Treatment of Malignant Pleural Effusion

Treatment of Malignant Pleural Effusion* Khaled Reshad, M.D .; Kenji lnui; Yoshiki Takeuchi; Yutaka Takahashi; and Shigeki Hitomi , M.D. , F.C.C.P.t

1\vo hundred consecutive patients with malignant pleural

effusion were reviewed. The pathologic etiology of malignant pleurisy was: primary lung cancer in 123 cases; five, mesothelioma; and 72 cases secondary to metastatic tumors. Adenocarcinoma of the lung and mammary cancer were the most frequent tumors causing malignant pleural effusion. The modalities employed in local treatment consisted of thoracocentesis in 62 patients, tube thoracotomy in ill cases with local instillation of adriamycin, MMC, CQ, 5FU, OK432 or talc. Surgical procedures including pleuropneumonectomy or reduction surgery of the tumor with decortication were performed in ten patients. Tube drainage with

Carcinomatous pleurisy is not uncommon as a manifestation of cancer, and often results in significant pulmonary and cardiac insufficiency threatening the life of the patient. The ideal treatment is to remove the fluid, and also to prevent the reaccumulation of effusion. Despite the many methods tried in the past and in use today, no single method of treatment is entirely satisfactory. Various methods have been advocated to prevent this recurrent fluid, including multiple thoracocentesis or tube pleural drainage with or without injection of antineoplastic agents , radioactive isotopes and sclerosing materials such as talc, quinacrine and tetracycline. Radiation to the chest wall, open thoracotomy with decortication, and pleurectomy have also been described. This report presents a review ofour experience since 1975 with a series of 200 consecutive patients with carcinomatous pleurisy. The results were analyzed to determine the effect of therapy and its significance in prognosis. CLINICAL MATERIAL AND METHODS

Diagnosis

of Malignont

Pleurisy

The diagnosis of malignant pleurisy was provided by chest x-ray film, chest computed tomography, and cytologic examinations of the pleural fluid obtained by initial thoracocentesis. More invasive diagnostic procedures such as needle biopsy, pleuroscopy or pleural biopsy during open drainage and decortication were performed in patients with several negative cytologic investigations of pleural effusions. The records of 200 consecutive patients treated at Kansai Denryoku Hospital , Tenri Hosp ital and Shimada Municipal Hospital *From the Department of Chest Diseases, Shimada Municipal Hospital , Shimada City, Japan . tChest Diseases Research Institute, Kyoto University, Kyoto, Japan. Manuscript received November 19; revision accepted February 26. Reprint requests: Dr. Beshad , 1200-5 Noda , Shima Municipal Hospital , Shimada City, Shizuoka , Japan 427

local instillation of drugs was more effective than thoracocentesis with or without local therapy. Excellent initial results were obtained in patients who received reduction surgery with decortication and pleurodesis. Results of cytologic investigation were positive in 157 cases (78.5 percent), The tumor cells disappeared in 79.4 percent of primary cancer pleurisy cases and 81.1percent of patients with metastases while disappearance or signi6cant decrease in pleural effusion following treatment was obtained in 75.2 and 77.8 percent respectively. The median survival was n.3 months in primary cases, and n.7 months in patients with metastases.

for malignant pleural effusion between January, 1975and December, 1983 were reviewed in this series . There were 123 malignant pleural effusions due to primary lung cancer with an average patient 67.8 years of age, ranging from 32 to 85 years. Seventy-six patients were men and 47 were women . Nine patients had bilateral malignant pleural effusion; 65 had right sided, and 49 had left sided hemithorax. The histologic distribution of primary lung cancer causing malignant pleural effusion is listed in Table 1. Malignant pleurisy secondary to metastatic tumors and mesothelioma involved 52 women and 25 men, of which 29 were right-Sided , 32 left-sided and 16 bilateral pleurisy. The ir average age was 53 years, with the range 13 to 84 years. The pathologic etiology of metastatic malignant pleurisy is listed in Table 2. A variety of modalities was employed in local treatment of malignant pleural effusion. They included thoracocentesis or tube intercostal drainage with or without instillation of antineoplastic drugs , sclerosing agents, and surgical procedures such as pleurapneumonectomy (Table 3). Thoracocentesis was applied in 62 patients, four times pe r patient on average , and tube intercostal drainage was performed in ill cases with an average of 16 days of therapy. Ten patients were subjected to surgical procedures which included pleuropneumonectomy in four cases, and lobectomy or partial resection of the primary site of the tumor with decortication and pleurodesis in six patients with malignant pleural effusion. Palliative therapy with a systemic chemotherapy without local instillation was performed in 16 patients because of rejection of the local therapy. The drugs instilled into the pleural cavity during tube drainage were adriamycin (20 mg), mitomycin C (10 to 20 mg), 5FU (500 mg) and carbazilquinone (10mg) as antineoplastic drugs ; OK432 (10to 20 KE) as an immunotherapeutic agent and talc or tetracycline as sclerosing materials . These agents were selected randomly and used singly or in combination, dissolved in 20 ml of saline solution and injected into the pleural cavity through a chest tube which was then

