Malignant pleural effusions and the role of talc poudrage and talc slurry: a&nbsp;systematic review and meta-analysis

Srinivas Mummadi; Anusha Kumbam; Peter Y. Hahn

doi:10.12688/f1000research.5538.1

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Systematic Review

Malignant pleural effusions and the role of talc poudrage and talc slurry: a systematic review and meta-analysis

[version 1; peer review: 1 approved, 1 approved with reservations]

Srinivas Mummadi^1,2, Anusha Kumbam^1,3, Peter Y. Hahn^1,2

PUBLISHED 27 Oct 2014

Author details Author details

¹ Division of Pulmonary and Critical Care Medicine, Tuality Healthcare, Hillsboro, OR, 97123, USA
² Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, OR, 97239, USA
³ Department of Internal Medicine, John H. Stroger Hospital, Chicago, IL, 60614, USA

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background: Malignant Pleural Effusion (MPE) is common with advanced malignancy. Palliative care with minimal adverse events is the cornerstone of management. Although talc pleurodesis plays an important role in treatment, the best modality of talc application remains controversial.
Objective: To compare recurrence rates, rates of respiratory and non-respiratory complications between thoracoscopic talc insufflation/poudrage (TTI) and talc slurry (TS).
Data sources and study selection: MEDLINE (PubMed, OVID), EBM Reviews (Cochrane database of Systematic Reviews, ACP Journal Club, DARE, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment and NHS Economic Evaluation Database), EMBASE and Scopus. Randomized controlled trials published between 01/01/1980 - 10/1/2014 and comparing the two strategies were selected.
Results: Twenty-eight potential studies were identified of which 24 studies were further excluded, leaving four studies. No statistically significant difference in the risk of recurrent pleural effusions was observed between TS and TTI groups (RR 0.72; 95 % CI 0.50-1.05; Q statistic, 3.58). There was a higher risk of post procedural respiratory complications in the TTI group compared to the TS group (RR 1.91, 95% CI= 1.24-2.93, Q statistic 3.15). No statistically significant difference in the incidence of non-respiratory complications between the TTI group and the TS group was observed (RR 0.88, 95% CI= 0.72-1.07, Q statistic 4.61).
Conclusions: There is no difference in MPE recurrence based on patient centered outcomes between talc poudrage and talc slurry treatments. Respiratory complications are more common with talc poudrage via thoracoscopy.

Keywords

malignant pleural effusion, palliation, pleurodesis

Corresponding author: Srinivas Mummadi

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2014 Mummadi S et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

How to cite: Mummadi S, Kumbam A and Hahn PY. Malignant pleural effusions and the role of talc poudrage and talc slurry: a systematic review and meta-analysis [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2014, 3:254 (https://doi.org/10.12688/f1000research.5538.1) First published: 27 Oct 2014, 3:254 (https://doi.org/10.12688/f1000research.5538.1) Latest published: 17 Feb 2015, 3:254 (https://doi.org/10.12688/f1000research.5538.2)

Introduction

Malignant Pleural Effusion (MPE) is a well described event in the natural history of advanced malignancy. Malignant etiology accounts for 22% of the diagnosed pleural effusions¹. Using data from the 2012 Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP) and Agency for Healthcare Research and Quality, it is estimated that the aggregate charges (the “national bill”) were 722 million dollars in the USA².

Palliation with minimal adverse events remains the cornerstone of management³. Talc pleurodesis and Indwelling Pleural Catheters (IPC) are the two most commonly used palliative approaches.

Talc pleurodesis can be achieved either by thoracoscopic instillation i.e.; talc insufflation/poudrage (TTI) or via a bedside chest tube i.e. talc slurry (TS). Existing systematic reviews concluded that thoracoscopic talc insufflation/poudrage was more efficacious in preventing recurrences when compared to bedside chest tube talc slurry^4,5. New prospectively designed studies comparing TTI and TS have been published since then^6–8. However the best initial approach for talc pleurodesis remains still unclear. To address the need for an update, a systematic review and meta-analysis of studies comparing thoracoscopic talc insufflation/poudrage and talc slurry in terms of patient centered outcomes was performed.

Materials and methods

Data sources and search

We conducted a systematic review with meta-analysis of studies undertaken between 01/01/1980 and 10/1/2014 using MEDLINE (PubMed, OVID), EBM Reviews (Cochrane database of Systematic Reviews, ACP Journal Club, DARE, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment and NHS Economic Evaluation Database), EMBASE and Scopus. Unpublished data sets such as conference abstracts and ClinicalTrials.gov were also included in the full review phase to reduce the effect of publication bias⁹.

The following keywords were used: chemical pleurodesis, pleurodesis, talc pleurodesis, bedside pleurodesis, surgical pleurodesis, medical pleurodesis, thoracoscopic pleurodesis, thoracoscopic talc pleurodesis, thoracoscopic poudrage, thoracoscopic talc poudrage, talc insufflation, thoracoscopic talc insufflation, pleuroscopy, medical thoracoscopy, talc poudrage, talc slurry, tube thoracostomy, chest tube talc slurry and malignant pleural effusion. Both keywords and medical subject headings were used in a Boolean search strategy. An example search strategy can be found in the Appendix 1.

In addition, a pearl growing strategy was employed using frequently cited reviews of malignant pleural effusion treatments. They were included to be analyzed in the full review phase of the study. Approval from the Institutional Review Board was unnecessary because this is a meta-analysis.

Study selection

Inclusion and exclusion criteria were framed prior to the implementation of the search strategy. To evaluate outcomes in adult malignant pleural effusion patients (18 + years) undergoing talc pleurodesis, we included studies based on the following criteria:

1) A randomized design was used in studying talc pleurodesis in patients with malignant pleural effusion between 01/01/1980 and 10/1/2014.
2) Patients undergoing bedside TS were compared with patients undergoing thoracoscopic talc insufflation/poudrage (TTI) in the above fashion.
3) Sufficient outcomes data were reported [Risk of recurrence of the pleural effusion, respiratory complications and non-respiratory complications].

Non-English publications, case reports and series, pediatric studies, descriptive studies without a control group, retrospective studies and prospective controlled studies without randomization were excluded. Eligible articles were reviewed by two reviewers for inclusion; disagreements were resolved via discussion. An examination of the full-length articles was carried with the intent of eliminating duplicate studies or same patient cohorts.

Data extraction and outcome measures

Two reviewers independently extracted and rated the data from the selected full length articles using a standardized form. From each study, the data abstracted included study name/year, study design (prospective controlled, randomized controlled trial, retrospective etc.), cancer cell type, patient inclusion criteria, sample sizes for the bedside/surgical pleurodesis arms, technique employed in the bedside/surgical arms and the follow-up schedule.

Outcomes data pertaining to the risk of recurrent pleural effusions, respiratory complications, and non-respiratory complications were also extracted.

