BTS guidelines for the management of malignant pleural effusions
- G Antunes1,
- E Neville2,
- J Duffy3,
- N Ali4,
- on behalf of the BTS Pleural Disease Group, a subgroup of the BTS Standards of Care Committee
- 1Department of Respiratory Medicine, James Cook University Hospital, Middlesborough TS4 3BW, UK
- 2Respiratory Centre, St Mary’s Hospital, Portsmouth PO3 6AD, UK
- 3Cardiothoracic Surgery Department, Nottingham City Hospital, Nottingham NG5 1PB, UK
- 4Kings Mill Centre, Sutton in Ashfield, Nottingham NG17 4LJ, UK
- Correspondence to:
Dr G Antunes, Department of Respiratory Medicine, James Cook University Hospital, Marton Road, Middlesborough TS4 3BW, UK;
The discovery of malignant cells in pleural fluid and/or parietal pleura signifies disseminated or advanced disease and a reduced life expectancy in cancer patients.1 Median survival following diagnosis ranges from 3 to 12 months and is dependent on the stage and type of the underlying malignancy. The shortest survival time is observed in malignant effusions secondary to lung cancer and the longest in ovarian cancer, while malignant effusions due to an unknown primary have an intermediate survival time.2–5
Currently, lung cancer is the most common metastatic tumour to the pleura in men and breast cancer in women.6 Together, both malignancies account for approximately 50–65% of all malignant effusions (table 1). Lymphomas, tumours of the genitourinary tract and gastrointestinal tract as a group account for a further 25%.5,7–9 Pleural effusions from an unknown primary are responsible for 7–15% of all malignant pleural effusions.3,7,8
An algorithm for the management of malignant pleural effusions is shown in fig 1.
The pleura consists of five main anatomical compartments (fig 2): the parietal systemic circulation (branches of the intercostal and internal mammary arteries), the parietal interstitial space, the pleural space lined on either side by mesothelial cells, the pulmonary interstitium, and the visceral circulation (bronchial and pulmonary arterioles).
Pleural fluid is filtered in the parietal pleural compartment from the systemic capillaries down a small pressure gradient into the pleural space. Under normal conditions the visceral pleura plays an insignificant role in pleural fluid turnover.10
Experiments using radioactive albumin and other labelled proteins have shown that pleural fluid secretion is greatest at the apex and absorption is increased towards the diaphragm and mediastinum.11,12 Pleural fluid is drained out of the pleural space predominantly through the stomata of the parietal lymphatics lying between the parietal mesothelial cells. The number of parietal lymphatics is greatest at the diaphragm and mediastinum. These stomata merge into small lymphatic channels which, in turn, form larger vessels ultimately draining into the mediastinal lymph nodes.
Any disruption or obstruction by tumour cells along this intricate lymphatic network may result in a pleural effusion. This mechanism for pleural fluid accumulation has been confirmed by necroscopic studies which reveal that involvement of the regional lymph nodes is usually associated with the presence of a pleural effusion.1,13 Typically, adenocarcinoma of the lung spreads to the parietal pleura from the visceral pleura along existing pleural adhesions. This is preceded by migration of tumour cells to the visceral pleura from underlying pulmonary capillaries—that is, haematogenous spread.14 Pleural metastases from a primary site other than the lung result from haematogenous or lymphatic spread. Malignant effusions secondary to breast cancer arise either through chest wall lymphatics or via hepatic metastases resulting in either contralateral or bilateral effusions.15
Haemorrhagic malignant effusions usually result from invasion of blood vessels directly and/or tumour induced angiogenesis.13 Vascular endothelial growth factor (VEGF), a cytokine possessing potent angiogenic activity and promoting endothelial permeability, may play a significant role in the formation of malignant effusions and local tumour growth.16,17
3 CLINICAL PRESENTATION
Massive pleural effusions are most commonly due to malignancy. [B]
The majority of malignant effusions are symptomatic. [C]
Massive pleural effusions, defined as complete or almost complete opacification of a hemithorax on the chest radiograph, are more commonly associated with a malignant aetiology.18 However, a modest number of patients (up to 25%) are asymptomatic at presentation—that is, they are found incidentally with physical examination or by chest radiography.1 Dyspnoea is the most common presenting symptom and is occasionally accompanied by chest pain and cough. Dyspnoea is due to a combination of reduced compliance of the chest wall, depression of the ipsilateral diaphragm, mediastinal shift, and reduction in lung volume stimulating neurogenic reflexes. Chest pain is usually related to involvement of the parietal pleura, ribs, and other intercostal structures.19 Constitutional symptoms including weight loss, malaise, and anorexia also generally accompany respiratory symptoms. The diagnosis of a malignant pleural effusion is discussed in the section on the investigation of a unilateral pleural effusion (page ii8).
