The Optimal Treatment of Malignant Pleural Effusions A Continuing Dilemma

Abstract

Malignant pleural effusions are a common and often morbid problem in patients with advanced cancer.1Freidman MA Slater E Malignant pleural effusions.Cancer Treat Rev. 1978; 5: 49-66Abstract Full Text PDF PubMed Scopus (24) Google Scholar The optimal treatment of malignant pleural effusions remains controversial. While nonsclerosing cytotoxic intrapleural chemotherapy has occasionally been used to treat both the effusion and the underlying malignancy,2Rusch VW Figlin R Godwin D Piantadosi S Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial.J Clin Oncol. 1991; 9: 313-319Crossref PubMed Scopus (105) Google Scholar the usual approach is to inject a sclerosing agent into the pleural space after draining the effusion by tube thoracostomy. Tetracycline is the most widely accepted sclerosant, but many other agents have been used, attesting to the fact that no single agent is uniformly satisfactory.3Hausheer FH Yarbro JW Diagnosis and treatment of malignant pleural effusions.Semin Oncol. 1985; 12: 54-75PubMed Google ScholarThe information on pleurodesis for malignant pleural effusions is derived mainly from small retrospective series.4Wallach HW Intrapleural tetracycline for malignant pleural effusions.Chest. 1975; 68: 510-512Crossref PubMed Scopus (84) Google Scholar, 5Jones GR Treatment of recurrent malignant pleural effusion by iodized talc pleurodesis.Thorax. 1969; 24: 69-73Crossref PubMed Scopus (55) Google Scholar, 6Bitran JD Brown C Desser RK Kozloff MF Shapiro C Billings AA Intracavitary bleomycin for the control of malignant effusions.J Surg Oncol. 1981; 16: 273-277Crossref PubMed Scopus (49) Google Scholar The few reported prospective clinical trials leave a great deal to be desired in their study design.7Ostrowski MJ An assessment of the long-term results of controlling the reaccumulation of malignant effusions using intracavitary bleomycin.Cancer. 1986; 57: 721-727Crossref PubMed Scopus (94) Google Scholar, 8Bayly TC Kisner D Sybert A Macdonald JS Tsou E Schein PS Tetracycline and quinacrine in the control of malignant pleural effusions.Cancer. 1978; 41: 1188-1192Crossref PubMed Scopus (81) Google Scholar, 9Zaloznik AJ Oswald SG Langin M Intrapleural tetracycline in malignant pleural effusions.Cancer. 1983; 51: 752-755Crossref PubMed Scopus (76) Google Scholar, 10Tattersall MHN Intracavitary Adriamycin, nitrogen mustard and tetracycline in control of malignant effusions.Med J Aust. 1980; 2: 447-448PubMed Google Scholar Problems with these trials include small numbers of patients; loosely defined eligibility criteria; variable criteria for assessing response; lack of central review of chest radiographs to verify response rates; lack of long-term follow-up; and lack of randomized comparison to other forms of treatment. There has also been considerable variation in the doses and the methods of administration used for sclerosing agents. By and large, published literature in this area serves more to confuse than to enlighten us.In this issue (see page 1528), Ruckdeschel and coauthors report their experience with a prospective multi-institutional trial designed to compare bleomycin pleurodesis to tetracycline pleurodesis for the treatment of malignant pleural effusions. To be eligible for this trial, patients were required to have a cytologically positive pleural effusion or a positive pleural biopsy, could not have had previous intrapleural therapy, and had to be ECOG performance status 0–2. Concurrent radiotherapy to the chest or recent changes in systemic chemo- or hormonotherapy were not allowed. Radiographic evidence of reexpansion of the affected lung following chest tube drainage was required. Eligible patients were randomized to receive either 60 units of bleomycin or 1 g of tetracycline intrapleurally. Specific guidelines were set for the administration of these agents. Patients were classified as having recurrent disease if they had radiographic evidence of any fluid reaccumulation following complete drainage of the pleural space and reexpansion of the lung. The two patient groups were compared for the rates of recurrence at 30 and 90 days after treatment and for the time to recurrence within 90 days. Toxicity was similar between the two arms of this study. The rate of recurrence was significantly lower and the time to recurrence significantly longer in the bleomycin arm compared to the tetracycline arm.Patients with malignant pleural effusions pose some special