- Email: [email protected]
Clinical Efficacy and Safety of Thoracoscopic Talc Pleurodesis in Malignant Pleural Effusions
Clinical Efficacy and Safety of Thoracoscopic Talc Pleurodesis in Malignant Pleural Effusions* Steffen Kolschmann; Arndt Ballin, MD; and Adrian Gillissen, MD, PhD
Study objectives: In patients with disseminated neoplastic disease, recurrent pleural effusion is frequently observed. The purpose of this study was to determine the long-term efficacy and safety of pleurodesis by thoracoscopic talc poudrage (TTP) in malignant pleural effusions (MPEs). Methods: We report a consecutive series of 102 patients (45 women, 57 men; 20 to 83 years of age) who underwent medical thoracoscopy and TTP for recurrent MPE between 1999 and 2001. Thoracoscopy was performed utilizing local anesthesia and IV sedation (medical thoracoscopy). For pleurodesis, an average of 8 g of sterile talc powder was used. One hundred eighty-day follow-up was completed for all patients, and outcome measures included time to recurrence of the effusion and survival. Efficacy was judged by clinical examination, chest radiograph, and/or thoracic ultrasound examination. Procedure-related complications were documented. Results: The most common primary neoplasms were lung cancer (n ⴝ 48), breast cancer (n ⴝ 16), and malignant pleural mesothelioma (n ⴝ 10). Twenty-eight patients had other types of tumors, including renal cell carcinoma, ovarian carcinoma, GI tumors, prostate, malignant lymphoma, and unknown primary cancer. At the end of the primary observation period of 180 days, 38 of 46 surviving patients (82.6%) had a successful pleurodesis. Type of primary neoplasm had no significant influence on success rate. The 30-day mortality rate was 16.7% (n ⴝ 17). Survival curves after 180 days showed significant differences, with best survival in mesothelioma and shortest life expectancy in lung cancer (p ⴝ 0.005). Adverse effects included empyema in one case and malignant invasion of the scar. No episode of talc-induced ARDS was observed. Conclusion: Thoracoscopic talc pleurodesis is a safe and effective method to stop recurrent MPEs. Lasting pleural symphysis is obtained. (CHEST 2005; 128:1431–1435) Key words: malignant pleural effusions; talc pleurodesis; thoracoscopy Abbreviations: MPE ⫽ malignant pleural effusion; TTP ⫽ thoracoscopic talc poudrage
pleural effusions (MPEs) are one of M alignant the leading causes of recurrent pleural effusions worldwide, with an estimated annual incidence of 150,000 cases in the United States.1 It occurs regularly in patients with disseminated and advanced neoplastic disease, signaling a reduced life expectancy,2 with median survival after the diagnosis ranging from 3 to 12 months.3 The most common metastatic tumors to the pleura are lung cancer in men and breast cancer in women. Malignant pleural mesothe*From the St. George Medical Center, Robert-Koch-Hospital, Leipzig, Germany. Manuscript received September 1, 2004; revision accepted February 23, 2005. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Steffen Kolschmann, c/o Adrian Gillissen, MD, PhD, St. George Medical Center, Robert-Koch-Hospital, Nikolai-Rumjanzew-Str 100, D-04207 Leipzig, Germany; e-mail: [email protected] www.chestjournal.org
lioma is less common but has a predicted rising incidence and mortality rate.4 Frequent distressing symptoms, like dyspnea and cough, emerging from pleural fluid accumulation diminish life quality substantially in the remaining short life span. Pleurodesis is accepted to provide effective control of recurrent MPE. In contrast, there is no existing consensus on the best way to achieve pleurodesis. Data from an international survey among pulmonologists revealed wide variations in the use of sclerosing agents and pleurodesis practices. Talc is the most commonly used and the most effective sclerosant available for pleurodesis. However, the success rates of thoracoscopic talc poudrage (TTP) vary substantially.5–9 A recent meta-analysis confirmed the superiority of talc as a sclerosing agent.10 Furthermore, reports5,7,11,12 on ARDS following talc pleurodesis have raised concerns about the safety of talc in the last few years. In order to evaluate the safety and efficacy of the procedure, we CHEST / 128 / 3 / SEPTEMBER, 2005
1431
reviewed the clinical outcome of 102 patients who were treated for MPE between January 1999 and 2001 in our institution.
