Journal of Surgical Oncology 10:361-368 (1978)
Management of Malignant Pleural Effusion .......................................................................................... .......................................................................................... DAVID W. GREENWALD, MD, CLAY PHILLIPS, MD, and JOHN M. BENNETT, MD A pleural effusion is a frequent complication of malignant disease. Essential to the care of oncology patients is a fundamental knowledge o f the pathophysiology and treatment of such effusions. This article discusses the current thoughts concerning the occurrence of malignant effusions, outlines the current available methods and agents employed for control, and presents a modification o f the thoracostomy procedure that appears t o be more effective than the standard procedure.
.................................................................................... .................................................................................... Key words: malignant, pleural effusion, thoracostomy
INTRODUCTION In the normal person, the continuous secretion of fluid from the parietal pleural capillaries and its continuous absorption into the visceral pleural capillaries and lymphatics is in equilibrium with only small quantities of residual fluid (1-10 cc) present in the pleural space t o lubricate pleural surfaces. Secretion rates determined in study of pleural effusions average approximately 30 cc/hr. Lymphatic absorption accounts for almost 90% of fluid removal, including all protein and cellular elements [ I ] . Formation of pleural fluid collections results from an inblance between secretion and reabsorption. Effusions occurring in association with malignant disease may arise either from excess fluid production secondary to increased capillary premeability (from tumor irritation and erosion, and sometimes, from localized pleuritis related to obstructive pulmonary pneumonitis near pleural surfaces), or from decreased removal of fluid because of mediastinal lymphatic or venous obstruction. The latter mechanism, lymphatic or venous obstruction, more often results in a transudate consisting of protein less than 3 gm%, specific gravity less than 1.016, lactic dehydrogenase (LDH) less than 200, and few tumor cells. Most malignant effusions are exudates with cell counts of 100-3,000 cells/cubic centimeter. In rare instances, an effusion will be the result of free-growing cancer cells in the pleural space with a cell count over 4,000 cells/cubic centimeter [2]. From the Departments of Medicine and Surgery, University of Rochester Cancer Center, University of Rochester School of Medicine and Dentistry Address reprint requests to John M. Bennett, MD, Professor of Oncology in Medicine, Cancer Center of the University of Rochester Medical Center, 601 Elmwood Ave, PO Box 704, Rochester, NY 14642.
0022-4790/78/1004-0361$01.70 0 1978 Alan R. Liss, Inc
362
Greenwald, Phillips, and Bennett
The medical management of pleural effusions includes both diagnosis and treatment. Although 50% of patients with metastatic breast and lung tumors will eventually form effusions, and 25%of all effusions are caused by neoplasms, other etiologies (such as pleural infections, tuberculosis, cirrhosis, heart failure, collagen vascular diseases, and others) must be kept in mind [ 3 ] . Sanguineous exudative fluid in a patient with known pulmonary metastatic tumor would most likely be a result of that tumor, but a transudative effusion in the face of limited pulmonary involvement requires further diagnostic evaluation, with studies such as skin tests, cultures, cytology and pleural biopsy.
METHODS OF CONTROL Systemic chemotherapy of the underlying malignancy may be effective in causing resolution of the effusion. Often, however, effusions are difficult to control and local measures are necessary. The easiest and most frequently employed method is a simple thoracentesis. Depending on the general condition, respiratory status, and life expectancy of the patient, repeated thoracenteses may be the treatment of choice. The average time until recurrence, however, is 4.2 days with many effusions recurring in 1-3 days [4]. In a patient with a reasonable life expectancy, thoracentesis alone is too temporary and of little long-term benefit. Improved methods of controlling effusions are available. In general, a successful treatment should remove all the fluid so that the lung can fully expand and obliterate the pleural space to prevent reaccumulation of fluid. Prior t o consideration of a more definitive procedure, such as tube thoracostomy, a single routine thoracentesis should be performed in an effort t o determine the clinical benefits of fluid removal. Patients with preexisting severe restrictive or obstructive pulmonary disease and those with far-advanced pulmonary metastases may not experience sufficient clinical improvement t o justify such a procedure.
