Current Treatment Options in Oncology (2014) 15:625–643 DOI 10.1007/s11864-014-0312-6

Head and Neck Cancer (J-P Machiels, Section Editor)

Interventional Pulmonologist Perspective: Treatment of Malignant Pleural Effusion Andrew J. Sweatt, MD Arthur Sung, MD* Address * Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA, USA Email: [email protected]

Published online: 21 September 2014 * Springer Science+Business Media New York 2014

Keywords Malignant pleural effusion I Therapy I Pleurodesis I Talc I Thoracoscopy I Pleuroscopy I Chest tubes I Indwelling catheters

Opinion Statement The management of known malignant pleural effusions focuses around the initial thoracentesis and subsequent objective and subjective findings. A completely reexpanded lung after fluid removal and with symptomatic improvement predicts successful pleurodesis. Pleurodesis method depends on center expertise as well as patient preference. Medical thoracoscopy does not require the operating room setting and is performed on the spontaneously breathing patient with similar success rate to surgical thoracoscopy in the appropriately selected patients. However, it is not widely available. Talc insufflation is preferred for even distribution of sprayed particles to pleural surfaces. Most often, patients can be discharged home within 24 to 48 hours after continuous chest tube suction. Indwelling pleural catheter has become popular given the ease of insertion and patient centered home drainage. Coordinated care with good patient and family education and support is paramount to maximizing the beneficial potential of the catheter. Complications are minimal, and catheters are easily removed if patients can no longer benefit from drainage, or if pleurodesis has occurred. In the setting of trapped lung as a result of visceral pleura encasement from tumor, indwelling catheter can still be useful if the patient improves with thoracentesis. However, if no subjective improvement is seen after thoracentesis for trapped lung, then no procedure is recommended and other modes of palliation should be sought.

Introduction Malignant pleural effusions (MPEs) cause disabling patient morbidity and significant healthcare burden. The

estimated annual incidence of MPE is 150,000-200,000 in the United States [1]. Malignancy is the third-leading

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cause of pleural effusions behind heart failure and pneumonia and accounts for 44-77 % of exudates [2]. Lung and breast cancers cause 45-65 % of all MPEs (Table 1) [3–10]. MPE develops in nearly half of patients with disseminated malignancy and 8-15 % of all lung cancer stages combined [2, 11, 12]. MPE pathophysiology is incompletely understood, but fluid accumulation is likely multifactorial from direct and indirect tumor effects [13]. Pleural space homeostasis is ultimately disrupted, due to increased rate of fluid formation and reduced lymphatic clearance (Fig. 1). Tumors can metastasize to the visceral pleura with secondary spread to parietal pleura, hematogenous seeding of the parietal pleura, or invasion of pleurae from nearby structures [14]. Tumor infiltration indirectly causes increased microvascular permeability, through local inflammatory mediators and cellular expression of vascular endothelial growth factor (VEGF) [15]. The

parietal pleura functions to remove pleural fluid, as small lymphatic openings in its surface (stomata) drain into lacunae that coalesce into larger lymphatics. Lymphatic blockage by tumor (anywhere between parietal stomata and mediastinal lymph nodes) impairs fluid clearance and is a major factor in MPE formation [16]. The presence of a MPE signifies advanced disease with median overall survival following diagnosis of 4-6 months, although prognosis varies by malignancy stage and type [17, 18]. Because MPE portends limited life expectancy, treatment is aimed at palliation and patientcentered outcomes. The ideal therapeutic intervention minimizes duration of hospitalization, risk of adverse effect, and need for repeat invasive procedures. Available options include serial pleural aspirations, pleurodesis (via tube thoracostomy, video-assisted thoracoscopic surgery, or medical thoracoscopy), and tunneled pleural catheter placement.

