Malignant pleural effusion is a major problem as- sociated with primary and metastatic pleural malignan- cies, seen in approximately 50% of patients.1,2 After ...
Surg Today (2005) 35:634–638 DOI 10.1007/s00595-005-2996-5
Management of Recurrent Malignant Pleural Effusion with Chemical Pleurodesis Dalokay Kilic1, Hadi Akay2, S¸evket Kavukçu2, Hakan Kutlay2, Ayten Kayi Cangir2, Serkan Enön2, and Cem Kadilar3 1 Department of Thoracic Surgery, Bas¸kent University School of Medicine, Bas¸kent University Hospital, Dadaloglu Mah. Serin Evler 39. Sokak No: 6, 01250, Yuregir Adana, Turkey 2 Department of Thoracic Surgery, Ankara University School of Medicine, Ankara, Turkey 3 Department of Statistics, Hacettepe University, Ankara, Turkey
Abstract Purpose. Malignant pleural effusion is a common complication of primary and metastatic pleural malignancies. It is usually managed by drainage and pleurodesis, but there is no consensus as to the best method of pleurodesis. We compared the effectiveness, side effects, and cost of different chemical pleurodesis agents used in patients with malignant pleural effusion. Methods. Between January 1990 and December 2001, 108 patients with malignant pleural effusion underwent chemical pleurodesis in our department. Thoracoscopy was performed in 64 patients (59%), a minithoracotomy in 18 (17%), tube thoracostomy in 11 (10%), and a small-bore catheter was inserted in 15 (14%). Talc was used in 68 (63%) patients, tetracycline in 26 (24%), and bleomycin in 14 (13%). Talc was instilled by insufflation during surgery after drainage, whereas tetracycline and bleomycin were instilled via tube or catheter for pleural analgesia. Results. Talc resulted in significantly earlier tube and catheter removal, after an average 4.1 days versus 5.1 days after tetracyline, and 6.3 days after bleomycin (P = 0.026, P = 0.001, respectively). A significantly lower reaccumulation ratio in 90 days was achieved by the talc group, with nine (13.2%) patients, representing an 86.8% success rate, than in the tetracyline and bleomycin groups, with seven (26.7%) and five (35.7%) patients, respectively, representing 73.8% and 64.3% success rates (P = 0.04). Conclusions. Talc resulted in the earliest expansion, minimal drainage, and the earliest tube and catheter removal. Key words Malignant pleural effusion · Chemical pleurodesis · Talc · Tetracycline · Bleomycin
Reprint requests to: D. Kilic Received: September 9, 2003 / Accepted: November 16, 2004
Introduction Malignant pleural effusion is a major problem associated with primary and metastatic pleural malignancies, seen in approximately 50% of patients.1,2 After the detection of pleural effusion, mean survival is only 3–12 months;3,4 therefore, the main goals of treatment for pleural effusion are to decrease symptoms and improve quality of life. The most common approaches are pleural effusion drainage and pleurodesis. For symptomatic and recurrent pleural effusion, drainage can be achieved by many different methods, including thoracentesis, small-bore catheter (SBC), tube thoracostomy, and video-assisted thoracoscopic surgery (VATS), all of which can be used for diagnosis as well as for treatment. After drainage, obliteration of the pleural space is achieved by either chemical or biological sclerosing agents. However, there is still much controversy about which method of pleurodesis is most effective. Thus, we compared different chemical pleurodesis agents in a study of 108 patients with malignant pleural effusion.