Thoracentesis Plus Instillation of Chemotherapeutic Agents This is a very unsatisfactory approach for two reasons. First, complete fluid removal is rarely accomplished and the residual effusion dilutes the agent instilled and will limit the inflammatory reaction. The agent generally used, either nitrogen mustard or 5fluorouracil, has little antitumor activity, but will often produce systemic toxicity with resultant bone marrow depression. More important, however, it results in fluid loculations rendering further effusion treatment more difficult [S] .
Closed Tube Thoracostomy This is a more efficient method of fluid drainage and can be performed even in a very debilitated patient. It allows for adequate lung reexpansion, but by itself does not promise obliteration of the pleural space and is therefore an ineffective means of preventing reaccumulation.
Combined Thoracostomy and Instillation of Chemotherapeutic Agents At present, this is the most widely accepted and practiced method for fluid drainage, even over simple thoracentesis. Following insertion of a thoracostomy tube and allowing an adequate amount of time for fluid drainage (12-24 hours), a chemotherapeutic agent is instilled into the pleural cavity. One particular modification of this technique involves
Malignant Pleural Effusion
363
the creation of a pneumothorax (Clay Phillips, personal communication). The first step is the insertion of a thoracostomy tube under proper conditions and in a controlled environment such as the operating room and totally evacuating the effusion (Fig. 1). Next, air is introduced through the tube, creating a pneurnothorax which exposes a more generous and uniform pleural surface area and avoids the intense local reaction that usually occurs around the top of the thoracostomy tube (Fig. 2). The agent t o be utilized is now instilled into the empty pleural space and the tube is clamped for 4-6 hours (Fig. 3). During this
I
Fig. 1. Following thoracostomy tube insertion, the pleural fluid is completely drained.
I
Fig. 2. Following fluid drainage, air is instilled into the pleural cavity, creating a pneumo thorax.
364
Greenwald, Phillips and Bennett
time the patient is rotated in bed every 30 minutes t o insure adequate distribution of the agent over the pleural surfaces. Following this 4- to 6-hour distribution period the tube is unclamped and the pneumothorax is evacuated with the tube connected to suction t o remove excess agent and residual air and to fully reexpand the lung, allowing contact between the irritated visceral and parietal pleural surfaces (Fig. 4). It is the inflammatory response of these membranes that predicts total pleurodesis.
Fig. 3. Following creation of a pneumothorax, agent is instilled into pleural space.
Fig. 4. Following a 4- to 6-hour distribution period, excess fluid and residual air are removed and lung is reexpanded.
Malignant Pleural Effusion
365
Various agents have been utilized, and a review of those most frequently used will be discussed. Nitrogen mustard. This agent was first used in 1949 and remains one of the most preferred agents for the management of recurrent pleural effusions. Kinsey et a1 [ 51 had 87%, or 54 of 62 cases, in complete control with an average follow-up of nine months. He administered 30 mg of nitrogen mustard in one instillation. Leininger et a1 [6], using two instillations of 10 mg each, had successful control in 17 of 18 cases. The average dose of nitrogen mustard generally used is 0.4 mg/kg. Although a cytotoxic agent, the mode of action for nitrogen mustard is probably that of inciter of a chemical pleuritis, since tumor implants have been found at autopsy in patients whose pleural effusions have successfully been controlled. Sutton [7] believes most failures of nitrogen mustard instillation t o be related to poor technique, such as the allowance of prepared mustard to remain unused for lengthy periods of time. Also, adequate technique calls for frequent turning of the patient during the first five minutes of instillation, in order to evenly distribute the drug while it remains active. The major problems associated with the use of nitrogen mustard are pain, fever, nausea, vomiting, and bone marrow suppression. The latter factor is probably based more in theory than reality, except in those instances where a patient’s bone marrow is already suppressed. Major advantages to the use of nitrogen mustard include its ease of administration, availability, and inexpensiveness. Atabrine (quinacrine). This antimalarial drug is as popular as nitrogen mustard. Dollinger et a1 [8] report in their small series a control rate of 69%, and cite other studies with control rates ranging from 64% to 88%.Ultmann and his co-workers [9] had 19 of 22 patients respond t o atabrine instillation for an average of nine months. Atabrine was also used for the treatment of recurrent malignant ascites with a 75% response rate (9 of 12, 6 of 6 with ovarian carcinomas) for an average of five months. Although demonstrating cytotoxicity in some animal models, the mode of action for atabrine is probably through initiation of a chemical pleuritis. Its advantage over nitrogen mustard consists of a lack of bone marrow suppression, little systemic reaciton in doses of 400 mg or less, and relative painlessness, such that it can be instilled with the