Hong Kong Respiratory Medicine

Dr. Chee-Wung CHOW, Dr. Maureen ML WONG
Department of Medicine &Geriatrics , Caritas Medical Centre
Malignant pleural effusion (MPE) is a common and devastating complication of advanced malignancy, with an estimated annual incidence in the United States of over 150,000 patients [1]. Lung cancer is the most common metastatic tumour to the pleura in men while breast cancer is the most common cause of MPE in women. Both malignancies account for 50-65% of all malignant pleural effusions. Other common primaries are lymphoma, gastrointestinal cancer and mesothelioma [2]. The presence of MPEs in patients with non-small cell lung cancer (NSCLC) signify grave prognosis and upstage the classification from T4 (stage IIIB) to M1a (stage IV); patients with stage IV NSCLC has a median survival time of 6 months and a 5 year survival of 2% [3].

The common clinical manifestations of MPEs are dyspnea, cough, chest discomfort, pressure or pain but up to 25% patients may be asymptomatic [4].
The pathogenesis of the MPEs include direct extension of malignant cells from neighbouring structures, invasion of the pulmonary vasculature with embolisation of tumour cells to the visceral pleurae, or haematogenous metastasis from distant tumour to parietal pleurae. Tumour seeding to parietal pleurae and obstruct the lymphatic stomata which drain the intrapleural fluid. Pleural tumour deposits also stimulate cytokines release that increase vascular & pleural membrane permeability. [5]

Diagnosis of MPEs should be multimodal including clinical, radiological and pathological. Pleural computed tomography (CT) is important in distinguishing malignant from benign pleural disease with a sensitivity and specificity of 72% and 83% respectively [6]. CT findings suggestive of MPEs include circumferential pleural thickening, nodular pleural thickening, parietal pleural thickening more than 1cm, and mediastinal pleural involvement. Chest ultrasonography is complimentary to pleural CT. The relevant findings include solid pleural densities, hypoechoic pleural thickening with irregular borders, invasion of pleura-based masses into neighboring structures, and swirling patterns within pleural fluid that represent cellular debris [5].

An examination of the pleural fluid or a diagnostic biopsy of the pleura is required to confirm malignant pleural effusion. Diagnostic thoracentesis with pleural fluid tested for cell count, protein, lactate dehydrogenase, pH & cytology is recommended.
• The combined measurements of CEA, CA 15.3 & TAG 72 in pleural fluid have a sensitivity of 75% and a negative predictive value of 79% [6].
• pH values correlate with survival. In one study, patients with pleural fluids with pH <7.28 had a 3 month survival of 38.9% compared with 61.6% for patients with pleural fluids with pH >7.28 [7].
• The majority of MPEs are lymphocyte-predominant and about 30% have pH < 7.30 [6].
• Cytological examination of pleural fluid has an overall diagnostic yield of 62% for MPEs. Closed pleural biopsy has a yield of 44% for MPEs. Combination of both increases the diagnostic yield of MPEs to 74%. The diagnostic yield for medical thoracoscopy approaches 95% [8].

There are several factors to be considered in the management of MPEs such as patients’ symptoms, functional status, life expectancies and the types of tumour responsible for the MPEs. The goals of treatment can vary to include: relief of distressing symptoms such as dyspnea; reduction of morbidity; and promotion of independence by avoiding unnecessary clinic visits and hospital stay. Options for management include observation, therapeutic pleural aspiration, intercostal tube drainage and instillation of sclerosant, thoracoscopy and pleurodesis or placement of an indwelling pleural catheter [9].

Observation is recommended if the patient is asymptomatic and the tumour type is known. Therapeutic thoracentesis is typically the first step in managing MPE. It is recommended that 1-1.5L of fluid is aspirated at one setting [2]. It allows confirmation that MPE is the major cause for dyspnoea as considerable number of patients may not have significant improvement in breathlessness after thoracentesis. Other possible causes for dyspnea include microtumour emboli, lymphangitic cancer, airway obstruction, presence of extensive tumour with lung restriction, pericardial effusion or associated comorbidities or lung entrapment [5, 10].
Ideally, thoracentesis is performed with intrapleural pressure measurement. In Feller’s study, the relationship of pleural pressure to symptom development during therapeutic thoracentesis was being described. 29 of the 169 patients (17%) developed symptoms in which 11 patients had cough while 18 patients had chest discomfort. 4 of the 18 patients who developed chest discomfort had pleural pressure greater than -20cm water, which was a potentially dangerous level. This supported the practice of stopping thoracentesis in any patients who developed chest discomfort during the procedure when a potentially unsafe negative pleural pressure was reached [11].

However, the pleural fluid and symptoms recur in over 90% of patients within 30 days and repeated thoracentesis is recommended for patients with short life expectancy, poor performance status or for those patients with advanced disease[10].