TREATMENT OPTIONS FOR MPE Initial considerations In the setting of a known MPE, dyspnea is the primary indication for therapeutic pleural intervention. Up to 25 % of patients with MPE do not have respiratory complaints [14], and therefore fluid drainage is not necessary. One study of small-volume and asymptomatic effusions in lung cancer patients revealed a very low rate of symptomatic progression and need for pleural procedure [19]. Therapeutic thoracentesis is the first management step for symptomatic MPE, and ultrasound-guidance reduces pneumothorax risk. Reexpansion pulmonary edema (RPE) is rarely described following large-volume thoracentesis (G1 % frequency) but is associated with increased mortality that approaches 20 % [20]. Rapid expansion of atelectatic lung and excessively negative pleural pressure is thought to contribute to RPE, stemming from reperfusion injury and mechanical stress at the alveolar-capillary interface [21]. Some literature recommends maximum aspiration of 1.5 L to avoid RPE, although no evidence supports this practice. Larger-volume thoracentesis is likely safe if pleural manometry pressure, if obtained during aspiration, remains above -20 cm H2O [2]. Because chest pain or pressure correlates with increased negative intrapleural pressure, symptomatic monitoring may help indicate the safe limit of fluid drainage [22]. Thoracentesis is the first procedure of choice to evaluate if aspiration of pleural fluid accomplishes subjective benefit and allows for subsequent management strategies. Further therapy to control MPE reaccumulation is only indicated if dyspnea is relieved. Absence of a symptomatic response should prompt evaluation for other etiologies of persistent dyspnea. In an observational study of MPEs occupying 50-75 % of the hemithorax, 1.5 L of fluid drainage produced significant overall improvements in mean spirometric lung function, 6-minute walk distance, and Borg dyspnea score [23]. However, 50 %

29.1 % 10.3 % 6% 3.4 % 2.6 % 9.4 % 39.3 %

33 % 20.9 % 0% 13.5 % 13.5 % 5.2 % 13.5 %

Lung Breast Lymphoma/ leukemia Genitourinary Gastrointestinal Other Unknown primary

Hirsch [4] Paris, France (n=117) 4 years

Chernow [3] Denver, CO (n=96) 3 years

Primary tumor site (% of cohort)

8.9 % 8.7 % 1.9 % 8.3 %

19.6 % 11.5 % 3.3 % 3.3 %

41 % 19.7 % 1.6 %

Houston, TX (n=61) 5 years

Hong Kong (n=785) 10 years 52 % 12.9 % 7.1 %

Irani [6]

Hsu [5]

12.1 % 5.9 % 5.5 % 10.2 %

35.6 % 14.8 % 15.9 %

Johnston [7] Durham, NC (n=472) 14 years

7% 3.1 % 4.8 % 8.3 %

41.5 % 23.1 % 12.2 %

Leuallen [8] Rochester, MN (n=229) 3 years

4.2 % 4.2 % 6.3 % 17.9 %

44.2 % 11.6 % 11.6 %

Baltimore, MD (n=95) 6 years

Salyer [9]

8.6 % 5.4 % 14.9 % 12.8 %

18.9 % 23.8 % 15.5 %

(n=592) 3 years

Sears [10]

9.3 % 6.6 % 6.7 % 11.7 %

37.5 % 17.2 % 11 %

Pooled frequency

Table 1. Reported frequencies of primary tumor sites for malignant pleural effusion. Data are extracted from cohorts of consecutive patients who presented with undifferentiated pleural effusions and received a cytopatholo gic diagnosis of malignant effusion via thoracentesis, closed pleural biopsy, or surgical biopsy (n=number of patients with malignant pleural effusion in each cohort)

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Head and Neck Cancer (J-P Machiels, Section Editor) Fig. 1. Normal physiology of the pleural space. Because pleural space pressure is less than pleural interstitial pressure, a majority of the low-protein microvascular filtrate flows across leaky pleural mesothelial layers from the interstitium to pleural space (large blue arrows) at slow rate (normally 0.5 ml/hour). A minority of the interstitial filtrate is reabsorbed (dashed arrows). Pleural fluid largely exits the pleural space into parietal pleural stomata (1012 μm diameter) via bulk flow. A malignant effusion can accumulate when lymphatic removal rate is reduced and/or pleural fluid entry rate is markedly increased (in excess of the lymphatic clearance reserve capacity, which can accommodate fluid entry that is 30-fold above baseline). Schematic drawn by artist Douglas Regalia (Danville, California 2014).