patient fully awake. Atabrine utilized with the modified closed thoracostomy method described above has yielded almost 100% effectiveness with only one application, and the only discomfort is judged t o be secondary to the tube itself. At the present time atabrine is not being produced by Winthrop Laboratories and is therefore only available in those medical centers which can prepare their own. Thiotepa. This alkylating agent is less irritating and therefore less effective than nitrogen mustard or atabrine. Successful results often require repeated administration. Its major efficaciousness is more related to its cytotoxicity than to its causal relationship t o chemical pleuritis. Silverberg [3] prefers this agent for malignant ascites, since it causes minimal irritation resulting in less loculation of fluid to impede further paracentesis. 5-Fluorouracil(5-FU). This agent is not widely used. Suhrland and Weisberger [lo] reported successful control in 68% of 45 patients with either pleural effusion or ascites. Dollinger [2] states, however, that it is not very beneficial. The usual dose is 2-3 gm for ascites, where it has been found to be most useful. It is believed that 5-FU is absorbed through the peritoneal surfaces; its mode of action is systemic cytotoxicity. It will cause bone marrow suppression approximately seven t o ten days following instillation. Radioactive isotopes. Radioactive colloidal gold and colloidal phosphorus are the two most common isotopes employed. Ariel [ l l ] claims at 54% response rate for pleural
366
Greenwald, Phillips and Bennett
effusion and ascites. Radioactive gold is both a beta and gamma (10%) emitter. It being a gamma emitter, there exists a radiation hazard; and its beta emission probably penetrates no more than 2-3 mm beneath the surface, and therefore, may not reach subsurface tumor implants. Colloidal phosphorus, which is only a beta emitter and has a longer half-life, is considered the preferred isotope. Both are generally more effective for the control of recurrent ascites. Tetracycline. Rubinson and Bolooki [ 121 report instillation of tetracycline, 500 mg in 30 cc of saline for six hours, t o have produced an 88.3% response (10 of 12 patients). The extremely low pH of tetracycline in solution (pH = 2-3.5) is credited as the reason for its irritative property. It destroys mesothelial cells on contact. The advantage of tetracycline is stated to be its lack of interference with systemic chemotherapy. Theoretically, as an antibiotic, it could possibly protect against local infection caused by the procedure [9] . Inherent disadvantages are its lack of tumorcidal activity and its possible allergenicity. Also, tetracycline can cause significant pain when used in dosages of 5001,000 mg. Bleomycin. Paladine et a1 [13] recently reported their results with this antitumor antibiotic, most often instilling 60-120 mg of bleomycin when it was administered systemically. No major problems with local pain or discomfort were encountered. How bleomycin works t o prevent fluid reaccumulation is unknown, but an autopsy finding of fibrinous adhesions suggests that it causes an irritative pleuritis, like most of the other agents. Because it lacks bone marrow toxicity, bleomycin can be used in a leukopenic patient. Further use is required before it is known whether bleomycin’s antitumor property is of significance when given intracavitarily. Talc Poudrage The instillation of talc is extremely painful and usually only performed under general anesthesia at thoracotomy. Five grams of talc are insufflated over the pleural surfaces. This method is probably 90% effective. The instillation of talc through a closed thoracostomy tube has been tried and proven t o be effective. This latter procedure, however, is too painful for routine use. Talc poudrage requires a patient who can tolerate a thoracotomy and whose life expectancy justifies the procedure. Pleurectomy Pleurectomy, like talc poudrage, is indicated only for very selected patients. Anderson et a1 [4] reported good results in seven of nine patients. T h s procedure is most successful if thoracotomy is performed for diagnosis and/or resection when tumor is found t o be inoperable. The procedure is most difficult to perform following chemotherapy and radiation. The hazards of pleurectomy are those of a formal thoracotomy . Radiation Bruneau and Rubin [14] demonstrated that radiation t o the mediastinum was highly successful when pleural effusion was associated with lymphoma. The treatment was effective even in patients without x-ray evidence of hilar adenopathy and in patients who had exudative types of effusion. This may be a very significant finding and raises the question of the possible effectiveness of mediastinal radiation for solid tumors. An autopsy study of 52 patients with metastatic disease to pleura demonstrated that effusions were closely related to neoplastic infiltration of mediastinal lymph nodes and revealed minimal relation-
Malignant Pleural Effusion
367
ship to the extent of actual pleural seeding or involvement by tumor metastases. Hemithorax radiation has also been attempted with seven of eight lymphoma patients responding, but only three of seven patients with solid tumor demonstrating control. Radiation fibrosis of the lung is a major problem encountered [14] .