For patients with longer life expectancy, chest tube thoracotomy and chemical pleurodesis with talc is the standard of care for the management of MPE in the United States and many countries [10]. There is no consensus on the optimal agent or the method of pleurodesis. According to a survey on five English speaking countries including 859 pulmonologists from the United States, United Kingdom, Canada, Australia and Zealand, there were more than 8,300 pleurodesis performed annually and talc was the preferred agent (talc slurry 56% & talc pourdage 12%) , followed by tetracycline derivatives 26% and the bleomycin 7%. The reported success rate was averaged at 66%. Talc was perceived as significantly more effective but was associated with more pain and fever [12]. The action of talc on pleurodesis includes promotion of angiogenesis and stimulation of mesothelial cells to release fibroblast growth factor, interleukin-8 (IL-8), vascular endothelial growth factor, transforming growth factor and other proinflammatory mediators to stimulate pleural fibrosis. Talc poudrage had been believed to be superior to talc slurry but it was not supported by Dresler’s study. 242 patients with MPEs were randomized to talc insufflation (TTI) via thoracoscopy & 240 patients received talc slurry (TS) via thoracostomy. There was no significant difference between study arms in the percentage of patients with successful 30-day outcomes (TTI 78% vs TS 71% with p=0.169) [13].

Large-bore (24-32Fr) chest tubes were traditionally employed for chemical pleurodesis but randomized trial on efficiency of small-bore (10-14Fr) catheters for drainage and sclerotherapy of MPEs all concluded that they were equivalent. Patient rotation is not necessary after intrapleural instillation of sclerosant. The chest drain should be clamped for 1 hour after sclerosant administration [2]. Intercostal tube removal has been recommended when fluid drainage was less than 150ml/day but there is little evidence to support this practice. Goodman and Davies randomized patients with MPE to 24-hour versus 72-hour drainage following talc slurry pleurodesis regardless of volume of fluid drained. There was no difference in the success of pleurodesis (no recurrence of pleural effusion on CXR at one month) for the two groups but the length of stay was significantly reduced when the chest drain was removed at 24 hours (4 days versus 8 days, p< 0.01). They concluded that the shorter pleurodesis regime is safe and effective [14]. Early removal of intercostal tube within 24-48 hours after instillation of scleroscant is recommended, provided the lungs remained fully re-expanded and in the absence of excessive fluid drainage (less than 250ml/day) [2].

The safety of talc has been questioned and there were reports of acute respiratory distress syndrome (ARDS) following intrapleural instillation of talc [15]. The talc particle size actually matters and Maskell & Lee found that pleurodesis with mixed talc (50% < 10um) caused a greater systemic inflammatory response than graded talc (50% > 25um) as evidenced by more profound hypoxemia and significant lung inflammation. The severe hypoxia & ARDS could likely be minimized by using graded talc with the smallest particles removed [16]. Another prospective cohort study with 558 patients recruited shared similar findings. All patients undergoing thoracoscopic talc pleurodesis received large particle talc (mean particle size 24.5um, Novatech, La Cuotat, France). No patients developed acute respiratory distress syndrome (ARDS). Only one patient developed respiratory failure which was not related to ARDS. There was small increase in temperature & oxygen use after talc pleurodesis but they were not clinically significant [17]. Newer pleurodesis agents such as Lipoteichoic acid T (LTAT), Staphylococcal Superantigen (SSAg) & Iodopovidone were still under clinical trials.

Medical thoracoscopy (pleuroscopy) refers to a minimally invasive procedure which allows the pulmonologist to examine the pleural space in a spontaneously breathing patient under conscious sedation with local anesthesia. It typically involves the insertion of a rigid or semirigid pleuroscope through a single port into the pleural space, with evacuation of pleural fluid, biopsy of parietal pleural lesions, and insufflation of sclerosant into the pleural space. The procedure is safe and well tolerated. Complications include empyema, subcutaneous emphysema, and fever [18].

Video-assisted thoracic surgery (VATS) requires general anesthesia and single-lung mechanical ventilation. It is contra-indicated for patients who cannot tolerate single-lung ventilation. It allows thorough inspection of the pleural cavity, adhesiolysis, biopsy of the pleura or lung, if indicated. VATS with talc pourdage is an effective and safe procedure that yields a high successful rate and achieves a long-term control of MPE [19].
Indwelling pleural catheter (IPC) drainage is a less expensive, minimally invasive, and palliative modality for the management of MPEs developed over the last decade. It was approved by the US Food and Drug Administration in 1997. The pleural catheter is a 66cm long, 15.5Fr, silicone rubber catheter with fenestrations along the distal 24cm. A valve at the proximal end of the catheter prevents fluid or air from getting through the catheter until the matched drainage line is properly attached. A polyester cuff helps prevent infection & secures the catheter in place by inciting granulation in the subcutaneous tunnel. Catheter placement is usually performed under conscious sedation in the day surgery unit [19]. A systemic review on IPC revealed symptomatic improvement in 95.6% of patients and spontaneous pleurodesis in 45.6% of patients [20]. It is useful for patients with ‘trapped lung’ [9]. Complications rates are low which include symptomatic loculation, empyema and pneumothorax.

Pleuroperitoneal shunt is an option for patients who have failed chemical pleurodesis or those who cannot undergo surgery. Pleurectomy has been described as a treatment for MPEs but it is an invasive procedure with significant morbidity [18].

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