Interventions for the management of malignant pleural effusions: a network meta‐analysis New search for studies and content updated (conclusions changed)

Abstract

Abstract Background

Malignant pleural effusion (MPE) is a common problem for people with cancer and usually associated with considerable breathlessness. A number of treatment options are available to manage the uncontrolled accumulation of pleural fluid, including administration of a pleurodesis agent (via a chest tube or thoracoscopy) or placement of an indwelling pleural catheter (IPC). This is an update of a review published in Issue 5, 2016, which replaced the original, published in 2004.

Objectives

To ascertain the optimal management strategy for adults with malignant pleural effusion in terms of pleurodesis success and to quantify differences in patient‐reported outcomes and adverse effects between interventions.

Search methods

We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid) and three other databases to June 2019. We screened reference lists from other relevant publications and searched trial registries.

Selection criteria

We included randomised controlled trials of intrapleural interventions for adults with symptomatic MPE, comparing types of sclerosant, mode of administration and IPC use.

Data collection and analysis

Two review authors independently extracted data on study design, characteristics, outcome measures, potential effect modifiers and risk of bias.

The primary outcome was pleurodesis failure rate. Secondary outcomes were adverse events, patient‐reported breathlessness control, quality of life, cost, mortality, survival, duration of inpatient stay and patient acceptability.

We performed network meta‐analyses of primary outcome data and secondary outcomes with enough data. We also performed pair‐wise meta‐analyses of direct comparison data. If we deemed interventions not jointly randomisable, or we found insufficient available data, we reported results by narrative synthesis. For the primary outcome, we performed sensitivity analyses to explore potential causes of heterogeneity and to evaluate pleurodesis agents administered via a chest tube only.

We assessed the certainty of the evidence using GRADE.

Main results

We identified 80 randomised trials (18 new), including 5507 participants. We found all except three studies at high or unclear risk of bias for at least one domain. Due to the nature of the interventions, most studies were unblinded.

We included 55 studies of 21 interventions in the primary network meta‐analysis. We estimated the rank of each intervention's effectiveness. Talc slurry (ranked 6, 95% credible interval (Cr‐I) 3 to 10)  is an effective pleurodesis agent (moderate certainty for comparison with placebo) and may result in fewer pleurodesis failures than bleomycin and doxycycline (bleomycin versus talc slurry: odds ratio (OR) 2.24, 95% Cr‐I 1.10 to 4.68; low certainty; ranked 11, 95% Cr‐I 7 to 15; doxycycline versus talc slurry: OR 2.51, 95% Cr‐I 0.81 to 8.40; low certainty; ranked 12, 95% Cr‐I 5 to 18).

There is little evidence of a difference between the pleurodesis failure rate of talc poudrage and talc slurry (OR 0.50, 95% Cr‐I 0.21 to 1.02; moderate certainty). Evidence for any difference was further reduced when restricting analysis to studies at low risk of bias (defined as maximum one high risk domain in the risk of bias assessment) (pleurodesis failure talc poudrage versus talc slurry: OR 0.78, 95% Cr‐I 0.16 to 2.08).

IPCs without daily drainage are probably less effective at obtaining a definitive pleurodesis (cessation of pleural fluid drainage facilitating IPC removal) than talc slurry (OR 7.60, 95% Cr‐I 2.96 to 20.47; rank = 18/21, 95% Cr‐I 13 to 21; moderate certainty). Daily IPC drainage or instillation of talc slurry via IPC are likely to reduce pleurodesis failure rates.

Adverse effects were inconsistently reported. We performed network meta‐analyses for the risk of procedure‐related fever and pain.

The evidence for risk of developing fever was of low certainty, but suggested there may be little difference between interventions relative to talc slurry (talc poudrage: OR 0.89, 95% Cr‐I 0.11 to 6.67; bleomycin: OR 2.33, 95% Cr‐I 0.45 to 12.50; IPCs: OR 0.41, 95% Cr‐I 0.00 to 50.00; doxycycline: OR 0.85, 95% Cr‐I 0.05 to 14.29).

Evidence also suggested there may be little difference between interventions in the risk of developing procedure‐related pain, relative to talc slurry (talc poudrage: OR 1.26, 95% Cr‐I 0.45 to 6.04; very‐low certainty; bleomycin: OR 2.85, 95% Cr‐I 0.78 to 11.53; low certainty; IPCs: OR 1.30, 95% Cr‐I 0.29 to 5.87; low certainty; doxycycline: OR 3.35, 95% Cr‐I 0.64 to 19.72; low certainty).