of subjects in another cohort did not have symptomatic relief or enhanced exercise capacity due to comorbid disease, debility, or trapped lung [24]. The degree of lung reexpansion following initial fluid drainage should be ascertained, because inadequate expansion precludes certain MPE management strategies. Trapped lung causing inability to reexpand is caused by thickened visceral peel, loculations/adhesions, endobronchial obstruction with distal atelectasis, or extensive pleural tumor burden. Imaging modalities including computed tomography and thoracic ultrasound can readily verify if there is lung reexpansion and provide etiological insight (Fig. 2). Significant chest pain during pleural aspiration correlates with degree of negative pleural pressure and lack of lung reexpansion. Furthermore, pleural manometry use during thoracentesis is diagnostically helpful, as high elastance measured (pleural pressure change per Liter of volume removed) indicates trapped lung [25].

Serial thoracentesis Serial thoracentesis is a reasonable therapeutic modality in select patients. Appropriate candidates include patients with advanced malignancies, limited survival to weeks or months, poor functional status, and slowly reaccumulating or chemotherapy-responsive effusions. MPEs that are most sensitive to chemotherapy include those associated with lymphoma, small-cell lung cancer, and breast cancer [2]. Unfortunately, MPE resolution with cytotoxic therapy alone is the exception rather than rule, and further intervention often is necessary. Serial thoracentesis intermittently relieves dyspnea without providing long-term palliation. In a retrospective cohort, symptomatic MPE recurred in 97 % within 1 month of therapeutic aspiration (at mean of 4.2 days) [26].

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Fig. 2. Imaging of the un-expandable lung. A Coronal CT image of trapped lung due to a visceral peel (bold white arrow), with visible pneumothorax ex vacuo (thin black arrow) following effusion drainage. B Pleural ultrasonography revealing the presence of loculations.

Furthermore, repeated pleural needle-sticks may provoke adhesions that reduce success of subsequent definitive interventions.

Pleurodesis Overview and patient selection The goal of pleurodesis is to prevent MPE reaccumulation by obliterating the pleural space through creation of adhesions and fibrosis. Following effusion evacuation, pleurodesis is performed chemically with an irritant sclerosant or mechanically by abrasion. The induced inflammatory response causes mesothelial recruitment of interleukin-8, transforming growth factor β, and basic growth factor, with ensuing coagulation-fibrinolysis imbalance, fibroblast proliferation, and collagen production [27]. Pleurodesis can be achieved with tube thoracostomy, video-assisted thoracic surgery, or pleuroscopy. Current evidence does not firmly favor a particular method, thus practice patterns are variable worldwide [28].

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Head and Neck Cancer (J-P Machiels, Section Editor) Pleurodesis should be reserved for patients with predicted survival beyond 1 to 3 months, whereas individuals with shorter life-span may incur more risks than benefits [17]. The prognostic ability of several clinical factors and pleural fluid biochemical characteristics has been studied for MPEs. Baseline patient functional status has good predictive validity for survival, whereas pleural fluid parameters, such as low pH and glucose lack reliability for prognostications [29, 30]. Overall, 3-month, all-cause mortality often exceeds 30 % in clinical trials postpleurodesis. Pleurodesis should be limited to patients with near-complete lung expansion following effusion drainage, which reflects proper apposition between the visceral and parietal pleurae. Lack of significant lung reexpansion portends pleurodesis failure and accounts for 30 % of evaluated patients who are deemed unsuitable candidates [31]. In these patients, thoracoscopic intervention (lysis of adhesions or decortication) or tunneled pleural catheter placement should be considered. Extensive tumor burden on pleural surface, which reduces the amount of mesothelial cells to mediate inflammation and with concomitant increased fibrinolytic activity, also is a factor for poor efficacy [32]. Furthermore, concurrent use of systemic corticosteroid or NSAID therapy may diminish the intended pleurodesis inflammatory response [33, 34]. The ideal timing for pleurodesis remains controversial. According to a worldwide survey, 82 % of physicians defer intervention until at least one symptomatic recurrence transpires [28]. Others advocate for early pleurodesis in appropriate candidates due to inevitable MPE reaccumulation, declining functional status and risk of trapped lung as malignancy advances with repeated aspirations. In one retrospective study involving thoracoscopic pleurodesis, poor patient functional status and delay in pleurodesis following MPE diagnosis were associated with in-hospital mortality [35].

