Management of Pleural Effusions in Breast Cancer" Alan
w. Lees, B.M.~ B.Ch.;oO and Wayne Hoyt
Ninety-seven patients with breast amcer developed pleural effusions between January, 1971 ad December, 1976. A retrospective analysis of 170 treatment pr0cedures showed that 75 iDvolved thoracoceDtR ~ 23 iDvolved thoracocentesis phis tllerapJ wItIa aD IIIkyIating agent, 22 iDvolved draIDage via a daest tube plus instillation of an alkylating agent, and SO Involved drainage via a chest tube plus IDsdIIatIon of tetracydine. Tbe results are presented _ ceasored Sllniv81 C1II'Yes. WIlen lII8IUIIement by chest tube plus IDstIIWIoB of _ IIIkyI-
ating Blent or tetracydiDe was comp8l'ed wItIa ____ ment by thoracocentesis plus therapy wi.. _ ..,....... apnt, -.lysis at • months lifter treaaae.t &bowed ... 42 percent (30/72) of the procedares left patients free of effusion usin& the former method, co...... witII 22 percent (5/23) of tile proad........ the latter JBetIIocL ThIs is not quite IipiIant .. tile 5 perceId left! . . . • summary x 2 procedure. 11ae re8IOII8 for preferrillc tetracycliDe _ a sderosba& aceat are disca.ed.
pleural effusion is common in patients with metastatic cancer of the breast,' The patient may have to contend with this distressing manifestation of the disease for many months," Aspiration alone may be adequate for the moribund patient, but in the patient with a longer life expectancy, an attempt at obliteration of the pleural space (pleurodesis) after complete evacuation of the fluid has been recommendedf Thorsrud! found that tetracycline was an effective agent for producing pleurodesis in animals, and he attributed its effectiveness to the low pH in solution (2.4) and its ability to destroy the cells of both the visceral and parietal pleura. The use of tetracycline to produce pleurodesis in clinical practice has been reported by Rubinson and Bolooki" and by Wallach. 8 The methods available for the treatment of pleural effusion in cancer of the breast" are as follows: systemic therapy with hormones or systemic chemotherapy; thoracocentesis, either alone or with treabnent with chemotherapeutic agents or quina. crine; thoracocentesis and therapy with radioactive isotopes ( 1989old, 32phosphorus, and 9Oyttrium) ; and drainage via a chest tube, either alone or with
treatment with chemotherapeutic agents, quinacrine, or tetracycline. Other methods described are poudrage with talc, irradiation of the hemithorax, or pleurectomy. Pleurodesis has been a common form of treatment in Edmonton, Alberta for the past six years; its proponents agree with Anderson et ala that obliteration of the pleural space is the prime objective of treabnent, rather than selective modification of the production and absorption of fluid.' Initially, this obliteration was achieved by drainage via a chest tube, along with the instillation of alkylating agents; but since 1974, tetracycline has been the agent of choice. This retrospective review of the latter treatment compares it with the former and with thoracocentesis plus therapy with an alkylating agent. The results of using thoracocentesis alone are also presented
• From the Departments of Radiation Oncology, Cross Cancer Institute, Provincial Cancer Hospitals Board, and the Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada. Supported in part by the Vessey Heckbert Memorial Summer Research Award (Mr. Hoy). • ·Senior Radiation Oncologist tMedical student. Manuscript received April 24; revision accepted June 7. Reprint reguesl8: Dr. Lees, 11560 Univemtr/ Aoenue~ Edmonton~ Alberta, Canada TOO IZZ
CHEST, 75: 1, JANUARY, 1979
MATERIALS AND METHolJS
Each patient had closed tube thoracostomy in the 10west convenient intercostal space determined by the physical signs. The fluid was drained via underwater seal, with interruption of the process by clamping the tube if the patient became distressed, until drainage stopped. Gentle suction was continued for a further 12 to 24 hours, and then at 30 minutes after administration of a narcotic analgesic agent, 1.500 mg of tetracycline in 40 ml of physiologic saline solution was injected into the tube. The patient was told to expect some discomfort at this point. The tube was clamped for 12 hours, and the patient was told to move around and to change position frequently in bed. Subsequently, underwater suction of 18 to 20 em H 20 was maintained for the next three to four days. The tube was withdrawn when fluid stopped draining. when clots of fibrin were visible in the tube, and
