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. 2020 Apr 21;4(4):CD010529.
doi: 10.1002/14651858.CD010529.pub3.

Interventions for the management of malignant pleural effusions: a network meta-analysis

Alexandra Dipper  1 , Hayley E Jones  2 , Rahul Bhatnagar  1 , Nancy J Preston  3 , Nick Maskell  1 , Amelia O Clive  1
Affiliations

Interventions for the management of malignant pleural effusions: a network meta-analysis

Alexandra Dipper et al. Cochrane Database Syst Rev. .

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. Pleurodesis failure rate 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 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). Patient-reported control of breathlessness 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). Overall mortality 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. Patient acceptability 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.

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Conflict of interest statement

AD: none known.

HJ: none known.

RB was the trial co‐ordinator for the TAPPS and IPC‐Plus studies (Bhatnagar 2018; Bhatnagar 2020), but did not perform the data extractions, or any assessments of risk of bias or GRADE, for these studies for the purposes of this review.

NJP: none known.

NM was a member of the trial steering committee for TIME‐1 and TIME‐3 trials (Mishra 2018; Rahman 2015). NM is a co‐author for one of the included studies (Maskell 2004). However, he did not perform the data extractions, nor any assessments of risk of bias or GRADE, for these studies for the purposes of this review. North Bristol NHS Trust received unrestricted research funding from CareFusion, to run the IPC‐Plus trial (Bhatnagar 2018) (2012 to 2016) for which NM was the chief investigator. NM also received honoraria from CareFusion for medical advisory board meetings (2015 to 2019).