Materials and Methods Patients One hundred two consecutive patients with documented rapidly recurrent MPE (57 men and 45 women; median age, 66 years; age range, 20 to 83 years) who underwent medical thoracoscopy and TTP between January 1999 and December 2001 were included. Only those patients who were judged to be capable of undergoing this procedure were enrolled in the study. The patients with a poor performance status who were unable to care for themselves were excluded from the procedure. Chest radiography and thoracic ultrasound were used to determine the extent of pleural effusion. Thoracentesis was performed prior to thoracoscopy for cytopathologic and microbiological analysis and for symptom relief. Procedure The medical thoracoscopy was done by a pulmonary physician in an endoscopy suite assisted by two trained nurses. Patients were placed in the lateral decubitus position. The patient’s BP, pulse rate, and oxygen saturation were monitored continuously. Supplemental oxygen was given to the patients to maintain oxygen saturation. Lidocaine 2% was used for local anesthesia, and sedation was achieved by a combination of midazolam and fentanyl. We used a 6.5-mm thoracoscope (0° and 30°; Karl Storz; Tuttlingen, Germany) with a single 7-mm trocar. After complete aspiration of all of the remaining fluid, a thorough inspection of the pleural surface was made. The adhesions were taken down with the biopsy forceps, if possible. Biopsy specimens were made for histopathologic examination, if necessary. Under visual control, an average of 8 g of sterile asbestos-free talc (Steritalc; Novatech; France) were distributed onto the pleural surface. After removal of the thoracoscope, a thoracostomy tube (24 Charrie`re) was inserted. Suction (⫺20 cm H2O) was started after 1 h, and the chest tube was left in place until ⬍ 100 mL of fluid was drained in 24 h. Chest radiography was performed the same day after the procedure and before discharge. The tumor type, initial response, and duration of suction treatment were noted. The side effects and procedure-related complications were documented. Outcome Measures Successful pleurodesis was described as an absence of fluid reaccumulation with long-term symptom relief. All of the cases with recurrent symptomatic effusion that needed to be drained were judged as failures, as recommended by the American Thoracic Society.1 The success rate and survival were calculated from the day of the procedure. Follow-up was obtained by periodical clinical examination combined with chest radiography and/or thoracic ultrasound in our own outpatient clinic. In addition, referring practitioners and oncologists were contacted for supplementary outcome information. Follow-up information was available for all of the patients for a period of 180 days, and follow-up continued until a maximum of 1,337 days. The primary end point was symptomatic recurrence of pleural fluid that needed to be drained. 1432
Statistical Analysis Statistical analysis was based on data after 180 days of followup. The success rate and survival curves were calculated using the Kaplan-Meier method. Cases in which patients who had undergone successful pleurodesis and died before day 180 were censored, as well as those in which all patients were alive at day 180 and had undergone successful pleurodesis. The impact of different primary malignancies on the outcome was analyzed using the log-rank test. We compared the three main tumor types: lung cancer, breast cancer, and malignant pleural mesothelioma. Differences were considered significant with p values of ⬍ 0.05.
Results One hundred two patients were treated within the 3-year survey period. The presenting symptom in the majority of patients (86.3%) was dyspnea. Also common was cough (22.5%) and thoracic pain (23.5%) as secondary symptoms. The characteristics of the study population are noted in Table 1. The main tumor types were lung cancer (n ⫽ 48), breast cancer (n ⫽ 16), and malignant pleural mesothelioma (n ⫽ 10), and the remainder was a heterogeneous group of malignancies. Median duration of suction treatment was 6 days (range, 1 to 26 days). The side effects included transient mild fever in 29 cases (28.4%), which required no additional therapy. Thorax pain was present in most of the patients and could be controlled with routine analgesics. Under no circumstances was talc-induced ARDS observed. One patient developed empyema because of a pro-
Table 1—Patient Characteristics* Characteristics
Value
