Malignant Pleurisy Associated with Primary Lung Cancer Well Controlled by Pleurodesis Using Distilled Water

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1 CASE REPORT Malignant Pleurisy Associated with Primary Lung Cancer Well Controlled by Pleurodesis Using Distilled Water Mitsuaki Sekiya, Toshiji Ishiwata, Kaku Yoshimi, Tetsutaro Nagaoka, Yoshiteru Morio, Satomi Shiota, Tsutomu Suzuki, Kuniaki Seyama and Kazuhisa Takahashi Abstract The patient was an 84-year-old man patient diagnosed as malignant pleurisy associated with lung cancer. After drainage of the right pleural effusion, pleurodesis with distilled water was performed. Despite the enlargement of the primary lesion of the lung cancer during the follow-up period, the amount of pleural effusion did not increase for more than one year. No adverse effects associated with pleurodesis were noted. Pleurodesis with distilled water should be considered as one of the choices for treatment in the management of malignant pleurisy especially in elderly. Key words: pleuritis carcinomatosa, pleural effusion, hypotonic () () Introduction It is well known that malignant pleurisy is complicated with various malignant diseases. Massive pleural effusion aggravates the patient s cough and dyspnea, resulting in impairment of their quality of life (QOL). Lung cancer is the leading cause of malignant pleurisy, and 15% of lung cancer cases are complicated with concomitant pleural effusion at the time of diagnosis (1). Pleurodesis with chemical agents is often performed in patients with malignant pleurisy associated with lung cancer, especially for non-small cell lung cancer (NSCLC) due to the difficulty in management of malignant pleural effusion with systemic chemotherapy. As a consequence of acute pleuritis resulting from chemical pleurodesis, most patients have a high grade fever and pleuritic pain. Moreover, insertion of an adequate sized chest tube is necessary. Thus, we sometimes encounter difficulties in performing pleurodesis in patients with advanced age and/or poor performance status. Recently, Seto T et al. reported that instillation of cisplatin diluted with distilled water (DW) into the pleural space is effective in controlling malignant pleurisy caused by NSCLC (2). Additionally, it has been demonstrated that DW itself has an inhibitory effect on the growth of tumor cells in vitro (3). However, there are no cases reported to the best of our knowledge concerning malignant pleurisy associated with lung cancer treated with pleurodesis using DW alone. We herein present a case of malignant pleurisy associated with lung cancer where the pleural effusion was controlled with pleurodesis using DW over a long-term period. Case Report An 84 year-old-man was admitted to a different hospital due to chest oppression on effort in October He had a smoking history of 90 pack-year and past medical history revealed that the patient underwent surgery for esophageal cancer 17 years previously. After a series of examinations, diagnosis of unstable angina pectoris was established and chest radiograph revealed a mass located at S 6 region of the right lung. Then he was referred to our hospital for cardiovascular surgery for his heart condition. Although the mass identified in the lung was suspected of lung cancer, coronary-artery bypass surgery was first conducted in January 2006 due to the severity of the coronary artery disease. After discharge and postsurgical recovery, he was readmitted to our hospital for evaluation and treatment for his lung disease. We performed aspiration needle cytology under ultrasonic guidance for the mass located at S 6 of the right Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo Received for publication October 8, 2008; Accepted for publication January 28, 2009 Correspondence to Dr. Mitsuaki Sekiya, msekiya@med.juntendo.ac.jp 1051