PLEURAL EFFUSIONS IN BREAST CANeo 51
when the chest x-ray film showed the absence of fluid and no pneumothorax. Charts of patients with breast cancer who were recorded as having pleural effusions from 1971 through 1976 were obtained from the Department of Medical Records at the Cross Cancer Institute, Edmonton, Alberta. by the use of the P.A.S. systems and also by the use of the computerized registry of breast cancer.' One hundred and two files were reviewed, 97 patients were confirmed as having pleural effusions. and 80 of these had treatment by thoracocentesis or drainage via a chest tube. One hundred and seventy therapeutic procedures were recorded. A patient with a pleural eJfusion and a history of cancer of the breast was regarded as having metastatic disease unless there was clear evidence of another cause for the effusion. The diagnosis was pursued by cytologic studies or pleural biopsy only in patients with no evidence of metastases except a pleural effusion. Because many patients had multiple treatments and bilateral effusions, we decided to regard each treatment of a pleural effusion as a separate procedure. Therefore, one patient may be assessed several times for different treatments. The three types of treatment assessed were as follows: thoracocentesis with therapy with an alkylating agent, 23 procedures (20 with triethylenethiophosphoramide [ThioTEPA] and three with mechlorethamine [nitrogen mustard]); drainage via a chest tube with instillation of an alkylating agent, 22 procedures (18 with triethylenethiophosphoramide and four with mechlorethamine); and drainage via a chest tube with instillation of tetracycline. 50 procedures. Thoracocentesis alone was carried out on 75 occasions. and these form a group for comparison. Assessing the response to treatment of a pleural effusion is difficult because measuring the exact interval of time or the amount of fluid when recurrence can be said to be present is impossible. X-ray 6Ims frequently record small amounts of
75
~ o
fluid or pleural thickening soon after treatment, when the patient is asymptomatic. The duration of response has therefore been assessed as the time from the definitive procedure until the patient has another procedure performed for recurrence of effusion or until the time of the development of symptoms, whichever is less. There must be some subjective element in reporting these results. but the patients have been reviewed by both authors independently. and a compromise of the two opinions is reported. The majority of situations were clear-cut. where the treatment had to be repeated because the patient was symptomatic. A minority of patients had symptoms from recurrent effusion for some time before further treatment. The minimum length of follow-up is 12 months. Because ten of the patients are alive without recurrence of the effusion at the time of reporting. the results are presented graphically by the use of the technique for calculating censored survival curves. to RESULTS
The percentage of patients remaining free of effusion at a given time for each of the methods of treatment is shown in Figure 1 as censored survival curves. One patient in the group with thoracocentesis only and nine patients in the group with chest tubes and therapy with tetracycline are alive without recurrence of effusion at the time of reporting. At six months after treatment, 21 of the 50 procedures in the group with chest tubes plus therapy with tetracycline left the patient free of effusion. as did nine of the 22 procedures in the group with chest tubes plus therapy with an alkylating agent, compared with five of the 23 procedures in the group
Chest Tube Tetracycline II II Alkylating Agent • Thoracentesis Alkyl. Agent • Thoracentesis
A
50 22 23 75
25
o FICURE
52 LEES, HOY
6
12
18
1. Pleural effusions in breast cancer.
24
30
MONTHS
36
42
48
54
CHEST, 75: 1, JANUARY, 1979
with thoracocentesis plus therapy with an alkylating agent. This is not significant at the 5 percent level test of Mantel and using the summary Haenszel."