AOC was involved in co‐ordinating and recruiting to the TIME‐3 trial (Mishra 2018). She also recruited to the TAPPS trial (Bhatnagar 2020), and assisted with the data analysis. She did not perform the data extraction, nor any assessments of risk of bias or GRADE, for these studies for the purpose of this review.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Network plot of the pleurodesis efficacy network. The nodes are weighted according to the number of participants randomised to the intervention. The edges (line thicknesses) are weighted according to the number of studies included in each comparison. IFN: interferon; IPC: indwelling pleural catheter without daily drainage; thioTEPA: triethylenephosphoramide; TMP: thoracoscopic mechanical pleurodesis.
5
5
Estimated (95% credible interval (Cr‐I)) ranks for each of the pleurodesis methods from the main network. IFN: interferon; IPC: indwelling pleural catheter without daily drainage; thioTEPA: triethylenephosphoramide; TMP: thoracoscopic mechanical pleurodesis.
6
6
Inconsistency plot for the main network. Treatment codes: 01: adriamycin; 02:autologous blood; 03:bleomycin; 04:C parvum; 05:doxycycline; 06:interferon; 07:indwelling pleural catheter (IPC) –daily drainage; 08:IPC –not daily drainage; 09:iodine; 10:mepacrine; 11:mistletoe (viscum); 12:mitoxantrone; 13:mustine; 14:placebo; 15:silver nitrate; 16:thoracoscopic mechanical pleurodesis (TMP); 17:talc poudrage; 18:talc slurry; 19:talc via IPC; 20:tetracycline; 21:triethylenethiophosphoramide. Abbreviations: ROR:ratio of odds ratios; 95% CI:95% confidence interval. Heterogeneity variance was set at 0.4929 (reflecting the estimation of Tau from the network).
7
7
Residual deviance contribution plot for the main network meta‐analysis. * indicates 0 events.
8
8
Estimated rank (95% credible interval (Cr‐I)) for causing fever (a low rank suggests increased risk of fever).
9
9
Residual deviance contribution plot for the fever network meta‐analysis. * indicates 0 events.
10
10
Residual deviance contribution plot for the pain network meta‐analysis. * indicates 0 events.
1.1
1.1. Analysis
Comparison 1 Bleomycin, Outcome 1 Pleurodesis failure rate.
1.2
1.2. Analysis
Comparison 1 Bleomycin, Outcome 2 Fever.
1.3
1.3. Analysis
Comparison 1 Bleomycin, Outcome 3 Pain.
1.4
1.4. Analysis
Comparison 1 Bleomycin, Outcome 4 Mortality.
1.5
1.5. Analysis
Comparison 1 Bleomycin, Outcome 5 Repeat pleural intervention.
2.1
2.1. Analysis
Comparison 2 Talc slurry, Outcome 1 Pleurodesis failure rate.
2.2
2.2. Analysis
Comparison 2 Talc slurry, Outcome 2 Fever.
2.3
2.3. Analysis
Comparison 2 Talc slurry, Outcome 3 Pain.
2.4
2.4. Analysis
Comparison 2 Talc slurry, Outcome 4 Breathlessness.
2.5
2.5. Analysis
Comparison 2 Talc slurry, Outcome 5 Mortality.
2.6
2.6. Analysis
Comparison 2 Talc slurry, Outcome 6 Repeat pleural intervention.
3.1
3.1. Analysis
Comparison 3 Talc poudrage, Outcome 1 Pleurodesis failure rate.
3.2
3.2. Analysis
Comparison 3 Talc poudrage, Outcome 2 Fever.
3.3
3.3. Analysis
Comparison 3 Talc poudrage, Outcome 3 Pain.
3.4
3.4. Analysis
Comparison 3 Talc poudrage, Outcome 4 Breathlessness.
3.5
3.5. Analysis
Comparison 3 Talc poudrage, Outcome 5 Mortality.
3.6
3.6. Analysis
Comparison 3 Talc poudrage, Outcome 6 Repeat pleural intervention.
4.1
4.1. Analysis
Comparison 4 Tetracycline, Outcome 1 Pleurodesis failure rate.
4.2
4.2. Analysis
Comparison 4 Tetracycline, Outcome 2 Fever.
4.3
4.3. Analysis
Comparison 4 Tetracycline, Outcome 3 Pain.
4.4
4.4. Analysis
Comparison 4 Tetracycline, Outcome 4 Mortality.
5.1
5.1. Analysis
Comparison 5 C parvum, Outcome 1 Pleurodesis failure rate.
5.2
5.2. Analysis
Comparison 5 C parvum, Outcome 2 Fever.
5.3
5.3. Analysis
Comparison 5 C parvum, Outcome 3 Pain.
5.4
5.4. Analysis
Comparison 5 C parvum, Outcome 4 Mortality.
6.1
6.1. Analysis
Comparison 6 Indwelling pleural catheter (IPC) – not daily drainage, Outcome 1 Pleurodesis failure rate.
6.2
6.2. Analysis
Comparison 6 Indwelling pleural catheter (IPC) – not daily drainage, Outcome 2 Fever.
6.3
6.3. Analysis
Comparison 6 Indwelling pleural catheter (IPC) – not daily drainage, Outcome 3 Pain.
6.4
6.4. Analysis
Comparison 6 Indwelling pleural catheter (IPC) – not daily drainage, Outcome 4 Breathlessness.
6.5
6.5. Analysis
Comparison 6 Indwelling pleural catheter (IPC) – not daily drainage, Outcome 5 Mortality.
6.6
6.6. Analysis
Comparison 6 Indwelling pleural catheter (IPC) – not daily drainage, Outcome 6 Repeat pleural procedure.
7.1
7.1. Analysis
Comparison 7 Iodine, Outcome 1 Pleurodesis failure rate.
7.2
7.2. Analysis
Comparison 7 Iodine, Outcome 2 Fever.
7.3
7.3. Analysis
Comparison 7 Iodine, Outcome 3 Pain.
7.4
7.4. Analysis
Comparison 7 Iodine, Outcome 4 Mortality.
8.1
8.1. Analysis
Comparison 8 Doxycycline, Outcome 1 Pleurodesis failure rate.
8.2
8.2. Analysis
Comparison 8 Doxycycline, Outcome 2 Fever.
8.3
8.3. Analysis
Comparison 8 Doxycycline, Outcome 3 Pain.
8.4
8.4. Analysis
Comparison 8 Doxycycline, Outcome 4 Mortality.
9.1
9.1. Analysis
Comparison 9 Duration of drainage after pleurodesis administration, Outcome 1 Pleurodesis failure rate.
9.2
9.2. Analysis
Comparison 9 Duration of drainage after pleurodesis administration, Outcome 2 Mortality.
10.1
10.1. Analysis
Comparison 10 OK‐432, Outcome 1 Pleurodesis failure rate.
10.2