4 MANAGEMENT OPTIONS
Treatment options for malignant pleural effusions are determined by several factors: symptoms and performance status of the patient, the primary tumour and its response to systemic therapy, and lung re-expansion following pleural fluid evacuation (table 2). Although small cell lung cancer, lymphoma, and breast cancer usually respond to chemotherapy, associated secondary pleural effusions may require intervention during the course of treatment. Common and less common management options will be discussed below.
Observation is recommended if the patient is asymptomatic or there is no recurrence of symptoms after initial thoracentesis. [C]
Advice should be sought from the thoracic malignancy multidisciplinary team for symptomatic or recurrent malignant effusions. [C]
The majority of these patients will become symptomatic in due course and require further intervention. There is no evidence that initial thoracentesis carried out according to standard technique will reduce the chances of subsequent effective pleurodesis.
4.2 Therapeutic pleural aspiration
Repeat pleural aspiration is recommended for the palliation of breathlessness in patients with a very short life expectancy. [C]
Caution should be taken if removing more than 1.5 l on a single occasion. [C]
The recurrence rate at 1 month after pleural aspiration alone is close to 100%. [B]
Intercostal tube drainage without pleurodesis is not recommended because of a high recurrence rate. [B]
Repeated therapeutic pleural aspiration provides transient relief of symptoms and avoids hospitalisation for patients with limited survival expectancy and poor performance status. This option is appropriate for frail or terminally ill patients but individual patient preference may also dictate its use in patients who have had a previous failed intercostal tube and pleurodesis.20 The amount of fluid evacuated will be guided by patient symptoms (cough, chest discomfort) and should be limited to 1–1.5 l (see section 4.3.2). Pleural aspiration alone and intercostal tube drainage without instillation of a sclerosant are associated with a high recurrence rate and a small risk of iatrogenic pneumothorax and empyema.21–26
4.3 Intercostal tube drainage and intrapleural instillation of sclerosant
Pleurodesis requires a diffuse inflammatory reaction and local activation of the coagulation system with fibrin deposition.27 Antony and colleagues have demonstrated increased growth factor-like activity in mesothelial cells exposed to tetracycline leading to fibroblast proliferation. This activity gradually decays once the tetracycline is removed.28 Increased pleural fibrinolytic activity is associated with failure of pleurodesis. Rodriguez-Panadero showed that rapid reduction in fibrinolytic activity within 24 hours using pleural d-dimer levels was associated with good outcome of talc pleurodesis. In contrast, the group in whom the d-dimer level took longer to return to baseline (>24 hours) had a greater number of treatment failures.29
In animals the effectiveness of pleurodesis may be reduced by concomitant use of corticosteroids. Recent evidence in rabbits has shown reduced pleural inflammatory reaction and, in some cases, prevention of pleurodesis with administration of corticosteroids at the time of talc pleurodesis.30 The administration of non-steroidal anti-inflammatory agents at the time of pleurodesis is more contentious and, at present, evidence against their use is lacking.
Belani and colleagues, using a simulation model, compared the cost effectiveness of intercostal tube insertion and chemical pleurodesis (tetracycline, doxycyline and bleomycin) with operative talc poudrage. The cost of symptom free days was used to determine cost effectiveness. Intercostal tube insertion and chemical pleurodesis was found to be more cost effective than talc poudrage where theatre time and personnel contributed significantly to the extra cost.31 The method of chemical pleurodesis will be discussed below and is summarised in box 1.
Box 1 Chemical pleurodesis
Insert small bore intercostal tube (10–14 F).
