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

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 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

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.

Measures of successful pleurodesis

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 proportion of successful pleurodesis between the bedside TS (successful pleurodesis/patients who underwent pleurodesis, n/N = 167/218 pts) and the TTI groups (successful pleurodesis/patients who underwent pleurodesis, n/N = 197/236 pts, pooled RR 1.06; 95% CI 0.99-1.14; Q statistic, 4.84; I² statistic, 38%). 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- 1.04, 95% CI = 0.97-1.11, Q statistic, 9).

Figure 2. Pooled relative risks (RRs) of success rates post talc pleurodesis.

RR, risk ratio, CI, confidence interval.

Figure 3. Filled funnel plot using the trim and fill method for succesful pleurodesis rates post talc pleurodesis: imputed studies - ●, observed studies - ○, CI – confidence interval.

The definitions of an efficacious pleurodesis intervention varied in the included studies. Three studies^10,16,17 reported procedure failure by measuring clinically significant recurrences and one study reported the number of successful procedures defined as the lack of recurrence. This study defined 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 1.07; 95% CI 0.92-1.25; Q statistic, 4.49; I² statistic 55.53%).

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).

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, Potential “recycling” of patients into intervention arms
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

*Study published only as an abstract form

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

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

RR, risk ratio, CI, confidence interval.

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).

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

Study/Year Country	Intervention Design	Immediate 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, Potential “recycling” of patients into intervention arms
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

*Study published only as an abstract form

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

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

RR, risk ratio, CI, confidence interval.

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 rates of efficacy. There was no difference in the rates of successful pleurodesis (i.e., lack of need for further 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. Likewise, there are no data to substantiate an existing notion that TTI would result in a superior dispersion of talc in the pleural space. Mager et al. used 99m Tc-labeled talc to show 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 success a priori as the lack of need for further 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. Of note, one of the included studies (Manes et al., 2000) has several potential quality concerns as reflected by a modified Jadad score of 1. These include existing only in an abstract form, inappropriate randomization allocation and possible recycling of patients into treatment arms. We included this study due to its unique conclusion (TTI is superior to TS in terms of efficacy) and a large treatment effect. Reassuringly, sensitivity analysis performed by leaving this study out did not change the final estimates of all the studied outcomes. 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 success rates of pleurodesis 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.