10.2. Analysis
Comparison 10 OK‐432, Outcome 2 Fever.
10.3
10.3. Analysis
Comparison 10 OK‐432, Outcome 3 Pain.
10.4
10.4. Analysis
Comparison 10 OK‐432, Outcome 4 Mortality.
11.1
11.1. Analysis
Comparison 11 Mepacrine, Outcome 1 Pleurodesis failure rate.
11.2
11.2. Analysis
Comparison 11 Mepacrine, Outcome 2 Fever.
11.3
11.3. Analysis
Comparison 11 Mepacrine, Outcome 3 Pain.
11.4
11.4. Analysis
Comparison 11 Mepacrine, Outcome 4 Mortality.
12.1
12.1. Analysis
Comparison 12 Interferon (IFN), Outcome 1 Pleurodesis failure rate.
12.2
12.2. Analysis
Comparison 12 Interferon (IFN), Outcome 2 Fever.
12.3
12.3. Analysis
Comparison 12 Interferon (IFN), Outcome 3 Pain.
12.4
12.4. Analysis
Comparison 12 Interferon (IFN), Outcome 4 Mortality.
13.1
13.1. Analysis
Comparison 13 Triethylenethiophosphoramide, Outcome 1 Pleurodesis failure rate.
13.2
13.2. Analysis
Comparison 13 Triethylenethiophosphoramide, Outcome 2 Fever.
13.3
13.3. Analysis
Comparison 13 Triethylenethiophosphoramide, Outcome 3 Pain.
14.1
14.1. Analysis
Comparison 14 Adriamycin, Outcome 1 Pleurodesis failure rate.
14.2
14.2. Analysis
Comparison 14 Adriamycin, Outcome 2 Fever.
14.3
14.3. Analysis
Comparison 14 Adriamycin, Outcome 3 Pain.
15.1
15.1. Analysis
Comparison 15 Placebo, Outcome 1 Pleurodesis failure rate.
15.2
15.2. Analysis
Comparison 15 Placebo, Outcome 2 Fever.
15.3
15.3. Analysis
Comparison 15 Placebo, Outcome 3 Pain.
15.4
15.4. Analysis
Comparison 15 Placebo, Outcome 4 Mortality.
16.1
16.1. Analysis
Comparison 16 Mustine, Outcome 1 Pleurodesis failure rate.
16.2
16.2. Analysis
Comparison 16 Mustine, Outcome 2 Fever.
16.3
16.3. Analysis
Comparison 16 Mustine, Outcome 3 Pain.
16.4
16.4. Analysis
Comparison 16 Mustine, Outcome 4 Mortality.
17.1
17.1. Analysis
Comparison 17 Mitoxantrone, Outcome 1 Pleurodesis failure rate.
17.2
17.2. Analysis
Comparison 17 Mitoxantrone, Outcome 2 Pain.
17.3
17.3. Analysis
Comparison 17 Mitoxantrone, Outcome 3 Fever.
17.4
17.4. Analysis
Comparison 17 Mitoxantrone, Outcome 4 Mortality.
18.1
18.1. Analysis
Comparison 18 Drain size, Outcome 1 Pleurodesis failure rate.
18.2
18.2. Analysis
Comparison 18 Drain size, Outcome 2 Pain.
18.3
18.3. Analysis
Comparison 18 Drain size, Outcome 3 Mortality.
19.1
19.1. Analysis
Comparison 19 Thoracoscopic mechanical pleurodesis (TMP), Outcome 1 Pleurodesis failure rate.
19.2
19.2. Analysis
Comparison 19 Thoracoscopic mechanical pleurodesis (TMP), Outcome 2 Mortality.
20.1
20.1. Analysis
Comparison 20 Other, Outcome 1 Pleurodesis failure rate.
20.2
20.2. Analysis
Comparison 20 Other, Outcome 2 Fever.
20.3
20.3. Analysis
Comparison 20 Other, Outcome 3 Pain.
20.4
20.4. Analysis
Comparison 20 Other, Outcome 4 Mortality.
21.1
21.1. Analysis
Comparison 21 Silver nitrate, Outcome 1 Pleurodesis failure rate.
21.2
21.2. Analysis
Comparison 21 Silver nitrate, Outcome 2 Fever.
21.3
21.3. Analysis
Comparison 21 Silver nitrate, Outcome 3 Pain.
21.4
21.4. Analysis
Comparison 21 Silver nitrate, Outcome 4 Mortality.
22.1
22.1. Analysis
Comparison 22 Cisplatin, Outcome 1 Pleurodesis failure rate.
22.2
22.2. Analysis
Comparison 22 Cisplatin, Outcome 2 Fever.
22.3
22.3. Analysis
Comparison 22 Cisplatin, Outcome 3 Pain.
22.4
22.4. Analysis
Comparison 22 Cisplatin, Outcome 4 Mortality.
23.1
23.1. Analysis
Comparison 23 Duration of drainage prior to administration of sclerosant, Outcome 1 Pleurodesis failure rate.
24.1
24.1. Analysis
Comparison 24 Dose of silver nitrate, Outcome 1 Pleurodesis failure rate.
24.2
24.2. Analysis
Comparison 24 Dose of silver nitrate, Outcome 2 Fever.
24.3
24.3. Analysis
Comparison 24 Dose of silver nitrate, Outcome 3 Pain.
24.4
24.4. Analysis
Comparison 24 Dose of silver nitrate, Outcome 4 Mortality.
25.1
25.1. Analysis
Comparison 25 Talc via indwelling pleural catheter (IPC), Outcome 1 Pleurodesis failure rate.
25.2
25.2. Analysis
Comparison 25 Talc via indwelling pleural catheter (IPC), Outcome 2 Pain.
25.3
25.3. Analysis
Comparison 25 Talc via indwelling pleural catheter (IPC), Outcome 3 Mortality.
26.1
26.1. Analysis
Comparison 26 Autologous blood, Outcome 1 Pleurodesis failure rate.
26.2
26.2. Analysis
Comparison 26 Autologous blood, Outcome 2 Fever.
26.3
26.3. Analysis
Comparison 26 Autologous blood, Outcome 3 Pain.
26.4
26.4. Analysis
Comparison 26 Autologous blood, Outcome 4 Mortality.
27.1
27.1. Analysis
Comparison 27 Urokinase, Outcome 1 Pleurodesis failure rate.
27.2
27.2. Analysis
Comparison 27 Urokinase, Outcome 2 Mortality.
28.1
28.1. Analysis
Comparison 28 Streptokinase, Outcome 1 Pleurodesis failure rate.
28.2
28.2. Analysis
Comparison 28 Streptokinase, Outcome 2 Pain.
29.1
29.1. Analysis
Comparison 29 Endostatin, Outcome 1 Pleurodesis failure rate.
29.2
29.2. Analysis
Comparison 29 Endostatin, Outcome 2 Mortality.
30.1
30.1. Analysis
Comparison 30 Dose of iodine, Outcome 1 Pleurodesis failure rate.
31.1
31.1. Analysis
Comparison 31 Indwelling pleural catheter (IPC) – daily drainage, Outcome 1 Pleurodesis failure rate.
31.2
31.2. Analysis
Comparison 31 Indwelling pleural catheter (IPC) – daily drainage, Outcome 2 Pain.
31.3
31.3. Analysis
Comparison 31 Indwelling pleural catheter (IPC) – daily drainage, Outcome 3 Mortality.
32.1
32.1. Analysis
Comparison 32 Mistletoe (viscum), Outcome 1 Pleurodesis failure rate.
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Update of