Table I-Histology ofCarcinomatom Pleurisy (Primary Lung Cancer, 123 Cases)

Adeno car Sq cell car Large cell car

71 24 7

Small cell car Alv cell car Others

CHEST I 88 13 I SEPTEMBER, 1985

6

5 10 393

Table 2-Histology ofCarcinomat0fJ8 Pleurisy

Table 4-Treatment Effectiveness in Carcinomat0fJ8 Pleurisy

Metastatic Tumors and Mesothelioma (77 Cases) Mammary c Gastroint t Utero-ovar t Mal Lymph Mal Thym

3 2 2 2 5

Thyroid t Sarcomas Kidney t Others Mesoth

25 22 6 5 5

Table 3-Treatment ofCarcinomat0fJ8 Pleurisy Palliative therapy Thoracocenteses

17 Cases 62 Cases (Av 4 times/pt) 111 Cases (Av 16 days/pt) 10 Cases

Tube thoracostomy Surgical operation

clamped for two hours . The patient's position was varied every few minutes to ensure the contact of the drugs over the entire pleural cavity. The chest tube was reconnected under water-sealed drainage, and 15 cm of constant water suction was used. The intercostal drainage tube was removed when the chest roentgenograms indicated full reexpansion of the lungs . In some cases, thoracography through the chest tube was performed to evaluate the appropriate time for removal of the drain . RESULTS

Results of Cytologic Investigations

Results of cytologic investigation of the pleural effusion showed that 157 of the 200 effusions were positive for tumor cells (78.5 percent). Needle biopsy of the pleura was performed 22 times in 18 patients with 12 positive results (55.5 percent). When the results of cytologic investigations and needle biopsy failed, pleuroscopy was performed in nine cases with eight positive pleural biopsies ; open biopsy during surgical procedures was performed in ten cases with 100 percent positive results . Disappearance of Tunwr Cells and Control of Pleural Effusion with Survival Time in Relation to Treatment

The results of treatment in 183patients who received

Primary Ca Pleurisy Metastatic Pleurisy

Disappearance of Tumor cells in PI Fluid

Decrease of PI Fluid

Survival TIme (Months)

79.4%

75.2%

11.3

81.1%

77.8%

11.7

local instillation ofantineoplastic drugs , immunotherapeutic agent or sclerosing materials are listed in Table

4.

Disappearance or significant decrease of pleural fluid stable fur more than four weeks was evaluated as effective treatment according to the Japan Lung Cancer Society. In our protocol, significant decrease constitutes a 75 percent decrement in treated pleural effusion. One hundred thirty-seven of 183 primary lung cancer, mesothelioma and metastatic pleural effusions responded to therapy. In contrast, the effectiveness of systemic chemotherapy in patients who did not receive local instillation of the drugs was 50 percent in both primary and metastatic pleural patients. The survival time of those responding to local therapy was 11.3 months on average in primary cancer patients, and 11.7 months in patients with secondary pleurisies due to metastatic lesions (p
Various antineoplastic drugs have been used in attempts to treat malignant pleural effusion. Although these drugs have specific antitumor activity and also have the ability to cause pleural sclerosis and obliteration of the pleural space, doses used were the same as the usual systemic doses. A local combination chemotherapy along with chest tube drainage provided in 103 cases.

