409
50
Pleural Sclerosis for Malignant Pleural Effusion: Optimal Sclerosing Agent
Zane T. Hammoud and Kenneth A. Kesler
egy to achieve pleurodesis. If there is evidence to support the superiority of one strategy over other strategies, then it may be possible to achieve stan- dardization of the treatment of symptomatic malignant pleural effusions. The aim of this chapter is to determine the optimal sclerosing agent as well as to determine the optimal tech- nique to achieve successful pleurodesis in the palliative treatment of symptomatic malignant pleural effusions based on current evidence.
50.1. Sclerosing Agents
50.1.1. Talc
Talc is considered to be one of the most success- ful sclerosing agents that achieves pleurodesis.
A recent survey of pulmonologists from fi ve English-speaking countries found talc to be the sclerosing agent of choice in 68% of respondents.2 Talc is a soft anhydrous compound mainly com- posed of magnesium silicate and contains parti- cles of varying size. Talc can be aerosolized into the pleural space as a powder or instilled as a slurry. While the precise mechanism by which talc induces pleural sclerosis is unclear, there is evidence to suggest that basic fi broblast growth factor plays an important role in this process.3
50.1.2. Bleomycin
Bleomycin is an anti-neoplastic antibiotic used to treat head and neck, cervical, and germ cell malignancies. As an anti-neoplastic agent, bleo- mycin has well-known pulmonary and cutaneous Malignant pleural effusions are frequent sequelae
of metastatic cancer. Approximately half of all patients with metastatic cancer will develop a pleural effusion, with lung and breast cancer accounting for 75% of cases.1 The development of a malignant pleural effusion often leads to symp- toms, such as dyspnea and cough, which signifi - cantly reduce the quality of life. Unfortunately, most malignant effusions do not respond to sys- temic therapy, thereby necessitating other forms of treatment when symptomatic. Currently the main options for the palliative treatment of symptomatic malignant pleural effusion include repeated thoracenteses, placement of indwelling pleural catheters, and pleurodesis. Repeated tho- racenteses and indwelling pleural catheters are reasonable options for patients with very short life expectancies. Over time, repeated thoracen- teses are inconvenient and the patient must tolerate recurrent symptoms as the fl uid re- accumulates. Indwelling pleural catheters mini- mize the recurrence of symptoms but can be burdensome to patients.
Pleurodesis is a treatment with the goal of pro- ducing fi brosis between the visceral and parietal pleura, thereby obliterating the pleural space.
If successful, pleurodesis prevents the re- accumulation of the effusion with permanent relief of symptoms. A variety of techniques have been used to achieve pleurodesis. Most com- monly, a chemical sclerosant is instilled into the pleural space during thoracoscopy or through an indwelling tube thoracostomy. A number of pro- spective and retrospective clinical studies have been undertaken to determine the optimal strat-
toxicities, which limits total intravenous dosage.
Bleomycin has been successfully utilized as a pleural sclerosing agent for many years.
50.1.3. Tetracycline (Doxycycline)
Tetracycline is a broad spectrum antibiotic derived from Streptomyces. The parenteral form of the drug is no longer commercially available in United States, thereby precluding its use as a sclerosing agent. Doxycycline, a close pharmaco- logical relative, has been used as an alternative agent with similar effi cacy.
50.1.4. Other Agents
Silver nitrate was one of the fi rst agents described for pleural sclerosis, abandoned for unclear reasons. There are recent reports of silver nitrate being reintroduced as a sclerosing agent.4 Pas- choalini and colleagues, in a prospective, ran- domized trial, found 0.5% silver nitrate to be at least equally effi cacious to talc slurry for produc- ing a pleurodesis.5 OK-432 is a preparation of Streptococcus pyogenes that is widely used for pleural sclerosis in Japan, where talc is not com- mercially available.6 Mitoxantrone is a synthetic anti-neoplastic drug that has been used for pleural sclerosis in patients with malignant effu- sion secondary to ovarian cancer.7 Other rarely employed agents include interferon α and quinacrine.4,8
50.2. Choice of Sclerosing Agent
Chemical sclerosing agents have been the subject of many reports. The agents most frequently studied have been talc, either in powder or slurry form, bleomycin, and tetracycline or tetracycline derivatives. In a prospective, randomized trial involving 29 patients, Zimmer and colleagues9 reported no statistically signifi cant difference in the control of malignant effusions between talc slurry and bleomycin. At a mean follow-up of 1.7 months, control of effusion, defi ned as no evi- dence of fl uid re-accumulation by routine chest radiograph, was achieved in 79% of patients receiving bleomycin and in 90% of those receiv- ing talc. These authors concluded that talc, in
slurry form, is the agent of choice, due only to a signifi cant cost advantage over bleomycin. Diacon and colleagues10 reported the results of a prospec- tive, randomized trial comparing talc aerosol- ized under thoracoscopic guidance versus bleomycin instillation. In this study involving 31 patients, talc was superior with respect to reduc- ing the recurrent effusion rates. After 180 days, 65% of patients who underwent pleurodesis with bleomycin recurred compared to only 13% of patients who received talc. After a preliminary interval of 30 days the two agents had similar effi cacy however. Haddad and coworkers11 found no signifi cant difference in success rate between talc slurry and bleomycin instilled through an indwelling chest catheter in a prospective, ran- domized trial of 71 patients after a median follow- up of 2.5 months. These authors also however recommend the use of talc slurry on the basis of lower costs.