Patients and Methods Patient Characteristics We retrospectively reviewed the data of 108 patients who underwent chemical pleurodesis for malignant pleural effusion in the Department of Thoracic Surgery, Ankara University School of Medicine, between January 1990 and December 2001. There were 69 (64%) men and 39 (36%) women, with a mean age of 53.6 years (range, 28 to 82 years). The surgical methods were thoracoscopy in 64 patients (59%), minithoracotomy in 18 (17%), insertion of an SBC in 5 (14%), and tube thoracostomy in 10 (10%). Talc was the agent of choice in 68 (63%) patients, whereas tetracycline was used in
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D. Kilic et al.: Chemical Pleurodesis in Pleural Effusion Table 1. Comparison of three sclerosing agents used to achieve pleurodesis in patients with malignant pleural effusions Sclerosing agents
No. of patients (dose)
Chest tube or catheter removal (days, mean ± SD)
Success rate (%) (in 90 days)
Talc
68 (5 g)
4.1 ± 1.8
87
Tetracycline
26 (20 mg/kg)
5.1 ± 2.2
74
Bleomycin
14 (1 IU/kg)
6.3 ± 1.3
64
26 (24%) and bleomycin was used in 14 (13%) (Table 1). Methods of Pleurodesis After drainage, 5 g talc (without asbestos fibers) sterilized by gamma rays was applied by insufflation during surgery. Tetracycline (oxytetracycline) and bleomycin were instilled after pleural drainage. Full expansion of the lungs and less than 150 ml of daily drainage were achieved. Before tetracycline administration, 1% lidocaine (3 ml/kg) in 30 ml 0.9% NaCl was instilled into the intrapleural cavity via the thoracostomy tube (24F–32F) or a SBC (Pleuracan catheter, 8F, B. Braun, Melsungen, Germany) to achieve pleural analgesia. The tube or catheter was clamped for 15 min, and then tetracycline, 20 mg/kg in 30 ml 0.9% NaCl, was instilled and the tube or catheter was clamped for another 2–4 h. The same pleural analgesia was given before bleomycin administration. Bleomycin was instilled at 1 IU/kg (average 60 IU) in 100 ml 0.9 NaCl through the tube or catheter, which was clamped for 2 h. The drainage system was removed when the daily drainage was less than 100 ml. Statistical Analysis Statistical comparisons of baseline data between groups were performed by c-squared, Fisher’s exact, or analysis of variance (ANOVA) tests, as appropriate. A P value of less than 0.05 was considered significant. All statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS, version 11.0, Chicago, IL, USA).
Results The malignant diseases underlying the pleural effusion were malignant mesothelioma in 59 (65%) patients, bronchial carcinoma metastasis in 21 (19.4%), breast carcinoma metastasis in 12 (11.1%), thyroid carcinoma metastasis in 2 (1.8%), malignant melanoma metastasis
Adverse effects (%)
Cost ($) (per application)
Fever 7.3 Chest pain 1.4 Chest Pain 19.2 Fever 23 Fever 14
19 10 400
in 2 (1.8%), and renal cell carcinoma metastasis in 1 (0.9%). The complications included fever in 14 (12.9%) patients, postoperative prolonged air leak in 7 (6.4%), subcutaneous emphysema in 2 (1.8%), and empyema in 3 (2.7%). There were five (4.6%) deaths, caused by pulmonary embolism in two patients, cardiac insufficiency in two, and myocardial infarction in one. The shortest thoracostomy tube and catheter discontinuation time was achieved with talc (average, 4.1 ± 1.8 days), followed by oxytetracycline (mean ± SD, 5.1 ± 2.2 days; P = 0.026), and then bleomycin (average, 6.3 ± 1.3 days; P = 0.001) (Table 1). Pleural fluid reaccumulated within 90 days in nine (13.2%) patients in the talc group, representing an 86.8% success rate, in seven (26.7%) patients in the oxytetracyline group, representing a 73.8% success rate, and in five patients (35.7%) in the bleomycin group, representing a 64.3% success rate (Table 1). Talc was more effective than tetracyline or bleomycin (P = 0.034). After talc administration, fever developed in five (7.3%) patients, chest pain in three (4.4%), and pneumonia in one (1.4%). After tetracycline administration, fever developed in six (23%) patients, and chest pain in five (19.2%). After bleomycin administration fever developed in three (21.4%) patients. Tetracyline was associated with a higher incidence of fever and chest pain than the other two agents.