Controlled evacuation of pleural fluid.
Confirm full lung re-expansion and position of intercostal tube with chest radiograph.
Administer premedication prior to pleurodesis.
Instill lignocaine solution (3 mg/kg; maximum 250 mg) into pleural space followed by sclerosant of choice (for sclerosants, see text).
Clamp tube for 1 hour and consider patient rotation for talc slurry.
Remove intercostal tube within 12–72 hours if lung remains fully re-expanded and there is satisfactory evacuation of pleural fluid.
4.3.1 Size of intercostal tube
Small bore (10–14 F) intercostal catheters should be the initial choice for effusion drainage and pleurodesis. [B]
Conventional large bore intercostal tubes (24–32 F) have been employed in most studies involving sclerosing agents.32 They have traditionally been used because they are thought to be less prone to obstruction by clots, but there is little published evidence to confirm this. The placement of large bore tubes is perceived to be associated with significant discomfort33 and this has led to the assessment of smaller bore tubes (10–14 F) for the drainage and administration of sclerosing agents. Studies using small bore intercostal tubes with commonly used sclerosants have reported similar success rates to large bore tubes.34–38 The small bore tubes in these studies were inserted either at the patient’s bedside by a physician or under radiological guidance.
Comparison between small bore and large bore intercostal tubes has been considered in two studies. Clementsen et al,38 in a randomised study using tetracycline as a sclerosing agent, compared a small bore tube (10 F) placed at bedside with a large bore tube (24 F). Although no significant difference in success rate was observed between the two groups, the small bore catheter was associated with less discomfort. Small bore tubes (10 F) were also considered more successful than large bore tubes (32–38 F) in a non-randomised study .34 Both studies recruited only a small number of patients and larger randomised studies are necessary to support these findings.
Small bore tubes have been used for ambulatory or outpatient pleurodesis. Patz et al39 used a fluoroscopically placed tube (10 F) connected to a closed gravity drainage bag system for this purpose. Bleomycin was the preferred sclerosing agent and the pleurodesis success rate approached 80%. Six patients complained of mild chest pain during insertion of the intercostal tube. Two of the intercostal tubes became blocked but were successfully cleared with a guidewire.
In view of the potential advantages (reduced patient discomfort, ease of placement, and comparable pleurodesis success rates), small bore tubes (10–14 F) should be considered initially for the drainage of malignant effusions.
4.3.2 Lung re-expansion, fluid drainage, and suction
Large pleural effusions should be drained in a controlled fashion to reduce the risk of re-expansion pulmonary oedema (RPO). [C]
Suction to aid pleural drainage before and after pleurodesis is usually unnecessary but, if applied, a high volume, low pressure system is recommended. [C]
In patients where only partial pleural apposition can be achieved, chemical pleurodesis should still be attempted and may provide symptomatic relief. [B]
Once effusion drainage and lung re-expansion have been radiographically confirmed, pleurodesis should not be delayed while the cessation of pleural fluid drainage is awaited. [B]
The most important requirement for successful pleurodesis is satisfactory apposition of the parietal and visceral pleura, confirmed radiologically.32,40,41 Incomplete lung re-expansion may be due to a thick visceral peel (“trapped lung”), pleural loculations, proximal large airway obstruction, or a persistent air leak. Most studies indicate that the lack of a response following instillation of a sclerosant is predominantly due to incomplete lung expansion.41,42 Where complete lung re-expansion or pleural apposition is not achieved and the patient is unsuitable for surgical intervention, pleurodesis should still be attempted. Robinson and colleagues,43 in a study using doxycycline as a sclerosing agent, reported a favourable response in nine out of 10 patients with partial re-expansion of the lung.