Tube thoracostomy pleurodesis Chemical pleurodesis can be performed through a temporary thoracostomy tube or pigtail catheter for initial drainage, followed by sclerosant instillation. Various pleurodesis protocols have been applied successfully. Large chest tubes (20-32 Fr) were employed historically, although recent studies demonstrate equivalent pleurodesis efficacy and improved patient comfort with small-bore catheters (10-14 Fr) [36]. Chemical sclerosant instillation should occur promptly once effusion evacuation and lung reexpansion is confirmed by radiograph or ultrasound. Compared with traditional practice of deferring sclerosant until tube output falls below 150 mL/day [28], imaging-guided timing to instill sclerosant, such as ultrasound confirmation of pleural apposition, leads to shorter hospitalization and optimal pleurodesis efficacy [37, 38]. Before instillation of sclerosant, intrapleural lidocaine and adjunctive analgesic premedication is administered. Following intrapleural sclerosant infusion, the thoracostomy tube remains clamped for an hour. The common practice of patient rotation to enhance sclerosant dispersion is unlikely helpful, because studies show no difference in pleurodesis efficacy as evident with radiolabeled sclerosant distribution with rotation [39, 40]. After unclamping the intercostal tube and applying suction, many defer tube removal until drained volume drops below 150-250 mL/day. However, pleurodesis success is equivalent for postsclerosant tube durations of 24 and 72 hours, irrespective of drain output [41].

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Tube thoracostomy pleurodesis is less invasive than surgical pleurodesis and is easily performed in institutions lacking resources and expertise for more advanced MPE management. An often-cited drawback of pleurodesis is the accompanying protracted hospital course (5-7 days). However, “rapid pleurodesis protocols” have achieved shorter hospitalization without apparent pleurodesis compromise. In a 38-patient cohort that had pleural catheter placement, sclerosant instillation, and catheter removal within 4 hours, 79 % attained pleurodesis success without need for repeat procedure at 1 month [42]. Another study compared a standard protocol (required lung reexpansion and pleural drainage below 150 mL/day prior to sclerosant) to an accelerated approach (concurrent interval effusion drainage and fractionated sclerosant doses) [43]. The accelerated protocol achieved shorter hospitalization (2.3 vs. 8.3 days) and equivalent pleurodesis success. The 24–48-hour pleurodesis success was attributed to ultrasonography use, as it facilitates pleural apposition visualization, optimal sclerosant timing, and selective loculation aspiration [38].

Chemical pleurodesis sclerosants and associated complications Sclerosants most often utilized for pleurodesis include talc (in suspension via thoracostomy tube as “slurry,” or atomized during thoracoscopy as “poudrage”), doxycycline (requires repeated instillations), and antineoplastic drugs (bleomycin, cisplatin, or mitoxantrone) [30, 44]. Successful use of alternative agents also is described, such as antiseptics (iodopovidone and silver nitrate) or bacterial products and components (Corynebacterium parvum and Streptococcus OK432) [2, 45]. Sclerosant choice remains controversial, because no available agent is fail-proof or without adverse effects. Large, high-quality, randomized studies comparing sclerosants are lacking. Each individual agent has a wide efficacy range reported for tube thoracostomy pleurodesis, with success rates typically varying from 65–95 % [30]. This variability reflects poorly defined inclusion criteria, heterogeneous patient populations, and inconsistent definitions of “pleurodesis success.” Talc is used most frequently worldwide, because it is readily available, inexpensive, and perceived by physicians to be most efficacious [28]. Talc had the lowest risk of MPE recurrence in a 2004 Cochrane meta-analysis (compared most rigorously to bleomycin and tetracycline), with a number needed to benefit of five patients (CI 3.3-9.7) [44]. A systematic review also demonstrated a nonstatistically significant trend toward less treatment failure with talc compared with other agents [45]. Moreover, talc promotes selective apoptosis of malignant cells in vitro [46]. Common adverse effects shared by the sclerosants include pain (7-55 % agent-dependent frequency) and fever (10-24 %) [47]. Talc pleurodesis is relatively well tolerated (7-10 % pain rate, 10-17 % fever), whereas doxycycline and antineoplastic agents cause more discomfort [48]. Rare adverse effects common to sclerosants include systemic inflammatory response syndrome, hypotension, arrhythmia, and myocardial infarction. A major safety concern unique to intrapleural talc involves reports of pneumonitis and acute respiratory distress syndrome (ARDS) [49]. Published incidence of talc-associated ARDS has varied, as risk may relate to dose and particle size. In one cohort, ARDS only occurred in patients receiving 95 g of talc [48]. Reports of