Talc pleurodesis for recurrent malignant pleural effusion is a palliative procedure and does not aim to have a mortality benefit. Therefore, measuring mortality outcomes was not the focus of the meta-analysis.

Various definitions for recurrent pleural effusions have been used in prior studies^6,10. A clinically significant recurrent pleural effusion was defined a priori as accompanied by symptoms or a need for repeat pleural procedures. Where possible, asymptomatic radiological recurrences were not included in the meta-analysis.

Respiratory complications were defined as occurrence of respiratory conditions such as pneumonia, Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, re-expansion pulmonary edema, bronchospasm, empyema, pulmonary embolism, prolonged air leak, bronchopleural fistula, atelectasis requiring bronchoscopy and subcutaneous emphysema.

Immediate non-respiratory complications were tabulated from the complications mentioned in the full length articles. These included fever, wound infection, chest pain, tumor recurrence at site, myocardial infarction, need for blood transfusions, arrhythmias and immediate post procedural death.

Quality assessment criteria

The randomized controlled trials that met inclusion criteria were evaluated for quality using components of the modified Jadad scale¹¹. The presence of the following features was appraised:

A) A description of the study confirming the randomized nature.
B) Method of allocation to the study arms described and whether adequate/inadequate.
C) Description of withdrawals and dropouts.

Due to the nature of the comparison (surgical vs bedside procedure), we felt that other features of the scale (description of a double blind nature) could not be appraised during our quality assessment. Two raters independently determined the quality of the studies included. Disagreements were resolved by discussions and final consensus.

Statistical analysis

Outcomes data for recurrent pleural effusions, respiratory and non-respiratory complications were summarized using descriptive statistics (simple count, proportion of the study sample). They were visually presented in Forest plots. The Mantel-Haenszel method¹² was used to combine data from individual studies and the results were reported as pooled relative risks (RR). Heterogeneity among the studies included was investigated by performing the I² test¹³. Meta-analyses were conducted using the fixed effects model when heterogeneity between studies was low (I² <40%) and the random effects model otherwise⁹.

To confirm the robust nature of the results, a sensitivity analysis was performed by removing one study at a time and determining the outcome.

Publication bias was examined by visually examining the filled funnel plots using trim and fill method. Other methods (Begg’s correlation¹⁴ and Egger’s linear regression intercept)¹⁵ were additionally used.

All analyses were performed using a statistical software package (Comprehensive Meta-Analysis, version 2.2.064; Biostat, Englewood, NJ).

Results

Based on initial search, 137 articles were obtained and reviewed independently by two reviewers. Pearl growing strategy was employed to seek additional articles and resulted in five articles. A clinical trial registry (www.ClinicalTrials.gov) was also examined and resulted in one additional article. These 143 articles were reviewed and 115 articles were excluded based on title and abstract. A total of 28 potential studies were thus identified with our search strategy. Twenty-four studies were further excluded, leaving four studies^6,10,16,17 for the final analysis. The sequence describing the above process can be found in Figure 1.

Figure 1. Flowsheet of study selection process.

None of the studies restricted the study population to a single cancerous cell type.

None of the included studies employed thoracoscopic evacuation of the malignant pleural effusion prior to bedside TS insertion via a chest tube.

Follow-up periods varied through the studies (Range = 30–425 days). Where available, recurrence data for the most distal available time point were selected for the meta-analysis.

All of the studies included in the analysis underwent quality assessment. The average Jadad score¹¹ was 1.5 out of a maximum possible score of 4 (Ranges 1–2). Out of the possible seven ways to assess the quality¹¹, only four questions could be answered due to the nature of the intervention. It was not possible reliably or ethically for the original investigators to have carried out efficient blinding in a surgical versus bedside clinical experiment.

Risk of recurrent pleural effusions

The results of the pooled RR are shown in Figure 2. The four studies included in this analysis enrolled a total of 454 patients with malignant pleural effusion (Table 1). There was no statistically significant difference in the risk of recurrent pleural effusions between the bedside TS (recurrences/patients who underwent pleurodesis, n/N = 51/218 pts) and the TTI groups (recurrences/patients who underwent pleurodesis, n/N = 39/236 pts, pooled RR 0.72; 95% CI 0.50-1.05; Q statistic, 3.58; I² statistic, 16.27%). There was no evidence of publication bias (P-value = 0.49 for the Begg’s test, P-value = 0.54 for the Egger’s regression intercept). After using the trim and fill methodology (Figure 3), these results did not change (RR- 0.78, 95% CI = 0.54-1.12, Q statistic, 6.8).

Figure 2. Pooled relative risks (RRs) for recurrent pleural effusions post talc pleurodesis.

RR, risk ratio, CI, confidence interval.

Table 1. Characteristics of studies included for studying risk of recurrent pleural effusions.

Study/Year Country	Intervention Design	Cancer Type	Definition of Recurrence	Recurrence in TTI Group n/N, (%)	Recurrence in TS group n/N, (%)	Follow up schedule	Quality score	Quality problems
Terra/2009 Brazil	TTI vs TS RCT	All cancers	Symptoms and further need for pleural procedures	5/30 (16%)	4/30 (13.3%)	1,3,6 months followed by q3 months or if symptoms arose	2	Allocation process unclear
Dresler/2005 USA	TTI vs TS RCT	All cancers	Radiological recurrence	33/152 (21.7%)	38/130 (29.2%)	1–6 months	2	Allocation process unclear
Manes/2000 Spain	TTI vs TS RCT	All cancers	Not defined but recurrences randomized to further pleural procedures	1/26 (3.8%)	8/29 (27.5%)	1–12 months	1	Inappropriate allocation process
Yim/1996 China	TTI vs TS RCT	All cancers	Radiological recurrence, however symptomatic patients who needed further procedures clearly identified	0/28 (0%)	1/29 (3.4%)	q6 weeks from 1–4.5 months, then q3 months	2	Allocation process unclear

TTI, Thoracoscopic talc insufflation, Also known as Thoracoscopic talc poudrage

TS, Talc slurry applied via a bedside chest tube

RCT, Randomized Controlled Trials

q- Every

Figure 3. Filled funnel plot using the trim and fill method for risk of recurrent effusions: imputed studies - ●, observed studies - ○, CI – confidence interval.

The definitions of a recurrent pleural effusion in the included studies varied. One study defined the recurrence based on radiological data alone⁶. The remainder of the studies clearly mentioned the number of patients who were symptomatic and required further pleural procedures once a recurrent pleural effusion was diagnosed^10,16,17.

A sensitivity analysis pooling data from studies reporting only clinically significant recurrences was performed leaving out one study⁶. This did not result in a different statistical outcome (pooled RR 0.49; 95% CI 0.11-2.22; Q statistic, 3.52; I² statistic 43.22%).