t
DISCUSSION
The technique described has evolved over three years and now differs from other accounts of drainage via a chest tube. 3,5,6 It has been found radiologically that drainage is usually complete when performed as described, and a chest x-ray film is not routinely obtained prior to instillation of tetracycline. The dose of tetracycline and the time of underwater suction after therapy with tetracycline have been increased because it was thought that better sealing of parietal and visceral pleural layers ensued. It has not been possible to demonstrate an improvement of results by altering the technique, but there has been no demonstrable increase in morbidity. One patient had a pneumothorax which required prolonged underwater suction, and another had severe continuous pain that was thought to be due toirritation of the diaphragm by the chest tube. No problems occurred, either with fever and other manifestations of a reaction to this instillation of tetracycline or with prolonged drainage of fluid from the site of the insertion of the tube for drainage. The low morbidity agrees with the reports by Wallach" and by Rubinson and Bolooki" and contrasts with that by Anderson et al.3 The latter group prefers mechlorethamine as the sclerosing agent and reports results similar to ours.P Although not statistically significant, there is a strong trend in favor of drainage via a chest tube, but there is no clear advantage of tetracycline over alkylating agents as a means of securing pleurodesis (when measured as the time of freedom from recurrence ). The advantage of instillation of tetracycline lies in the fact that it does not interfere with the anticancer therapy and that as an antibiotic, tetracycline discourages the development of infection in the pleural cavity. The impression that the patients treated with drainage via a chest tube and therapy with tetracycline are doing better than those patients treated with a chest tube and therapy with alkylating agents may be related to the more aggressive chemotherapy practiced in the years of 1974 to 1977, compared
CHEST, 75: 1, JANUARY, 1979
with that between 1971 and 1973; however, there was no demonstrable difference in overall survival between the two groups of patients. The complexities of controlling for the influence of systemic treatment preclude a definitive analysis of its effect on the outcome of localized procedures, and the assumption has been made that the effect evens itself out as the number of patients in each group increases. We conclude that complete drainage of fluid by a chest tube, followed by pleurodesis with tetracycline, is an effective means of long-term control of pleural effusions in breast cancer and has an acceptable morbidity and that the technique is superior to therapeutic measures designed to alter the production or absorption of pleural fluid ACKNOWLEDGMENT: We thank Dr. Colin Ross, Thoracic Surgeon. for his advice on technical matters and the Medical Services Research Foundation of Alberta for a grant supporting the computerized registry of breast cancer.
REFERENCES 1 Fracchia AA. Knapper WH, Carey J. et al: Intrapleural chemotherapy for effusion for metastatic breast cancer. Cancer 26:626-629, 1970 2 Ariel 1M, Oropeza R, Pack GT: Intracavitary administration of radioactive isotopes in the control of effusions due to cancer. Cancer 19:1096-1102, 1966 3 Anderson CB, Roper CL. Ferguson TB: Management of pleural effusions, In Stoll BA (ed): Breast Cancer Management: Early and Late. Chicago, Year Book Medical Publishers, 1977, pp 175-183 4 Thorsrud GK: Pleural reaction to irritants: An experimental study with special reference to pleural adhesions and concrescence in relation to pleural turnover of fluid. Acta Chir Scand (suppl) 355:1-74, 1965 5 Rubinson R. Bolooki H: Intrapleural tetracycline for control of malignant pleural effusion. South Med J 65:847849, 1972 6 Wallach HW: Intrapleural tetracycline for malignant pleural effusions. Chest 68:510-512.1975 7 Dollinger MR: Management of recurrent malignant effusions. Cancer 22:138-147,1972 8 P.A.S.: Professional Activity System (manual). Ann Arbor, Mich, Commission on Professional and Hospital Activities, 1969 9 Burns PE, Kredentser S, Grace M. et al: Breast cancer in northern Alberta: A pilot study in computerized registration. Can Med Assoc J 116:1131-1135,1977 10 Burdette WJ, Gehan EA: Planning and Analysis of Clinical Studies. Springfield, Ill, Charles C. Thomas, 1970, PP 72-77 11 Mantel N, Haenszel B: Statistical aspects of the analysis of data from retrospective studies of disease. J Nat! Cancer Inst 22:719-748,1959 12 Anderson CB, Philpott GW, Ferguson TB: The treatment of maglignant pleural effusions. Cancer 33:916-922, 1974