Pair‐wise meta‐analysis suggests there is likely no difference in breathlessness control, relative to talc slurry, of talc poudrage ((mean difference (MD) 4.00 mm, 95% CI –6.26 to 14.26) on a 100 mm visual analogue scale for breathlessness; studies = 1; participants = 184; moderate certainty) and IPCs without daily drainage (MD –6.12 mm, 95% CI –16.32 to 4.08; studies = 2; participants = 160; low certainty).

There may be little difference between interventions when compared to talc slurry (bleomycin and IPC without daily drainage; low certainty) but evidence is uncertain for talc poudrage and doxycycline.

Pair‐wise meta‐analysis demonstrated that IPCs probably result in a reduced risk of requiring a repeat invasive pleural intervention (OR 0.25, 95% Cr‐I 0.13 to 0.48; moderate certainty) relative to talc slurry. There is likely little difference in the risk of repeat invasive pleural intervention with talc poudrage relative to talc slurry (OR 0.96, 95% CI 0.59 to 1.56; moderate certainty).

Authors' conclusions

Based on the available evidence, talc poudrage and talc slurry are effective methods for achieving a pleurodesis, with lower failure rates than a number of other commonly used interventions.

IPCs provide an alternative approach; whilst associated with inferior definitive pleurodesis rates, comparable control of breathlessness can probably be achieved, with a lower risk of requiring repeat invasive pleural intervention. 

Local availability, global experience of agents and adverse events (which may not be identified in randomised trials) and patient preference must be considered when selecting an intervention.

Further research is required to delineate the roles of different treatments according to patient characteristics, such as presence of trapped lung. Greater attention to patient‐centred outcomes, including breathlessness, quality of life and patient preference is essential to inform clinical decision‐making. Careful consideration to minimise the risk of bias and standardise outcome measures is essential for future trial design.

Author(s)

Alexandra Dipper, Hayley E Jones, Rahul Bhatnagar, Nancy J Preston, Nick Maskell, Amelia O Clive

Abstract

Plain language summary

Interventions for the management of fluid around the lungs (pleural fluid) caused by cancer

We reviewed the evidence on the effectiveness of different methods to manage a build‐up of fluid around the lungs in people where this is caused by cancer.  

Malignant pleural effusion (MPE) is a condition that affects people with cancer of the lining of the lung. This can cause fluid to build up in the space between the outside of the lungs and rib cage (pleural cavity), often resulting in breathlessness. Treatment options focus on controlling symptoms. These include removal of the fluid using a temporary chest drain, a camera examination of the pleural cavity (thoracoscopy) or a semi‐permanent chest drain tunnelled under the skin (an indwelling pleural catheter). Introducing a chemical into the pleural cavity can also be used to prevent the fluid coming back (pleurodesis). We wanted to find out which method was the most effective for preventing fluid re‐accumulation (pleurodesis failure) and which was best in terms of side effects (including pain and fever) and other important outcomes such as breathlessness and quality of life.

We collected and analysed relevant studies to answer this question. We were interested in high quality research, so only searched for randomised controlled trials (in which participants are randomly allocated to the treatments being tested). We analysed most data using 'network meta‐analysis', which allows lots of different interventions to be compared in one analysis. This analysis ranks the interventions in order of their effectiveness.

We rated the certainty of the evidence from studies using four levels: very low, low, moderate or high. Very low‐certainty evidence means that we are very uncertain about the results. High‐certainty evidence means that we are very confident in the results. Many of the studies were of low quality and the individual studies were quite different to each other. This made it difficult to reach definite conclusions.

From our searches in June 2019, we found 80 studies (18 new) involving 5507 participants (2079 new).

In the network meta‐analysis, we found that giving talc through a chest tube after draining the fluid (talc slurry) resulted in fewer pleurodesis failures than other commonly used methods, such as the medicines doxycycline or bleomycin through a chest tube (low certainty). Using a thoracoscopy procedure to remove the fluid and blow talc into the chest (talc poudrage) is likely to be as effective as talc slurry (moderate certainty).

We had a low level of certainty that the risk of having a fever is similar between treatments. There may be little difference between treatments in the chance of having pain (low certainty for bleomycin, IPCs and doxycycline; very‐low certainty for talc poudrage).

Using an IPC, which allows intermittent drainage of fluid at home, may relieve breathlessness as much as a talc slurry procedure (low certainty).