2 A Figure2. Chest radiograph on re-admision showed a markedincreaseintherightpleuralefusion. B Figure1. Chestradiographrevealedamaslesioninthe righthilum oflungandrightpleuralefusion(1a).thoracic computedtomography(ct)revealedamaslesionlocatedat S 6 oftherightlungandrightpleuralefusion(1b). lung and the diagnosis for pulmonary adenocarcinoma was established. Moreover, we also detected a small amount of right pleural effusion (Fig. 1A). We aspirated the fluid and cytological examination confirmed the diagnosis for malignant pleurisy, class V (adenocarcinoma). His thoracic computed tomography revealed mediastinal lymphadenopathy (N 2) other than the primary lesion of lung cancer and right pleural effusion (Fig. 1B). His bone scintigraphy identified multiple bone metastases (M1). Thus, the clinical stage of the lung cancer was diagnosed as T4N2M1 stage IV. Due to his advanced age, underlying cardiac disease, and his will, he was discharged without undergoing any systemic chemotherapy and pleurodesis. In April 2006, he was readmitted to our hospital due to massive right pleural effusion identified on chest radiographic and complete atrioventricular (A-V) block on electrocardiogram. His vital signs revealed the blood pressure to be 150/60 mmhg, pulse rate of 70/minute, and body temperature of Neither anemia nor icterus was observed. Although no accessory sounds and cardiac murmurs were detected, vesicular sound at the right lower lung field was decreased on auscultation. His tumor marker, cytokeratin fragment 21-1 (CYFRA) was 10.6 ng/ml. The chest radiograph revealed a mass measuring 3.5 cm in diameter, at the middle lung field. Despite the fact that no increase in cardiac-thoracic ratio (CTR) was observed, massive right pleural effusion was detected (Fig. 2). On the day of admission, he received surgery for implantation of a pacemaker for treatment of his complete A-V block. Echocardiography was immediately performed to rule out congestive heart failure associated with AV block. Echocardiography confirmed that the wall motion of the left ventricle was not impaired on the basis of the value of left ventricular ejection fraction of 64%. In addition, the diameter of inferior vena cava was 13 mm, which is within the normal range. Moreover, the increase in pleural effusion was unilateral. Therefore, we speculated that the increase in pleural effusion resulted from the progression of malignant pleurisy and not due to congestive heart failure. It was thought to be risky to perform pleurodesis with chemical agents due to his advanced age and underlying cardiac diseases, which were treated within a few months. We then inserted a small bore catheter (14 gauge), which is usually used as a central venous catheter, into the pleural space. We, then, drained the right pleural effusion and removed a total amount of 2000 ml of bloody exudative fluid during two days. Then, we instilled 200 ml of DW into the pleural space via the chest tube and closed the tube immediately. We changed his posture every 15 minutes to an hour and then opened the tube to permit drainage of the fluid. After drainage of the residual fluid and instilled DW, we removed the tube. We observed no adverse effects, such as fever, pain, and significant changes in laboratory data (Table 1), associated with instillation of DW. His clinical symptom, dyspnea immediately improved. The following day, he was discharged and followed up without administration of any systemic chemotherapies. Approximately one year has passed without treatment since undergoing pleurodesis with DW, we detected no increase of the right pleural effusion in spite of the marked enlargement of his primary lesion, the lung cancer (Figs. 3A, 3B). He died of pneumonia 15 months after undergoing pleurodesis with DW. 1052

3 Table1. LaboratoryDatabeforeandafterPleurodesiswithDW Before pleurodesis with D.W (April 17 th ) <Hematology> WBC /L After pleurodesis with D.W (April 19 th ) <Hematology> WBC /L Neu 64.9% Lym 23.8% Eo 3.6% Neu Lym Eo Hb 11.3 g/dl Plt /L <Blood chemistry> AST 21 IU/L ALT 11 IU/L LDH 250 IU/L γgtp 14 IU/L BUN 25.0 mg/dl Cre 1.23 mg/dl Na 135 mmol/l K 4.3 mmol/l Cl 96 mmol/l <Serology> CRP 4.7 mg/dl Hb 11.8 g/dl Plt /L <Blood chemistry> AST 22 IU/L ALT 13 IU/L LDH 263 IU/L γgtp 14 IU/L BUN 26.0 mg/dl Cre 1.35 mg/dl Na 134 mmol/l K 4.3 mmol/l Cl 94 mmol/l <Serology> CRP 5.5 mg/dl : not available Discussion Pleural effusion is known to be produced from the parietal pleura and absorbed into the visceral pleura. In general, the balance between production and absorption of fluid is spontaneously achieved, thus, pleural effusion is maintained at the level of 5-20 ml in normal subjects (4). In patients with malignant pleurisy, both increased production of fluid in the pleural space and decreased absorption of fluid into the visceral pleura are postulated to be the main mechanisms involved. The conventional chemical pleurodesis is the treatment that leads to the decrease of the pleural space by adhesion between the visceral and parietal pleura using chemical agents, such as OK-432 (5, 6, 8), talc (7, 8), and so on. Although the success rates of pleurodesis using OK- 432 and talc are 88% (5) and over 90% (8), respectively, these procedures are often accompanied with the incidence of the chest pain and high grade fever. Moreover, in order to perform pleurodesis, the insertion of an appropriate sized catheter is necessary since pleurodesis induces a temporary increase in fluid production for several days. Although Fr sized catheters are considered to be appropriate, it has been reported that there is no significant difference in the success rate of pleurodesis between the groups using smallbore catheter, such as 12 Fr, and that with standard sized catheter (9). However, a very small-bore catheter should be avoided since continuous drainage of the temporarily increased fluid is required for several days after chemical pleurodesis. In addition, we often encounter difficulties in insertion of the drainage tube, even a small-bore tube in elderly patients with a poor general state. In the present case, we used a small-bore catheter, 14-gauge. This small bore catheter did not cause any pain during insertion. Absolutely, no increase in production of fluid was observed after instillation of DW. Recently, it has been reported that pleurodesis using lowdose cisplatin diluted with DW (hypotonic cisplatin treatment) is effective for malignant effusion resulting from NSCLC (2). This phase II study demonstrated that overall response rate of the hypotonic cisplatin treatment was 83% in respect to the control group with pleural effusion. This finding indicates that hypotonic cisplatin treatment is comparable with the conventional chemical pleurodesis. One possible mechanism supporting the effectiveness of this treatment is considered to be the hyposmotic cytotoxic effect of DW itself. Ichinose Y et al. demonstrated that approximately half of the cancer cells were killed by DW in vitro. Additionally, the cell growth was shown to be markedly inhibited up to 80% in the control group (3). Fujishima et al. 1053