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Head and Neck Cancer (J-P Machiels, Section Editor) pneumonitis predominate in U.S. and UK series utilizing talc preparations without small particles removed [50]. In patients randomized to graded talc (particles 915 microns) or nongraded talc (some particles G15 microns), the nongraded group had greater alveolar-arterial oxygen gradient and C-reactive protein levels postpleurodesis [51]. The talc-related death rate from respiratory failure was 2.9 % in a large U.S. trial [31], whereas no episodes of pleurodesisassociated ARDS occurred in a substantial European cohort treated with largeparticle talc [52]. The mechanism and risk of talc pulmonary toxicity is undefined, but use should be restricted to the graded preparation.

Video-assisted thoracoscopic surgery pleurodesis Pleurodesis also is often performed in the operating room through video-assisted thoracoscopic surgery (VATS). Appropriate patients possess good functional status and adequate cardiopulmonary reserve, as general anesthesia and single-lung ventilation is required. The procedure traditionally involves lateral decubitus patient positioning with midaxillary and inframammary trocar insertion (2-3 ports), which permits rigid thoracoscope and surgical instrument introduction [53]. A recently described alternative approach using only one trocar site reduced postoperative and chronic neuropathic pain, without compromising pleurodesis [54]. During VATS, initial lung deflation facilitates pleural cavity visualization, the MPE is drained, and thereafter lung reexpansion is evaluated with application of positive pressure. If reexpansion is deemed adequate, pleurodesis is performed chemically or mechanically. Chemical pleurodesis typically involves talc poudrage insufflation (usually 4-5 g), although alternate sclerosants may be used. Mechanical pleurodesis entails abrasion of the visceral and parietal pleurae (with dry gauze) to provoke diffuse petechial hemorrhage and inflammatory reaction. Variable efficacy has been reported for VATS talc poudrage, with success ranging from 71-95 % in prior cohorts [31, 55–62]. This variation may be due to institution discordance in surgical technique and patient selection, variable time to follow-up, and differences in outcome measures. While some studies defined pleurodesis success as radiographic freedom from effusion reaccumulation, others delineated efficacy by lack of recurrent symptoms or combined imaging and subjective criteria. Advantages of thoracoscopic pleurodesis relate to the capacity for direct pleural visualization. If pathologic confirmation is not yet established for suspected MPE, VATS can provide simultaneous diagnosis and therapeutic palliation. The diagnostic yield of thoracoscopy (95 % sensitivity) far exceeds thoracentesis pleural cytology, as biopsy of ample tissue and hilar lymph nodes is feasible [63]. Following effusion drainage, VATS allows the extent of lung reexpansion to be observed in real-time with the application of positive pressure. When loculation or adhesions are encountered, there is potential for lysis of adhesions or minimally invasive decortication [60, 63]. Furthermore, thoracoscopic guidance facilitates more extensive sclerosant distribution over pleurae. While thoracoscopy is generally safe and well tolerated with less than 0.5 % perioperative mortality rate [63], it is more invasive than other modalities. The drawbacks of VATS pleurodesis include limitation to surgical candidates,

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associated morbidity, and respiratory complications, and increased costs associated postprocedure care and hospitalization (5–10-day length of stay in prior cohorts) [31, 56–62].