As follow-up periods varied widely, a sensitivity analysis pooling the data from studies reporting 30 day outcomes was carried out and did not result in a different statistical outcome.

Risk of respiratory complications

The results of the pooled RR are shown in Figure 4. The four studies included in this analysis reported outcomes on a total of 591 patients who underwent talc pleurodesis for palliation of malignant pleural effusion (Table 2).

Figure 4. Pooled relative risks (RRs) for respiratory complications post talc pleurodesis.

RR, risk ratio, CI, confidence interval.

Table 2. Characteristics of studies included for studying risk of respiratory complications.

Study/Year Country	Intervention Design	Talc description	Anesthesia	Respiratory complications	Incidence in TTI Group n/N, (%)	Incidence in TS Group n/N, (%)	Quality score	Quality problems
Terra/2009 Brazil	TTI vs TS RCT	Noncalibrated talc (Mean diameter = 25 μm, 10% of the particles had a diameter < 10 μm)	TTI- General anesthesia TS- IV, Local anesthesia	Pneumonia, Pulmonary edema, Subcutaneous emphysema	3/30 (10%)	4/30 (13.3%)	2	Allocation process unclear
Dresler/2005 USA	TTI vs TS RCT	Non calibrated talc	TTI- General anesthesia TS- N/A	Empyema, BP fistula, Atelectasis, Pneumonia, Respiratory failure, PE	53/223 (23.7%)	21/196 (10.7%)	2	Allocation process unclear
Manes/2000 Spain	TTI vs TS RCT	N/A	TTI- Local anesthesia TS- Local anesthesia	Empyema, Bronchospasm	1/29 (3.4%)	2/29 (6.8%)	1	Inappropriate allocation process
Yim/1996 China	TTI vs TS RCT	Purified talc from the U.K, no information on calibration	TTI-General anesthesia TS-Local anesthesia	Acute respiratory failure, Reexpansion pulmonary edema, Persistent air leak	2/28 (7.1%)	1/29 (3.4%)	2	Allocation process unclear

TTI, Thoracoscopic talc insufflation, also known as Thoracoscopic talc poudrage

TS, Talc slurry via a bedside chest tube

RCT, Randomized Controlled Trials

N/A, Not available

U.K, United Kingdom

IV, Intravenous

BP fistula, Bronchopleural fistula

PE, Pulmonary Embolism

There was a statistically significant higher risk of post procedural respiratory complications in the TTI group (Incidence of respiratory complications/Pts who underwent pleurodesis, n/N = 59/307 pts) compared to the TS group (Incidence of respiratory complications/Pts who underwent pleurodesis, n/N = 28/284 pts, pooled RR 1.91, 95% CI = 1.24-2.93, Q statistic 3.15, I² statistic 4.79%). There was no evidence of publication bias (P-value = 1.0 for the Begg’s test, P-value = 0.24 for the Egger’s regression intercept). After using the trim and fill methodology (Figure 5), these results did not change (RR- 1.99, 95% CI = 1.30-3.04, Q statistic, 4.32).

Figure 5. Filled funnel plot using the trim and fill method for risk of respiratory complications: imputed studies - ●, observed studies - ○, CI – confidence interval.

A sensitivity analysis pooling data from studies with ≥ 2 score on the Modified Jadad scale was performed leaving out one study with a score of 1¹⁷. This did not result in a different statistical outcome (pooled RR 1.99, 95% CI = 1.29-3.08, Q statistic 2.05, I² statistic 2.49).

Risk of non-respiratory complications

The results of the pooled RR are shown in Figure 6. The four studies included in this analysis reported outcomes on a total of 591 patients who underwent talc pleurodesis for palliation of malignant pleural effusion (Table 3).

Figure 6. Pooled relative risks (RRs) for non-respiratory complications post talc pleurodesis.

RR, risk ratio, CI, confidence interval.

Table 3. Characteristics of studies included for studying risk of non-respiratory complications.

Study/Year Country	Intervention Design	Non-respiratory complications	Incidence in TTI Group n/N, (%)	Incidence in TS Group n/N, (%)	Quality score	Quality problems
Terra/2009 Brazil	TTI vs TS RCT	Fever, Wound infection, prolonged drainage	4/30 (13.3%)	5/30 (16.6%)	2	Allocation process unclear
Dresler/2005 USA	TTI vs TS RCT	Fever, Wound infection, RBC transfusion, Dysrhythmia, MI, DVT, Immediate post procedural death	99/223 (44.3%)	93/196 (47.4%)	2	Allocation process unclear
Manes/2000 Spain	TTI vs TS RCT	Fever, Chest pain	6/26 (23%)	17/29 (58.6%)	1	Inappropriate allocation process
Yim/1996 China	TTI vs TS RCT	Tumor recurrence at wound site, Wound infection	1/28 (3.5%)	1/29 (3.4%)	2	Allocation process unclear

TTI, Thoracoscopic talc insufflation, Also known as Thoracoscopic talc poudrage

TS, Talc slurry applied via a bedside chest tube

RCT, Randomized Controlled Trials

RBC- Red Blood Cell

MI- Myocardial Infarction

DVT- Deep Venous Thrombosis

There was no statistically significant difference in the incidence of non-respiratory complications between the TTI group (Incidence of non-respiratory complications/Pts who underwent pleurodesis, n/N = 110/307 pts) and the TS group (Incidence of non-respiratory complications/Pts who underwent pleurodesis, n/N = 116/284 pts, pooled RR 0.88, 95% CI = 0.72-1.07, Q statistic 4.61, I² statistic 34.96%). There was no evidence of publication bias (P-value = 1.0 for the Begg’s test, P-value = 0.48 for the Egger’s regression intercept). After using the trim and fill methodology (Figure 7), these results did not change (RR- 0.93, 95% CI = 0.76-1.12, Q statistic, 9.8).

Figure 7. Filled funnel plot using the trim and fill method for risk of non-respiratory complications: imputed studies - ●, observed studies - ○, CI – confidence interval.

A sensitivity analysis pooling data from studies with ≥2 score on the Modified Jadad scale was performed leaving out one study with a score of 1¹⁷. This did not result in a different statistical outcome (pooled RR 0.93, 95% CI = 0.76-1.14, Q statistic 0.06, I² statistic 0.0).

Discussion

Many experts believe that serial thoracentesis is not an ideal choice for treating the recurrent malignant pleural effusion^18,19.

Talc pleurodesis was first performed in 1935²⁰ and is still commonly employed in the treatment of malignant pleural effusions. Although studies have shown talc to be the best chemical agent in terms of pleurodesis success and risk of recurrence^21,22, the best method of applying talc remains controversial. Our meta-analysis demonstrates that both talc poudrage (TTI) and talc slurry (TS) offer similar protection against clinically significant recurrences. There was no difference in the risk of clinically significant recurrence (i.e., further need for pleural procedures or symptoms). TTI did have a greater risk of respiratory complications. There was, however, no difference in the rate of non-respiratory complications such as fever and need for blood transfusions.