SUMMARY The accumulation of pleural fluid is the result of an imbalance between secretion and reabsorption. With respect t o the presence of malignant disease, effusions occur as a result of tumor seeding of the pleural surfaces causing an irritative pleuritis with excess fluid production, or from tumor infiltration and obstruction of hilar lymph nodes and capillary vessels causing diminished fluid reabsorption. At times, simple thoracentesis is adequate t o control recurrent collections of fluid and t o maintain patient comfort. In other selected cases, insertion of a thoracostomy tube in order t o insure complete and thorough drainage, and the instillation of a chemotherapeutic agent, such as nitrogen mustard, atabrine, or tetracycline, is the preferred approach. Other procedures such as talc poudrage, pleurectomy, radioisotopic instillation, and radiation have limited applications, only on rare occasions being indicated. Because recurrent pleural effusions are such a frequent clinical problem in the total management of patients with neoplastic disease, all clinicians who treat such patients should become familiar with the various methods that become available for both diagnosis and control of malignancy. We favor the specific technique described here because it has proved to be a predictable and safe procedure without undue discomfort or systemic reaction.
ACKNOWLEDGMENTS This work was supported in part by USPHS grants CA 17988-02, CA 11083-09,and CA 11 198-09 from the National Cancer Institute, National Institutes of Health.
REFERENCES 1. Black LF: The pleural space and pleural fluid. Mayo Clin Proc 47:493-506, 1972. 2. Dollinger MR: Management of recurrent malignant effusions. Cancer 22: 138-147, 1972. 3. Silverberg I: Management of effusion. Oncology 24: 26-30, 1969. 4. Anderson CB, Philpott GW, Ferguson TB: The treatment of malignant pleural effusions. Cancer 16:916-922, 1974. 5. Kinsey DL, Carter I>, Klassen KP: Simplified management of malignant pleural effusion. Arch Surg 89:389-391, 1964. 6. Leininger BJ, Baker WL, Langston HT: A simplified method for management of malignant pleural effusion. J Thorac Cardiovasc Surg 58:758-763, 1969. 7. Sutton ML: The management of malignant pleural effusion. Postgrad Med J 49:729-731, 1973. 8. Dollinger MR, Krakoff IH, Karnofsky DA: Quinacrine (atabrine) in the treatment of neoplastic effusions. Ann Intern Med 66:248-257, 1967. 9. Gellhorn A, Osnos M, Ultmann JE, et al: The effect of quinacrine o n neoplastic effusions and certain of their enzymes. Cancer 16:283-288, 1963. 10. Suhrland LG, Weisberger HS: Intracavitary 5-fluorouracil in malignant effusions. Arch Intern Med 116:431-433, 1965. 1 1 . Ariel IM, Oropeza R, Pack GT: Intracavitary administrations of radioactive isotopes in the control of effusions due to cancer. Cancer 19:1096-1102, 1966.
368
Greenwald, Phillips and Bennett
12. Rubinson RM, Bolooki H: Intrapleural tetracycline for control of malignant pleural effusion. South Med J 65:847-849,1972. 13. Paladine W, Cunningham T, Sponzo R : Intracavitary bleomycin in the management of malignant effusions. Cancer 35: 1903-1908, 1976. 14. Bruneau R, Rubin P: The management of pleural effusions and chylothorax in lymphoma. Radiology 85:1085-1092, 1965.