Pleurodesis with medical thoracoscopy Medical thoracoscopy (or pleuroscopy) is available in select institutions using pleural optical telescope for diagnostic and therapeutic purposes. Pleuroscopy permits inspection of the pleural cavity, directed biopsy, effusion drainage, and pleurodesis with talc poudrage. In contrast to VATS, pleuroscopy is performed on spontaneously breathing patients under conscious sedation and local anesthesia. It requires fewer chest wall ports than VATS (only 1-2) and employs either a smaller rigid thoracoscope or semi-rigid pleuroscope with a working channel for instruments insertion (Fig. 3) [64]. The semi-rigid pleuroscope has increased maneuverability but accommodates less therapeutic and diagnostic tools due to a smaller working channel [65]. Medical thoracoscopy can be feasible in patients with less cardiopulmonary reserve, as single-lung ventilation and general anesthesia are not utilized. According to a large pooled dataset, the rates of pleuroscopy-associated mortality and major complication are only 0.34 % and 2.1 %, respectively [66]. Compared to single-port VATS in a retrospective case-matched study, medical thoracoscopy had equivalent pleurodesis outcome but lower rates of perioperative mortality (0 vs. 2.3 %) and postoperative major morbidity (5.2 % vs. 9.0 %), earlier improvement in quality of life, and shorter hospitalization (3 vs. 5 days) [67••]. In general, diagnostic sensitivity of pleuroscopy in malignancies is similar to VATS (93-97 %) [64, 66]. However, pleuroscopy cannot address trapped lung, as lysis of adhesions and minimally invasive decortication is not possible. There is limited published data for medical thoracoscopy pleurodesis, although therapeutic efficacy appears similar to VATS. In one of the largest cohorts (n=102), 89 % of survivors at 1 month and 82 % at 6 months were free from symptomatic MPE recurrence [68]. Two smaller series quoted comparable 30-day efficacy (81-87 %) [69, 70].

Evidence-based comparison of pleurodesis methods There is lack of consensus as to whether tube thoracostomy or thoracoscopy is the preferred pleurodesis method [71, 72]. Overall, thoracoscopic chemical pleurodesis outperformed the tube thoracostomy approach in a 2004 Cochrane meta-analysis, although findings were confounded by variable sclerosants used in pooled studies [44]. Comparison restricted to talc poudrage versus talc slurry slightly favored thoracoscopy (RR of pleurodesis success 1.19, CI 1.04-1.36); however, only two smaller randomized trials (n=112) were included [73, 74]. On closer inspection, only one of the studies observed modest benefit for thoracoscopy [74]. Therefore, the Cochrane review does not offer convincing support for VATS. The most rigorous trial to date comparing thoracoscopic and tube thoracostomy chemical pleurodesis was published in 2005 by Dresler [31]. This multicenter, multinational study randomized 482 patients to pleurodesis with talc poudrage or slurry (4-5 g). Complete lung reexpansion was required prior to undergoing pleurodesis. No significant difference between groups was

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Head and Neck Cancer (J-P Machiels, Section Editor) Fig. 3. Medical thoracoscopy. A The semirigid pleuroscope with flexible tip (Olympus, Center Valley, PA). B Thoracoscopic view of pleural surface following talc poudrage insufflation during pleurodesis.

demonstrated for pleurodesis success (30-day radiographic freedom from MPE recurrence): 78 % talc poudrage vs. 71 % talc slurry (p=0.169). The KaplanMeier curves of time to recurrence in both groups were essentially superimposable until complete follow-up (180 days). However, in subgroup analysis restricted to primary breast and lung cancer, VATS achieved significantly better 30-day pleurodesis outcome (82 % vs. 67 %, p=0.02). Patient perception of comfort and safety was higher for talc poudrage than slurry, but VATS had higher rates of treatment-related respiratory complications (14 % vs. 6 %, p= 0.007) and acute respiratory failure (8 % vs. 4 %). In Stefani’s 2006 Italian prospective study (n=109), pleurodesis efficacy (lack of symptomatic recurrence and repeat pleural intervention) was significantly better for VATS than chest tube approach at 3 months (88 % vs. 70 %, p= 0.047) and until death (82 % vs. 62 %, p=0.027) [55]. This robust effect may be