The amount of pleural fluid drained per day before the instillation of a sclerosant (<150 ml/day) is less relevant for successful pleurodesis than radiographic confirmation of fluid evacuation and lung re-expansion. In a randomised study, a shorter period of intercostal tube drainage and hospital stay was seen in the group in whom sclerotherapy was undertaken as soon as complete lung re-expansion was documented (majority <24 hours) than in the group in whom pleurodesis was attempted only when the fluid drainage was <150 ml/day. The success rate in both groups approached 80%.41
Large pleural effusions should be drained in a controlled fashion avoiding evacuation of more than 1–1.5 l at one time or slowed to about 500 ml/hour, and aspiration discontinued if the patient develops chest discomfort, persistent cough, or vasovagal symptoms. Re-expansion pulmonary oedema (RPO) is a well described but rare complication following rapid expansion of a collapsed lung through evacuation of large amounts of pleural fluid at a single time and the use of early and excessive pleural suction.44,45 Putative pathophysiological mechanisms include reperfusion injury of the underlying hypoxic lung, increased capillary permeability, and local production of neutrophil chemotactic factors such as interleukin (IL)-8.46 Suction may be required for incomplete lung expansion and a persistent air leak. When suction is applied, the use of high volume, low pressure systems is recommended with a gradual increment in pressure to about −20 cm H2O.
4.3.3 Analgesia and premedication
Lignocaine (3 mg/kg; maximum 250 mg) should be administered intrapleurally just prior to sclerosant administration. [B]
Premedication should be considered to alleviate anxiety and pain associated with pleurodesis. [C]
Intrapleural administration of sclerosing agents is associated with chest pain and the incidence varies from 7% in the case of talc to 40% with doxycycline.43,47 Lignocaine is the best studied local anaesthetic for intrapleural administration. The onset of action of lignocaine is almost immediate and it should therefore be administered just before the sclerosant. The issue of safety has been highlighted in two studies. Wooten et al48 showed that the mean peak serum concentration of lignocaine following 150 mg of intrapleural lignocaine was 1.3 μg/ml, well below the serum concentration associated with central nervous system side effects (that is >3 μg/ml). In an earlier study of 20 patients larger doses of lignocaine were necessary to achieve acceptable levels of local anaesthesia. The patients receiving 250 mg lignocaine had more frequent pain-free episodes than those given 200 mg, while serum levels remained within the therapeutic range. Side effects were limited to transient paraesthesia in a single patient.49 The reason for the significant difference in analgesia between the two groups with only a small increment in the lignocaine dose was unclear.
In the context of pleurodesis, premedication and sedation is poorly studied and no evidence based guidelines exist. Pleurodesis is an uncomfortable procedure and is associated with anxiety for the patient. The use of sedation may be helpful to allay such fears and induce amnesia. The level of sedation using either an opioid (with a suitable anti-emetic) or benzodiazepine should be appropriate—that is, maintenance of verbal communication and cooperation. Sedation employed before pleurodesis should be conducted with continuous monitoring with pulse oximetry and in a setting where resuscitation equipment is available.50
4.3.4 Selecting a sclerosing agent
Talc is the most effective sclerosant available for pleurodesis. [B]
A small number of patients (<1%) may develop acute respiratory failure following talc administration. [B]
Tetracycline is modestly effective, has few severe side effects, and is the preferred sclerosant to minimise adverse event rates. [B]
Bleomycin is an alternative sclerosant with a modest efficacy rate but is expensive. [B]
Pleuritic chest pain and fever are the most common side effects of sclerosant administration. [B]
Despite the evaluation of a wide variety of agents, to date no ideal sclerosing agent exists. Comparison of sclerosing agents is hampered by the lack of comparative randomised trials, different eligibility criteria, and disparate criteria for measuring response and end points. A complete response is usually defined as no re-accumulation of pleural fluid after pleurodesis until death, and a partial response as partial re-accumulation of fluid radiographically but not requiring further pleural intervention such as aspiration. An ideal sclerosing agent must possess several essential qualities: a high molecular weight and chemical polarity, low regional clearance, rapid systemic clearance, a steep dose-response curve, and be well tolerated with minimal or no side effects. The choice of a sclerosing agent will be determined by the efficacy or success rate of the agent, accessibility, safety, ease of administration, number of administrations to achieve a complete response, and cost (table 3). Sclerosing agents available for routine use will be discussed first.