Our results are in contrast to those of previous meta-analyses⁵, including the recently withdrawn Cochrane analysis which suggested improved success rates of talc pleurodesis utilizing TTI. The conclusion of these analyses was that thoracoscopic pleurodesis with talc was the optimal method for pleurodesis in patients with malignant pleural effusions. However, several newer prospective studies have been published since^6,7 and have been incorporated into the present analysis.

Arguments in favor of TTI include the observation that there is more complete lung expansion after the procedure¹⁸. This is certainly understandable given that take-down of adhesions is typically performed during the procedure itself as opposed to TS. Interestingly, Terra et al. using CT scanning post-TTI and TS to assess degree of post procedure lung expansion did not find a correlation between clinical outcomes and initial degree of lung expansion⁷. These authors postulated that factors other than the degree of visceral and parietal pleura apposition were important in determining the success of pleurodesis. Similarly, Mager et al. using 99m Tc-labeled talc showed that rotation protocols did not affect the overall dispersion of talc suspensions after TS²³. The degree of dispersion also did not affect pleurodesis success²³.

In comparing TTI and TS, several difficulties arise. Pleurodesis success rates vary in the literature, due to the inconsistent definition of pleurodesis success and failure used in different studies. Failure or recurrence has been defined radiologically in some studies⁶ but it has been argued that patient centered outcomes such as new symptoms and need for further pleural procedures are more pertinent outcomes⁷. In our meta-analysis, we determined recurrence a priori as the development of symptoms or the further need for pleural procedures and disregarded asymptomatic radiological recurrences where possible.

The technique of both TS and TTI vary significantly between centers and this is evident in the included studies. TS varied in regard to length of chest tube clamping, rotating or not-rotating the patient, size of chest tube, and timing of chest tube removal. With regard to TTI, in three of the four studies TTI was performed under general anesthesia and the ability to tolerate general anesthesia was in fact an entry criteria. Overall, 88% of patients in our analysis underwent general anesthesia for TTI. One could argue that the increased respiratory complications observed with TTI may be related to general anesthesia and single lung ventilation. Despite the concerns of ARDS with the use of ungraded talc, the studies included in our meta-analysis did not report specific cases of ARDS. Non-specific respiratory failure was, however, reported in patients in the study by Dresler⁶ and Yim et al. reported a case of acute respiratory failure in the TS group¹⁶.

With the increasing numbers of interventional pulmonologists performing pleuroscopy (medical thoracoscopy)²⁴ under local and/or moderate sedation, the question of which procedure is the most optimal for talc pleurodesis is increasingly relevant. Whether talc poudrage performed during pleuroscopy with local or moderate sedation and dual lung ventilation is equivalent to surgical thoracoscopy (VATS) in terms of pleurodesis success and complications is unknown. Further studies are needed to compare talc poudrage performed with pleuroscopy versus TS.

One may wonder whether the question of TTI versus TS is still relevant in the era of indwelling pleural catheters (IPCs). Certainly, in the patient with trapped lung, both TS and TTI would likely be ineffective and indeed all of the studies in this meta-analysis excluded patients with possible trapped lung physiology. In the patient with malignant effusion without trapped lung, however, clear superiority of IPCs has not been demonstrated³. In fact, talc pleurodesis may be more economical compared to IPC in patients with good performance status and projected life expectancy of > 6 weeks^25,26. The issue of cost is especially relevant in the era of health care reform and accountable care organizations. With the advent of newer molecular/hormonal therapies especially in breast cancer, malignant pleural effusion is increasingly recognized as a non-terminal event²⁷. Perhaps most importantly, patient preference is paramount²⁸ and no study has clearly demonstrated the superiority of IPCs compared to talc pleurodesis.

Our study has several limitations. The results of meta-analyses are dependent on the quality of the studies included. The inclusion of only randomized controlled trials was necessary due to significant bias inherent in non-randomized prospective studies. Despite the lack of heterogeneity between studies, the individual studies varied substantially (technique of talc pleurodesis, varying definitions of recurrence and follow-up schedule). Sensitivity analyses performed leaving out one study at a time did not impact the results, suggesting robust data. Publication bias is an inherent limitation of meta-analyses. It is reassuring to see that accounting for it did not result in a statistically significant departure from the original point estimates.

In conclusion, our meta-analysis demonstrates that there is no difference in malignant pleural effusion recurrence based on patient centered outcomes between talc poudrage and talc slurry. Respiratory complications are more common with talc poudrage via thoracoscopy. Further studies are needed, however, to look at the role of talc pleurodesis via pleuroscopy. The decision of which procedure to perform needs to take into account also the patient preferences.

Author contributions

SM co-conceived the study, participated in the design of the study, search strategy execution, performance of the statistical analysis, and writing of the manuscript.

AK participated in the search strategy execution, performance of the statistical analysis and writing of the manuscript.

PH co-conceived the study, participated in the design of the study, performance of the statistical analysis, and writing of the manuscript.

All authors read and approved the final manuscript.

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Faculty Opinions recommended

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23. Mager HJ, Maesen B, Verzijlbergen F, et al.: Distribution of talc suspension during treatment of malignant pleural effusion with talc pleurodesis. Lung Cancer. 2002; 36(1): 77–81. PubMed Abstract | Publisher Full Text
24. Mori PA, Casalini AG: Therapeutic medical thoracoscopy. Monaldi Arch Chest Dis. 2011; 75(1): 89–94. PubMed Abstract
25. Olden AM, Holloway R: Treatment of malignant pleural effusion: PleuRx catheter or talc pleurodesis? A cost-effectiveness analysis. J Palliat Med. 2010; 13(1): 59–65. PubMed Abstract | Publisher Full Text | Free Full Text
26. Puri V, Pyrdeck TL, Crabtree TD, et al.: Treatment of malignant pleural effusion: a cost-effectiveness analysis. Ann Thorac Surg. 2012; 94(2): 374–379. PubMed Abstract | Publisher Full Text | Free Full Text
27. Mohsen TA, Zeid AA, Meshref M, et al.: Local iodine pleurodesis versus thoracoscopic talc insufflation in recurrent malignant pleural effusion: a prospective randomized control trial. Eur J Cardiothorac Surg. 2011; 40(2): 282–286. PubMed Abstract | Publisher Full Text
28. Maskell NA: Treatment options for malignant pleural effusions: patient preference does matter. JAMA. 2012; 307(22): 2432–2433. PubMed Abstract | Publisher Full Text