PLEURAL EFFUSIONS IN BREAST CANCER 53
w. Lees, B.M.~ B.Ch.;oO and Wayne Hoyt
Ninety-seven patients with breast amcer developed pleural effusions between January, 1971 ad December, 1976. A retrospective analysis of 170 treatment pr0cedures showed that 75 iDvolved thoracoceDtR ~ 23 iDvolved thoracocentesis phis tllerapJ wItIa aD IIIkyIating agent, 22 iDvolved draIDage via a daest tube plus instillation of an alkylating agent, and SO Involved drainage via a chest tube plus IDsdIIatIon of tetracydine. Tbe results are presented _ ceasored Sllniv81 C1II'Yes. WIlen lII8IUIIement by chest tube plus IDstIIWIoB of _ IIIkyI-
ating Blent or tetracydiDe was comp8l'ed wItIa ____ ment by thoracocentesis plus therapy wi.. _ ..,....... apnt, -.lysis at • months lifter treaaae.t &bowed ... 42 percent (30/72) of the procedares left patients free of effusion usin& the former method, co...... witII 22 percent (5/23) of tile proad........ the latter JBetIIocL ThIs is not quite IipiIant .. tile 5 perceId left! . . . • summary x 2 procedure. 11ae re8IOII8 for preferrillc tetracycliDe _ a sderosba& aceat are disca.ed.
pleural effusion is common in patients with metastatic cancer of the breast,' The patient may have to contend with this distressing manifestation of the disease for many months," Aspiration alone may be adequate for the moribund patient, but in the patient with a longer life expectancy, an attempt at obliteration of the pleural space (pleurodesis) after complete evacuation of the fluid has been recommendedf Thorsrud! found that tetracycline was an effective agent for producing pleurodesis in animals, and he attributed its effectiveness to the low pH in solution (2.4) and its ability to destroy the cells of both the visceral and parietal pleura. The use of tetracycline to produce pleurodesis in clinical practice has been reported by Rubinson and Bolooki" and by Wallach. 8 The methods available for the treatment of pleural effusion in cancer of the breast" are as follows: systemic therapy with hormones or systemic chemotherapy; thoracocentesis, either alone or with treabnent with chemotherapeutic agents or quina. crine; thoracocentesis and therapy with radioactive isotopes ( 1989old, 32phosphorus, and 9Oyttrium) ; and drainage via a chest tube, either alone or with
treatment with chemotherapeutic agents, quinacrine, or tetracycline. Other methods described are poudrage with talc, irradiation of the hemithorax, or pleurectomy. Pleurodesis has been a common form of treatment in Edmonton, Alberta for the past six years; its proponents agree with Anderson et ala that obliteration of the pleural space is the prime objective of treabnent, rather than selective modification of the production and absorption of fluid.' Initially, this obliteration was achieved by drainage via a chest tube, along with the instillation of alkylating agents; but since 1974, tetracycline has been the agent of choice. This retrospective review of the latter treatment compares it with the former and with thoracocentesis plus therapy with an alkylating agent. The results of using thoracocentesis alone are also presented
• From the Departments of Radiation Oncology, Cross Cancer Institute, Provincial Cancer Hospitals Board, and the Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada. Supported in part by the Vessey Heckbert Memorial Summer Research Award (Mr. Hoy). • ·Senior Radiation Oncologist tMedical student. Manuscript received April 24; revision accepted June 7. Reprint reguesl8: Dr. Lees, 11560 Univemtr/ Aoenue~ Edmonton~ Alberta, Canada TOO IZZ
CHEST, 75: 1, JANUARY, 1979
MATERIALS AND METHolJS
Each patient had closed tube thoracostomy in the 10west convenient intercostal space determined by the physical signs. The fluid was drained via underwater seal, with interruption of the process by clamping the tube if the patient became distressed, until drainage stopped. Gentle suction was continued for a further 12 to 24 hours, and then at 30 minutes after administration of a narcotic analgesic agent, 1.500 mg of tetracycline in 40 ml of physiologic saline solution was injected into the tube. The patient was told to expect some discomfort at this point. The tube was clamped for 12 hours, and the patient was told to move around and to change position frequently in bed. Subsequently, underwater suction of 18 to 20 em H 20 was maintained for the next three to four days. The tube was withdrawn when fluid stopped draining. when clots of fibrin were visible in the tube, and