Discussion Malignant pleural effusion occurs secondary to obstruction and disruption of the lymphatic vessels by malignant cells. Vascular endothelial growth factor (VEGF), a potent angiogenic mediator and promotor of endothelial permeability, is produced in large amounts by diseased pleural tissue and is thought to play a role in the formation of malignant effusions and local tumor growth.3,4 The prognosis associated with malignant pleural effusion is generally poor, the expected survival after its detection being only months. In some series, the 30-day mortality was 29%–50%.5,6 Thus, the aim of treatment
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for malignant pleural effusion should be to alleviate symptoms and improve quality of life. The most common methods of treatment are pleural effusion drainage and pleurodesis. Drainage is achieved by thoracentesis, SBC, tube thoracostomy, or VATS, which are also used for diagnosis. Alternatively, pleuroperitoneal shunt and pleurectomy, or other surgical approaches, can be used for drainage. After drainage, reaccumulation is prevented by causing the parietal and visceral pleural surfaces to adhere together, using chemical and biological sclerosing agents or mechanical abrasion. If the cause of malignant effusion is established by a percutaneous biopsy or cytopathological investigation of the pleural fluid, directly proceeding with pleurodesis through the tube thoracostomy or SBC would be more appropriate than performing VATS or thoracotomy. Treatment with drainage and a sclerosing agent via a thoracostomy tube was first described in 1976 by Adler and Sayek.7 Initially, large-bore tubes of 24F or 32F were used, but it soon became apparent that smaller tubes (8–14F) and catheters were more comfortable for the patient. Moreover, studies on the use of large- and small-bore tubes did not show any difference in effectiveness against pleurodesis.8 If the underlying cause of the effusion has not been diagnosed, thoracoscopy can be used for drainage with the intraoperative application of a sclerosing agent.9–11 In our series, 15 (14%) patients with a definitive diagnosis underwent drainage and pleurodesis with SBC and 11 (10%) underwent tube thoracostomy. It is important to time the application of the sclerosing agent well. The most important factor for pleural adhesion is reexpansion of the lung, and the success of pleurodesis depends on complete reexpansion of the lung. Optimal pleurodesis is achieved when the daily drainage is less than 150 ml/day, although it has been claimed that the daily drainage amount is not as important as full expansion of the lung.1 In our series, the sclerosing agent was applied after full expansion of the lung was achieved, except when talc was applied intraoperatively. Because a previous study found that the patient’s rotation in bed after application of the agent for pleurodesis did not affect the success rate,12 we did not place our patients in any particular position after pleurodesis. The sclerosing agent is instilled after clamping the drainage tube, and it is generally suggested that the intercostal tube and the catheter be removed 72 h later when the drainage amount has decreased to an acceptable level.1 In our study, the tubes were unclamped about 3 h after the agent application, and removed an average of 4.7 days later, when the drainage was less than 100 ml/day. Chemical pleurodesis with sclerosing agents and mechanical pleurodesis with abrasion and a pleuroperitoneal shunt are the most widely used methods of
D. Kilic et al.: Chemical Pleurodesis in Pleural Effusion
pleurodesis. The effectiveness of chemical pleurodesis in patients with recurrent, symptomatic malignant pleural effusions has been proven by many studies and is now widely accepted, but there is still much discussion about the best agent to be used. It is very difficult to compare the effectiveness of these agents because of the different application techniques used, the different criteria for success, and the high rate of disease progression resulting in death within 90 days. The ideal sclerosing agent should have a high rate of success, with minimal side effects. The cost of the agent is another important factor that must be taken into consideration. Currently, talc, tetracycline, and bleomycin are the most commonly used sclerosing agents. Talc was the first agent to be used for pleurodesis, originally described by Bethune in 1935, who applied talc for pleural adhesion after a lobectomy.10 Talc is composed of magnesium wrapped in salicylate (Mg3Si4O10 [OH]).13 In nature, it is found mixed with asbestos, but today asbestos-free talc is applied through a thoracostomy tube as a solution, or insufflated during surgery, in the amount of 5 g on average (2–10 g). Walker et al.14 reported success in 93% (153/165) of patients with malignant pleural effusion. Viallat et al.10 reported a 79% success rate in patients with malignant mesothelioma and an 89% success rate in patients with other malignancies underlying pleural metastasis. In our study, the success rates with talc insufflation by VATS were 81% in patients with pleural malignant mesothelioma and 91% in those with other malignancies, defined by a reacculumation ratio in 90 days of 19% (6/31) and 9% (2/24), respectively. A negative correlation between the success rate of pleurodesis and the stage of malignant mesothelioma was also observed in these patients (P = 0.001, Fig. 1).15