Age, yr Gender Women Men Diagnosis NSCLC SCLC Carcinoma of the breast Malignant pleural mesothelioma Other Ovarian carcinoma Renal cell carcinoma Gastric cancer Colon cancer Pancreatic cancer Granular cell tumor Hodgkin lymphoma Non-Hodgkin lymphoma Prostatic cancer Unknown primary carcinoma
66 (20–83) 45 57 44 (43.1) 4 (3.9) 16 (15.7) 10 (9.8) 28 (27.5) 5 4 3 1 1 3 1 1 1 7
*Values given as median (range) or No. (%). NSCLC ⫽ non-small cell lung cancer; SCLC ⫽ small cell lung cancer. Clinical Investigations
longed time with the chest tube and a contamination of the pleural space. The patient was successfully treated with antibiotics. Malignant invasion of the scar at the drainage site occurred in one case. There were no procedure-related deaths. The 30-day mortality rate was 16.7% (n ⫽ 17). Fifteen of these patients died from rapid progression of their end-stage disease, and 2 patients died from paraneoplastic thromboembolism. Thus, 85 patients could be assessed at 1 month. Seventy-six of them (89.4%) had a positive response with complete effusion control. Table 2 shows the success rates after 30, 90, and 180 days. The tumor type had no significant influence on the success rate (p ⫽ 0.61). When reviewing the nonresponders, high tumor burden of the pleural surface was described in the thoracoscopy reports in 17 cases. Three patients failed to have complete reexpansion of the lung after TTP; one patient experienced empyema following pleurodesis and, subsequently, developed recurrent MPE. In one patient, we had to stop suction treatment after 2 days because of therapy-resistant dry cough. In four patients who were experiencing a rapid reaccumulation of fluid, pleurodesis with repeat TTP was attempted, but without success. Fifty-six patients (54.9%) died within the primary observation period of 6 months. The median duration of follow-up (46 patients) was 361.5 days (range, 181 to 1,337 days). Thirty-five patients had a lasting pleural symphysis until death or the date of last follow-up. Eighteen cases were unavailable for follow-up after day 180. Based on the underlying disease, Figure 1 demonstrates the Kaplan-Meier function of success rate. The analysis of the survival curves after 180 days displayed significant differences between the primary neoplasms (Fig 2). The best survival was seen in mesothelioma, followed by breast cancer, with the shortest life expectancy in lung cancer, both being statistically significant (p ⫽ 0.005 and p ⫽ 0.048, respectively) [Table 3]. No significant difference in 180-day survival was seen when comparing the survival curves of patients with successful pleurodesis vs patients with pleurodesis failure (p ⫽ 0.44).
Table 2—Success Rate* Time After Pleurodesis, d 30 90 180
Values 76/85 (89.4) 49/59 (83.1) 38/46 (82.6)
*Values are given as the No. of patients in whom pleurodesis was successful/No. of patients alive (success rate for patient survival). www.chestjournal.org
Figure 1. Kaplan-Meier function demonstrating time to failure according to primary disease based on the maximum follow-up period (⫹) excluding data for death or end of follow-up without recurrent MPE.
Discussion In symptomatic patients with recurrent MPE of known or unknown etiology, medical thorascopy and TTP is recommended.1,13–15 Talc is superior to other agents in producing pleurodesis,16 but the clinical success rate of TTP varies, and the safety of this procedure is currently being intensively discussed. Therefore, we conducted this analysis in order to address both issues. Unfortunately, the definition of success, as well as the length of follow-up, differs in the literature, which complicates the comparative assessment within studies. In our study, pleurodesis was successful in 82.6% of all of the cases within the follow-up period of 180 days. Three of 22 nonresponders failed to show complete reexpansion of the lung after the procedure; thus, the lungs were judged as trapped. Our findings confirmed the results by Lee et al,5 who reported in an international survey a clinical success rate of 72%. However, the success rates seen in other trials were around 90%,6 –9 which seems to contradict the data reported by Lee et al,5 as well as our own. This difference can be related to the inclusion criteria chosen. Because we did not exclude patients with trapped lungs, a lower success rate was observed. Also, Lee et al5 hypothesized that this apparent discrepancy might be attributable to the strict exclusion criteria in clinical studies (eg, patients with trapped lungs). Success rates seen in CHEST / 128 / 3 / SEPTEMBER, 2005
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Figure 2. Kaplan-Meier function demonstrating 180-day survival according to primary disease (⫹) excluding data for all patients alive at day 180.