Tetracycline, and its derivative doxycycline, has been compared to other sclerosing agents.
Martinez-Moragon and colleagues12 reported no difference in successful pleurodesis between tet- racycline and bleomycin in a randomized, con- trolled trial of 62 patients with malignant pleural effusion. In a prospective, randomized trial of bleomycin versus doxycycline for pleurodesis, Patz and coworkers13 found no signifi cant differ- ence in effi cacy between the two agents in a total of 58 evaluable patients after 30 days of follow-up.
Hartman and associates14 reported their results of aerosolized talc under thoracoscopic guidance compared with historical controls treated with either tetracycline or bleomycin. These authors found talc to be superior to the other two agents for control of malignant pleural effusions.
A recently published Cochrane Database review attempted to establish the optimal scle- rosing agent as well as the optimal technique to accomplish pleurodesis in the treatment of malig- nant pleural effusion.15 This review encompassed a total of 36 randomized, controlled trials, which enrolled 1499 patients. In 10 trials, comprising 308 patients, talc was compared to other agents.
Overall, talc was found to be the more effective sclerosing agent, with a relative risk to achieve successful pleurodesis of 1.34 [95% confi dence interval (95% CI), 1.16–1.55). Five of these 10 trials compared talc to bleomycin, with a relative
risk of 1.23 (95% CI, 1.00–1.50) favoring talc.
Three of the trials studied talc and tetracycline or doxycycline, which again favored talc at a rela- tive risk for success of 1.32 (95% CI, 1.01–1.72).
Bleomycin was evaluated against other sclerosing agents in a total of 18 trials comprising 718 patients. There was no overall benefi t of utilizing bleomycin compared to any other agent. Specifi - cally, bleomycin was compared to tetracycline or doxycycline in eight trials, with the relative risk for successful pleurodesis of 1.03 (95% CI, 0.89–
1.20). Tetracycline or doxycycline was compared to several other agents in 18 trials. The relative risk of successful pleurodesis was 0.98 (95% CI, 0.88–1.09), suggesting that tetracycline or its derivative were also not superior to any other agents studied.
Although talc has been shown to be an effec- tive sclerosing agent, concern has been raised regarding safety. Reports of respiratory failure secondary to adult respiratory distress syndrome after talc administration have led some authors to voice caution.16–18 The exact incidence of this complication is unknown but appears to be uncommon, with most reports citing rates below 3%. There is also evidence to suggest that the risk of pulmonary complications is dose related (>5g) and related to smaller talc particles (<15µm).19 Long-term side effects20 are not relevant to the vast majority of patients with malignant pleural effusion and limited life expectancy.
50.3. Technique of Pleurodesis
The Cochrane Database review also attempted to determine the optimal technique of achieving pleurodesis by analyzing studies that compared delivery of a sclerosing agent during operative thoracoscopy to bedside instillation through an indwelling thoracostomy tube. Overall, a total of fi ve studies were included. The relative risk of successful pleurodesis favored thoracoscopic delivery, with a ratio of 1.68 (95% CI, 1.35–2.10).
Of these fi ve studies, two, with a total of 112 patients, used talc in both arms. The pooled esti- mate of these two studies favored talc aerosolized under thoracoscopic guidance with a success ratio of 1.19 (95% CI, 1.04–1.36). Moreover, there was no difference in mortality or morbidity
between thoracoscopic and bedside talc pleurodesis.
A multi-institutional cooperative trial led by the Cancer and Leukemia Group B (CALGB) ran- domized 501 patients with malignant pleural effusion to receive talc aerosolized under thora- coscopic guidance or talc slurry instilled at bedside through a thoracostomy tube.16 In this large trial, there was no statistical difference in the rate of successful pleurodesis between the two treatment approaches at 30 days. In subset analysis however, the thoracoscopic approach was signifi cantly favored in the group of patients who demonstrated >90% lung re-expansion as well as patients with effusions secondary to breast or lung cancer. Among patients who were avail- able for 30-day follow-up and who had >90%
lung re-expansion, the thoracoscopic approach achieved successful pleurodesis in 82% while talc slurry achieved successful pleurodesis in only 67% (p = 0.02). A report by Yim and colleagues21 randomized 57 patients with good performance status and symptomatic malignant pleural effu- sions to thoracoscopic talc insuffl ation versus talc slurry instilled through tube thoracostomy.