PLEURAL EFFUSIONS IN BREAST CANeo 51
when the chest x-ray film showed the absence of fluid and no pneumothorax. Charts of patients with breast cancer who were recorded as having pleural effusions from 1971 through 1976 were obtained from the Department of Medical Records at the Cross Cancer Institute, Edmonton, Alberta. by the use of the P.A.S. systems and also by the use of the computerized registry of breast cancer.' One hundred and two files were reviewed, 97 patients were confirmed as having pleural effusions. and 80 of these had treatment by thoracocentesis or drainage via a chest tube. One hundred and seventy therapeutic procedures were recorded. A patient with a pleural eJfusion and a history of cancer of the breast was regarded as having metastatic disease unless there was clear evidence of another cause for the effusion. The diagnosis was pursued by cytologic studies or pleural biopsy only in patients with no evidence of metastases except a pleural effusion. Because many patients had multiple treatments and bilateral effusions, we decided to regard each treatment of a pleural effusion as a separate procedure. Therefore, one patient may be assessed several times for different treatments. The three types of treatment assessed were as follows: thoracocentesis with therapy with an alkylating agent, 23 procedures (20 with triethylenethiophosphoramide [ThioTEPA] and three with mechlorethamine [nitrogen mustard]); drainage via a chest tube with instillation of an alkylating agent, 22 procedures (18 with triethylenethiophosphoramide and four with mechlorethamine); and drainage via a chest tube with instillation of tetracycline. 50 procedures. Thoracocentesis alone was carried out on 75 occasions. and these form a group for comparison. Assessing the response to treatment of a pleural effusion is difficult because measuring the exact interval of time or the amount of fluid when recurrence can be said to be present is impossible. X-ray 6Ims frequently record small amounts of
75
~ o
fluid or pleural thickening soon after treatment, when the patient is asymptomatic. The duration of response has therefore been assessed as the time from the definitive procedure until the patient has another procedure performed for recurrence of effusion or until the time of the development of symptoms, whichever is less. There must be some subjective element in reporting these results. but the patients have been reviewed by both authors independently. and a compromise of the two opinions is reported. The majority of situations were clear-cut. where the treatment had to be repeated because the patient was symptomatic. A minority of patients had symptoms from recurrent effusion for some time before further treatment. The minimum length of follow-up is 12 months. Because ten of the patients are alive without recurrence of the effusion at the time of reporting. the results are presented graphically by the use of the technique for calculating censored survival curves. to RESULTS
The percentage of patients remaining free of effusion at a given time for each of the methods of treatment is shown in Figure 1 as censored survival curves. One patient in the group with thoracocentesis only and nine patients in the group with chest tubes and therapy with tetracycline are alive without recurrence of effusion at the time of reporting. At six months after treatment, 21 of the 50 procedures in the group with chest tubes plus therapy with tetracycline left the patient free of effusion. as did nine of the 22 procedures in the group with chest tubes plus therapy with an alkylating agent, compared with five of the 23 procedures in the group
Chest Tube Tetracycline II II Alkylating Agent • Thoracentesis Alkyl. Agent • Thoracentesis
A
50 22 23 75
25
o FICURE
52 LEES, HOY
6
12
18
1. Pleural effusions in breast cancer.
24
30
MONTHS
36
42
48
54
CHEST, 75: 1, JANUARY, 1979
with thoracocentesis plus therapy with an alkylating agent. This is not significant at the 5 percent level test of Mantel and using the summary Haenszel."