everyday clinical practice with more unselected patients are, therefore, likely to be lower.5 In addition, we assessed the long-term efficacy of TTP. The patients surviving the primary observation period of 180 days were additionally observed (median time, 361.5 days). In 35 of 46 patients (76%), permanent pleural symphysis was obtained. Only 24% of patients experienced a recurrence of MPE. When referring a patient with MPE for therapy with TTP, careful selection is essential. In general, the selection criteria for pleurodesis are based on the patient’s performance status and the pleural fluid pH, although the latter is controversial. SanchezArmengol and Rodriguez-Panadero17 found a strong correlation between pleural fluid pH and survival. In
Table 3—Kaplan-Meier Estimates for Survival According to Malignant Disease* Cancer Type
Cumulative Survival Rate
p Value†
Mesothelioma Breast cancer Lung cancer
0.80 0.56 0.29
0.16‡ 0.048§
*Based on data obtained after a primary observation period of 180 days. †Log-rank test. Overall p value of 0.005 for comparison of all three cancer types. ‡Mesothelioma vs breast cancer. §Breast cancer vs lung cancer. 1434
contrast, Heffner et al18 stated in a meta-analysis that pleural fluid pH has insufficient predictive accuracy for selecting patients for pleurodesis. The same authors found in another study19 only a modest predictive value for pleural fluid pH as a predictor of pleurodesis failure. Because of this controversy, we decided to exclude pleural fluid pH quantification from our evaluation. The decision whether to perform TTP in our patients was based on the following criteria: (1) general medical conditions and comorbidity (eg, coagulation disorders and severity of concurrent diseases, such as cardiovascular diseases); and (2) performance status. In our study, patients with poor performance status, which was defined as an incapability to care for themselves, were excluded, which is in accordance with Burrows et al, 3 who found the Karnofsky performance scale score to be predictive for survival. de Campos et al7 stressed the importance of excluding malnourished patients with advanced malignancy and Karnofsky performance scale scores ⱕ 40 from TTP, because they have a very limited life expectancy. We observed a 30-day mortality rate of 16.7% (n ⫽ 17). Fifteen of these patients died from rapid progression of their malignant disorder and should initially have been excluded from the procedure. Additional measures to identify patients with a life expectancy of ⬍ 30 days are needed. In our series, the response to pleurodesis did not predict the survival outcome (p ⫽ 0.44), which is in contrast to those reported in previous investigations,9,20 in which differences in survival between responders and nonresponders were found. As expected from the predicted median survival time (malignant pleural mesothelioma patients, 4 to 18 months; stage IIIB to IV lung cancer patients, 6 to 9 months),21 survival was strongly linked to the primary cancer diagnosis such that the 180-day survival rate was higher in patients with pleural mesothelioma than in those with lung cancer (p ⫽ 0.005). Although TTP was reported to induce ARDS, we did not encounter such complications. The only severe adverse effect that we saw was pleural empyema in one case. This particular patient needed prolonged suction treatment and antibiotic therapy, and, subsequently, experienced a lack of response to pleurodesis. This seems comparable with the literature,7,9,22 in which incidence rates of empyema, ranging from 0 to 4%, have been reported. There are, however, potential limitations to our study. The retrospective study design could have introduced systemic bias, including patients who were unavailable for follow-up. This problem was eliminated by using data that were derived from a 180-day period with complete outcome information for statistical analysis. Furthermore, the quality of Clinical Investigations
life was not documented in the months following the procedure. Successful pleurodesis is linked to marked improvement in dyspnea. However, the patient benefit regarding quality of life still remains to be elucidated. In conclusion, TTP has been proven to provide safe and effective symptom control in rapidly recurrent MPEs. Lasting pleural symphysis is obtained in most cases, avoiding repetitious interventions. Therefore, TTP is a favorable method for palliation therapy in patients with advanced neoplasms due to MPE.
9
10 11 12 13
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References 1 American Thoracic Society. Management of malignant pleural effusions. Am J Respir Crit Care Med 2000; 162:1987– 2001 2 Chernow B, Sahn SA. Carcinomatous involvement of the pleura. Am J Med 1977; 63:695–702 3 Burrows CM, Mathews WC, Colt HG. Predicting survival in patients with recurrent symptomatic malignant pleural effusions. Chest 2000; 117:73–78 4 Peto J, Decarli A, La Vecchia C, et al. The European mesothelioma epidemic. Br J Cancer 1999; 79:666 – 672 5 Lee YCG, Baumann MH, Maskell NA, et al. Pleurodesis practice for malignant pleural effusions in five Englishspeaking countries: survey of pulmonologists. Chest 2003; 124:2229 –2238 6 Cardillo GF, Facciolo F, Carbone L, et al. Long-term follow-up of video-assisted talc pleurodesis in malignant recurrent pleural effusions. Eur J Cardiothorac Surg 2002; 21:302–305 7 de Campos JR, Vargas FS, de Campos Werebe E, et al. Thoracoscopic talc poudrage: a 15-year experience. Chest 2001; 119:801– 806 8 Diacon AH, Wyser C, Bollinger CT, et al. Prospective randomized comparison of thoracoscopic talc poudrage under