This study found no statistical difference in the rate of recurrent effusion at a mean follow-up of 10 months, with recurrence in 1 of 28 patients after thoracoscopy and in 3 of 29 patients after talc slurry.
Viallat and coworkers22 reported on their expe- rience with thoracoscopic talc insuffl ation in a review of 360 cases. Of the 327 patients who could be assessed at 1 month, 90.2% had successful pleurodesis. Furthermore, 265 of these patients were followed up to 12 months. In this group of patients with longer follow-up 82.1% continued to demonstrate no evidence of recurrent effusion.
Although no other agent or technique was studied, these authors recommended thoraco- scopic insuffl ation over talc slurry on the basis of the excellent long-term results achieved in their series. In another large single-institution series of patients undergoing thoracoscopic talc instil- lation, Cardillo and colleagues23 reported suc- cessful pleurodesis in 92.7% of patients available for long-term follow-up. The total number of patients in this study was 690, 611 of whom had a malignant effusion. These authors also recom- mended the thoracoscopic approach due to
effi cacy and safety. Level of evidence 1 studies for pleurodesis strategy in the treatment of malig- nant pleural effusions are given in Table 50.1.
Table 50.2 lists studies with other levels of evidence.
50.4. Conclusions
Based on current evidence, talc is the sclerosing agent of choice for the treatment of symptomatic malignant pleural effusion (level of evidence 1;
recommendation grade A). Talc is widely avail- able, inexpensive, and highly effective. There have, however, been pulmonary complications reported including deaths secondary to respira- tory failure. Such toxicity appears uncommon and possibly can be avoided by using talc doses under 5 g and talc preparations with large parti- cle size.
adhesions, resulting in maximal lung re- expansion. Under thoracoscopic guidance, talc can be evenly distributed over the entire visceral and parietal pleural surfaces. These features of thoracoscopy can only serve to increase the chance of successful pleurodesis and are diffi cult if not impossible to duplicate by other methods.
Therefore, a patient with the diagnosis of a malig- nant pleural effusion who is deemed a candidate for pleurodesis should be offered thoracoscopic insuffl ation of talc to optimize the likelihood of achieving durable symptomatic relief (level of evidence 1; recommendation grade A).
TABLE 50.1. Selected reports with level of evidence 1.
Level of
Author Comparison evidence Shaw15 Various agents 1a Martinez-Moragon12 Tetracycline vs. bleomycin 1b Haddad11 Talc vs. bleomycin 1b Diacon10 Talc vs. bleomycin 1b Zimmer9 Talc vs. bleomycin 1b Patz13 Bleomycin vs. doxycycline 1b Yim21 VATS vs. talc slurry 1b Dresler16 VATS vs. talc slurry 1b Paschoalini5 Silver nitrate vs. talc 1b Source: Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001).
TABLE 50.2. Selected reports with other levels of evidence.
Level of Recommendation Author Subject evidence grade Hartmann14 VATS talc vs. 4 C
tetracycline/
bleomycin
Brega-Massone24 Chemical 4 C pleurodesis
Viallat22 VATS talc 4 C Dikensoy4 Pleurodesis agents 2a B Source: Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001).
Talc is the sclerosing agent of choice for the treatment of symptomatic malignant pleural effusion (level of evidence 1; recommendation grade A).
A patient with a malignant pleural effusion who is deemed a candidate for pleurodesis should be offered thoracoscopic insuffl ation of talc to optimize the likelihood of achieving durable symptomatic relief (level of evidence 1; recommendation grade A).
References
1. American Thoracic Society. Management of malignant pleural effusions. Am J Respir Crit Care Med 2000;162:1987–2001.
2. Lee YCG, Baumann MH, Maskell NA, et al.
Pleurodesis practice for malignant pleural effu- sions in fi ve English-speaking countries. Chest 2003;124:2229–2238.
3. Antony VB, Nasreen N, Mohammed KA, et al. Talc pleurodesis: basic fi broblast growth factor medi- ates pleural fi brosis. Chest 2004;126:1522–1528.
4. Dikensoy O, Light RW. Alternative widely avail- able, inexpensive agents for pleurodesis. Curr Opin Pulm Med 2005;11:340–344.