Until recently, tetracycline had been the most popular and widely used sclerosing agent in the UK.51 The manufacturer of parenteral tetracycline discontinued production and distribution of the agent in the US in 1993 and a similar fate may follow in the UK.52 However, currently the parenteral preparation is available in Germany and may be imported via international wholesalers. These suppliers state that supplies are expected to remain available for the foreseeable future. The advantages of tetracycline are its reasonable efficacy, excellent safety profile, ease of administration, and low cost. Success rates (complete and partial response rates) from the larger studies have varied from 50% to 92% with a mean of 65%.41,49,53–55 Side effects include fever (10%) and pleuritic chest pain (30%), which are usually transient and respond readily to antipyretics and analgesia. The optimal dose for intrapleural administration is 1.0–1.5 g or 20 mg/kg. Studies using smaller doses such as 500 mg have reported lower response rates, while there is no evidence to support the use of larger doses of tetracycline.56,57
Thoracoscopic instillation of tetracycline has been studied in two randomised trials for malignant effusions in breast cancer. Evans et al compared thoracoscopic instillation of 500 mg tetracycline with 1.5 g via chest tube. The complete response rate at 1 month for both groups was 76%.58 Fentiman et al,59 on the other hand, compared talc poudrage with thoracoscopically administered tetracycline (500 mg). The talc group was found to be superior with a successful palliation at 1 month of 92% compared with 48% for the tetracycline group. Tetracycline pleurodesis may also be attempted using a needle aspiration technique where the agent is administered after draining an effusion to dryness. A recent randomised study employing this method reported a disappointingly low pleurodesis success rate of 29% at 6 weeks compared with 80% with intercostal tube drainage.60
Talc (Mg3Si4O10(OH)2) is a trilayered magnesium silicate sheet that is inert and was first used as a sclerosing agent in 1935.61 Talc used for intrapleural administration is asbestos-free and sterilised effectively by dry heat exposure, ethylene oxide, and gamma radiation. It may be administered in two ways: at thoracoscopy using an atomiser termed “talc poudrage” or via an intercostal tube in the form of a suspension termed “talc slurry”.62,63
Success rates (complete and partial response) for talc slurry range from 88% to 100% with a mean of 90%.24,42,64,65 The majority of studies have used talc slurry alone and only a limited number of comparative studies have been published. A truncated randomised study by Lynch and colleagues66 compared talc slurry (5 g) with bleomycin (60 units) and tetracycline (750 mg). Although the study was terminated early because of the removal of tetracycline from the US market, analysis of the data to that point revealed no differences between the three treatment groups 1 month after pleurodesis. In a recent randomised trial between talc slurry (5 g) and bleomycin (60 units), 90% of the talc group achieved a complete response at 2 weeks compared with 79% of the bleomycin group, which was statistically insignificant.67 Yim et al68 compared talc slurry (5 g) with talc poudrage (5 g) and found no significant difference between the two groups with respect to complete response rate (both over 90%), chest drainage duration, length of hospital stay, and complication rate.
Talc slurry is usually well tolerated and pleuritic chest pain and mild fever are the most common side effects observed. A serious complication associated with the use of talc is adult respiratory distress syndrome (ARDS) or acute pneumonitis leading to acute respiratory failure. The mechanism of acute talc pneumonitis is unclear and has been reported with both talc poudrage and slurry.42,69 The dose of talc and the physical characteristics (size and type) appear to be the most important determinants for the development of this complication.70 In a case series reported by Kennedy et al42 five patients developed respiratory failure with talc slurry pleurodesis (10 g). Three patients required mechanical ventilation but were later successfully extubated. Studies using lower doses (2–5 g) have reported excellent complete response rates with a lower incidence of serious adverse effects including acute respiratory failure.64,65 The diagnosis of talc pneumonitis is made after exclusion of other possible mechanisms for pulmonary infiltrates and respiratory failure—that is, re-expansion pulmonary oedema and lymphangitis carcinomatosa.
