title: Interventions for the management of malignant pleural effusions: a network meta-analysis.
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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  We included randomised controlled trials of intrapleural interventions for adults with symptomatic MPE in the review.
  
  
  METHODS
  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.
  
  
  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).
  
  
  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.
authors.affiliation: Academic Respiratory Unit, University of Bristol, Southmead Road, Bristol, UK, BS10 5NB.
authors.forename: Amelia O
authors.initials: AO
authors.lastname: Clive
authors.forename: Hayley E
authors.initials: HE
authors.lastname: Jones
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhatnagar
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Preston
authors.forename: Nick
authors.initials: N
authors.lastname: Maskell
mesh_terms: D000328:Adult; D001761:Bleomycin / Q000627:therapeutic use; D004318:Doxycycline / Q000627:therapeutic use; D005334:Fever / Q000209:etiology; D006801:Humans; D007455:Iodine / Q000627:therapeutic use; D016066:Pleural Effusion, Malignant / Q000209:etiology / Q000628:therapy*; D018700:Pleurodesis / Q000379:methods*; D011796:Quinacrine / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D013627:Talc / Q000627:therapeutic use; D017211:Treatment Failure
chemical_list: D001761:Bleomycin; D013627:Talc; D007455:Iodine; D011796:Quinacrine; D004318:Doxycycline