Efficacy and Safety of Talc Pleurodesis for Malignant Pleural Effusion: A Meta-Analysis

Background Talc pleurodesis has been widely used to control malignant pleural effusion; however, it is still not clear whether talc pleurodesis is more effective than other local therapies. We performed a meta-analysis to evaluate the efficacy and safety of talc pleurodesis in the management of malignant pleural effusion. Methods PubMed, Embase, and Web of Science were searched for English-language studies of clinical controlled trials comparing talc pleurodesis with control therapies until August 8, 2013. Success rate and incidence of adverse events were evaluated. Relative risks were estimated using random- or fixed- effects model and statistical heterogeneity was assessed using I2 test. Results Twenty trials involving 1,525 patients with malignant pleural effusion were included. The success rate of talc pleurodesis was significantly higher than that of control therapies (relative risk, 1.21; 95% confidence interval, 1.01–1.45; p = 0.035) with similar adverse events. In addition, thoracoscopic talc poudrage was more effective than bedside talc slurry (relative risk, 1.12; 95% confidence interval, 1.01–1.23; p = 0.026). Conclusions The current evidences suggested the benefit for talc pleurodesis in the treatment of malignant pleural effusion. Talc pleurodesis, especially thoracoscopic talc poudrage pleurodesis, should be performed in patients with malignant pleural effusion, especially those with life-expectancy longer than one month.


Introduction
Malignant pleural effusion (MPE) is a common complication of advanced malignancy with a poor prognosis. It's estimated that MPE affects more than 150,000 people each year in the United States [1]. Progressive dyspnea is the most common symptom in patients with MPE followed by cough and chest pain that affect the quality of life [2]. Although some malignancies such as small cell lung cancer, lymphoma, or breast cancer might respond to systemic treatment, local therapy for MPE may still be needed [3]. Local palliative procedures are more required to relieve dyspnea, improve life quality, and avoid repeated thoracentesis for patients not responding to systemic treatment [4]. Current local managements include thoracentesis, pleurodesis, chest tube drainage, indwelling pleural catheters drainage, pleurectomy, and pleuroperitoneal shunting [1,5].
Pleurodesis is a procedure aiming at the adhesion of the visceral and parietal pleura that prevents the accumulation of MPE and subsequently improves symptoms [6]. Pleurodesis can be completed by chemical sclerosants or by physical abrasion of pleural surfaces during thoracoscopy or thoracotomy [6]. Pleurodesis after intercostal drainage is recommended for MPE management unless the lung is significantly trapped according to the current British Thoracic Society guideline [5].
Among the wide variety of sclerosing agents used to produce pleurodesis, talc is considered the most effective [1,5]. A Cochrane review demonstrated that talc was the most effective sclerosant comparing with other sclerosants and a significant reduction in MPE recurrence [7]. Another systemic review revealed that talc tended to be associated with fewer recurrence of MPE when compared with other sclerosants, but there was no significant difference [8]. On the other hand, a few complications of talc pleurodesis existed, such as acute respiratory failure, pneumonia, and treat-related death [9,10]. Actually, there is still controversy about the use of talc pleurodesis in clinical practice [11,12]. We thus performed the current meta-analysis based on published controlled clinical trials to evaluate the overall efficacy and safety of talc pleurodesis compared with the other local therapies in patients with MPE.

Literature Search
PubMed, Embase, and Web of Science were searched for suitable studies up to August 8, 2013; no lower date limit was employed. Search keywords included: ''malignant pleural effusion'', ''pleurodesis'', and ''talc''. Articles were also identified by use of the related-articles function in PubMed. References of articles identified were also searched manually. Although no language restrictions were imposed initially, for the full-text review and final analysis our resources only permitted review of English articles.

Study Eligibility
We included full-text publications that investigated MPE patients treated with talc pleurodesis compared with other sclerosants or other local palliative methods, as well as those compared different routes of talc administration (talc poudrage versus talc slurry). We only selected randomized controlled trials and prospective unrandomized trials. Retrospective studies, case studies, letter reports, and conference abstracts were excluded. Publications with evidence of possible overlap of patients with other studies were discussed by HX, XJW, and QZ and only the best-quality study was used. Two reviewers (HZS and ZHT) independently judged study eligibility while screening the citations. Disagreements were resolved by consensus.