Bleomycin is the most widely used antineoplastic agent for the management of malignant pleural effusions. Its mechanism of action is predominantly as a chemical sclerosant similar to talc and tetracycline. Although 45% of the administered bleomycin is absorbed systemically, it has been shown to cause minimal or no myelosuppression.71 Bleomycin is an effective sclerosant with success rates after a single administration ranging from 58% to 85% with a mean of 61%.56,67,72–74 Large comparative trials have found it to be superior to tetracycline.56,74,75 It has an acceptable side effect profile with fever, chest pain, and nausea the most common adverse effects. The recommended dose is 60 units mixed in normal saline. Bleomycin has also been used in studies evaluating small bore intercostal tubes placed under radiological guidance with similar efficacy rates.37,39,76,77 The major disadvantages of bleomycin are the cost per treatment compared with other sclerosants and that it needs to be performed by trained personnel familiar with the administration of cytotoxic drugs (table 3).
Rarely used and historical agents
(1) Doxycyline: Although doxycycline is widely used in the US and is available in Continental Europe, it is not available or licensed for intrapleural administration in the UK. It has been evaluated in several small trials with success rates varying from 65% to 100% with a mean of 76%.43,47,78,79 All but one of the trials used a dose of 500 mg mixed in normal saline. Prevost et al80 used doses in excess of 2 g with a reported success rate of 82%. Side effects are similar to those with tetracycline—that is, fever (30%) and mild to moderate pleuritic chest pain (up to 60%). Doxycycline has been used with small bore tubes in two studies. Patz et al37 in a large randomised study compared bleomycin with doxycycline (500 mg) in 106 patients. The complete response rate at 1 month for doxycycline was 79%. In a similar study, Seaton et al36 reported a complete response rate of 81% with a low incidence of side effects. The major disadvantage of doxycycline is the need for repeated instillations to obtain a satisfactory success rate. This may lead to prolonged catheter or intercostal tube indwelling times with a potential increase in infection, patient discomfort, and overall cost in treatment.
(2) Minocycline: Minocycline has been used as a sclerosing agent but experience in humans is limited to a single small and uncontrolled study.81 A recent study in rabbits suggests that it may be as effective as tetracycline at inducing pleurodesis.82 Minocycline is not available or licensed for intrapleural administration in the UK.
(3) Other sclerosants: Corynebacterium parvum extract,83–89 interferons (interferon-α and -β),90–94 interleukins (IL-2),95,96 and several chemotherapeutic drugs (cisplatin, cytosine arabinoside, and mitoxantrone)97–99 have been used for pleurodesis with variable and usually disappointing efficacy rates. Most of the trials have been uncontrolled and recruited small numbers of patients. Corynebacterium parvum, interferons, and interleukins require multiple administrations, while significant toxicity is encountered with the use of the chemotherapeutic drugs.
4.3.5 Rotation following pleurodesis
Patient rotation is not necessary after intrapleural instillation of tetracycline class agents. [A]
Rotation of the patient following intrapleural administration of a sclerosing agent is described in most pleurodesis studies in order to achieve adequate distribution of the agent over the pleura. However, patient rotation is time consuming and may cause further discomfort for these patients. A study using radiolabelled tetracycline has shown that tetracycline is dispersed throughout the pleural space within seconds and rotation of the patient did not influence the distribution of the agent.100 A subsequent randomised trial using tetracycline, minocycline, and doxycycline revealed no significant difference in the success rate of the procedure or duration of fluid drainage between the rotation and non-rotation groups.101 Patient rotation is still required when using talc slurry until further evidence is available.
4.3.6 Clamping of intercostal tube
The intercostal tube should be clamped for 1 hour after sclerosant administration. [C]
In the absence of excessive fluid drainage (>250 ml/day) the intercostal tube should be removed within 12–72 hours of sclerosant administration. [C]
Clamping of the intercostal tube following intrapleural administration of the sclerosant should be brief (1 hour). This will prevent the sclerosant from immediately draining back out of the pleural space, although this may not be important.100 Intercostal tube removal has been recommended when fluid drainage reached less than 150 ml/day, but there is a lack of evidence to support this action.102–104 In the absence of any evidence that protracted drainage is beneficial, and given the discomfort associated with prolonged drainage, we arbitrarily recommend removal of the intercostal tube within 12–72 hours after the instillation of the sclerosant provided the lung remains fully re-expanded and there is satisfactory evacuation of pleural fluid on the chest radiograph. Where excessive fluid drainage persists (>250 ml/day), repeat pleurodesis may be attempted with an alternative sclerosant. In the event of incomplete lung expansion any treatable cause for this should be excluded and the drain may then be removed as pleurodesis is unlikely to succeed.
