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

Review Question

We reviewed the evidence about the effectiveness of different methods to manage fluid around the lung in patients with a build up of this fluid caused by cancer.

Background

Malignant pleural effusion (MPE) is a condition whereby cancer of the lining of the lung results in fluid building up in the space between the lung and rib cage (pleural cavity), often resulting in breathlessness. Treatment options include removal of the fluid using either 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 in terms of preventing fluid build up and which was best in terms of side effects and patient-reported outcomes such as pain, fever, breathlessness and quality of life.

Study Characteristics

We searched databases for trials comparing different interventions in adults with symptomatic MPE to April 2015, written in any language. Since we were only interested in rigorously conducted research, we restricted our search to randomised controlled trials (in which participants are randomly allocated to the methods being tested). We analysed the majority of the data using a technique called '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.

Key Results

We found 62 studies involving 3428 patients.

In the network meta-analysis, the use of thoracoscopy to remove the fluid and blow talc into the pleural cavity (talc poudrage) appeared to be more effective in preventing fluid build up than a number of other commonly used methods. However, we could not say definitely that it is better than some other methods such as giving talc or doxycycline through a chest drain.

Side effects, quality of life and patient satisfaction were reported inconsistently by the included studies, but are important factors to consider when selecting the best management strategy for a patient. There was enough data to perform network meta-analysis for pain, fever and mortality. We found placebo caused the least fever and Corynebacterium parvum (C. parvum) and mepacrine were likely to cause the most. We found no differences in the pain caused by the interventions evaluated. Only one comparison showed a possible difference, revealing that those receiving tetracycline may live longer than those receiving mitoxantrone. As we only evaluated randomised controlled trials, it is possible some harms of treatments were not identified by this review.

Quality of the Evidence

Many of the studies were of low quality and the characteristics of the individual studies were quite different to each other. This high risk of bias makes it difficult to reach definite conclusions.

Conclusions

The available evidence shows that talc poudrage can stop fluid building up. However, we can not be sure that this is definitely the best method, and further research is needed. 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. Indwelling pleural catheters may help improve patient breathlessness, but may be less good at stopping the fluid coming back.

Further research is also required to look at particular patient groups and explore patient-centred 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.

Authors' conclusions: 

Based on the available evidence, talc poudrage is a more effective pleurodesis method in MPE than a number of other frequently used methods, including tetracycline and bleomycin. However further data are required to definitively confirm whether it is more effective than certain other commonly used interventions such as talc slurry and doxycycline, particularly in view of the high statistical and clinical heterogeneity within the network and the high risk of bias of many of the included studies. Based on the strength of the evidence from both direct and indirect comparisons of randomised data of sclerosants administered at the bedside, there is no evidence to suggest large differences between the other highly effective methods (talc slurry, mepacrine, iodine and C. parvum). However, local availability, global experience of these agents and their adverse events, which may not be identified in randomised trials, must also be considered when selecting a sclerosant. Further research is required to delineate the roles of different treatments according to patient characteristics (e.g. according to their prognosis or presence of trapped lung) and to explore patient-centred outcomes, such as breathlessness and quality of life, in more detail. Careful consideration to minimise the risk of bias and standardise outcome measures is essential for future trial design.

Read the full abstract...
Background: 

Malignant pleural effusion (MPE) is a common problem for people with cancer as a result of malignant infiltration of the pleura. It is 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 (either via a chest tube or at thoracoscopy) or indwelling pleural catheter insertion.

Objectives: 

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

Search strategy: 

We searched The Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid EMBASE; EBSCO CINAHL; SCI-EXPANDED and SSCI (ISI Web of Science) to April 2015.

Selection criteria: 

We included randomised controlled trials of intrapleural interventions for adults with symptomatic MPE in the review.

Data collection and analysis: 

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

The primary outcome measure was pleurodesis failure rate. Secondary outcome measures were adverse effects and complications, patient-reported control of breathlessness, quality of life, cost, mortality, duration of inpatient stay and patient acceptability.

We performed network meta-analysis with random effects to analyse the primary outcome data and those secondary outcomes with enough data. We also performed pair-wise random-effects meta-analyses of direct comparison data. If interventions were not deemed jointly randomisable, or insufficient data were available, we reported the results by narrative synthesis. We performed sensitivity analyses to explore heterogeneity and to evaluate only those pleurodesis agents administered via a chest tube at the bedside.

Main results: 

Of the 1888 records identified, 62 randomised trials, including a total of 3428 patients, were eligible for inclusion. All studies were at high or uncertain risk of bias for at least one domain.

Network meta-analysis evaluating the rate of pleurodesis failure, suggested talc poudrage to be a highly effective method (ranked second of 16 (95% credible interval (Cr-I) 1 to 5)) and provided evidence that it resulted in fewer pleurodesis failures than eight other methods. The estimated ranks of other commonly used agents were: talc slurry (fourth; 95% Cr-I 2 to 8), mepacrine (fourth; 95% Cr-I 1 to 10), iodine (fifth; 95% Cr-I 1 to 12), bleomycin (eighth; 95% Cr-I 5 to 11) and doxycyline (tenth; 95% Cr-I 4 to 15). The estimates were imprecise as evidenced by the wide credible intervals and both high statistical and clinical heterogeneity.

Most of the secondary outcomes, including adverse events, were inconsistently reported by the included studies and the methods used to describe them varied widely. Hence the majority of the secondary outcomes were reported descriptively in this review. We obtained sufficient data to perform network meta-analysis for the most commonly reported adverse events: pain, fever and mortality. The fever network was imprecise and showed substantial heterogeneity, but suggested placebo caused the least fever (ranked first of 11 (95% Cr-I 1 to 7)) and mepacrine and Corynebacterium parvum (C. parvum) appeared to be associated with the most fever (ranked tenth (95% Cr-I 6 to 11) and eleventh (95% Cr-I 7 to 11) respectively). No differences between interventions were revealed by the network meta-analysis of the pain data. The only potential difference in mortality identified in the mortality network was that those receiving tetracycline appeared to have a longer survival than those receiving mitoxantrone (OR 0.16 (95% Confidence Interval (CI) 0.03 to 0.72)). Indwelling pleural catheters were examined in two randomised studies, both of which reported improved breathlessness when compared to talc slurry pleurodesis, despite lower pleurodesis success rates.

The risk of bias in a number of the included studies was substantial, for example the vast majority of studies were unblinded, and the methods used for sequence generation and allocation concealment were often unclear. Overall, however, the risk of bias for all studies was moderate. We have not reported the GRADE quality of evidence for the outcomes, as the role of GRADE is not well established in the context of Network Meta-analysis (NMA).

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