Table 5-Treatment Effectiveness and Survival Time (Chemotherapy) in Primary LC Pleurisy (%)

Systemic Chemotherapy Only Systemic Chemoth.

in Metastatic Pleurisy (%)

Number

(n=85)

Survival TIme (Months)

Number

(n=55)

Survival TIme (Months)

9

50.0

3.9

7

50.0

4.0

28

79.0 67.7 85.0 75.0 85.0 80.0

14.8 7.8 10.6 9.5 14.0 12.0

15 10 4 5 8 6

90.0 75.0 60.0 95.0 100.0 80.0

12.8 5.0 10.0 11.2 10.3 13.5

+ Local Chemoth. MMC ADM MMC+ADM MMC+5FU CQ+5FU Others

394

18 4 4 19 3

batment of Malignant Pleural Effusion (Rashad et aI)

Table 6-Treatment Effectiveness and Survival Time (Chemotherapy + Immunotherapy) in Primary LC Pleurisy (%)

in Metastatic Pleurisy (%)

Numbe r

(n=38)

Survival lime (Months)

16 10

83.4 55.0

12.2 6.2

9 5

71.5 75.0

12.0 7.0

2

75.0

7.5

3

67.0

8.0

4 6

90.0 67.7

9.8 4.5

1 3

88.0 67.7

11.3 5.0

MMC+OK432 ADM+OK432 MMC+ADM +OK432 Others +OK432 OK432

Table 5 shows the treatment effectiveness and survival time of140 patients, who received antineoplastic drugs by local instillation (124 cases), compared with those who received systemic chemotherapy without local instillation of the drugs (16 cases). Improvement in 67 to 85 percent of primary cancer patients and in 75 to 100percent of metastatic pleurisy was obtained by intraple ural instillation of antineoplastic agents . More successful therapeutic response with intrapleural instillation of MMC singly and CQ plus 5FU therapy in combinat ion was obtained in 79 to 90 percent and 85 to 100 percent of primary lung cancers and metastatic pleural effusions, respe ctively (p
Adenoc.r ,

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pleurally instilled chemoimmunotherapeutic agents is shown in Table 6. The effectiveness of these agents in 38 primary lung cancer patients varied from 55 to 90 percent and 67 to 88 percent in 21 patients whose pleural effusion was secondary to metastatic tumor. Although all combinations showed better improvement rates than OK432 instilled alone, there was also a significant difference in survival time between these two groups (p<0.01). Treatment Effectiveness and Survival TIme in Relation to Tunwr Type

The response to local treatment according to tumor type in primary lung cancer and methothelioma is shown in Figure 1. Sixty seven patients with primary adenocarcinoma treated with local instillation of chemotherapeutics, immunotherapeutic or sclerosing agents showed tumor cells in the pleural fluid becoming negative in 49 patients (73.5 percent) and pleural effusion disappearing in 48 patients (72 percent). The

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FIGURE 1. Effectiveness of local treatment and survival time (primary lung cancer, 113 cases; mesothelioma, five cases).

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CHEST I 88 I 3 I SEPTEMBER, 1985

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cancer and one with malignant mesothelioma underwent pleuropneumonectomy. One patient died suddenly one month after surgery, and two patients two to three months after the operation. The last patient survived for eight months . Because of this high mortality rate after pleuro-pneumonectomy, two patients were subjected to lobectomy and pleurodesis after decortication of the pleura, and four patients to partial resection of the tumor with pleurodesis. Two patients who received partial resection with pleurodesis died ten and 24 months after surgery. Four patients are alive six, ten , 18, 36 months after this procedure with no recurrence of malignant effusion (Fig 3). Mitomycin C and OK432 insufflation over the pleural surface was performed during open thoracotomy to prevent the recurrence of malignant pleural effusion. DISCUSSION