Management of Malignant Pleural Effusion .......................................................................................... .......................................................................................... DAVID W. GREENWALD, MD, CLAY PHILLIPS, MD, and JOHN M. BENNETT, MD A pleural effusion is a frequent complication of malignant disease. Essential to the care of oncology patients is a fundamental knowledge o f the pathophysiology and treatment of such effusions. This article discusses the current thoughts concerning the occurrence of malignant effusions, outlines the current available methods and agents employed for control, and presents a modification o f the thoracostomy procedure that appears t o be more effective than the standard procedure.
.................................................................................... .................................................................................... Key words: malignant, pleural effusion, thoracostomy
INTRODUCTION In the normal person, the continuous secretion of fluid from the parietal pleural capillaries and its continuous absorption into the visceral pleural capillaries and lymphatics is in equilibrium with only small quantities of residual fluid (1-10 cc) present in the pleural space t o lubricate pleural surfaces. Secretion rates determined in study of pleural effusions average approximately 30 cc/hr. Lymphatic absorption accounts for almost 90% of fluid removal, including all protein and cellular elements [ I ] . Formation of pleural fluid collections results from an inblance between secretion and reabsorption. Effusions occurring in association with malignant disease may arise either from excess fluid production secondary to increased capillary premeability (from tumor irritation and erosion, and sometimes, from localized pleuritis related to obstructive pulmonary pneumonitis near pleural surfaces), or from decreased removal of fluid because of mediastinal lymphatic or venous obstruction. The latter mechanism, lymphatic or venous obstruction, more often results in a transudate consisting of protein less than 3 gm%, specific gravity less than 1.016, lactic dehydrogenase (LDH) less than 200, and few tumor cells. Most malignant effusions are exudates with cell counts of 100-3,000 cells/cubic centimeter. In rare instances, an effusion will be the result of free-growing cancer cells in the pleural space with a cell count over 4,000 cells/cubic centimeter [2]. From the Departments of Medicine and Surgery, University of Rochester Cancer Center, University of Rochester School of Medicine and Dentistry Address reprint requests to John M. Bennett, MD, Professor of Oncology in Medicine, Cancer Center of the University of Rochester Medical Center, 601 Elmwood Ave, PO Box 704, Rochester, NY 14642.
0022-4790/78/1004-0361$01.70 0 1978 Alan R. Liss, Inc
362
Greenwald, Phillips, and Bennett
The medical management of pleural effusions includes both diagnosis and treatment. Although 50% of patients with metastatic breast and lung tumors will eventually form effusions, and 25%of all effusions are caused by neoplasms, other etiologies (such as pleural infections, tuberculosis, cirrhosis, heart failure, collagen vascular diseases, and others) must be kept in mind [ 3 ] . Sanguineous exudative fluid in a patient with known pulmonary metastatic tumor would most likely be a result of that tumor, but a transudative effusion in the face of limited pulmonary involvement requires further diagnostic evaluation, with studies such as skin tests, cultures, cytology and pleural biopsy.
METHODS OF CONTROL Systemic chemotherapy of the underlying malignancy may be effective in causing resolution of the effusion. Often, however, effusions are difficult to control and local measures are necessary. The easiest and most frequently employed method is a simple thoracentesis. Depending on the general condition, respiratory status, and life expectancy of the patient, repeated thoracenteses may be the treatment of choice. The average time until recurrence, however, is 4.2 days with many effusions recurring in 1-3 days [4]. In a patient with a reasonable life expectancy, thoracentesis alone is too temporary and of little long-term benefit. Improved methods of controlling effusions are available. In general, a successful treatment should remove all the fluid so that the lung can fully expand and obliterate the pleural space to prevent reaccumulation of fluid. Prior t o consideration of a more definitive procedure, such as tube thoracostomy, a single routine thoracentesis should be performed in an effort t o determine the clinical benefits of fluid removal. Patients with preexisting severe restrictive or obstructive pulmonary disease and those with far-advanced pulmonary metastases may not experience sufficient clinical improvement t o justify such a procedure.