problems with respect to the design of clinical trials. They have a limited life expectancy even if they have a good performance status at the time of entry into the study. As the authors point out in their discussion, about half of the patients die within three months. Thus, large numbers of patients must be entered into a study in order to have statistically adequate numbers of patients available to analyze response rates. Many of these patients require ongoing radiotherapy or systemic treatment for disease in extrathoracic sites. The numbers of patients in whom such treatment can be withheld or stabilized in order to evaluate pleurodesis as the sole variable is limited. Patients with malignant pleural effusions often have underlying pulmonary parenchymal disease, bulky pleural disease, or some degree of a “trapped” lung, which makes it difficult to interpret radiologic response after pleurodesis. Ideally, such patients should be excluded from a clinical trial, and central review of all chest radiographs should be performed by a radiologist in order to control for these variables. Unlike other clinical trials, studies of malignant pleural effusions have no standard way of measuring response. The definition of response has varied greatly in previously published studies from using no radiographic evidence of any pleural fluid reaccumulation, to attempting to quantitate the amount of pleural fluid seen on chest radiograph as a partial or a complete response, to simply recording whether patients redeveloped symptoms.2Rusch VW Figlin R Godwin D Piantadosi S Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial.J Clin Oncol. 1991; 9: 313-319Crossref PubMed Scopus (105) Google Scholar, 3Hausheer FH Yarbro JW Diagnosis and treatment of malignant pleural effusions.Semin Oncol. 1985; 12: 54-75PubMed Google Scholar, 4Wallach HW Intrapleural tetracycline for malignant pleural effusions.Chest. 1975; 68: 510-512Crossref PubMed Scopus (84) Google Scholar, 5Jones GR Treatment of recurrent malignant pleural effusion by iodized talc pleurodesis.Thorax. 1969; 24: 69-73Crossref PubMed Scopus (55) Google Scholar, 6Bitran JD Brown C Desser RK Kozloff MF Shapiro C Billings AA Intracavitary bleomycin for the control of malignant effusions.J Surg Oncol. 1981; 16: 273-277Crossref PubMed Scopus (49) Google Scholar, 7Ostrowski MJ An assessment of the long-term results of controlling the reaccumulation of malignant effusions using intracavitary bleomycin.Cancer. 1986; 57: 721-727Crossref PubMed Scopus (94) Google Scholar, 8Bayly TC Kisner D Sybert A Macdonald JS Tsou E Schein PS Tetracycline and quinacrine in the control of malignant pleural effusions.Cancer. 1978; 41: 1188-1192Crossref PubMed Scopus (81) Google Scholar, 9Zaloznik AJ Oswald SG Langin M Intrapleural tetracycline in malignant pleural effusions.Cancer. 1983; 51: 752-755Crossref PubMed Scopus (76) Google Scholar, 10Tattersall MHN Intracavitary Adriamycin, nitrogen mustard and tetracycline in control of malignant effusions.Med J Aust. 1980; 2: 447-448PubMed Google Scholar, 11Paladine W Cunningham TJ Sponzo R Donavan M Olson K Horton J Intracavitary bleomycin in the management of malignant effusions.Cancer. 1976; 38: 1903-1908Crossref PubMed Scopus (139) Google Scholar The latter is an unacceptable method of assessment in a clinical trial, particularly in patients who have many other causes of dyspnea. Unfortunately, the issue of how best to define response remains unsettled. Finally, since the management of malignant pleural effusions is primarily palliative, clinical trials should carefully examine the toxicity and cost of treatment and the need for retreatment in patients who have a recurrence of disease. Ruckdeschel and coauthors did not include central radiology review and did not examine the costs of treatment or the need for retreatment. They have clearly tried, however, to select a homogeneous group of patients. They have also set clear-cut eligibility and treatment guidelines and have chosen the simplest and most reproducible measurement of recurrence.In spite of some flaws in study design, this trial represents an important effort to evaluate the management of a major clinical problem in an organized and objective manner. This approach has been deplorably infrequent in the past. Treatment for malignant pleural effusions remains suboptimal, with a 40 percent recurrence rate in the better treatment arm of this trial. Other methods of managing this problem should be evaluated in the future, using guidelines similar to those set forth in this study. Malignant pleural effusions are a common and often morbid problem in patients with advanced cancer.1Freidman MA Slater E Malignant pleural effusions.Cancer Treat Rev. 1978; 5: 49-66Abstract Full Text PDF PubMed Scopus (24) Google Scholar The optimal treatment of malignant pleural effusions remains controversial. While nonsclerosing cytotoxic intrapleural chemotherapy has occasionally been used to treat both the effusion and the underlying malignancy,2Rusch VW Figlin R Godwin D Piantadosi S Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial.J Clin Oncol. 