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effectiveness of the treatment shown by disappearance of tumor cells and significant decrease of pleural fluid was 77 and 74 percent in squamous cell carcinoma, both 83 percent in large cell carcinoma, and 67.7 percent in other types of primary malignancies respectively. The mean survival time was 17 months in small cell carcinoma, with the longest survival time 58 months. The mean survival time was 11.3 months on average in all patients with primary cancer pleurisy. Figure 2 shows the effectiveness and survival oflocal instillation of drugs in 65 patients with pleural effusion secondary to metastatic tumors. The median survival time in 23 breast cancer patients was 18.2 months after drug instillation, with 85 percent disappearance of the tumor cells in pleural effusion and decrease of pleural fluid. On the whole, the tumor cells disappeared in 54 of65 patients (81.1 percent), and in 49 of65 patients the pleural effusion disappeared or decreased; the mean survival time was 11.7 months. Surgical Procedures Against Malignant Pleural Effusion

Pleuropneumonectomy has been shown to be highly effective in patients with malignant pleural effusion who experienced recurrences after other methods of treatment. However, persistent air leakage, bleeding, pneumonia, empyema and decreased pulmonary function or secondary heart failure complicated more than 20 percent of the cases postoperatively, and mortality from this procedure is also high. Four patients with malignant pleural effusion, three with primary lung

Malignant pleural effusion is a common complication of malignant diseases, occurring in 50 to 70 percent of all cancers in the course of the illness. Although the exact pathogenesis of malignant pleural effusion is often obscure, direct invasion of the pleura by tumor cells and obstruction of lymphatic and venous channels are probably the usual mechanisms. Some malignant pleural effusion may respond to effective systemic chemotherapy, but too often malignant effusion remains intractable. There continue to be various therapies advocated for the treatment of malignant effusion. Each therapy has some level of morbidity and mortality, so it is difficult to determine which therapy is most beneficial to the patient. It is now generally accepted that repeated thoracocentesis is inferior to other forms of therapy because it leads to protein depletion, high risk of infection, trapped lung, etc . Tube thoracotomy with continued evacuation, especially with instillation of different types of agents, is a much more effective method. Adler and Sayenk' reported that talc powder controlled malignant pleural effusion when intruded at the time of open thoracotomy. Also, insuffiation of talc powder over the pleural surface through a tube thoracotomy has been described by [ones" with initial success in 90 percent of patients. Other sclerosing agents such as quinacrine and tetracycline have been administered for treatment of malignant pleural effusion with good to excellent results. Rocklin et al," Borja and Pugh,' and Hickman and [ones" reported successful treatment with quinacrine instillation intrapleurally. Nitrogen mustard has been used most frequently in the treatment of malignant effusion. Kinsey et al" reported complete control of pleural effusion from various metastatic tumors, and Leininger et aF achieved successful results in 90 percent of patients 1leatmenl 01 Malignant Pleural Effusion (Reshad st eJ)

with the instillation of nitrogen mustard into the pleural space through a tube thoracotomy, but Anderson and coworkers" obtained poor response with intracavitary administration of this drug in lymphomatous pleurisy. Adriamycin, carbazilquinone, mitomycin C, bleomycin and 5FU were instilled into the pleural cavity by several authors't" with results varying from good to excellent. Immunotherapeutic agents such as Norcadia CWS or OK432 were instilled via the intracavitary route by Saijo et al," Nagao," Ohta et al" and Egawa and Meguro." Successful initial results obtained in 15 out of 18 patients (83 percent), who received Norcadia CWS instilled intrapleurally have been reported by Saijo." The median survival period was six months and the most effective case survived for 27 months when OK432 was locally instilled in patients as reported by Nagao." Successful treatment results were obtained in up to 90 percent of the patients in our series, with a longer median survival period than in these reports. Instillation of radioactive isotopes into the pleural cavity has been reported to give improvement in 30 to 90 percent of cases . Sixty percent of patients with malignant pleural effusion were controlled with pleural drainage and 32p given intrapleurally in the study by Izbicki et al. 17 However, the use of radioactive isotopes is not available in ordinary hospitals and may constitute a radiation hazard to hospital staff. Pleuropneumonectomy has been shown to be a highly effective treatment for patients with malignant pleural effusion in properly selected patients." Martini et al12 performed this procedure in patients who had recurrent pleural effusion after other methods of treatment, and obtained successful results in 90 percent, but the mortality from this method is about 10 to 20 percent for the high incidence of postoperative complications. In our series, successful treatment results were obtained in up to 90 percent of primary cancer pleurisies and up to 100 percent in metastatic tumors, who received chest tube drainage with local therapy. Multiple drug instillation into pleural space was more effective in obliterating pleural fluid than single agent instillation. There was a high response rate obtained with intrapleural instillation of MMC combined with any other agent and CQ plus 5FU. Also, we achieved successful results in most of the patients who had a short interval between diagnosis and local therapy. In contrast, in most of the patients who failed to have obliteration the pleural effusion, trapped lung due to therapy delay was frequently the responsible reason. We obtained excellent initial results in definite lung resection with pleurodesis in malignant pleural effusion patients in whom other treatment methods were ineffective, but when this procedure is too radical and definitive for a majority of patients with malignant