Supplementary materials

PRISMA 2009 Checklist

Section/topic	#	Checklist item	Reported on Page
TITLE
Title	1	Identify the report as a systematic review, meta-analysis, or both.	Page 1
ABSTRACT
Structured summary	2	Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.	Page 1
INTRODUCTION
Rationale	3	Describe the rationale for the review in the context of what is already known.	Page 3
Objectives	4	Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).	Page 3
METHODS
Protocol and registration	5	Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.	N/A
Eligibility criteria	6	Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.	Page 3
Information sources	7	Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.	Page 3
Search	8	Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.	Appendix 1
Study selection	9	State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).	Page 3
Data collection process	10	Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.	Page 3
Data items	11	List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.	Page 3
Risk of bias in individual studies	12	Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.	Pages 3–4
Summary measures	13	State the principal summary measures (e.g., risk ratio, difference in means).	Pages 4–7
Synthesis of results	14	Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.	Pages 4–7
Risk of bias across studies	15	Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).	Pages 4–5
Additional analyses	16	Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta- regression), if done, indicating which were pre-specified.	Pages 4–7
RESULTS
Study selection	17	Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.	Figure 1, Pages 4–5
Study characteristics	18	For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.	Tables 1–3
Risk of bias within studies	19	Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).	Pages 4–7
Results of individual studies	20	For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.	Figures 2,4,6
Synthesis of results	21	Present results of each meta-analysis done, including confidence intervals and measures of consistency.	Pages 4–7
Risk of bias across studies	22	Present results of any assessment of risk of bias across studies (see Item 15).	Pages 4–7
Additional analysis	23	Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta- regression [see Item 16]).	Pages 4–7
DISCUSSION
Summary of evidence	24	Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).	Pages 7,9,10
Limitations	25	Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).	Page 10
Conclusions	26	Provide a general interpretation of the results in the context of other evidence, and implications for future research.	Page 10
FUNDING
Funding	27	Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.	Page 10

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

Appendix 1

Search strategy for MEDLINE using PubMed

1. Search “talc poudrage” [MeSH OR tw] – 162 results
2. Search “chemical pleurodesis” [MeSH OR tw] – 266 results
3. Search “pleurodesis” [MeSH OR tw] – 2154 results
4. Search “thoracoscopic pleurodesis” [MeSH OR tw] – 52
5. Search “thoracoscopic talc pleurodesis” [MeSH OR tw] -42
6. Search “thoracoscopic poudrage” [all terms] – 87
7. Search “thoracoscopic talc poudrage” [MeSH OR tw] – 49
8. Search “talc insufflation” [MeSH OR tw] – 57
9. Search “thoracoscopic talc insufflation” [MeSH OR tw] – 19
10. Search “pleuroscopy” and “talc pleurodesis” [All Fields] – 329
11. Search “pleuroscopy” and “talc insufflation” [All Fields] – 69
12. Search “pleuroscopy” and “talc poudrage” [All Fields] – 119
13. Search “talc slurry” [MeSH OR tw] – 95
14. Search 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 10 OR 11 OR 12 OR 13 – 2206 results
15. Search “malignant pleural effusion” [MeSH OR tw] -3426 results
16. Search “malignant pleuritis” [MeSH OR tw] -29
17. Search 14 and 15 – 580 results. Subsequently, the following filters were applied [Clinical trials including Phase I–IV, Controlled Clinical Trials, Randomized Controlled Trials, Reviews, Systematic Reviews, Meta-Analyses, observational studies, abstract availability, publication dates from 01/01/1989 to 12/31/2014, adult human studies, English-language publications] – 71 results.
18. Search 14 and 16. Filters applied [Clinical trials including Phase I–IV, Controlled Clinical Trials, Meta-Analyses, observational studies, randomized controlled trials, systematic reviews, review articles, abstract availability, publication dates from 01/01/1989 to 10/1/2014, adult human studies, English-language publications] – 0 results.
Terms such as thoracoscopic poudrage, chest tube talc slurry, thoracostomy talc slurry, chest tube talc pleurodesis, talc slurry sclerosis did not reveal any results in the [MeSH OR tw] category.

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© 2014 Mummadi S et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

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Mummadi S, Kumbam A and Hahn PY. Malignant pleural effusions and the role of talc poudrage and talc slurry: a systematic review and meta-analysis [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2014, 3:254 (https://doi.org/10.12688/f1000research.5538.1)

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Reviewer Report 31 Dec 2014

Pyng Lee, Division of Respiratory and Critical Care, National University Hospital, Singapore, Singapore

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https://doi.org/10.5256/f1000research.5917.r7143

Malignant pleural effusion is also one of the leading causes of exudative effusion; studies have demonstrated that 42 to ... Continue reading

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Reviewer Report 31 Oct 2014

Gary Lee, Pleural Medicine Unit, The Lung Institute of Western Australia, Nedlands, WA, Australia

Approved with Reservations

https://doi.org/10.5256/f1000research.5917.r6535

Overview:
The topic is important and clinically relevant. Talc pleurodesis is commonly practiced. The debate on the superiority of thoracoscopic poudrage (TTI) versus talc slurry (TS) has been ongoing for decades. A meta-analysis incorporating the most recent data is useful.

The methodology appears sound. The four selected articles are well described and acknowledged in most review articles as the only randomized studies directly addressing this topic.

The interpretation of the data is fair and balanced. The endpoints chosen are clinically relevant and important. Most other reviews or book chapters on the issue have only focused on the success/failure rate of the pleurodesis. The authors rightly highlighted the increased complication rates of TTI. The figures and graphs are clear and easy to understand.

The discussion is based on the analyses and the postulations for the observed results are sound and reasonable.

Overall this is an excellent paper and I would support its indexing.

There are several few points that the authors may wish to consider. I believe that this article may be improved if the authors can address the following:

The study by Manes et al. (2000)

The authors quite rightly included not only peer reviewed papers but also all published abstracts. This approach is according to standard meta-analysis practice, in order to avoid publication bias such that ‘negative’ studies (often not published in full) are not excluded. However, including data from published abstracts preclude scrutiny of the detailed methods, analyses and thus raises questions on the quality of the results. The situation in the meta-analysis of TTI vs TS highlights the pros vs cons of including data that were not peer reviewed.

Three of the four selected studies were published in respected journals and were subjected to peer-reviewing processes. The study by Manes however was published only as an abstract 14 years ago, and to date had not been published as a full paper. This by itself raises great concerns. The results of this particular study deviated significantly from all the other three. The authors have identified clear methodological concerns (especially ‘recycling’ of patients into randomization after failing pleurodesis). Unless the authors have obtained details from the primary research group, it is doubtful that a short abstract could provide adequate details for proper critique of the methods and results. Including this study without qualifying its many limitations may distort the interpretation of the readers.

I suggest that the authors should:
1. Highlight the point that the Manes study was never published in full in the text/legends;
2. Perform and show a separate analysis excluding the Manes study;
3. Discuss the rationale of including/excluding this single study in the Discussion section.
  