Data Extraction and Quality Assessment
The final set of the English articles was assessed independently by two reviewers (HX and XJW). The following information was obtained from each trial: publication details (title, the first author, other citation details), study design, participants' details (the numbers of patients enrolled, participant demographics, cancer type), the intervention details, the duration of follow-up, primary outcome (success rate) and adverse events. All data were verified for internal consistency, and discrepancy was resolved by discussion among the reviewers.
In the present meta-analysis, complete response (no accumulation of pleural effusion on the basis of radiographic evidence till the end of follow-up or death) was defined as successful pleurodesis. However, a few studies did not use this assessment criterion. For these studies, partial response (re-accumulation of pleural effusion but not requiring further therapeutic thoracentesis till the end of follow-up or death) was also defined as successful pleurodesis.
Quality assessment of the included studies was done unblindly by 2 reviewers (QZ and HZS) using a 10 point scoring system [13].

Statistical Analysis
Relative risk (RR) with 95% confidence intervals (CI) was calculated using fixed-or random-effects model. Statistics heterogeneity was assessed by I 2 test with a value greater than 50% was recognized as indicative of substantial heterogeneity [14]. If substantial heterogeneity was observed, random-effects models were used. Meta-regression was performed to find the source of heterogeneity. Funnel plot was applied to assess the publication bias visually and Egger's test was used to evaluate publication bias statistically [15]. A p value ,0.05 was considered statistically significant. STATA 11.0 software was used in all analyses (Stata Corporation, College Station, TX).
The mean quality score was 6.7, with a range from 5 to 8 (Table 1). Therefore, the overall quality of all trials was not very good, especially none was blind designed.
Overall test for heterogeneity showed that I 2 = 71.1% (p,0.001), indicating a significant heterogeneity between studies. The funnel plots for publication bias showed some asymmetry ( Figure 3), and the Egger's test was significant (p = 0.015), indicating there was a publication bias.
Due to the significant heterogeneity between studies in assessing the overall efficacy of talc pleurodesis, we performed a metaregression to explore the source of the heterogeneity. It was noted that the routes of administration, control therapies, methods of assessing success rate, and cancer types were not the source of heterogeneity (all p.0.05).
Four studies [28,30,31,45] chose patients with MPE secondary to carcinoma of the breast as the study population and the other 11 studies [29,32,[34][35][36][37][38][39]43,46,47] included patients with MPE in spite of the types of malignancies. As a result, we did an analysis according to whether the patients were all with breast cancer or not. The results suggest that talc pleurodesis was more effective than control therapies in MPE patients with breast cancer (RR 1.42; 95% CI, 1.02-1.46; p = 0.035). The efficacy was similar in the group without limitation of cancer types (RR 1.43; 95% CI, 0.92-1.42; p = 0.233).