Fig. 1. There was a negative correlation between the success rate of talc pleurodesis by video-assisted thorocoscopic surgery and the stage of malignant mesothelioma (P = 0.001). Group 1, no recurrent pleural effusion in 90 days; group 2, recurrent pleural effusion in 90 days
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D. Kilic et al.: Chemical Pleurodesis in Pleural Effusion
Kennedy et al.9 reported an 81% success rate with pleurodesis using talc solution. According to some studies, talc is more effective and has fewer side effects when used as slurry,9 but recent studies did not demonstrate any difference between the two methods.16 In our study, 5 g of asbestos-free talc was instilled by insufflation, achieving a success rate of 87%. Talc was generally well tolerated, the most common side effects being pleuritic fever (16%) and chest pain (7%).14 Acute talc pneumonia followed by adult respiratory distress syndrome (ARDS) is a rare but potentially fatal complication, the incidence of which is not affected by the method of application.9 York et al.17 used talc slurry in 125 patients, and 8 patients suffered talc pneumonia, which progressed to ARDS in 5. Even though the mechanism of acute pneumonia is not fully understood, it is hypothesized that the talc is absorbed into the systemic circulation along with inflammatory mediators.18–20 Some studies point to a relationship between talc pneumonia and subsequent ARDS when doses >10 g of talc are used.21 However, a study on rats showed that dissemination of particles from the pleura to other organs was not dose-dependent.22 Pulmonary edema and cerebral microembolism have also been reported following talc administration,14 but these complications were not seen in our study. Moreover, we found that talc resulted in the earliest expansion, minimal drainage, and the earliest tube or catheter removal, followed by tetracyline and then bleomycin (Table 1). Talc, when compared with the other sclerosing agents, is less expensive and has a higher success rate. Thus, it stands out as the most ideal agent. Tetracycline hydrochloride is a very commonly used agent in chemical pleurodesis. Tetracycline acts directly, in a similar fashion to the growth factor secreted by fibroblasts. It also acts indirectly by stimulating pleural macrophages, which in turn activate the pleural mesothelial cells. Tetracycline can be instilled through an SBC or tube thoracostomy. No significant difference in success was found between a single application and multiple applications.23 Therefore, we used a single application. The most common side effects are chest pain and fever.14 In our series, tetracycline caused chest pain in 19.2% and fever in 23% of patients. Pleurodesis has an overall favorable success rate. In a study of 356 patients with pleurodesis achieved by tetracycline, 240 (67%) did not suffer pleural fluid recurrence.24 In our series, the success rate was 74%. Thus, even though tetracyline had a lower success rate than talc, it had the advantage of better patient mobilization and comfort, as well as of being administered through an SBC because of its solubility. Bleomycin, an antineoplastic agent, is used in pleurodesis as a sclerosing agent. The precise mechanism of action of bleomycin and other antineoplastic
agents is not fully understood, but the optimal dose is 1 IU/kg (average 60 IU). In a study on 199 patients with malignant pleural effusion, bleomycin achieved a 54% (108 patients) complete response rate.14 In the same study, 24% of patients had chest pain, 24% had fever, and 11% suffered nausea. Hemoptysis, rashes, and diarrhea were also reported. Other rare side effects of bleomycin include alopecia and pulmonary fibrosis. In our series, fever developed in 23% of the patients given bleomycin. Diacon et al.19 compared bleomycin with talc poudrage. The response to bleomycin was 59%, whereas it was 87% for talc poudrage.19 In our study, the success rate for bleomycin was 64%, which was lower than that for talc or tetracyline. The disadvantages of bleomycin are its lower success rate and higher cost compared with tetracycline and talc (Table 1). Other agents tested for use for pleurodesis include cisplatin, cytarabine, doxorubicin, 5-FU, b-interferon, mitomycin C, and Corynebacterium parvum; however, these agents are not commonly used because of their high cost, adverse effects, and low efficacy.14,25 Chemical pleurodesis is not effective against malignant pleural effusion in patients with thickened visceral pleural, which stops the lungs from fully expanding (trapped lung). For these patients, a pleuro-peritoneal shunt is a better palliative choice.26–28 We have placed pleuroperitoneal shunts in seven patients, all with success. In conclusion, chemical pleurodesis is a widely accepted method of treatment for recurrent, symptomatic malignant pleural effusion. The agent of choice should be safe, easy to apply, readily available, inexpensive, and associated with a high rate of success. Bleomycin is not commonly used because of its high cost and lower success rate. Tetracyline has a lower success rate than talc, but it has the advantage of better patient mobilization and comfort, with easy application through an SBC because of its solubility. Talc has a higher success rate than the other agents and is less expensive.
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