  I believe the above measures are justified as the Manes study was not a ‘negative’ study and would never have been biased against if ever submitted for full publication.
An alternate way of presenting the data

Although it would not change the actual conclusion or the raw data, presenting the results as ‘success’ rather than ‘failure’ rates would quite significantly change the ‘visual effects’ of the graphs. Take for example the Dresler study. The RR for failure is 0.74 but if expressed as ratio of success rates it would become 1.11, the Yim study 1.04 and the Terres study 0.96. This probably presents a more useful interpretation for clinicians and patients – that the magnitude of superiority of TTI in any of the studies is at best 1.11 times over TS (excluding Manes et al.).
Discussion

It would be useful to include that there are no scientific grounds why insufflation should be more advantageous than slurry. Talc does not work as a glue (otherwise we would have had major problems when talc was still included in baby nappy powders). Even distribution of talc over the pleural surface is not therefore critical. Radio-active isotope studies have shown that talc, even when applied as a slurry, can distribute around the pleural cavity via respiratory motions.

Competing Interests: No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Reader Comment 18 Feb 2015

Srinivas Mummadi, Tuality Community Hospital/Oregon Health and Science University, USA

18 Feb 2015

Reader Comment
Thank you very much your comments and a detailed critique of our manuscript.
1. Response to “The study by Manes et al. (2000)”
  
  We agree with your assessment of the pros and cons
... Continue reading
Thank you very much your comments and a detailed critique of our manuscript.

Response to “The study by Manes et al. (2000)”

We agree with your assessment of the pros and cons of including the study by Manes et al. (2000) published only as an abstract. As our inclusion criteria were defined a priori, we included the study in our analysis.

We agree with your comments that it suffers from potential quality concerns. In addition to our stated concerns regarding the inappropriate allocation of randomization, we have made efforts to highlight additional quality concerns outlined below.

Footnotes to the tabular data have been added, highlighting the existing form of publication as an abstract. We also discussed in detail the lack of change in point estimates for all the predefined outcomes after removing the study as a part of the sensitivity analysis.

Due to its unique conclusion (TTI is superior to TS in terms of pleurodesis success rates) and a relatively large treatment effect, we believe that the inclusion of this study with the clear mentioning of its inherent limitations gives us a unique opportunity to present both sides of the talc poudrage versus talc slurry debate in a systematic review.

Inclusion of this study in the analysis allows meta-analysis to play the role of an adjudicator.

As mentioned earlier, removal of this study in the sensitivity analysis did not influence the results.

For the sake of clarity, we would like to report the results for all the studied outcomes after removing the above mentioned study in this reply.

1) Pooled relative risks (RRs) of success rates post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 1.04, 95% CI (0.97-1.1), P-value – 0.24, Q statistic -1.28

2) Pooled relative risks (RRs) for respiratory complications post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 1.99, 95% CI (1.29-3.08), P-value – 0.002, Q statistic -2.05

3) Pooled relative risks (RRs) for non-respiratory complications post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 0.93, 95% CI (0.76-1.14), P-value – 0.5, Q statistic - 0.06

An alternate way of presenting the data

We agree with your suggestion that the clarity of the take-home message would be improved by presenting the data as rates of success rather than rates of failure. We have therefore renamed the outcome as “successful pleurodesis” [defined as no need for further pleural procedures despite asymptomatic radiological recurrence in a few cases]. Measuring patient centered outcomes was the predefined objective of the study, therefore asymptomatic radiological recurrences where clearly defined were counted towards success (3 patients)

Relevant changes have been made in the body of the manuscript, figures, and tables. Reassuringly, measuring the outcome as either relative rates of success or relative risks of recurrence did not influence the existing conclusion.

Discussion

We agree that there are no quality data to substantiate the “intuition” that thoracoscopic talc insufflation is superior to talc slurry in terms of talc dispersion in the pleural space. We would like to draw your attention to our mentioning of these points in the existing discussion section (Mager et al.). We have fine-tuned the write up to buttress the above point to increase the visibility to the reader.
Thank you very much your comments and a detailed critique of our manuscript.

Response to “The study by Manes et al. (2000)”

We agree with your assessment of the pros and cons of including the study by Manes et al. (2000) published only as an abstract. As our inclusion criteria were defined a priori, we included the study in our analysis.

We agree with your comments that it suffers from potential quality concerns. In addition to our stated concerns regarding the inappropriate allocation of randomization, we have made efforts to highlight additional quality concerns outlined below.

Footnotes to the tabular data have been added, highlighting the existing form of publication as an abstract. We also discussed in detail the lack of change in point estimates for all the predefined outcomes after removing the study as a part of the sensitivity analysis.

Due to its unique conclusion (TTI is superior to TS in terms of pleurodesis success rates) and a relatively large treatment effect, we believe that the inclusion of this study with the clear mentioning of its inherent limitations gives us a unique opportunity to present both sides of the talc poudrage versus talc slurry debate in a systematic review.

Inclusion of this study in the analysis allows meta-analysis to play the role of an adjudicator.

As mentioned earlier, removal of this study in the sensitivity analysis did not influence the results.

For the sake of clarity, we would like to report the results for all the studied outcomes after removing the above mentioned study in this reply.

1) Pooled relative risks (RRs) of success rates post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 1.04, 95% CI (0.97-1.1), P-value – 0.24, Q statistic -1.28

2) Pooled relative risks (RRs) for respiratory complications post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 1.99, 95% CI (1.29-3.08), P-value – 0.002, Q statistic -2.05

3) Pooled relative risks (RRs) for non-respiratory complications post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 0.93, 95% CI (0.76-1.14), P-value – 0.5, Q statistic - 0.06

An alternate way of presenting the data

We agree with your suggestion that the clarity of the take-home message would be improved by presenting the data as rates of success rather than rates of failure. We have therefore renamed the outcome as “successful pleurodesis” [defined as no need for further pleural procedures despite asymptomatic radiological recurrence in a few cases]. Measuring patient centered outcomes was the predefined objective of the study, therefore asymptomatic radiological recurrences where clearly defined were counted towards success (3 patients)

Relevant changes have been made in the body of the manuscript, figures, and tables. Reassuringly, measuring the outcome as either relative rates of success or relative risks of recurrence did not influence the existing conclusion.

Discussion

We agree that there are no quality data to substantiate the “intuition” that thoracoscopic talc insufflation is superior to talc slurry in terms of talc dispersion in the pleural space. We would like to draw your attention to our mentioning of these points in the existing discussion section (Mager et al.). We have fine-tuned the write up to buttress the above point to increase the visibility to the reader.
Competing Interests: None Close
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Reader Comment 18 Feb 2015

Srinivas Mummadi, Tuality Community Hospital/Oregon Health and Science University, USA

18 Feb 2015

Reader Comment
Thank you very much your comments and a detailed critique of our manuscript.
1. Response to “The study by Manes et al. (2000)”
  
  We agree with your assessment of the pros and cons
... Continue reading
Thank you very much your comments and a detailed critique of our manuscript.