References

References to studies included in this review

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Ishida 2006 {published data only (unpublished sought but not used)}
    1. Ishida A, Miyazawa T, Miyazu Y, Iwamoto Y, Zaima M, Kanoh K, et al. Intrapleural cisplatin and OK432 therapy for malignant pleural effusion caused by non‐small cell lung cancer. Respirology 2006;11:90‐7. - PubMed
Kasahara 2006 {published data only}
    1. Kasahara K, Shibata K, Shintani H, Iwasa K, Sone T, Kimura H, et al. Randomized phase II trial of OK‐432 in patients with malignant pleural effusion due to non‐small cell lung cancer. Anticancer Research 2006;26:1495‐9. - PubMed
Keeratichananont 2015 {published data only (unpublished sought but not used)}
    1. Keeratichananont W, Limthon T, Keeratichananont S. Efficacy and safety profile of autologous blood versus tetracycline pleurodesis for malignant pleural effusion. Therapeutic Advances in Respiratory Disease 2015;9(2):42‐8. - PubMed
Keeratichananont 2018 {published data only}
    1. Keeratichananont W, Kaewdech A, Keeratichananont S. Efficacy and safety profile of autologous blood versus talc pleurodesis for malignant pleural effusion: a randomised controlled trial. Therapeutic Advances in Respiratory Disease 2018;12:1‐10. - PMC - PubMed
Kefford 1980 {published data only}
    1. Kefford RF, Woods RL, Fox RM, Tattersall MH. Intracavitary adriamycin nitrogen mustard and tetracycline in the control of malignant effusions. A randomized study. Medical Journal of Australia 1980;2:447‐8. - PubMed
Kessinger 1987 {published data only}
    1. Kessinger A, Wigton RS. Intracavitary bleomycin and tetracycline in the management of malignant pleural effusions: a randomized study. Journal of Surgical Oncology 1987;36:81‐3. - PubMed
Koldsland 1993 {published and unpublished data}
    1. Koldsland S, Svennevig JL, Lehne G, Johnson E. Chemical pleurodesis in malignant pleural effusions: a randomised prospective study of mepacrine versus bleomycin. Thorax 1993;48:790‐3. - PMC - PubMed
Kuzdzal 2003 {published data only (unpublished sought but not used)}
    1. Kuzdzal J, Sladek K, Wasowski D, Soja J, Szlubowski A, Reifland A, et al. Talc powder vs doxycycline in the control of malignant pleural effusion: a prospective, randomized trial. Medical Science Monitor 2003;9:PI54‐9. - PubMed
Leahy 1985 {published data only}
    1. Leahy BC, Honeybourne D, Brear SG, Carroll KB, Thatcher N, Stretton TB. Treatment of malignant pleural effusions with intrapleural Corynebacterium parvum or tetracycline. European Journal of Respiratory Diseases 1985;66:50‐4. - PubMed
Loutsidis 1994 {published data only}
    1. Loutsidis A, Bellenis I, Argiriou M, Exarchos N. Tetracycline compared with mechlorethamine in the treatment of malignant pleural effusions. A randomized trial. Respiratory Medicine 1994;88:523‐6. - PubMed
Luh 1992 {published data only}
    1. Luh KT, Yang PC, Kuo SH, Chang DB, Yu CJ, Lee LN. Comparison of OK‐432 and mitomycin C pleurodesis for malignant pleural effusion caused by lung cancer. A randomized trial. Cancer 1992;69:674‐9. - PubMed
Lynch 1996 {published data only}
    1. Lynch TJ. Optimal therapy of malignant pleural effusions: report of a randomized trial of bleomycin, tetracycline, and talc and a meta‐analysis. International Journal of Oncology 1996;8:183‐90. - PubMed
Mager 2002 {published and unpublished data}
    1. Mager HJ, Maesen B, Verzijlbergen F, Schramel F. Distribution of talc suspension during treatment of malignant pleural effusion with talc pleurodesis. Lung Cancer 2002;36:77‐81. - PubMed
Martinez‐Moragon 1997 {published data only}
    1. Martinez‐Moragon E, Aparicio J, Rogado MC, Sanchis J, Sanchis F, Gil‐Suay V. Pleurodesis in malignant pleural effusions: a randomized study of tetracycline versus bleomycin. European Respiratory Journal 1997;10:2380‐3. - PubMed
Maskell 2004 {published and unpublished data}
    1. Maskell NA, Lee YC, Gleeson FV, Hedley EL, Pengelly G, Davies RJ. Randomized trials describing lung inflammation after pleurodesis with talc of varying particle size. American Journal of Respiratory and Critical Care Medicine 2004;170:377‐82. - PubMed
Masuno 1991 {published data only}
    1. Masuno T, Kishimoto S, Ogura T, Honma T, Niitani H, Fukuoka M, et al. A comparative trial of LC9018 plus doxorubicin and doxorubicin alone for the treatment of malignant pleural effusion secondary to lung cancer. Cancer 1991;68:1495‐500. - PubMed
Mejer 1977 {published data only}
    1. Mejer J, Mortensen KM, Hansen HH. Mepacrine hydrochloride in the treatment of malignant pleural effusion. A controlled randomized trial. Scandinavian Journal of Respiratory Diseases 1977;58:319‐23. - PubMed
Millar 1980 {published data only}
    1. Millar JW, Hunter AM, Horne NW. Intrapleural immunotherapy with Corynebacterium parvum in recurrent malignant pleural effusions. Thorax 1980;35:856‐8. - PMC - PubMed
Mishra 2018 {published data only (unpublished sought but not used)}