Discussion
Once a patient is diagnosed as MPE, his median survival is just 4 to 6 m depending on the type of malignancy [1]. Most patients with MPE are symptomatic and dyspnea is the most common symptom affecting the quality of life [2]. Therapeutic thoracentesis is effective in alleviating symptom, but MPE usually recur within 1 m [48,49]. Furthermore, repeated thoracentesis has the risk of pneumothorax, empyema and pleural adhesions which influence the following procedure such as drainage and thoracoscopy [5].
Talc pleurodesis results in the symphysis between the visceral and parietal pleura that prevents the accumulation of liquid in the pleural space, and usually has the advantage of a time-limited course of treatment and high pleurodesis rate. Moreover, talc has been demonstrated to possess a local antitumor effect of by triggering apoptosis in cancer cells [50] and by altering the angiostatic balance via endostatin [51], suggesting that talc might play a significant role in controlling not only MPE but also intrapleural tumor progression. In the present meta-analysis, we found that talc pleurodesis was associated with higher success rates compared with control therapies, and that thoracoscopic talc poudrage was more effective in controlling MPE than bedside talc slurry pleurodesis. The assessing time of success rate of talc pleurodesis in the included studies varied from 1 m to several months or until death, we therefore evaluated the short-term (1 m) and long-term (longer than 1 m) efficacy separately. We noted that the efficacy of talc pleurodesis compared with control therapies at 1 m was similar; whereas the efficacy evaluated at longer than 1 m favored talc pleurodesis other than the controls. These data indicated that MPE patients with life expectancy more than 1 m would benefit more from talc pleurodesis.
Although talc pleurodesis is now well recognized as the procedure of choice for the treatment of MPE, the optimal route of talc administration is still debated. Some authors prefer thoracoscopic talc poudrage, but the others advocate talc instillation through a chest tube because it was a simpler and less invasive procedure. Our subgroup analysis demonstrated that thoracoscopic talc poudrage was superior in managing MPE to control therapies, while the success rates of talc slurry and control therapies were not significantly different. Combining with the above results of comparing thoracoscopic talc poudrage and talc slurry, thoracoscopic talc poudrage could be regarded as the better choice of MPE management. It is reasonable that slurry procedure is not favorable because it does not allow the talc to be thoroughly distributed over the whole pleural surface [52].
In the overall analysis, the control therapies included chemical sclerosants and other local therapies such as indwelling pleural catheters, thoracoscopic mechanical pleurodesis, and drainage alone. Therefore, we divided the control groups into five arms and performed subgroup analysis: bleomycin, tetracycline, povidone iodine, indwelling pleural catheters, and the others. Our results supported that the RR of successful pleurodesis favors talc pleurodesis other than bleomycin pleurodesis, but not any other control therapies. Among total 6 studies comparing talc and The tumor type involved in the pleural surfaces may influence the success rate of pleurodesis [6]. Therefore, we conducted an analysis according to different study population. In the 4 studies which only included MPE patients with breast cancer, talc pleurodesis was more effective (RR 1.42; 95% CI 1.02-1.46; p = 0.035). However, in 11 studies which included MPE patients with breast cancer or other cancers, the success rate was similar. These results might suggest the superiority of talc pleurodesis for patients with MPE secondary to breast cancer. But the present study is not an individual patient data meta-analysis and the data is small. Further controlled studies are needed to confirm the influence of tumor type on the outcome of talc pleurodesis.
The current British Thoracic Society guideline [5] advocated talc pleurodesis as first-line therapy for MPE, with indwelling pleural catheters reserved for second-line treatment or for those without complete lung reexpansion. Intermittent external drainage through indwelling pleural catheters is gaining popularity, because indwelling pleural catheters can be inserted as an outpatient procedure and offer rapid relief of dyspnea through ambulatory drainage of MPE [53,54]. The results of this meta-analysis demonstrated that both talc pleurodesis and indwelling catheters were effective initial treatments for controlling MPE with similar success. There might be the other advantages to the use of indwelling pleural catheters, such as reduced hospital stay and decreased requirement for further pleural procedures [3,52], this procedure could therefore be alternative to talc pleurodesis, especially talc slurry pleurodesis.
Although talc has been used as sclerosing agents for a long time, not everyone accepted talc pleurodesis for treating MPE because of its complications [10,12]. Talc causes a severe chemical pleurisy resulting in effective pleurodesis, but can also worsen pain and dyspnea in these patients and can result in respiratory failure [1,6]. Other complications associated with talc pleurodesis include fever, acute pneumonitis, and empyema. However, only a few side effects or complications were reported in the included studies. Based on the limited data, we found no significant difference in incidence of fever, pain, emphysema, and wound infection between talc pleurodesis and control therapies. Unfortunately, no required data could be obtained from the included studies for pooled analyzing the incidence of respiratory failure and the other complications. Totally, compared with control therapies, talc pleurodesis is safe and more effective in managing MPE.
Importantly, it should be kept in mind that the goal of local palliative treatment is not survival but the prevention of MPE re-accumulation and relief of symptoms in patients' last months. When making choice in clinical practice, one should take into account the economic cost, patients' performance status and their preference, etc.
Several limitations of this present meta-analysis should be mentioned. First, this meta-analysis was based on the published literature, not on individual patient data. Meta-analysis based on published data tends to overestimate treatment effects compared with individual patient data analysis. The results of our metaanalysis must therefore be interpreted cautiously, since an  Table 2. Comparision of success rate between talc pleurodesis and control therapies at 1 month and longer than 1 month.   individual patient data-based meta-analysis would give more reliable estimation than one based on abstracted data [55]. Second, most studies were small and had limitations, including that none was blind designed, and the overall quality of all studies was not very good. On the other hand, the nature of the interventions used for MPE management means that blinding was not possible. Third, heterogeneity among trials may be another limitation of our meta-analysis, even though we applied a randomeffects model that takes possible heterogeneity into consideration. Fourth, publication bias is a significant threat to the validity of the results, which indeed existed in the present meta-analysis. Exclusion of conference abstracts, letters to the editors and non-English language studies may have led to publication bias. Since the remaining lifespan of patients with MPE is very limited, the goal of MPE treatment should be rapid and durable relief of symptoms. The ideal therapy should be simple, safe, well tolerated, of lifelong success, and with minimal recurrence rate.
The current evidence supported a benefit for talc pleurodesis in the treatment of patients with MPE. Thoracoscopic talc pleurodesis was highly effective and clearly superior to the other control therapies, especially bleomycin instillation, and especially for a longer term management of MPE.

Supporting Information
Checklist S1 A PRISMA checklist for this meta-analysis.