4.3.7 Malignant seeding at intercostal tube or port site
Patients with proven or suspected mesothelioma should receive prophylactic radiotherapy to the site of biopsy or chest drain insertion. [A]
Local tumour recurrence or seeding following diagnostic and therapeutic pleural aspiration, pleural biopsy, intercostal tube insertion, and thoracoscopy is uncommon in non-mesothelioma malignant effusions.105–108 However, in mesothelioma 40% of patients may develop malignant seeding at the site of diagnostic pleural procedures. In a randomised study Boutin et al109 found that local metastases were prevented in patients who received radiotherapy to the thoracoscopic tract site. All the patients received radiotherapy within 2 weeks of thoracoscopy. It should be noted that further clinical trials of procedure site radiotherapy in mesothelioma are currently recruiting. The role of prophylactic radiotherapy following pleural procedures in non-mesothelioma malignant effusions has not been established and therefore cannot be recommended.
4.3.8 Intrapleural fibrinolytics
Intrapleural instillation of fibrinolytic drugs is recommended for the relief of distressing dyspnoea due to multiloculated malignant effusion resistant to simple drainage. [C]
The use of fibrinolytic agents represents an advance in the management of multiloculated malignant effusions. Immune mediated or haemorrhagic complications have rarely been described with the administration of intrapleural fibrinolytics in contrast to systemic administration of these agents.110,111
Jerjes-Sanchez et al112 administered intrapleural streptokinase (250 000 IU) in an open study to four patients with multiloculated malignant effusions not considered suitable for pleurodesis at the time. In three of the four patients fibrinolytic administration allowed radiographic improvement and led to successful pleurodesis. A more recent study found that intrapleural streptokinase increased pleural fluid drainage and led to radiographic improvement and amelioration of symptoms in 10 patients with multiloculated or septated malignant effusions. Intrapleural streptokinase was well tolerated and no allergic or haemorrhagic complications were reported.113 Gilkeson et al114 preferred urokinase in their prospective but non-randomised study. Twenty two malignant pleural effusions were treated with urokinase resulting in substantial increase in pleural fluid output in patients both with and without radiographic evidence of loculations. The majority then underwent pleurodesis with doxycycline resulting in a complete response rate of 56%. Similarly, no allergic or haemorrhagic complications were encountered.
None of these studies is large enough to accurately describe the safety profile of fibrinolytic drugs in this setting. The physician should therefore use these agents with caution, carefully considering the risk/benefit balance for the individual patient. An appropriately experienced specialist should be involved in the care of all patients receiving this treatment.
4.4 Thoracoscopy in malignant pleural effusion
Thoracoscopy should be considered for the diagnosis of suspected but unproven malignant pleural effusion. [B]
Thoracoscopy should be considered for the control of recurrent malignant pleural effusion. [B]
Thoracoscopy is a safe procedure with low complication rates. [B]
Thoracoscopy (under sedation or general anaesthesia) has grown in popularity as a diagnostic and therapeutic tool for malignant effusions.115–117 The thoracoscopic appearance of pleural malignancy and a thoracic CT scan from the same patient are shown in fig 3. The diagnostic yield and accuracy of thoracoscopy for malignant effusions is greater than 90%.55,117,118 Patients with exudative pleural effusions of unknown aetiology after pleural fluid cytological and microbiological examination should proceed to pleural tissue biopsy (see guideline on the investigation of pleural effusions, page ii8).