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19 20 21 22
local anesthesia versus bleomycin instillation for pleurodesis in malignant pleural effusions. Am J Respir Crit Care Med 2000; 162:1445–1449 Viallat JR, Rey F, Astoul P, et al. Thoracoscopic talc poudrage pleurodesis for malignant effusions: a review of 360 cases. Chest 1996; 110:1387–1393 Shaw P, Agarwal R. Pleurodesis for malignant pleural effusions. Cochrane Database Syst Rev (database online). 2004 Rehse DH, Aye RW, Florence MG. Respiratory failure following talc pleurodesis. Am J Surg 1999; 177:437– 440 Light RW. Talc should not be used for pleurodesis. Am J Respir Crit Care Med 2000; 162:2024 –2026 Ernst A, Silvestri GA, Johnstone D. Interventional pulmonary procedures: guidelines from the American College of Chest Physicians. Chest 2003; 123:1693–1717 Antony VB, Loddenkemper R, Astoul P, et al. Management of malignant pleural effusions. Eur Respir J 2001; 18:402– 419 Antunes G, Neville E, Duffy J, et al. BTS guidelines for the management of malignant pleural effusions. Thorax 2003; 58(suppl):ii29 –ii38 Walker-Renard PB, Vaughan LM, Sahn SA. Chemical pleurodesis for malignant pleural effusions. Ann Intern Med 1994; 120:56 – 64 Sanchez-Armengol A, Rodriguez-Panadero F. Survival and talc pleurodesis in metastatic pleural carcinoma, revisited: report of 125 cases. Chest 1993; 104:1482–1485 Heffner JE, Nietert PJ, Barbieri C. Pleural fluid pH as a predictor of survival for patients with malignant pleural effusions. Chest 2000; 117:79 – 86 Heffner JE, Nietert PJ, Barbieri C. Pleural fluid pH as a predictor of pleurodesis failure: analysis of primary data. Chest 2000; 117:87–95 Love D, White D, Kiroff G. Thoracoscopic talc pleurodesis for malignant pleural effusion. Aust N Z J Surg 2003; 73:19 –22 Steele JP. Prognostic factors in mesothelioma. Semin Oncol 2002; 29:36 – 40 Yim APC, Chung SS, Lee TW, et al. Thoracoscopic management of malignant pleural effusions. Chest 1996; 109:1234 – 1238
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Study objectives: In patients with disseminated neoplastic disease, recurrent pleural effusion is frequently observed. The purpose of this study was to determine the long-term efficacy and safety of pleurodesis by thoracoscopic talc poudrage (TTP) in malignant pleural effusions (MPEs). Methods: We report a consecutive series of 102 patients (45 women, 57 men; 20 to 83 years of age) who underwent medical thoracoscopy and TTP for recurrent MPE between 1999 and 2001. Thoracoscopy was performed utilizing local anesthesia and IV sedation (medical thoracoscopy). For pleurodesis, an average of 8 g of sterile talc powder was used. One hundred eighty-day follow-up was completed for all patients, and outcome measures included time to recurrence of the effusion and survival. Efficacy was judged by clinical examination, chest radiograph, and/or thoracic ultrasound examination. Procedure-related complications were documented. Results: The most common primary neoplasms were lung cancer (n ⴝ 48), breast cancer (n ⴝ 16), and malignant pleural mesothelioma (n ⴝ 10). Twenty-eight patients had other types of tumors, including renal cell carcinoma, ovarian carcinoma, GI tumors, prostate, malignant lymphoma, and unknown primary cancer. At the end of the primary observation period of 180 days, 38 of 46 surviving patients (82.6%) had a successful pleurodesis. Type of primary neoplasm had no significant influence on success rate. The 30-day mortality rate was 16.7% (n ⴝ 17). Survival curves after 180 days showed significant differences, with best survival in mesothelioma and shortest life expectancy in lung cancer (p ⴝ 0.005). Adverse effects included empyema in one case and malignant invasion of the scar. No episode of talc-induced ARDS was observed. Conclusion: Thoracoscopic talc pleurodesis is a safe and effective method to stop recurrent MPEs. Lasting pleural symphysis is obtained. (CHEST 2005; 128:1431–1435) Key words: malignant pleural effusions; talc pleurodesis; thoracoscopy Abbreviations: MPE ⫽ malignant pleural effusion; TTP ⫽ thoracoscopic talc poudrage
pleural effusions (MPEs) are one of M alignant the leading causes of recurrent pleural effusions worldwide, with an estimated annual incidence of 150,000 cases in the United States.1 It occurs regularly in patients with disseminated and advanced neoplastic disease, signaling a reduced life expectancy,2 with median survival after the diagnosis ranging from 3 to 12 months.3 The most common metastatic tumors to the pleura are lung cancer in men and breast cancer in women. Malignant pleural mesothe*From the St. George Medical Center, Robert-Koch-Hospital, Leipzig, Germany. Manuscript received September 1, 2004; revision accepted February 23, 2005. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Steffen Kolschmann, c/o Adrian Gillissen, MD, PhD, St. George Medical Center, Robert-Koch-Hospital, Nikolai-Rumjanzew-Str 100, D-04207 Leipzig, Germany; e-mail: [email protected] www.chestjournal.org