    1. Mishra E, Clive A, Wills G, Davies H, Stanton A, Al‐Aloul M, et al. Randomized controlled trial of urokinase versus placebo for nondraining malignant pleural effusion. American Journal of Respiratory and Critical Care Medicine 2018;197(4):502‐8. - PubMed
Mohsen 2011 {published data only}
    1. Mohsen TA, Zeid AA, Meshref M, Tawfeek N, Redmond K, Ananiadou OG, et al. Local iodine pleurodesis versus thoracoscopic talc insufflation in recurrent malignant pleural effusion: a prospective randomized control trial. European Journal of Cardio‐thoracic Surgery 2011:282‐6. - PubMed
Muruganandan 2018 {published data only (unpublished sought but not used)}
    1. Muruganandan S, Azzopardi M, Fitzgerald D, Shrestha R, Kwan B, Lam D, et al. Aggressive versus symptom‐guided drainage of malignant pleural effusion via indwelling pleural catheters (AMPLE‐2): an open‐label randomised trial. Lancet Respiratory Medicine 2018;6:671‐80. - PubMed
Neto 2015 {published data only (unpublished sought but not used)}
    1. Neto J, Terra R, Teixeira R, Pereira S, Pego‐Fernandes P. Safety profile of the use of iodopovidone for pleurodesis in patients with malignant pleural effusion. Respiration 2015;90:369‐75. - PubMed
Noppen 1997 {published data only}
    1. Noppen M, Degreve J, Mignolet M, Vincken W. A prospective, randomised study comparing the efficacy of talc slurry and bleomycin in the treatment of malignant pleural effusions. Acta Clinica Belgica 1997;52:258‐62. - PubMed
Okur 2011 {published and unpublished data}
    1. Okur E, Baysungur V, Tezel C, Ergene G, Kuzu Okur H, Halezeroglu S. Streptokinase for malignant pleural effusions: a randomized controlled study. Asian Cardiovascular Thoracic Annals 2011;3/4:238‐43. - PubMed
Ong 2000 {published data only}
    1. Ong KC, Indumathi V, Raghuram J, Ong YY. A comparative study of pleurodesis using talc slurry and bleomycin in the management of malignant pleural effusions. Respirology 2000;5:99‐103. - PubMed
Ostrowski 1989 {published data only}
    1. Ostrowski MJ, Priestman TJ, Houston RF, Martin WM. A randomized trial of intracavitary bleomycin and Corynebacterium parvum in the control of malignant pleural effusions. Radiotherapy & Oncology 1989;14:19‐26. - PubMed
Ozkul 2014 {published data only (unpublished sought but not used)}
    1. Ozkul S, Turna A, Demirkaya A, Aksoy B, Kaynak K. Rapid pleurodesis is an outpatient alternative in patients with malignant pleural effusions: a prospective randomized controlled trial. Journal of Thoracic Disease 2014;6(12):1731‐5. - PMC - PubMed
Paschoalini 2005 {published data only}
    1. Paschoalini MS, Vargas FS, Marchi E, Pereira JR, Jatene FB, Antonangelo L, et al. Prospective randomized trial of silver nitrate vs talc slurry in pleurodesis for symptomatic malignant pleural effusions. Chest 2005;128:684‐9. - PubMed
Patz 1998 {published and unpublished data}
    1. Patz EF, McAdams HP, Erasmus JJ, Goodman PC, Culhane DK, Gilkeson RC, et al. Sclerotherapy for malignant pleural effusions: a prospective randomized trial of bleomycin vs doxycycline with small‐bore catheter drainage. Chest 1998;113:1305‐11. - PubMed
Putnam 1999 {published data only}
    1. Putnam JB, Light RW, Rodriguez RM, Ponn R, Olak J, Pollak JS, et al. A randomised comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions. Cancer 1999;86(10):1992‐9. - PubMed
Rafiei 2014 {published data only (unpublished sought but not used)}
    1. Rafiei R, Yazdani B, Ranjbar SM, Torabi Z, Asgary S, Najefi S, et al. Long‐term results of pleurodesis in malignant pleural effusions: doxycycline vs bleomycin. Advanced Biomedical Research 2014;3:149. - PMC - PubMed
Rahman 2015 {published data only}
    1. Rahman N, Pepperell J, Rehal S, Saba T, Tang A, Ali N, et al. Effect of opioids vs NSAIDs and larger vs smaller chest tube size on pain control and pleurodesis efficacy among patients with malignant pleural effusion. JAMA 2015;314(24):2641‐53. - PubMed
Rintoul 2014 {published and unpublished data}
    1. Rintoul RC, Ritchie AJ, Edwards JG, Waller DA, Coonar AS, Bennett M, et al. Efficacy and cost of video‐assisted thoracoscopic partial pleurectomy versus talc pleurodesis with malignant pleural mesothelioma (MesoVATS): an open‐label, randomised, controlled trial. Lancet 2014;384(9948):1118‐27. - PubMed
Ruckdeschel 1991 {published data only}
    1. Ruckdeschel JC, Moores D, Lee JY, Einhorn LH, Mandelbaum I, Koeller J, et al. Intrapleural therapy for malignant pleural effusions. A randomized comparison of bleomycin and tetracycline [Erratum appears in Chest 1993 May;103(5):1640]. Chest 1991;100:1528‐35. - PubMed
Salomaa 1995 {published data only}
    1. Salomaa E‐R, Pulkki K, Helenius H. Pleurodesis with doxycycline or Corynebacterium parvum in malignant pleural effusion. Acta Oncologica 1995;34(1):117‐21. - PubMed
Sartori 2004 {published data only}
    1. Sartori S, Tassinari D, Ceccotti P, Tombesi P, Nielsen I, Trevisani L, et al. Prospective randomized trial of intrapleural bleomycin versus interferon alfa‐2b via ultrasound‐guided small‐bore chest tube in the palliative treatment of malignant pleural effusions. Journal of Clinical Oncology 2004;22:1228‐33. - PubMed