1991; 9: 313-319Crossref PubMed Scopus (105) Google Scholar the usual approach is to inject a sclerosing agent into the pleural space after draining the effusion by tube thoracostomy. Tetracycline is the most widely accepted sclerosant, but many other agents have been used, attesting to the fact that no single agent is uniformly satisfactory.3Hausheer FH Yarbro JW Diagnosis and treatment of malignant pleural effusions.Semin Oncol. 1985; 12: 54-75PubMed Google Scholar The information on pleurodesis for malignant pleural effusions is derived mainly from small retrospective series.4Wallach HW Intrapleural tetracycline for malignant pleural effusions.Chest. 1975; 68: 510-512Crossref PubMed Scopus (84) Google Scholar, 5Jones GR Treatment of recurrent malignant pleural effusion by iodized talc pleurodesis.Thorax. 1969; 24: 69-73Crossref PubMed Scopus (55) Google Scholar, 6Bitran JD Brown C Desser RK Kozloff MF Shapiro C Billings AA Intracavitary bleomycin for the control of malignant effusions.J Surg Oncol. 1981; 16: 273-277Crossref PubMed Scopus (49) Google Scholar The few reported prospective clinical trials leave a great deal to be desired in their study design.7Ostrowski MJ An assessment of the long-term results of controlling the reaccumulation of malignant effusions using intracavitary bleomycin.Cancer. 1986; 57: 721-727Crossref PubMed Scopus (94) Google Scholar, 8Bayly TC Kisner D Sybert A Macdonald JS Tsou E Schein PS Tetracycline and quinacrine in the control of malignant pleural effusions.Cancer. 1978; 41: 1188-1192Crossref PubMed Scopus (81) Google Scholar, 9Zaloznik AJ Oswald SG Langin M Intrapleural tetracycline in malignant pleural effusions.Cancer. 1983; 51: 752-755Crossref PubMed Scopus (76) Google Scholar, 10Tattersall MHN Intracavitary Adriamycin, nitrogen mustard and tetracycline in control of malignant effusions.Med J Aust. 1980; 2: 447-448PubMed Google Scholar Problems with these trials include small numbers of patients; loosely defined eligibility criteria; variable criteria for assessing response; lack of central review of chest radiographs to verify response rates; lack of long-term follow-up; and lack of randomized comparison to other forms of treatment. There has also been considerable variation in the doses and the methods of administration used for sclerosing agents. By and large, published literature in this area serves more to confuse than to enlighten us. In this issue (see page 1528), Ruckdeschel and coauthors report their experience with a prospective multi-institutional trial designed to compare bleomycin pleurodesis to tetracycline pleurodesis for the treatment of malignant pleural effusions. To be eligible for this trial, patients were required to have a cytologically positive pleural effusion or a positive pleural biopsy, could not have had previous intrapleural therapy, and had to be ECOG performance status 0–2. Concurrent radiotherapy to the chest or recent changes in systemic chemo- or hormonotherapy were not allowed. Radiographic evidence of reexpansion of the affected lung following chest tube drainage was required. Eligible patients were randomized to receive either 60 units of bleomycin or 1 g of tetracycline intrapleurally. Specific guidelines were set for the administration of these agents. Patients were classified as having recurrent disease if they had radiographic evidence of any fluid reaccumulation following complete drainage of the pleural space and reexpansion of the lung. The two patient groups were compared for the rates of recurrence at 30 and 90 days after treatment and for the time to recurrence within 90 days. Toxicity was similar between the two arms of this study. The rate of recurrence was significantly lower and the time to recurrence significantly longer in the bleomycin arm compared to the tetracycline arm. Patients with malignant pleural effusions pose some special problems with respect to the design