There may be little difference in the risk of death between treatments when compared to talc slurry (low certainty for bleomycin and IPC without daily drainage; very low certainty for talc poudrage and doxycycline).

The chance of needing another invasive procedure to remove fluid was lower after having an IPC than after talc slurry pleurodesis (moderate certainty). 

The available evidence shows that talc poudrage and talc slurry are effective ways of managing MPEs, with lower pleurodesis failure rates than a number of other commonly used methods. However, it is also important to consider global experience of these agents and knowledge of their safety and side effects when selecting the most appropriate pleurodesis method.

IPCs are less likely to prevent pleural fluid from re‐accumulating than talc slurry, but may be as good at helping breathlessness. People who have an IPC are less likely to need another invasive procedure in the future to manage the pleural effusion.

Further research is required to look at particular patient groups and explore outcomes such as breathlessness and quality of life in more detail. Ideally a fuller understanding of the potential harms of the treatments from the patients' perspective would also be beneficial.

Author(s)

Alexandra Dipper, Hayley E Jones, Rahul Bhatnagar, Nancy J Preston, Nick Maskell, Amelia O Clive

Reviewer's Conclusions

Authors' conclusions

Implications for practice For clinicians and for people with malignant pleural effusions

This systematic review suggests that of the commonly available pleurodesis techniques, talc poudrage and talc slurry both rank highly and are more effective at achieving a pleurodesis than sclerosants such as bleomycin (rank 11th, 95% credible interval (Cr‐I) 7 to 15) and doxycycline (rank 12th, 95% Cr‐I 5 to 18).

Although indwelling pleural catheters (IPCs) are probably associated with higher pleurodesis failure rates than many of the other interventions described, this is likely to be improved by daily catheter drainage or instillation of talc slurry via the IPC. Moreover, pair‐wise meta‐analysis suggests that the use of IPCs results in less need for further invasive pleural interventions than talc slurry, which may be an important advantage for some patients. Talc poudrage was associated with a similar risk of requiring further invasive pleural procedures when compared to talc slurry (odds ratio (OR) 0.96, 95% Cr‐I 0.59 to 1.56).

Where breathlessness outcomes were reported, symptom relief for participants with IPCs may be comparable to talc slurry. For those undergoing talc poudrage pleurodesis, breathlessness relief was probably comparable to talc slurry pleurodesis. In four studies, IPCs were associated with a reduced length of hospital stay (Boshuizen 2017; Davies 2012; Putnam 1999; Thomas 2017), a clinically relevant outcome for a patient group where anticipated survival is often short. Where pleurodesis success is not the primary outcome of interest, such as for those with trapped lung or previous pleurodesis failure, or for patients who wish to minimise repeated invasive procedures or avoid a hospital admission, IPCs may be a favourable choice.

We have noted comparable improvements in postintervention quality of life outcomes in participants with IPCs (with or without daily drainage), talc slurry, talc poudrage and doxycycline pleurodesis (Bhatnagar 2020; Davies 2012; Muruganandan 2018; Putnam 1999; Thomas 2017; Wahidi 2017). The OPTIMUM study, which is currently recruiting in the UK, with health‐related quality of life as its primary outcome in participants undergoing IPC with talc via IPC and talc slurry pleurodesis, will further inform practice.

This review was not designed to evaluate rarer but potentially clinically important adverse effects. However, graded (large particle talc) has less systemic absorption than mixed particle size talc and should therefore be used to reduce the rare but important risk of acute respiratory distress syndrome (Maskell 2004). Concerns regarding the dose‐dependent systemic absorption of intrapleural mepacrine, and the subsequent risk of transient psychotic episodes and seizures, have not been identified in the randomised trials of these agents, but are likely to limit its routine use (Bjorkman 1989). Non‐steroidal anti‐inflammatory drug (NSAID) use has not been shown to adversely affect pleurodesis outcomes (Rahman 2015). Data from three studies suggest participants receiving an IPC may have a higher risk of cellulitis and pleural infection (Davies 2012; Putnam 1999; Thomas 2017). Therefore, appropriate information regarding IPC care and symptoms of infection should be given.

Worldwide, talc is reported to be the most commonly used pleurodesis agent (Lee 2003; Roberts 2010; Zarogoulidis 2013), and consequently it is likely to have the best appreciated adverse effect profile. Therefore, if graded talc is available, this would appear to be an effective choice for bedside pleurodesis, supported by the largest body of evidence.