Saydam 2015 {published data only (unpublished sought but not used)}
    1. Saydam O, Karapinar K, Gokce M, Kilic L, Metin M, Oz I, et al. The palliative treatment with intrapleural streptokinase in patients with multiloculated malignant pleural effusion: a double‐blind, placebo‐controlled, randomized study. Medical Oncology 2015;32:179. - PubMed
Schmidt 1997 {published data only}
    1. Schmidt M, Schaarschmidt G, Chemaissani A. Pleurodesis in malignant pleural effusion: bleomycin vs. mitoxantrone [Pleurodese bei malignem pleuraergub: bleomycin vs. mitoxantron]. Pneumologie 1997;51:367‐72. - PubMed
Sorensen 1984 {published data only}
    1. Sorensen PG, Svendsen TL, Enk B. Treatment of malignant pleural effusion with drainage, with and without instillation of talc. European Journal of Respiratory Diseases 1984;65:131‐5. - PubMed
Tabatabaei  2015 {published data only (unpublished sought but not used)}
    1. Tabatabaei SA, Hashemi SM, Kamali A. Silver nitrate versus tetracycline in pleurodesis for malignant pleural effusions; a prospective randomized trial. Advanced Biomedical Research 2015;4:178. - PMC - PubMed
Terra 2009 {published data only (unpublished sought but not used)}
    1. Terra RM, Junqueira JJ, Teixeira LR, Vargas FS, Pego‐Fernandes PM, Jatene FB. Is full postpleurodesis lung expansion a determinant of a successful outcome after talc pleurodesis?. Chest 2009;136:361‐8. - PubMed
Terra 2015 {published data only (unpublished sought but not used)}
    1. Terra RM, Bellato RT, Teixeira LR, Chate RC, Pego‐Fernandes PM. Safety and systemic consequences of pleurodesis with three different doses of silver nitrate in patients with malignant pleural effusion. Respiration 2015;89:276‐83. - PubMed
Thomas 2017 {published and unpublished data}
    1. Thomas R, Fysh E, Smith N, Lee P, Kwan B, Yap E, et al. Effect of an indwelling pleural catheter vs talc pleurodesis on hospitalization days in patients with malignant pleural effusion. The AMPLE randomized clinical trial. JAMA 2017;318(19):1903‐12. - PMC - PubMed
Ukale 2004 {published and unpublished data}
    1. Ukale V, Agrenius V, Hillerdal G, Mohlkert D, Widstrom O. Pleurodesis in recurrent pleural effusions: a randomized comparison of a classical and a currently popular drug. Lung Cancer 2004;43:323‐8. - PubMed
Villanueva 1994 {published data only}
    1. Villanueva AG, Gray AW, Shahian DM, Williamson WA, Beamis JF. Efficacy of short term versus long term tube thoracostomy drainage before tetracycline pleurodesis in the treatment of malignant pleural effusions. Thorax 1994;49:23‐5. - PMC - PubMed
Wahidi 2017 {published data only}
    1. Wahidi M, Reddy C, Yarmus L, Feller‐Kopman D, Musani A, Wesley Sheppard R, et al. Randomized trial of pleural fluid drainage frequency in patients with malignant pleural effusions. The ASAP trial. American Journal of Respiratory and Critical Care Medicine 2017;195(8):1050‐7. - PubMed
Wang 2018 {published data only (unpublished sought but not used)}
    1. Wang X, Miao K, Luo Y, Li R, Shou T, Wang P, et al. Randomized controlled trial of Endostar combined with cisplatin/pemetrexed chemotherapy for elderly patients with advanced malignant pleural effusion of lung adenocarcinoma. Journal of the Balkan Union of Oncology 2018;23(1):92‐7. - PubMed
Yildirim 2005 {published and unpublished data}
    1. Yildirim E, Dural K, Yazkan R, Zengin N, Yildirim D, Gunal N, et al. Rapid pleurodesis in symptomatic malignant pleural effusion. European Journal of Cardio‐Thoracic Surgery 2005;27:19‐22. - PubMed
Yim 1996 {published data only}
    1. Yim AP, Chan AT, Lee TW, Wan IY, Ho JK. Thoracoscopic talc insufflation versus talc slurry for symptomatic malignant pleural effusion. Annals of Thoracic Surgery 1996;62:1655‐8. - PubMed
Yoshida 2007 {published data only (unpublished sought but not used)}
    1. Yoshida K, Sugiura T, Takifuji N, Kawahara M, Matsui K, Kudoh S, et al. Randomized phase II trial of three intrapleural therapy regimens for the management of malignant pleural effusion in previously untreated non‐small cell lung cancer: JCOG 9515. Lung Cancer 2007;58:362‐8. - PubMed
Zaloznik 1983 {published data only}
    1. Zaloznik AJ, Oswald SG, Langin M. Intrapleural tetracycline in malignant pleural effusions. A randomized study. Cancer 1983;51:752‐5. - PubMed
Zhao 2009 {published data only (unpublished sought but not used)}
    1. Zhao WZ, Wang JK, Li W, Zhang XL. Clinical research on recombinant human Ad‐p53 injection combined with cisplatin in treatment of malignant pleural effusion induced by lung cancer. Chinese Journal of Cancer 2009;28:84‐7. - PubMed
Zimmer 1997 {published data only (unpublished sought but not used)}
    1. Zimmer PW, Hill M, Casey K, Harvey E, Low DE. Prospective randomized trial of talc slurry vs bleomycin in pleurodesis for symptomatic malignant pleural effusions. Chest 1997;112:430‐4. - PubMed

