect changes in cytokine levels over 5 time points, up to 2 weeks post-IPC insertion. Area under the curve correlates were used to compare the likelihood of IPC removal. High area under the curve levels for interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor were associated with IPC removal, suggesting that longitudinal analyses of these cytokines in MPE may serve as a biomarker for autopleurodesis.

The work by Grosu et al9 is the first study correlating longitudinal changes in pleural fluid cytokine levels to the removal of IPC. Causality cannot be inferred from this exploratory study, but researchers may feel encouraged that serial fluid sampling holds promise to inform on biological processes within a malignant pleural cavity.

However, to find a clinically useful cytokine biomarker signature that could help predict IPC removal will be challenging. Cytokine networks are complex and involve significant cross-talk and backup redundancy. First, the conditions of fluid collection and analyses can influence results. In the study by Grosu et al,9 only total TGF-β (which includes both active and latent forms) was measured, and they found no correlation. This should not be used to discount the role of TGF-β, as it is only the active TGF-β level that could influence pleural processes, and should be a subject of future studies.

Second, many factors affect autopleurodesis, such as fluid formation rate, presence of trapped lung, patient comorbidities (eg, cardiac failure) contributing to ongoing fluid synthesis, tumor heterogeneity and response to systemic therapy, etc. Prediction of removal is likely to require a model that involves not only cytokine mediators but also clinical and patient factors.

Never has the field of MPE care progressed as quickly as it did in the last decade. The very recent IPC-Plus Study showed the feasibility and benefits of combining IPC placement and talc slurry instillation. This changes the landscape of MPE care: IPC and chemical pleurodesis are no longer mutually exclusive but complementary. Two randomized trials10,19 further showed that aggressive daily drainage significantly enhances “autopleurodesis.” In the Australasian Malignant PLeural Effusion (AMPLE) trial-2,19 “autopleurodesis” developed even in over 40% of patients with trapped lung who drained daily, although the numbers were small and the results need validation. Any future cytokine biomarker studies will need to incorporate these practice changes in clinical care algorithms to be relevant.

This is an exciting time in pleural medicine and MPE research. In this new era, future prediction studies should focus on which patients can develop successful talc pleurodesis via IPC, who would benefit from late pleurodesis through aggressive daily drainage, and, perhaps, who are at risk of complications with intermediate-term to long-term IPC use, should pleurodesis fail.


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