For policy makers

We have identified that many of the available treatment options have their own advantages and disadvantages, in terms of their effectiveness at inducing a pleurodesis, their adverse event profile and the chance a patient will need a subsequent invasive pleural intervention. Therefore, it is important that a range of treatment strategies are accessible and available to patients depending on their clinical situation and their personal preference. For example, there should be adequate provision of both IPC and an inpatient pleurodesis to allow patients and clinicians to decide on an optimal treatment pathway for that individual.

For funders of the intervention

There are insufficient data regarding the relative costs of many of the interventions described in this review to provide robust conclusions regarding this. In the short term, IPCs have been found to be a cost‐effective choice but the longer‐term cost implications have not been formally established.

Implications for research General implications

There is a paucity of data regarding patient preference. Although people with an IPC are likely to spend less time in hospital, we found no data relating to considerations such as lifestyle restrictions imposed by drainage regimens, limitation on social and functional activities, and consequent impact on wellbeing. An improved understanding of the key outcomes which are important to people with malignant pleural effusion (MPE) would be beneficial. Carer burden is another significant consideration, particularly in regions where community healthcare services do not provide IPC drainage.

The health economic implications of the available interventions are additional important factors that warrant further research. Limited data suggest that IPCs are a cost‐effective choice in people with limited survival (Olfert 2017), but substantial uncertainty around this estimate remains, particularly in respect to long‐term outcomes. The cost of community nursing and environmental implications associated with single‐use drainage equipment may make IPCs a less favourable choice in some settings.

There is a lack of robust randomised evidence for surgical interventions in the MPE population. Our review has highlighted that pleurodesis success from thoracoscopic mechanical pleurodesis may yield results similar to talc poudrage, but further high‐quality evidence is required to delineate the role of this. The AMPLE 3 study, comparing talc slurry via IPC with video‐assisted thoracoscopic surgery (VATS) mechanical abrasion or talc poudrage may provide further clarity.

There is limited evidence regarding the most effective management of people with trapped lung. Case series suggest trapped lung affects 10% to 20% of people with MPE and the rapid recurrence of fluid after pleural interventions and the loss of elasticity of the visceral pleura often results in severe symptoms of recurrent breathlessness and pain during fluid aspirations (Brims 2012; Lan 1997; Warren 2008). Often these patients are excluded from MPE trials given the lack of efficacy of pleurodesis in this subgroup and hence there is a dearth of evidence on how best to manage them. Future randomised controlled trials (RCTs) to delineate the optimal management strategy specific to this population would be beneficial. Further understanding of how the disease course of mesothelioma may differ from metastatic pleural disease may influence future treatment choices when considering the management of MPE. The MesoTRAP pilot study, which is currently recruiting in the UK, may lead to a phase III study comparing the efficacy of IPC versus VATS partial pleurectomy/decortication for participants with malignant pleural mesothelioma with pleural effusion and trapped lung.

As our understanding of the pathology of MPE develops and our knowledge of the available management options expands, a universal approach to all patients with malignant effusions is likely to underestimate the complexity of this condition and a hunt for the 'best' pleurodesis technique to over‐simplify its challenges. Different strategies are already known to have unique advantages and disadvantages and may therefore be suited to different cohorts of patients. We have demonstrated the heterogeneity of this patient population. It is only by gaining an understanding of the priorities of patients themselves and the real‐life implications of the various treatment options that we will be able to select the most appropriate management strategy for an individual. Further patient‐centred qualitative research, as well as study of the methods to optimise current strategies (SIMPLE trial) and combine techniques to amalgamate the benefits of the varying modalities, are exciting potential areas of ongoing and future research.

Design

Understanding the factors contributing to the high risk of bias in a large number of the previous studies in this field is crucial when designing future clinical trials in MPE. Attempting to minimise these risks by careful trial design has the potential to improve our evidence base and ensure robust, valid conclusions are drawn from the available evidence.

Measurement (endpoints)

An important limitation of this review is the heterogeneous reporting of patient‐centred outcome measures across trials, which precluded network meta‐analyses of these clinically important outcomes. This has important implications for future research. Selection of appropriate, clinically relevant, standardised outcome measures is essential to aid robust, unbiased analysis of trial data and facilitate future systematic reviews (Williamson 2012). Specific to this review, an international agreement on the definition of pleurodesis success, the timing at which it should be assessed and development of MPE‐specific, validated patient‐reported outcome measurement tools would be hugely beneficial when combining data from future RCTs, along with a consensus about how to handle the inevitable patient attrition due to death.

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