lioma is less common but has a predicted rising incidence and mortality rate.4 Frequent distressing symptoms, like dyspnea and cough, emerging from pleural fluid accumulation diminish life quality substantially in the remaining short life span. Pleurodesis is accepted to provide effective control of recurrent MPE. In contrast, there is no existing consensus on the best way to achieve pleurodesis. Data from an international survey among pulmonologists revealed wide variations in the use of sclerosing agents and pleurodesis practices. Talc is the most commonly used and the most effective sclerosant available for pleurodesis. However, the success rates of thoracoscopic talc poudrage (TTP) vary substantially.5–9 A recent meta-analysis confirmed the superiority of talc as a sclerosing agent.10 Furthermore, reports5,7,11,12 on ARDS following talc pleurodesis have raised concerns about the safety of talc in the last few years. In order to evaluate the safety and efficacy of the procedure, we CHEST / 128 / 3 / SEPTEMBER, 2005
1431
reviewed the clinical outcome of 102 patients who were treated for MPE between January 1999 and 2001 in our institution.
Materials and Methods Patients One hundred two consecutive patients with documented rapidly recurrent MPE (57 men and 45 women; median age, 66 years; age range, 20 to 83 years) who underwent medical thoracoscopy and TTP between January 1999 and December 2001 were included. Only those patients who were judged to be capable of undergoing this procedure were enrolled in the study. The patients with a poor performance status who were unable to care for themselves were excluded from the procedure. Chest radiography and thoracic ultrasound were used to determine the extent of pleural effusion. Thoracentesis was performed prior to thoracoscopy for cytopathologic and microbiological analysis and for symptom relief. Procedure The medical thoracoscopy was done by a pulmonary physician in an endoscopy suite assisted by two trained nurses. Patients were placed in the lateral decubitus position. The patient’s BP, pulse rate, and oxygen saturation were monitored continuously. Supplemental oxygen was given to the patients to maintain oxygen saturation. Lidocaine 2% was used for local anesthesia, and sedation was achieved by a combination of midazolam and fentanyl. We used a 6.5-mm thoracoscope (0° and 30°; Karl Storz; Tuttlingen, Germany) with a single 7-mm trocar. After complete aspiration of all of the remaining fluid, a thorough inspection of the pleural surface was made. The adhesions were taken down with the biopsy forceps, if possible. Biopsy specimens were made for histopathologic examination, if necessary. Under visual control, an average of 8 g of sterile asbestos-free talc (Steritalc; Novatech; France) were distributed onto the pleural surface. After removal of the thoracoscope, a thoracostomy tube (24 Charrie`re) was inserted. Suction (⫺20 cm H2O) was started after 1 h, and the chest tube was left in place until ⬍ 100 mL of fluid was drained in 24 h. Chest radiography was performed the same day after the procedure and before discharge. The tumor type, initial response, and duration of suction treatment were noted. The side effects and procedure-related complications were documented. Outcome Measures Successful pleurodesis was described as an absence of fluid reaccumulation with long-term symptom relief. All of the cases with recurrent symptomatic effusion that needed to be drained were judged as failures, as recommended by the American Thoracic Society.1 The success rate and survival were calculated from the day of the procedure. Follow-up was obtained by periodical clinical examination combined with chest radiography and/or thoracic ultrasound in our own outpatient clinic. In addition, referring practitioners and oncologists were contacted for supplementary outcome information. Follow-up information was available for all of the patients for a period of 180 days, and follow-up continued until a maximum of 1,337 days. The primary end point was symptomatic recurrence of pleural fluid that needed to be drained. 1432
Statistical Analysis Statistical analysis was based on data after 180 days of followup. The success rate and survival curves were calculated using the Kaplan-Meier method. Cases in which patients who had undergone successful pleurodesis and died before day 180 were censored, as well as those in which all patients were alive at day 180 and had undergone successful pleurodesis. The impact of different primary malignancies on the outcome was analyzed using the log-rank test. We compared the three main tumor types: lung cancer, breast cancer, and malignant pleural mesothelioma. Differences were considered significant with p values of ⬍ 0.05.