Response to “The study by Manes et al. (2000)”

We agree with your assessment of the pros and cons of including the study by Manes et al. (2000) published only as an abstract. As our inclusion criteria were defined a priori, we included the study in our analysis.

We agree with your comments that it suffers from potential quality concerns. In addition to our stated concerns regarding the inappropriate allocation of randomization, we have made efforts to highlight additional quality concerns outlined below.

Footnotes to the tabular data have been added, highlighting the existing form of publication as an abstract. We also discussed in detail the lack of change in point estimates for all the predefined outcomes after removing the study as a part of the sensitivity analysis.

Due to its unique conclusion (TTI is superior to TS in terms of pleurodesis success rates) and a relatively large treatment effect, we believe that the inclusion of this study with the clear mentioning of its inherent limitations gives us a unique opportunity to present both sides of the talc poudrage versus talc slurry debate in a systematic review.

Inclusion of this study in the analysis allows meta-analysis to play the role of an adjudicator.

As mentioned earlier, removal of this study in the sensitivity analysis did not influence the results.

For the sake of clarity, we would like to report the results for all the studied outcomes after removing the above mentioned study in this reply.

1) Pooled relative risks (RRs) of success rates post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 1.04, 95% CI (0.97-1.1), P-value – 0.24, Q statistic -1.28

2) Pooled relative risks (RRs) for respiratory complications post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 1.99, 95% CI (1.29-3.08), P-value – 0.002, Q statistic -2.05

3) Pooled relative risks (RRs) for non-respiratory complications post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 0.93, 95% CI (0.76-1.14), P-value – 0.5, Q statistic - 0.06

An alternate way of presenting the data

We agree with your suggestion that the clarity of the take-home message would be improved by presenting the data as rates of success rather than rates of failure. We have therefore renamed the outcome as “successful pleurodesis” [defined as no need for further pleural procedures despite asymptomatic radiological recurrence in a few cases]. Measuring patient centered outcomes was the predefined objective of the study, therefore asymptomatic radiological recurrences where clearly defined were counted towards success (3 patients)

Relevant changes have been made in the body of the manuscript, figures, and tables. Reassuringly, measuring the outcome as either relative rates of success or relative risks of recurrence did not influence the existing conclusion.

Discussion

We agree that there are no quality data to substantiate the “intuition” that thoracoscopic talc insufflation is superior to talc slurry in terms of talc dispersion in the pleural space. We would like to draw your attention to our mentioning of these points in the existing discussion section (Mager et al.). We have fine-tuned the write up to buttress the above point to increase the visibility to the reader.
Thank you very much your comments and a detailed critique of our manuscript.

Response to “The study by Manes et al. (2000)”

We agree with your assessment of the pros and cons of including the study by Manes et al. (2000) published only as an abstract. As our inclusion criteria were defined a priori, we included the study in our analysis.

We agree with your comments that it suffers from potential quality concerns. In addition to our stated concerns regarding the inappropriate allocation of randomization, we have made efforts to highlight additional quality concerns outlined below.

Footnotes to the tabular data have been added, highlighting the existing form of publication as an abstract. We also discussed in detail the lack of change in point estimates for all the predefined outcomes after removing the study as a part of the sensitivity analysis.

Due to its unique conclusion (TTI is superior to TS in terms of pleurodesis success rates) and a relatively large treatment effect, we believe that the inclusion of this study with the clear mentioning of its inherent limitations gives us a unique opportunity to present both sides of the talc poudrage versus talc slurry debate in a systematic review.

Inclusion of this study in the analysis allows meta-analysis to play the role of an adjudicator.

As mentioned earlier, removal of this study in the sensitivity analysis did not influence the results.

For the sake of clarity, we would like to report the results for all the studied outcomes after removing the above mentioned study in this reply.

1) Pooled relative risks (RRs) of success rates post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 1.04, 95% CI (0.97-1.1), P-value – 0.24, Q statistic -1.28

2) Pooled relative risks (RRs) for respiratory complications post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 1.99, 95% CI (1.29-3.08), P-value – 0.002, Q statistic -2.05

3) Pooled relative risks (RRs) for non-respiratory complications post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 0.93, 95% CI (0.76-1.14), P-value – 0.5, Q statistic - 0.06

An alternate way of presenting the data

We agree with your suggestion that the clarity of the take-home message would be improved by presenting the data as rates of success rather than rates of failure. We have therefore renamed the outcome as “successful pleurodesis” [defined as no need for further pleural procedures despite asymptomatic radiological recurrence in a few cases]. Measuring patient centered outcomes was the predefined objective of the study, therefore asymptomatic radiological recurrences where clearly defined were counted towards success (3 patients)

Relevant changes have been made in the body of the manuscript, figures, and tables. Reassuringly, measuring the outcome as either relative rates of success or relative risks of recurrence did not influence the existing conclusion.

Discussion

We agree that there are no quality data to substantiate the “intuition” that thoracoscopic talc insufflation is superior to talc slurry in terms of talc dispersion in the pleural space. We would like to draw your attention to our mentioning of these points in the existing discussion section (Mager et al.). We have fine-tuned the write up to buttress the above point to increase the visibility to the reader.
Competing Interests: None Close
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Gary Lee, The Lung Institute of Western Australia, Nedlands, Australia
Pyng Lee, National University Hospital, Singapore, Singapore
Fabien Maldonado, Mayo Clinic, Rochester, USA

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Fabien Maldonado, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA

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Approved

This is a very well-written and conducted systematic review and metaanalysis.

I would have liked to get a sense of the level of agreement between the two reviewers for study inclusion, though I suspect the search was relatively straightforward.

It would be worthwhile pointing out in the discussion that the Dresler paper weighs heavily in the results, particularly with respect to respiratory complications, inherent in surgical procedures and perhaps, in some instances, unrelated to the talc pleurodesis itself. The methodological flaws of this study (exclusion of a substantial number of patients after randomization limiting the benefits of randomization) should have been specifically highlighted in my opinion.

Nonetheless, this is an important meta-analysis that should be indexed.

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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31 Dec 2014 | for Version 1

Pyng Lee, Division of Respiratory and Critical Care, National University Hospital, Singapore, Singapore

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Malignant pleural effusion is also one of the leading causes of exudative effusion; studies have demonstrated that 42 to 77% of exudative effusions are secondary to malignancy (Marel et al.,1993; Valdés et al.,1996)

Need statistician review.