Thoracentesis Plus Instillation of Chemotherapeutic Agents This is a very unsatisfactory approach for two reasons. First, complete fluid removal is rarely accomplished and the residual effusion dilutes the agent instilled and will limit the inflammatory reaction. The agent generally used, either nitrogen mustard or 5fluorouracil, has little antitumor activity, but will often produce systemic toxicity with resultant bone marrow depression. More important, however, it results in fluid loculations rendering further effusion treatment more difficult [S] .
Closed Tube Thoracostomy This is a more efficient method of fluid drainage and can be performed even in a very debilitated patient. It allows for adequate lung reexpansion, but by itself does not promise obliteration of the pleural space and is therefore an ineffective means of preventing reaccumulation.
Combined Thoracostomy and Instillation of Chemotherapeutic Agents At present, this is the most widely accepted and practiced method for fluid drainage, even over simple thoracentesis. Following insertion of a thoracostomy tube and allowing an adequate amount of time for fluid drainage (12-24 hours), a chemotherapeutic agent is instilled into the pleural cavity. One particular modification of this technique involves
Malignant Pleural Effusion
363
the creation of a pneumothorax (Clay Phillips, personal communication). The first step is the insertion of a thoracostomy tube under proper conditions and in a controlled environment such as the operating room and totally evacuating the effusion (Fig. 1). Next, air is introduced through the tube, creating a pneurnothorax which exposes a more generous and uniform pleural surface area and avoids the intense local reaction that usually occurs around the top of the thoracostomy tube (Fig. 2). The agent t o be utilized is now instilled into the empty pleural space and the tube is clamped for 4-6 hours (Fig. 3). During this
I
Fig. 1. Following thoracostomy tube insertion, the pleural fluid is completely drained.
I
Fig. 2. Following fluid drainage, air is instilled into the pleural cavity, creating a pneumo thorax.
364
Greenwald, Phillips and Bennett
time the patient is rotated in bed every 30 minutes t o insure adequate distribution of the agent over the pleural surfaces. Following this 4- to 6-hour distribution period the tube is unclamped and the pneumothorax is evacuated with the tube connected to suction t o remove excess agent and residual air and to fully reexpand the lung, allowing contact between the irritated visceral and parietal pleural surfaces (Fig. 4). It is the inflammatory response of these membranes that predicts total pleurodesis.
Fig. 3. Following creation of a pneumothorax, agent is instilled into pleural space.
Fig. 4. Following a 4- to 6-hour distribution period, excess fluid and residual air are removed and lung is reexpanded.
Malignant Pleural Effusion
365
Various agents have been utilized, and a review of those most frequently used will be discussed. Nitrogen mustard. This agent was first used in 1949 and remains one of the most preferred agents for the management of recurrent pleural effusions. Kinsey et a1 [ 51 had 87%, or 54 of 62 cases, in complete control with an average follow-up of nine months. He administered 30 mg of nitrogen mustard in one instillation. Leininger et a1 [6], using two instillations of 10 mg each, had successful control in 17 of 18 cases. The average dose of nitrogen mustard generally used is 0.4 mg/kg. Although a cytotoxic agent, the mode of action for nitrogen mustard is probably that of inciter of a chemical pleuritis, since tumor implants have been found at autopsy in patients whose pleural effusions have successfully been controlled. Sutton [7] believes most failures of nitrogen mustard instillation t o be related to poor technique, such as the allowance of prepared mustard to remain unused for lengthy periods of time. Also, adequate technique calls for frequent turning of the patient during the first five minutes of instillation, in order to evenly distribute the drug while it remains active. The major problems associated with the use of nitrogen mustard are pain, fever, nausea, vomiting, and bone marrow suppression. The latter factor is probably based more in theory than reality, except in those instances where a patient’s bone marrow is already suppressed. Major advantages to the use of nitrogen mustard include its ease of administration, availability, and inexpensiveness. Atabrine (quinacrine). This antimalarial drug is as popular as nitrogen mustard. Dollinger et a1 [8] report in their small series a control rate of 69%, and cite other studies with control rates ranging from 64% to 88%.Ultmann and his co-workers [9] had 19 of 22 patients respond t o atabrine instillation for an average of nine months. Atabrine was also used for the treatment of recurrent malignant ascites with a 75% response rate (9 of 12, 6 of 6 with ovarian carcinomas) for an average of five months. Although demonstrating cytotoxicity in some animal models, the mode of action for atabrine is probably through initiation of a chemical pleuritis. Its advantage over nitrogen mustard consists of a lack of bone marrow suppression, little systemic reaciton in doses of 400 mg or less, and relative painlessness, such that it can be instilled with the