References to studies excluded from this review

Caglayan 2008 {published data only}
    1. Caglayan B, Torun E, Turan D, Fidan A, Gemici C, Sarac G, et al. Efficacy of iodopovidone pleurodesis and comparison of small‐bore catheter versus large‐bore chest tube. Annals of Surgical Oncology 2008;15:2594‐9. - PubMed
Dryzer 1993 {published data only}
    1. Dryzer SR, Allen ML, Strange C, Sahn SA. A comparison of rotation and nonrotation in tetracycline pleurodesis. Chest 1993;104:1763‐6. - PubMed
Elayouty 2012 {published data only (unpublished sought but not used)}
    1. Elayouty HD, Hassan TM, Alhadad ZA. Povidone‐iodine versus bleomycin pleurodesis for malignant effusion in bronchogenic cancer guided by thoracic echography. Journal of Cancer Science & Therapy 2012;4(7):182‐4.
Engel 1981 {published data only}
    1. Engel J. Tetracyclin‐ und Na‐OH‐pleurodese in der palliativbehandlung maligner pleuraergasse. Praxis der Pneumologie 1981;35:1124‐8. - PubMed
Gust 1990 {published data only}
    1. Gust R, Kleine P, Fabel H. Fibrin glue and tetracycline pleurodesis in recurrent malignant pleural effusion – a randomised controlled trial. Medizinische Klinik 1990;85(1):18‐23. - PubMed
Kleontas  2019 {published and unpublished data}
    1. Kleontas A, Sioga A, Pandria N, Barbetakis N, Lazopoulos A, Katsikas I, et al. Clinical factors affecting the survival of patients diagnosed with non‐small cell lung cancer and metastatic malignant pleural effusion, treated with hyperthermic intrathoracic chemotherapy or chemical talc pleurodesis: a monocentric, prospective, randomized trial. Journal of Thoracic Disease 2019;11(5):1788‐98. - PMC - PubMed
Kwasniewska‐Rokicinska 1979 {published data only}
    1. Kwasniewska‐Rokicinska C, Zielonkowa I, Dedyk‐Drosik B, Drosik K. Results of ledakrin treatment of patients with neoplastic effusions. Nowotwory 1979;29:303‐6. - PubMed
Lissoni 1995 {published data only (unpublished sought but not used)}
    1. Lissoni P, Barni S, Tancini G, Ardizzoia A, Tisi E, Angeli M, et al. Intracavitary therapy of neoplastic effusions with cytokines: comparison among interferon alpha, beta and interleukin‐2. Supportive Care in Cancer 1995;3:78‐80. - PubMed
Liu 2017 {published data only (unpublished sought but not used)}
    1. Liu Y, Zhu Y, Fan G, Huang J, Weng C, Duan Q, et al. Clinical observation of verapamil combined with antitumour drugs in treating malignant pleural effusion. Biomedical Research 2017;28(19):8289‐94.
Maiche 1993 {published data only}
    1. Maiche AG, Virkkunen P, Kontkanen T, Moykkynen K, Porkka K. Bleomycin and mitoxantrone in the treatment of malignant pleural effusions. A comparative study. American Journal of Clinical Oncology 1993;16:50‐3. - PubMed
Manes 2000 {published data only}
    1. Manes N, Rodriguez‐Pandero F, Bravo JL, Hernandez H, Alix A. Talc pleurodesis. Prospective and randomised study. Clinical follow‐up. Chest 2000;118:131S.
Martin 2019 {published data only}
    1. Martin G, Tsim S, Kidd A, Foster J, McLoone P, Chalmers A, et al. Pre‐edit: a randomised feasibility trial of elastance‐directed intrapleural catheter or talc pleurodesis in malignant pleural effusion. Chest 2019;156(6):1204‐13. - PubMed
Nio 1999 {published data only}
    1. Nio Y, Nagami H, Tamura K, Tsubono M, Nio M, Sato M, et al. Multi‐institutional randomized clinical study on the comparative effects of intracavital chemotherapy alone versus immunotherapy alone versus immunochemotherapy for malignant effusion. British Journal of Cancer 1999;80:775‐85. - PMC - PubMed
Ogunrombi 2014 {published data only (unpublished sought but not used)}
    1. Ogunrombi AB, Onakpoya UU, Ekrikpo U, Aderibigbe AS, Aladesuru OA. Recurrence of malignant pleural effusion follow pleurodesis: is there a difference between use of povidone iodine or cyclophosphamide?. Annals of African Surgery 2014;11(2):21‐4.
Tattersall 1982 {published data only}
    1. Tattersall MH. Intracavitary treatment of malignant pleural effusions. Chemioterapia 1982;1:288‐92.