Results One hundred two patients were treated within the 3-year survey period. The presenting symptom in the majority of patients (86.3%) was dyspnea. Also common was cough (22.5%) and thoracic pain (23.5%) as secondary symptoms. The characteristics of the study population are noted in Table 1. The main tumor types were lung cancer (n ⫽ 48), breast cancer (n ⫽ 16), and malignant pleural mesothelioma (n ⫽ 10), and the remainder was a heterogeneous group of malignancies. Median duration of suction treatment was 6 days (range, 1 to 26 days). The side effects included transient mild fever in 29 cases (28.4%), which required no additional therapy. Thorax pain was present in most of the patients and could be controlled with routine analgesics. Under no circumstances was talc-induced ARDS observed. One patient developed empyema because of a pro-
Table 1—Patient Characteristics* Characteristics
Value
Age, yr Gender Women Men Diagnosis NSCLC SCLC Carcinoma of the breast Malignant pleural mesothelioma Other Ovarian carcinoma Renal cell carcinoma Gastric cancer Colon cancer Pancreatic cancer Granular cell tumor Hodgkin lymphoma Non-Hodgkin lymphoma Prostatic cancer Unknown primary carcinoma
66 (20–83) 45 57 44 (43.1) 4 (3.9) 16 (15.7) 10 (9.8) 28 (27.5) 5 4 3 1 1 3 1 1 1 7
*Values given as median (range) or No. (%). NSCLC ⫽ non-small cell lung cancer; SCLC ⫽ small cell lung cancer. Clinical Investigations
longed time with the chest tube and a contamination of the pleural space. The patient was successfully treated with antibiotics. Malignant invasion of the scar at the drainage site occurred in one case. There were no procedure-related deaths. The 30-day mortality rate was 16.7% (n ⫽ 17). Fifteen of these patients died from rapid progression of their end-stage disease, and 2 patients died from paraneoplastic thromboembolism. Thus, 85 patients could be assessed at 1 month. Seventy-six of them (89.4%) had a positive response with complete effusion control. Table 2 shows the success rates after 30, 90, and 180 days. The tumor type had no significant influence on the success rate (p ⫽ 0.61). When reviewing the nonresponders, high tumor burden of the pleural surface was described in the thoracoscopy reports in 17 cases. Three patients failed to have complete reexpansion of the lung after TTP; one patient experienced empyema following pleurodesis and, subsequently, developed recurrent MPE. In one patient, we had to stop suction treatment after 2 days because of therapy-resistant dry cough. In four patients who were experiencing a rapid reaccumulation of fluid, pleurodesis with repeat TTP was attempted, but without success. Fifty-six patients (54.9%) died within the primary observation period of 6 months. The median duration of follow-up (46 patients) was 361.5 days (range, 181 to 1,337 days). Thirty-five patients had a lasting pleural symphysis until death or the date of last follow-up. Eighteen cases were unavailable for follow-up after day 180. Based on the underlying disease, Figure 1 demonstrates the Kaplan-Meier function of success rate. The analysis of the survival curves after 180 days displayed significant differences between the primary neoplasms (Fig 2). The best survival was seen in mesothelioma, followed by breast cancer, with the shortest life expectancy in lung cancer, both being statistically significant (p ⫽ 0.005 and p ⫽ 0.048, respectively) [Table 3]. No significant difference in 180-day survival was seen when comparing the survival curves of patients with successful pleurodesis vs patients with pleurodesis failure (p ⫽ 0.44).
Table 2—Success Rate* Time After Pleurodesis, d 30 90 180
Values 76/85 (89.4) 49/59 (83.1) 38/46 (82.6)
*Values are given as the No. of patients in whom pleurodesis was successful/No. of patients alive (success rate for patient survival). www.chestjournal.org
Figure 1. Kaplan-Meier function demonstrating time to failure according to primary disease based on the maximum follow-up period (⫹) excluding data for death or end of follow-up without recurrent MPE.
Discussion In symptomatic patients with recurrent MPE of known or unknown etiology, medical thorascopy and TTP is recommended.1,13–15 Talc is superior to other agents in producing pleurodesis,16 but the clinical success rate of TTP varies, and the safety of this procedure is currently being intensively discussed. Therefore, we conducted this analysis in order to address both issues. Unfortunately, the definition of success, as well as the length of follow-up, differs in the literature, which complicates the comparative assessment within studies. In our study, pleurodesis was successful in 82.6% of all of the cases within the follow-up period of 180 days. Three of 22 nonresponders failed to show complete reexpansion of the lung after the procedure; thus, the lungs were judged as trapped. Our findings confirmed the results by Lee et al,5 who reported in an international survey a clinical success rate of 72%. However, the success rates seen in other trials were around 90%,6 –9 which seems to contradict the data reported by Lee et al,5 as well as our own. This difference can be related to the inclusion criteria chosen. Because we did not exclude patients with trapped lungs, a lower success rate was observed. Also, Lee et al5 hypothesized that this apparent discrepancy might be attributable to the strict exclusion criteria in clinical studies (eg, patients with trapped lungs). Success rates seen in CHEST / 128 / 3 / SEPTEMBER, 2005
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Figure 2. Kaplan-Meier function demonstrating 180-day survival according to primary disease (⫹) excluding data for all patients alive at day 180.