pleural effusion, it should be kept for situations where conservative approaches have failed . We conclude that, since the general approach to treatment of malignant pleural effusion is mostly palliative for alleviation of the symptoms, the method selected for treatment should be highly effective with low morbidity and mortality. Consequently, we recommend aggressive and immediate action consisting of chest tube drainage and local instillation of antineoplastic or immunotherapeutic agents in treatment of malignant pleural effusion, which may possibly prevent trapped lung in subacute cases. Also, a careful search for factors contributing to effusion or treatment of effusion such as decreasing pulmonary function, secondary heart failure, protein depletion or infection should be performed. REFERENCES

1 Adler RH, Sayenk I. Treatment of malignant pleural effusion: A method using tube thoracotomy and talc. Ann Thor Surg 1976: 22:8-15 2 Jones GR. Treatment of recurrent pleural effusion by iodized talc pleurodesis. Thorax 1969: 24:69-76 3 Rocklin DB, Smart CR, Wagner DE , Silvia ARM. Control of recurrent malignant effusions using quinacrine hydrochloride. Surg Gynecol Obstet 1964: 118:991-94 4 Borja RR, Pugh RP. Single dose quinacrine (Atabrine) and thoracotomy in the control of pleural effusions in patients with neoplastic diseases . Cancer 1973: 31:899-902 5 Hickman JA, Jones MC. Treatment of neoplastic pleural effusions with local instillation of quinacrine (Mepacrine) hydrochloride. Thorax 1970: 25:226-29 6 Kinsey DL, Klassen Kp, Carter D. Simplified management of malignant pleural effusion. Arch Surg 1964; 89:389-92 7 Leininger BJ, Barker WL , Langston NT. A simplified method for management of malignant pleural effusion. J Thorac Cardiovasc Surg 1969: 58:758-63 8 Anderson CB, Philpott GW, Ferguson TB. The treatment of malignant effusions. Cancer 1974; 33:916-22 9 Ohta M. Treatment of pleural effusion. Geka MOOK 1982: 25:114-21 10 Leff A, Hopewell PC, Costello J. Pleural effusion from malignancy, Ann Intern Med 1978; 88:532-37 11 Reshad K, Kitano M, Hitomi S. 'freatment of carcinomatous pleurisy and pleural permeability of anticancer agents . Jap J Lung Can 1982; 22:139-51 12 Martini N, Bains MS, Beattie EJ Jr. Indications for pleurectomy in malignant effusion. Cancer 1975: 35:734-38 13 Saijo N, Eguchi K, Tominaga K. Shinkai T, Shimizu E. Shibuya A. A randomized trial using NCWS in treatment of malignant pleural effusion. Gann to Kagakuryoho 1983: 10:290-95 14 Nagao K. Studies on treatment of pleural cinomatosis, with special reference to effect of OK432. Chiba Med J 1982; 58:345-53 15 Ohta K, Oyama A, Kurita S, Nishimura M, Ogawa M, Kamei Y. Effect of hemolytic streptococcal preparation OK432 on pleuritis and peritonitis carcinomatosa. Gann to Kagakuryoho 1980: 2:255-65 16 Egawa N, Meguro T. Local instillation of OK432 in treatment of malignant effusions. Shindan to Shinyaku 1982; 19:201-04 17 Izbicki R, Weihing BT, Baker L, Caoili EM, Vautkevicius VK. Pleural effusion in cancer patients. Cancer 1975: 36:1511-18 18 Takagi K. Cases of pleural carcinomatosis undergoing panpleuropneumonectomy. Japan J Lung Cancer 1981: 21:161-75 CHEST I 88 I 3 I SEPTEMBER, 1985

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