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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31 Oct 2014 | for Version 1

Gary Lee, Pleural Medicine Unit, The Lung Institute of Western Australia, Nedlands, WA, Australia

87 Views Cite this report Responses(1)

Approved With Reservations

The study by Manes et al. (2000)

The authors quite rightly included not only peer reviewed papers but also all published abstracts. This approach is according to standard meta-analysis practice, in order to avoid publication bias such that ‘negative’ studies (often not published in full) are not excluded. However, including data from published abstracts preclude scrutiny of the detailed methods, analyses and thus raises questions on the quality of the results. The situation in the meta-analysis of TTI vs TS highlights the pros vs cons of including data that were not peer reviewed.

Three of the four selected studies were published in respected journals and were subjected to peer-reviewing processes. The study by Manes however was published only as an abstract 14 years ago, and to date had not been published as a full paper. This by itself raises great concerns. The results of this particular study deviated significantly from all the other three. The authors have identified clear methodological concerns (especially ‘recycling’ of patients into randomization after failing pleurodesis). Unless the authors have obtained details from the primary research group, it is doubtful that a short abstract could provide adequate details for proper critique of the methods and results. Including this study without qualifying its many limitations may distort the interpretation of the readers.

I suggest that the authors should:
1. Highlight the point that the Manes study was never published in full in the text/legends;
2. Perform and show a separate analysis excluding the Manes study;
3. Discuss the rationale of including/excluding this single study in the Discussion section.
  
  I believe the above measures are justified as the Manes study was not a ‘negative’ study and would never have been biased against if ever submitted for full publication.
An alternate way of presenting the data

Although it would not change the actual conclusion or the raw data, presenting the results as ‘success’ rather than ‘failure’ rates would quite significantly change the ‘visual effects’ of the graphs. Take for example the Dresler study. The RR for failure is 0.74 but if expressed as ratio of success rates it would become 1.11, the Yim study 1.04 and the Terres study 0.96. This probably presents a more useful interpretation for clinicians and patients – that the magnitude of superiority of TTI in any of the studies is at best 1.11 times over TS (excluding Manes et al.).
Discussion

It would be useful to include that there are no scientific grounds why insufflation should be more advantageous than slurry. Talc does not work as a glue (otherwise we would have had major problems when talc was still included in baby nappy powders). Even distribution of talc over the pleural surface is not therefore critical. Radio-active isotope studies have shown that talc, even when applied as a slurry, can distribute around the pleural cavity via respiratory motions.

Competing Interests

No competing interests were disclosed.

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Reader Comment

18 Feb 2015

Srinivas Mummadi, Tuality Community Hospital/Oregon Health and Science University, USA

Thank you very much your comments and a detailed critique of our manuscript.

Response to “The study by Manes et al. (2000)”

We agree with your assessment of the pros and cons of including the study by Manes et al. (2000) published only as an abstract. As our inclusion criteria were defined a priori, we included the study in our analysis.

We agree with your comments that it suffers from potential quality concerns. In addition to our stated concerns regarding the inappropriate allocation of randomization, we have made efforts to highlight additional quality concerns outlined below.

Footnotes to the tabular data have been added, highlighting the existing form of publication as an abstract. We also discussed in detail the lack of change in point estimates for all the predefined outcomes after removing the study as a part of the sensitivity analysis.

Due to its unique conclusion (TTI is superior to TS in terms of pleurodesis success rates) and a relatively large treatment effect, we believe that the inclusion of this study with the clear mentioning of its inherent limitations gives us a unique opportunity to present both sides of the talc poudrage versus talc slurry debate in a systematic review.

Inclusion of this study in the analysis allows meta-analysis to play the role of an adjudicator.

As mentioned earlier, removal of this study in the sensitivity analysis did not influence the results.

For the sake of clarity, we would like to report the results for all the studied outcomes after removing the above mentioned study in this reply.

1) Pooled relative risks (RRs) of success rates post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 1.04, 95% CI (0.97-1.1), P-value – 0.24, Q statistic -1.28

2) Pooled relative risks (RRs) for respiratory complications post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 1.99, 95% CI (1.29-3.08), P-value – 0.002, Q statistic -2.05

3) Pooled relative risks (RRs) for non-respiratory complications post talc pleurodesis (TTI vs TS)

Point estimate (RR) = 0.93, 95% CI (0.76-1.14), P-value – 0.5, Q statistic - 0.06
An alternate way of presenting the data

We agree with your suggestion that the clarity of the take-home message would be improved by presenting the data as rates of success rather than rates of failure. We have therefore renamed the outcome as “successful pleurodesis” [defined as no need for further pleural procedures despite asymptomatic radiological recurrence in a few cases]. Measuring patient centered outcomes was the predefined objective of the study, therefore asymptomatic radiological recurrences where clearly defined were counted towards success (3 patients)

Relevant changes have been made in the body of the manuscript, figures, and tables. Reassuringly, measuring the outcome as either relative rates of success or relative risks of recurrence did not influence the existing conclusion.
Discussion

We agree that there are no quality data to substantiate the “intuition” that thoracoscopic talc insufflation is superior to talc slurry in terms of talc dispersion in the pleural space. We would like to draw your attention to our mentioning of these points in the existing discussion section (Mager et al.). We have fine-tuned the write up to buttress the above point to increase the visibility to the reader.

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Competing Interests

None

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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Malignant pleural effusions and the role of talc poudrage and talc slurry: a systematic review and meta-analysis

Abstract

Keywords

Introduction

Materials and methods

Data sources and search

Study selection

Data extraction and outcome measures

Quality assessment criteria

Statistical analysis

Results

Figure 1. Flowsheet of study selection process.

Risk of recurrent pleural effusions

Figure 2. Pooled relative risks (RRs) for recurrent pleural effusions post talc pleurodesis.

Table 1. Characteristics of studies included for studying risk of recurrent pleural effusions.

Figure 3. Filled funnel plot using the trim and fill method for risk of recurrent effusions: imputed studies - ●, observed studies - ○, CI – confidence interval.

Risk of respiratory complications

Figure 4. Pooled relative risks (RRs) for respiratory complications post talc pleurodesis.

Table 2. Characteristics of studies included for studying risk of respiratory complications.

Figure 5. Filled funnel plot using the trim and fill method for risk of respiratory complications: imputed studies - ●, observed studies - ○, CI – confidence interval.

Risk of non-respiratory complications

Figure 6. Pooled relative risks (RRs) for non-respiratory complications post talc pleurodesis.

Table 3. Characteristics of studies included for studying risk of non-respiratory complications.

Figure 7. Filled funnel plot using the trim and fill method for risk of non-respiratory complications: imputed studies - ●, observed studies - ○, CI – confidence interval.

Discussion

Author contributions

Competing interests

Grant information

References

Supplementary materials

PRISMA 2009 Checklist

Appendix 1

Search strategy for MEDLINE using PubMed

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