everyday clinical practice with more unselected patients are, therefore, likely to be lower.5 In addition, we assessed the long-term efficacy of TTP. The patients surviving the primary observation period of 180 days were additionally observed (median time, 361.5 days). In 35 of 46 patients (76%), permanent pleural symphysis was obtained. Only 24% of patients experienced a recurrence of MPE. When referring a patient with MPE for therapy with TTP, careful selection is essential. In general, the selection criteria for pleurodesis are based on the patient’s performance status and the pleural fluid pH, although the latter is controversial. SanchezArmengol and Rodriguez-Panadero17 found a strong correlation between pleural fluid pH and survival. In
Table 3—Kaplan-Meier Estimates for Survival According to Malignant Disease* Cancer Type
Cumulative Survival Rate
p Value†
Mesothelioma Breast cancer Lung cancer
0.80 0.56 0.29
0.16‡ 0.048§
*Based on data obtained after a primary observation period of 180 days. †Log-rank test. Overall p value of 0.005 for comparison of all three cancer types. ‡Mesothelioma vs breast cancer. §Breast cancer vs lung cancer. 1434
contrast, Heffner et al18 stated in a meta-analysis that pleural fluid pH has insufficient predictive accuracy for selecting patients for pleurodesis. The same authors found in another study19 only a modest predictive value for pleural fluid pH as a predictor of pleurodesis failure. Because of this controversy, we decided to exclude pleural fluid pH quantification from our evaluation. The decision whether to perform TTP in our patients was based on the following criteria: (1) general medical conditions and comorbidity (eg, coagulation disorders and severity of concurrent diseases, such as cardiovascular diseases); and (2) performance status. In our study, patients with poor performance status, which was defined as an incapability to care for themselves, were excluded, which is in accordance with Burrows et al, 3 who found the Karnofsky performance scale score to be predictive for survival. de Campos et al7 stressed the importance of excluding malnourished patients with advanced malignancy and Karnofsky performance scale scores ⱕ 40 from TTP, because they have a very limited life expectancy. We observed a 30-day mortality rate of 16.7% (n ⫽ 17). Fifteen of these patients died from rapid progression of their malignant disorder and should initially have been excluded from the procedure. Additional measures to identify patients with a life expectancy of ⬍ 30 days are needed. In our series, the response to pleurodesis did not predict the survival outcome (p ⫽ 0.44), which is in contrast to those reported in previous investigations,9,20 in which differences in survival between responders and nonresponders were found. As expected from the predicted median survival time (malignant pleural mesothelioma patients, 4 to 18 months; stage IIIB to IV lung cancer patients, 6 to 9 months),21 survival was strongly linked to the primary cancer diagnosis such that the 180-day survival rate was higher in patients with pleural mesothelioma than in those with lung cancer (p ⫽ 0.005). Although TTP was reported to induce ARDS, we did not encounter such complications. The only severe adverse effect that we saw was pleural empyema in one case. This particular patient needed prolonged suction treatment and antibiotic therapy, and, subsequently, experienced a lack of response to pleurodesis. This seems comparable with the literature,7,9,22 in which incidence rates of empyema, ranging from 0 to 4%, have been reported. There are, however, potential limitations to our study. The retrospective study design could have introduced systemic bias, including patients who were unavailable for follow-up. This problem was eliminated by using data that were derived from a 180-day period with complete outcome information for statistical analysis. Furthermore, the quality of Clinical Investigations
life was not documented in the months following the procedure. Successful pleurodesis is linked to marked improvement in dyspnea. However, the patient benefit regarding quality of life still remains to be elucidated. In conclusion, TTP has been proven to provide safe and effective symptom control in rapidly recurrent MPEs. Lasting pleural symphysis is obtained in most cases, avoiding repetitious interventions. Therefore, TTP is a favorable method for palliation therapy in patients with advanced neoplasms due to MPE.
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