The therapeutic role of thoracoscopy has been evaluated extensively. Talc poudrage is an effective method for controlling malignant effusions with a mean pleurodesis success rate of more than 90%.115,116,119,120 Patient selection for thoracoscopy and talc poudrage is important in view of the invasive nature of the procedure and cost. The role of surgical thoracoscopy in patients with trapped lung is less clear. The procedure can facilitate breaking up of loculations and release of adhesions and thereby aid lung re-expansion and apposition of the pleura for talc poudrage.121
Thoracoscopy is a safe and well tolerated procedure with a low perioperative mortality rate (<0.5%).116,122 The most common major complications are empyema and acute respiratory failure secondary to infection or re-expansion pulmonary oedema.115,123
4.5 Long term indwelling pleural catheter drainage
Chronic indwelling pleural catheters are effective in controlling recurrent and symptomatic malignant effusions in selected patents. [B]
Insertion of a long term tunnelled pleural catheter is an alternative method for controlling recurrent and symptomatic malignant effusions including patients with trapped lung. A specific catheter has been developed for this purpose and the published studies employing this catheter have reported encouraging results.124,125
In the only randomised and controlled study to date, Putnam and colleagues124 compared a long term indwelling pleural catheter with doxycycline pleurodesis via a standard intercostal tube. The length of hospitalisation for the indwelling catheter group was significantly shorter (1 day) than that of the doxycycline pleurodesis group (6 days). Spontaneous pleurodesis was achieved in 42 of the 91 patients in the indwelling catheter group. A late failure rate (defined as reaccumulation of pleural fluid after initial successful control) of 13% was reported compared with 21% for the doxycycline pleurodesis group. There was a modest improvement in the quality of life and dyspnoea scores in both groups. The complication rate was higher (14%) in the indwelling catheter group and included local cellulitis (most common) and, rarely, tumour seeding of the catheter tract.
An indwelling pleural catheter is therefore an effective option for controlling recurrent malignant effusions when length of hospitalisation is to be kept to a minimum (reduced life expectancy) and expertise and facilities exist for outpatient management of these catheters.
4.6 Pleuroperitoneal shunting
Pleuroperitoneal shunts are an alternative and effective option in patients with a trapped lung or failed pleurodesis. [B]
In selected patients with trapped lung and large effusions refractory to chemical pleurodesis, pleuroperitoneal shunting is an acceptable palliative option. The shunt consists of a valved chamber (containing two unidirectional valves) with fenestrated pleural and peritoneal catheters attached at either end. The device is pressure activated but spontaneous flow will also occur when the pressure gradient between the pleural and peritoneal space is more than 1 cm H2O. More often the pressure gradient is low and requires manual compression of the pump chamber percutaneously, sometimes over 400 times per day.126,127 The insertion of the shunt is facilitated by thoracoscopy or a mini-thoracotomy and the duration of hospital stay varies between 4 and 6 days. The procedure is usually well tolerated and postoperative morbidity and mortality are low.128
Complications include shunt occlusion, infection, and tumour seeding or implantation into the peritoneal cavity. Shunt occlusion rates vary from 12% to 25% and normally requires replacement of the shunt.128,129 The presence of pleural infection, multiple pleural loculations, and inability to compress the pump chamber are contraindications to pleuroperitoneal shunting.
Pleurectomy is an effective but invasive method for treating malignant pleural effusions. Complications may include empyema, haemorrhage, and cardiorespiratory failure (operative mortality rates of 10–13%). Patient selection is therefore important and this method should be reserved for those who have failed to respond to other forms of treatment.130,131 The advent of video assisted thoracic surgery (VATS) has enabled parietal pleurectomy to be performed without a formal thoracotomy. A study of 19 patients (13 with mesothelioma, six with metastatic adenocarcinoma) found this thoracoscopic method to be safe and associated with an effusion recurrence rate of 10%. The median postoperative stay was 5 days and all patients were discharged home.132
Performance status at time of chemical pleurodesis.
Use of small bore catheters in the management of malignant pleural effusions.
Assessment of lung re-expansion prior to pleurodesis.
Assessment of pain during and after pleurodesis using a pain scale or score.
Complete and partial response rates of sclerosing agents.
Surgical referral rates for the management of malignant pleural effusions.
Future potential areas for research
Large prospective randomised trials comparing small bore catheters and large bore intercostal tubes for pleural fluid drainage and pleurodesis in malignant pleural effusions.
Role of premedication before pleurodesis in malignant pleural effusion.
Clinical trials of promising new sclerosants such as transforming growth factor beta (TGFβ) and iodopovidone.
Place of suction after pleurodesis in terms of duration of fluid drainage and length of hospital stay.