4 A B Figure3. Afteroneyearofpleurodesis,bothchestradio graph(3a)andct(3b)revealedamarkedincreaseinthe sizeofthepulmonarytumor.however,noincreaseinpleural efusionwasobserved. References reported that pleurodesis using DW was effective in two patients with malignant effusion complicated with breast cancer (10). Although they were followed up for only 30 days after pleurodesis, this period is sufficient to reveal the cytotoxicity and the inhibitory effect of DW on the cell growth of cancer cells (3). In the present case, a detailed mechanism of pleurodesis with distilled water was unclear due to refusal to consent for autopsy. No localized pleural effusion, which is often observed after usual chemical pleurodesis, was detected with thoracic CT. Therefore, it was speculated that the cytotoxic effect against cancer cells mainly contributed to the control of right pleural effusion. Additionally, in part, pleural adhesion resulting from inflammation due to impairment of mesothelial cells of pleura could occur. Palliative thoracentesis is often performed to relieve a clinical symptom, such as dyspnea. The possibility might be excluded that that the present case had spontaneous remission of malignant pleural effusion after palliative thoracentesis (11). However, recurrence of pleural fluid occurs in % of all patients not receiving pleurodesis for malignant pleurisy. There was no increase in the right pleural effusion observed for more than one year during the follow-up period, despite the fact that there was no palliative thoracentesis performed or systemic chemotherapy administered. This suggests that the inhibitory effect on the production of pleural effusion resulted from pleurodesis using DW. To our best knowledge, there are no reports that describe such a case like the present case which was followed for such a long period treated with pleurodesis using DW. In the present and previous reported cases (10), no adverse effects with the instillation of DW occurred. On the other hand, it has been reported that 77% of cases who underwent pleurodesis with OK-432 complained of high grade fever of more than 38. Additionally, in patients with pleurodesis using other commonly used agents, such as talc, doxycycline, tetracycline, and bleomycin, adverse effects, such as chest pain (7-43%) and fever (16-59%), are commonly observed. Even in patients treated with hypotonic cisplatin treatment, the incidence of adverse effects over grade 1 was not so low, i.e. nausea (43.8%), vomiting (20%) and fever (13.8%) (2). On the basis of the in vitro study (3), it is possible that the success rate of the pleurodesis using DW could be inferior to hypotonic cisplatin treatment. However, in the elderly with a poor general state, pleurodesis using DW may be more suitable than the hypotonic cisplatin treatment in terms of the safeness of the treatment. Infectious pleurisy is known to be one of possible complications arising secondary to thoracentesis. In the present case, after instillation of DW into the pleural space, no clinical symptom, such as fever, chest pain or a significant increase in C-reactive protein was seen. Moreover, although we did not use any antibiotics before and after pleurodesis, the pleural effusion did not increase. Therefore, we consider that successful management of the effusion in the present case is not due to the pleural adhesion resulting from temporal infectious pleurisy complicated with palliative thoracentesis. In conclusion, pleurodesis with DW should be considered for the management and control of malignant pleurisy in the elderly or in patients with a poor general state. Presently, there is not enough data to analyze the efficacy and mechanism of this treatment; further investigation and evaluation are necessary. 1. Light RW. Pleural disease. Williams & Wilkins, Baltimore, Seto T, Ushijima S, Yamamoto H, et al. Thoracic Oncology Group. Intrapleural hypotonic cisplatin treatment for malignant pleural effusion in 80 patients with non-small-cell lung cancer: a multi-institutional phase II trial. Br J Cancer 95: , Ichinose Y, Hara N, Ohta M, et al. Hypotonic cisplatin treatment for carcinomatous pleuritis found at thoracotomy in patients with lung cancer. In vitro experiments and preliminary clinical results. J Thorac Cardiovasc Surg 105: , Black LF. The pleural space and pleural fluid. Mayo Clin Proc 47: , Luh KT, Yang PC, Kuo SH, Chang DB, Yu CJ, Lee LN. Comparison of OK-432 and mitomycin C pleurodesis for malignant pleural effusion caused by lung cancer. A randomized trial. Cancer 69: 1054

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