t
DISCUSSION
The technique described has evolved over three years and now differs from other accounts of drainage via a chest tube. 3,5,6 It has been found radiologically that drainage is usually complete when performed as described, and a chest x-ray film is not routinely obtained prior to instillation of tetracycline. The dose of tetracycline and the time of underwater suction after therapy with tetracycline have been increased because it was thought that better sealing of parietal and visceral pleural layers ensued. It has not been possible to demonstrate an improvement of results by altering the technique, but there has been no demonstrable increase in morbidity. One patient had a pneumothorax which required prolonged underwater suction, and another had severe continuous pain that was thought to be due toirritation of the diaphragm by the chest tube. No problems occurred, either with fever and other manifestations of a reaction to this instillation of tetracycline or with prolonged drainage of fluid from the site of the insertion of the tube for drainage. The low morbidity agrees with the reports by Wallach" and by Rubinson and Bolooki" and contrasts with that by Anderson et al.3 The latter group prefers mechlorethamine as the sclerosing agent and reports results similar to ours.P Although not statistically significant, there is a strong trend in favor of drainage via a chest tube, but there is no clear advantage of tetracycline over alkylating agents as a means of securing pleurodesis (when measured as the time of freedom from recurrence ). The advantage of instillation of tetracycline lies in the fact that it does not interfere with the anticancer therapy and that as an antibiotic, tetracycline discourages the development of infection in the pleural cavity. The impression that the patients treated with drainage via a chest tube and therapy with tetracycline are doing better than those patients treated with a chest tube and therapy with alkylating agents may be related to the more aggressive chemotherapy practiced in the years of 1974 to 1977, compared
CHEST, 75: 1, JANUARY, 1979
with that between 1971 and 1973; however, there was no demonstrable difference in overall survival between the two groups of patients. The complexities of controlling for the influence of systemic treatment preclude a definitive analysis of its effect on the outcome of localized procedures, and the assumption has been made that the effect evens itself out as the number of patients in each group increases. We conclude that complete drainage of fluid by a chest tube, followed by pleurodesis with tetracycline, is an effective means of long-term control of pleural effusions in breast cancer and has an acceptable morbidity and that the technique is superior to therapeutic measures designed to alter the production or absorption of pleural fluid ACKNOWLEDGMENT: We thank Dr. Colin Ross, Thoracic Surgeon. for his advice on technical matters and the Medical Services Research Foundation of Alberta for a grant supporting the computerized registry of breast cancer.
REFERENCES 1 Fracchia AA. Knapper WH, Carey J. et al: Intrapleural chemotherapy for effusion for metastatic breast cancer. Cancer 26:626-629, 1970 2 Ariel 1M, Oropeza R, Pack GT: Intracavitary administration of radioactive isotopes in the control of effusions due to cancer. Cancer 19:1096-1102, 1966 3 Anderson CB, Roper CL. Ferguson TB: Management of pleural effusions, In Stoll BA (ed): Breast Cancer Management: Early and Late. Chicago, Year Book Medical Publishers, 1977, pp 175-183 4 Thorsrud GK: Pleural reaction to irritants: An experimental study with special reference to pleural adhesions and concrescence in relation to pleural turnover of fluid. Acta Chir Scand (suppl) 355:1-74, 1965 5 Rubinson R. Bolooki H: Intrapleural tetracycline for control of malignant pleural effusion. South Med J 65:847849, 1972 6 Wallach HW: Intrapleural tetracycline for malignant pleural effusions. Chest 68:510-512.1975 7 Dollinger MR: Management of recurrent malignant effusions. Cancer 22:138-147,1972 8 P.A.S.: Professional Activity System (manual). Ann Arbor, Mich, Commission on Professional and Hospital Activities, 1969 9 Burns PE, Kredentser S, Grace M. et al: Breast cancer in northern Alberta: A pilot study in computerized registration. Can Med Assoc J 116:1131-1135,1977 10 Burdette WJ, Gehan EA: Planning and Analysis of Clinical Studies. Springfield, Ill, Charles C. Thomas, 1970, PP 72-77 11 Mantel N, Haenszel B: Statistical aspects of the analysis of data from retrospective studies of disease. J Nat! Cancer Inst 22:719-748,1959 12 Anderson CB, Philpott GW, Ferguson TB: The treatment of maglignant pleural effusions. Cancer 33:916-922, 1974
PLEURAL EFFUSIONS IN BREAST CANCER 53