of clinical trials. They have a limited life expectancy even if they have a good performance status at the time of entry into the study. As the authors point out in their discussion, about half of the patients die within three months. Thus, large numbers of patients must be entered into a study in order to have statistically adequate numbers of patients available to analyze response rates. Many of these patients require ongoing radiotherapy or systemic treatment for disease in extrathoracic sites. The numbers of patients in whom such treatment can be withheld or stabilized in order to evaluate pleurodesis as the sole variable is limited. Patients with malignant pleural effusions often have underlying pulmonary parenchymal disease, bulky pleural disease, or some degree of a “trapped” lung, which makes it difficult to interpret radiologic response after pleurodesis. Ideally, such patients should be excluded from a clinical trial, and central review of all chest radiographs should be performed by a radiologist in order to control for these variables. Unlike other clinical trials, studies of malignant pleural effusions have no standard way of measuring response. The definition of response has varied greatly in previously published studies from using no radiographic evidence of any pleural fluid reaccumulation, to attempting to quantitate the amount of pleural fluid seen on chest radiograph as a partial or a complete response, to simply recording whether patients redeveloped symptoms.2Rusch VW Figlin R Godwin D Piantadosi S Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial.J Clin Oncol. 1991; 9: 313-319Crossref PubMed Scopus (105) Google Scholar, 3Hausheer FH Yarbro JW Diagnosis and treatment of malignant pleural effusions.Semin Oncol. 1985; 12: 54-75PubMed Google Scholar, 4Wallach HW Intrapleural tetracycline for malignant pleural effusions.Chest. 1975; 68: 510-512Crossref PubMed Scopus (84) Google Scholar, 5Jones GR Treatment of recurrent malignant pleural effusion by iodized talc pleurodesis.Thorax. 1969; 24: 69-73Crossref PubMed Scopus (55) Google Scholar, 6Bitran JD Brown C Desser RK Kozloff MF Shapiro C Billings AA Intracavitary bleomycin for the control of malignant effusions.J Surg Oncol. 1981; 16: 273-277Crossref PubMed Scopus (49) Google Scholar, 7Ostrowski MJ An assessment of the long-term results of controlling the reaccumulation of malignant effusions using intracavitary bleomycin.Cancer. 1986; 57: 721-727Crossref PubMed Scopus (94) Google Scholar, 8Bayly TC Kisner D Sybert A Macdonald JS Tsou E Schein PS Tetracycline and quinacrine in the control of malignant pleural effusions.Cancer. 1978; 41: 1188-1192Crossref PubMed Scopus (81) Google Scholar, 9Zaloznik AJ Oswald SG Langin M Intrapleural tetracycline in malignant pleural effusions.Cancer. 1983; 51: 752-755Crossref PubMed Scopus (76) Google Scholar, 10Tattersall MHN Intracavitary Adriamycin, nitrogen mustard and tetracycline in control of malignant effusions.Med J Aust. 1980; 2: 447-448PubMed Google Scholar, 11Paladine W Cunningham TJ Sponzo R Donavan M Olson K Horton J Intracavitary bleomycin in the management of malignant effusions.Cancer. 1976; 38: 1903-1908Crossref PubMed Scopus (139) Google Scholar The latter is an unacceptable method of assessment in a clinical trial, particularly in patients who have many other causes of dyspnea. Unfortunately, the issue of how best to define response remains unsettled. Finally, since the management of malignant pleural effusions is primarily palliative, clinical trials should carefully examine the toxicity and cost of treatment and the need for retreatment in patients who have a recurrence of disease. Ruckdeschel and coauthors did not include central radiology review and did not examine the costs of treatment or the need for retreatment. They have clearly tried, however, to select a homogeneous group of patients. They have also set clear-cut eligibility and treatment guidelines and have chosen the simplest and most reproducible measurement of recurrence. In spite of some flaws in study design, this trial represents an important effort to evaluate the management of a major clinical problem in an organized and objective manner. This approach has been deplorably infrequent in the past. Treatment for malignant pleural effusions remains suboptimal, with a 40 percent recurrence rate in the better treatment arm of this trial. Other methods of managing this problem should be evaluated in the future, using guidelines similar to those set forth in this study.