Abstract: 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). 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.

Plain-language summary: 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. 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. 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. 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.