The optimal method of talc delivery is some- what more controversial. There appears to be suf- fi cient evidence to favor thoracoscopic-guided insuffl ation over bedside instillation through indwelling chest catheters. The use of thoracos- copy facilitates fl uid evacuation, including locu- lated fl uid, and allows lysis of pleural space
5. Paschoalini M, Vargas FS, Marchi E, et al. Pro- spective randomized trial of silver nitrate vs talc slurry in pleurodesis for symptomatic malignant pleural effusions. Chest 2005;128:684–689.
6. Kishi K, Homma S, Sakamoto S, et al. Effi cacious pleurodesis with OK-432 and doxorubicin against malignant pleural effusions. Eur Respir J 2004;24:
263–266.
7. Barbetakis N, Vassiliadis M, Kaplanis K, Valeri R, Tsilikas C. Mitoxantrone pleurodesis to palliate malignant pleural effusion secondary to ovarian cancer. BMC Palliative Care 2004;3:4.
8. Sartori S, Tssinari D, Ceccoti P, et al. Prospective randomized trial of intrapleural bleomycin versus interferon alfa-2b via ultrasound-guided small- bore chest tube in the palliative treatment of malignant pleural effusions. J Clin Oncol 2004;22:
1228–1233.
9. Zimmer PW, Hill M, Casey K, Harvey E, Low DE. Prospective randomized trial of talc slurry vs bleomycin in pleurodesis for symptomatic malignant pleural effusions. Chest 1997;112:430–
434.
10. Diacon AH, Wyser C, Bolliger CT, et al. Prospec- tive randomized comparison of thoracoscopic talc poudrage under local anesthesia versus bleomycin instillation for pleurodesis in malignant pleural effusions. Am J Respir Crit Care Med 2000;162:
1445–1449.
11. Haddad FJ, Younes RN, Gross JL, Deheinzelin D.
Pleurodesis in patients with malignant pleural effusions: talc slurry or bleomycin? Results of a prospective randomized trial. World J Surg 2004;
28:749–754.
12. Martinez-Moragon E, Aparicio J, Rogado MC, Sanchis J, Sanchis F, Gil-Wuay V. Pleurodesis in malignant pleural effusions: a randomized study of tetracycline versus bleomycin. Eur Respir J 1997;10:2380–2383.
13. Patz EF, McAdams HP, Erasmus JJ, et al. Sclero- therapy for malignant pleural effusions: a pro- spective randomized trial of bleomycin vs doxycycline with small-bore catheter drainage.
Chest 1998;113:1305–1311.
14. Hartman DL, Gaither JM, Kesler KA, Mylet DM, Brown J, Mathur PN. Comparison of insuffl ated talc under thoracoscopic guidance with standard tetracycline and bleomycin pleurodesis for control of malignant pleural effusions. J Thorac Cardio- vasc Surg 1993;105:743–748.
15. Shaw P, Agarwal R. Pleurodesis for malignant pleural effusions. The Cochrane Library 2005;2.
16. Dresler CM, Olak J, Herndon JE, et al. Phase III intergroup study of talc poudrage vs talc slurry sclerosis for malignant pleural effusions. Chest 2005;127:909–915.
17. Light RW. Talc should not be used for pleurodesis.
Am J Respir Crit Care Med 2000;162:2024–2026.
18. Rehse DH, Aye RW, Florence MG. Respiratory failure following talc pleurodesis. Am J Surg 1999;177:437–440.
19. Maskell NA, Lee YCG, Gleeson FV, Hedley EL, Pengelly G, Davies RJO. Randomized trials describing lung infl ammation after pleurodesis with talc of varying particle size. Am J Respir Crit Care Med 2004;170:377–382.
20. Lange PJ, Mortensen J, Groth S. Lung function 22–35 years after treatment of idiopathic sponta- neous pneumothorax with talc poudrage or simple drainage. Thorax 1988;43:753–758.
21. Yim APC, Chan ATC, Lee TW, Wan IYP, Ho JKS.
Thoracoscopic talc insuffl ation versus talc slurry for symptomatic malignant pleural effusion. Ann Thorac Surg 1996;62:1655–1658.
22. Viallat JR, Rey F, Astoul P, Boutin C. Thoraco- scopic talc poudrage pleurodesis for malignant effusions: a review of 360 cases. Chest 1996;110:
1387–1393.
23. Cardillo G, Facciolo F, Carbone L, et al. Long-term follow-up of video-assisted talc pleurodesis in malignant recurrent pleural effusions. Eur J Car- diothorac Surg 2002;21:302–306.
24. Brega-Massone PB, Lequaglie C, Magnani B, Ferro F, Cataldo I. Chemical pleurodesis to improve patients’ quality of life in the management of malignant pleural effusions: the 15 year experi- ence of the national cancer institute of Milan. Surg Laparosc Endosc Percutan Tech 2004;14:73–79.