patient fully awake. Atabrine utilized with the modified closed thoracostomy method described above has yielded almost 100% effectiveness with only one application, and the only discomfort is judged t o be secondary to the tube itself. At the present time atabrine is not being produced by Winthrop Laboratories and is therefore only available in those medical centers which can prepare their own. Thiotepa. This alkylating agent is less irritating and therefore less effective than nitrogen mustard or atabrine. Successful results often require repeated administration. Its major efficaciousness is more related to its cytotoxicity than to its causal relationship t o chemical pleuritis. Silverberg [3] prefers this agent for malignant ascites, since it causes minimal irritation resulting in less loculation of fluid to impede further paracentesis. 5-Fluorouracil(5-FU). This agent is not widely used. Suhrland and Weisberger [lo] reported successful control in 68% of 45 patients with either pleural effusion or ascites. Dollinger [2] states, however, that it is not very beneficial. The usual dose is 2-3 gm for ascites, where it has been found to be most useful. It is believed that 5-FU is absorbed through the peritoneal surfaces; its mode of action is systemic cytotoxicity. It will cause bone marrow suppression approximately seven t o ten days following instillation. Radioactive isotopes. Radioactive colloidal gold and colloidal phosphorus are the two most common isotopes employed. Ariel [ l l ] claims at 54% response rate for pleural
366
Greenwald, Phillips and Bennett
effusion and ascites. Radioactive gold is both a beta and gamma (10%) emitter. It being a gamma emitter, there exists a radiation hazard; and its beta emission probably penetrates no more than 2-3 mm beneath the surface, and therefore, may not reach subsurface tumor implants. Colloidal phosphorus, which is only a beta emitter and has a longer half-life, is considered the preferred isotope. Both are generally more effective for the control of recurrent ascites. Tetracycline. Rubinson and Bolooki [ 121 report instillation of tetracycline, 500 mg in 30 cc of saline for six hours, t o have produced an 88.3% response (10 of 12 patients). The extremely low pH of tetracycline in solution (pH = 2-3.5) is credited as the reason for its irritative property. It destroys mesothelial cells on contact. The advantage of tetracycline is stated to be its lack of interference with systemic chemotherapy. Theoretically, as an antibiotic, it could possibly protect against local infection caused by the procedure [9] . Inherent disadvantages are its lack of tumorcidal activity and its possible allergenicity. Also, tetracycline can cause significant pain when used in dosages of 5001,000 mg. Bleomycin. Paladine et a1 [13] recently reported their results with this antitumor antibiotic, most often instilling 60-120 mg of bleomycin when it was administered systemically. No major problems with local pain or discomfort were encountered. How bleomycin works t o prevent fluid reaccumulation is unknown, but an autopsy finding of fibrinous adhesions suggests that it causes an irritative pleuritis, like most of the other agents. Because it lacks bone marrow toxicity, bleomycin can be used in a leukopenic patient. Further use is required before it is known whether bleomycin’s antitumor property is of significance when given intracavitarily. Talc Poudrage The instillation of talc is extremely painful and usually only performed under general anesthesia at thoracotomy. Five grams of talc are insufflated over the pleural surfaces. This method is probably 90% effective. The instillation of talc through a closed thoracostomy tube has been tried and proven t o be effective. This latter procedure, however, is too painful for routine use. Talc poudrage requires a patient who can tolerate a thoracotomy and whose life expectancy justifies the procedure. Pleurectomy Pleurectomy, like talc poudrage, is indicated only for very selected patients. Anderson et a1 [4] reported good results in seven of nine patients. T h s procedure is most successful if thoracotomy is performed for diagnosis and/or resection when tumor is found t o be inoperable. The procedure is most difficult to perform following chemotherapy and radiation. The hazards of pleurectomy are those of a formal thoracotomy . Radiation Bruneau and Rubin [14] demonstrated that radiation t o the mediastinum was highly successful when pleural effusion was associated with lymphoma. The treatment was effective even in patients without x-ray evidence of hilar adenopathy and in patients who had exudative types of effusion. This may be a very significant finding and raises the question of the possible effectiveness of mediastinal radiation for solid tumors. An autopsy study of 52 patients with metastatic disease to pleura demonstrated that effusions were closely related to neoplastic infiltration of mediastinal lymph nodes and revealed minimal relation-
Malignant Pleural Effusion
367
ship to the extent of actual pleural seeding or involvement by tumor metastases. Hemithorax radiation has also been attempted with seven of eight lymphoma patients responding, but only three of seven patients with solid tumor demonstrating control. Radiation fibrosis of the lung is a major problem encountered [14] .