References to studies awaiting assessment

Amjadi – OPUS Trial {published data only (unpublished sought but not used)}
    1. Amjadi K, Labelle R. Effectiveness of doxycycline for treating pleural effusions related to cancer in an outpatient population (OPUS). clinicaltrials.gov/ct2/show/NCT01411202 (first received 8 August 2011).
Bo 1998 {published data only}
    1. Bo H, Yaohua W. Curative effect of highly agglutinative staphylococcin plus cisplatin in treatment of malignant pleural effusion and ascites. Chinese Journal of Clinical Oncology 1998;25:623‐4.
Chen 2015 {published data only}
    1. Chen L, Xia S. Therapeutic effect and safety of bevacizumab combined with cisplatin on malignant pleural effusion of patients with non‐small cell lung cancer. Journal of Shanghai Jiaotong University (Medical Science) 2015;35(8):1194‐8.
Cong 2010 {published data only}
    1. Cong YY, Liu MY, Cai L. Comparison of the therapeutic effects of pleural perfusion of NDP and cDDP in NSCLC patients with malignant pleural effusion. Chung‐Hua Chung Liu Tsa Chih [Chinese Journal of Oncology] 2010;32:467‐9. - PubMed
Fukuoka 1984 {published data only}
    1. Fukuoka M, Takada M, Tamai S, Negoro S, Matsui K, Ryu S, et al. Local application of anti‐cancer drugs for the treatment of malignant pleural and pericardial effusion. Gan to Kagaku Ryoho [Japanese Journal of Cancer & Chemotherapy] 1984;11:1543‐9. - PubMed
Miyanaga 2011 {published data only}
    1. Miyanaga A, Gemma A. Pleuritis carcinomatosa. Gan to Kagaku Ryoho. Cancer & Chemotherapy 2011;38:524‐7. - PubMed
Mohamed 2013 {published data only}
    1. Mohamed E, Ali E, Mahmoud H. Pleurodesis for malignant pleural effusions: a comparison of bleomycin or tranexamic acid alone versus a combination of both. European Respiratory Journal 2013;42(Suppl 57):298.
Song 2013 {published data only}
    1. Song F, Pei X, Jin Q, Peng Y, Zhao J, Xie J. Clinical effect of pseudomonas aeruginosa injection on malignant pleural effusion. Chinese Journal of Clinical Oncology 2013;40(18):1127‐9.
Sun 2002 {published data only}
    1. Sun DX, Shen HD, Ji CL, Wei QL. Clinical observation of Yadanzhi grease and DDP on treating malignant pleural effusion. Chinese Traditional Patent Medicine 2002; Vol. 24:604‐6.
Won 1997 {published data only}
    1. Won SO, Choi J, Yong SK, Yong HD, Tae WJ, Maan HJ. Intrapleural doxycycline and bleomycin in the management of malignant pleural effusions: a randomized study. Tuberculosis and Respiratory Diseases 1997;44:85‐92.
Xu 2010 {published data only}
    1. Xu T, Gao H, Zhang T, Yang B. Clinical observation of highly agglutinative staphylococcin combined with nedaplatin for malignant pleural effusion as local treatment. Chinese Journal of Cancer Prevention and Treatment 2010;17:1229‐30.
Yu 2003 {published data only}
    1. Yu HY. Observation of curative effect of cisplatin and lentinan on patients with malignant pleural effusions. Journal of Postgraduates of Medicine 2003; Vol. 26:16‐7.
Zhuang 2012 {published data only}
    1. Zhuang HF, Ren JX, Zhou YH, Chen XY, Wu YF, Li FF, et al. Matrine injection combined with intrapleural cisplatin in treatment of 24 patients with hematologic malignancies complicated by pleural effusion. Chinese Journal of New Drugs 2012;21:1013‐5.

References to ongoing studies

AMPLE 3 {published data only}
    1. Lee G. The Australasian malignant pleural effusion (AMPLE) trial – 3: a randomised study of the relative benefits of combined indwelling pleural catheter (IPC) and talc pleurodesis therapy or video‐assisted thoracoscopic surgery (VATS) in the management of patients with malignant pleural effusion. www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373133 (first received 18 June 2018).
MesoTRAP {published data only}
    1. Matthews C, Freeman C, Sharples L, Fox‐Rushby J, Tod A, Maskell N, et al. MesoTRAP: a feasibility study that includes a pilot clinical trial comparing video assisted thoracoscopic partial pleurectomy decortication with indwelling pleural catheter in patients with trapped lung due to malignant pleural mesothelioma designed to address recruitment and randomisation uncertainties and sample size requirements for a phase III trial. BMJ Open Respiratory Research 2019;6:e000368. - PMC - PubMed
NCT02583282 {published data only}
    1. NCT02583282. A study to compare the efficacy and safety of intrapleural doxycycline versus iodopovidone for performing pleurodesis in malignant pleural effusion. clinicaltrials.gov/ct2/show/NCT02583282 (first received 22 October 2015).
OPTIMUM {published data only}
    1. Sivakumar P, Douiri A, West A, Rao D, Warwick G, Chen T, et al. OPTIMUM: a protocol for a multicenter randomised controlled trial comparing out patient talc slurry via indwelling pleural catheter for malignant pleural effusion vs usual inpatient management. BMJ Open 2016;6:e012795. - PMC - PubMed
SIMPLE {published data only}
    1. Psallidas I, Piotrowska H, Yousuf A, Kanellakis N, Kagithala G, Mohammed S, et al. Efficacy of sonographic and biological pleurodesis indicators of malignant pleural effusion (SIMPLE): protocol of a randomised controlled trial. BMJ Open Respiratory Research 2017;4:e000225. - PMC - PubMed
Sterile‐graded talc versus OK‐432 {published and unpublished data}
    1. A randomised comparative phase 3 trial of pleurodesis in malignant pleural effusions: sterile graded talc vs. OK‐432 (WJOG8415L).. Ongoing study 2016.
SWIFT {published data only}
    1. Shrager J. Pivotal multi center, randomized, controlled, single‐blinded study comparing the silver nitrate coated indwelling pleural catheter to the uncoated PleurX catheter for the management of symptomatic, recurrent, malignant pleural effusions. clinicaltrials.gov/ct2/show/record/NCT02649894 (first received 8 January 2016).
TILT {published data only}
    1. Bibby A. A trial of Intra‐pleural bacterial immunotherapy in mesothelioma (TILT): a feasibility study using the 'trial within a cohort' methodology. www.isrctn.com/ISRCTN10432197 (first received 5 December 2017).

Additional references

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