SUMMARY The accumulation of pleural fluid is the result of an imbalance between secretion and reabsorption. With respect t o the presence of malignant disease, effusions occur as a result of tumor seeding of the pleural surfaces causing an irritative pleuritis with excess fluid production, or from tumor infiltration and obstruction of hilar lymph nodes and capillary vessels causing diminished fluid reabsorption. At times, simple thoracentesis is adequate t o control recurrent collections of fluid and t o maintain patient comfort. In other selected cases, insertion of a thoracostomy tube in order t o insure complete and thorough drainage, and the instillation of a chemotherapeutic agent, such as nitrogen mustard, atabrine, or tetracycline, is the preferred approach. Other procedures such as talc poudrage, pleurectomy, radioisotopic instillation, and radiation have limited applications, only on rare occasions being indicated. Because recurrent pleural effusions are such a frequent clinical problem in the total management of patients with neoplastic disease, all clinicians who treat such patients should become familiar with the various methods that become available for both diagnosis and control of malignancy. We favor the specific technique described here because it has proved to be a predictable and safe procedure without undue discomfort or systemic reaction.
ACKNOWLEDGMENTS This work was supported in part by USPHS grants CA 17988-02, CA 11083-09,and CA 11 198-09 from the National Cancer Institute, National Institutes of Health.
REFERENCES 1. Black LF: The pleural space and pleural fluid. Mayo Clin Proc 47:493-506, 1972. 2. Dollinger MR: Management of recurrent malignant effusions. Cancer 22: 138-147, 1972. 3. Silverberg I: Management of effusion. Oncology 24: 26-30, 1969. 4. Anderson CB, Philpott GW, Ferguson TB: The treatment of malignant pleural effusions. Cancer 16:916-922, 1974. 5. Kinsey DL, Carter I>, Klassen KP: Simplified management of malignant pleural effusion. Arch Surg 89:389-391, 1964. 6. Leininger BJ, Baker WL, Langston HT: A simplified method for management of malignant pleural effusion. J Thorac Cardiovasc Surg 58:758-763, 1969. 7. Sutton ML: The management of malignant pleural effusion. Postgrad Med J 49:729-731, 1973. 8. Dollinger MR, Krakoff IH, Karnofsky DA: Quinacrine (atabrine) in the treatment of neoplastic effusions. Ann Intern Med 66:248-257, 1967. 9. Gellhorn A, Osnos M, Ultmann JE, et al: The effect of quinacrine o n neoplastic effusions and certain of their enzymes. Cancer 16:283-288, 1963. 10. Suhrland LG, Weisberger HS: Intracavitary 5-fluorouracil in malignant effusions. Arch Intern Med 116:431-433, 1965. 1 1 . Ariel IM, Oropeza R, Pack GT: Intracavitary administrations of radioactive isotopes in the control of effusions due to cancer. Cancer 19:1096-1102, 1966.
368
Greenwald, Phillips and Bennett
12. Rubinson RM, Bolooki H: Intrapleural tetracycline for control of malignant pleural effusion. South Med J 65:847-849,1972. 13. Paladine W, Cunningham T, Sponzo R : Intracavitary bleomycin in the management of malignant effusions. Cancer 35: 1903-1908, 1976. 14. Bruneau R, Rubin P: The management of pleural effusions and chylothorax in lymphoma. Radiology 85:1085-1092, 1965.