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explained by selection bias, due to lack of study randomization and markedly worse baseline functional status in the talc slurry arm. A 2009 Brazilian study randomized 60 well-matched patients and demonstrated equivalent efficacy for VATS and chest tube talc pleurodesis [75]. In a recent meta-analysis [76••], comprised of the aforementioned talc slurry versus poudrage studies [31, 55, 73, 75], thoracoscopic pleurodesis was marginally favored to a similar magnitude as the prior Cochrane review (RR pleurodesis success 1.12, CI 1.01-1.23). There is limited data available regarding mechanical pleurodesis. In a study of MPE associated with breast cancer (n=87), 6-month pleurodesis efficacy was statistically equivalent between VATS mechanical abrasion (87 %) and chest tube talc slurry (74 %) [77]. However, in those with pleural fluid pHG7.3, mechanical pleurodesis was significantly more effective with shorter associated hospitalization. No randomized study has compared thoracoscopic talc insufflation with mechanical pleurodesis.

Tunneled pleural catheter Ambulatory indwelling pleural catheters are being used increasingly as an alternative to pleurodesis for MPEs. Tunneled pleural catheters (TPCs) are placed in an outpatient setting under conscious sedation and local anesthesia. The 15.5-French soft silicone TPC has distal fenestrations positioned in the pleural space, a proximal polyester cuff just deep to skin level (reduces inadvertent dislodgment and infection), and a one-way safety valve (prohibits air/ fluid flow toward the pleural cavity) [78]. To permit outpatient pleural drainage, the proximal TPC end is connected to a vacuum bottle or manual pump inline with a collection bag (Fig. 4). The patient and caregivers require education about proper catheter care and intermittent self-drainage. Pleural fluid is typically drained every 2-3 days for palliation, with 1 liter at maximum evacuation volume each time to minimize RPE risk. Mild chest pain may accompany initial drainage sessions, due to reapproximation of pleurae with intervening catheter. Significant pain during later sessions suggests negative pleural pressure from trapped lung, and these patients should be advised to reduce the volume and/or frequency of drainage [79]. A growing body of literature highlights the utility and advantages of TPCs. While 20-30 % of chemical pleurodesis attempts fail, in-dwelling catheters consistently palliate. In the largest published consecutive series (Tremblay n= 223, Suzuki n=355, and Warren n=202), TPC insertion attained symptomatic improvement in 89-100 %, and approximately 90 % did not need subsequent pleural procedure [80–82]. The pooled rate of symptomatic improvement was 96 % in a systematic review (n=1,370 from 19 cohorts), but subjective outcome definitions varied widely [83]. While the fundamental TPC goal is symptom control via repeated drainage, spontaneous pleurodesis often is accomplished without a sclerosant. The spontaneous pleurodesis rates were 28-56 % in aforementioned series [80–82] and 46 % (at median 52 days) in the systematic review [83]. Spontaneous pleurodesis is likely due to induced inflammation from catheter contact with pleural surfaces over time, which leads to adhesions and apposition. Beyond symptom control, a “dry pleural space” from scheduled TPC drainage theoretically promotes pleurodesis [78]. A current multicenter trial is comparing daily to less frequent drainages to determine if spontaneous pleurodesis is better

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Head and Neck Cancer (J-P Machiels, Section Editor) Fig 4. Modern tunneled pleural catheter. The PleurX® tunneled pleural catheter (Care Fusion, San Diego, CA) is pictured with emphasis placed on the fenestrated distal catheter tip (red arrow), and proximal polyester cuff (blue arrow).

achieved. Pleurodesis is suggested when catheter output remains negligible and effusion is absent by imaging. The TPC can be discontinued with low risk of symptomatic MPE recurrence (3.8-5.1 %) [82, 83]. TPC removal is plagued by catheter fracture in 10 %, although retained tubing does not typically cause pain or complications [84]. TPCs also are practical and effective for difficult to manage MPEs, such as nonexpandable lung in poor VATS decortication or surgical candidates. In the setting of trapped lung, confirming subjective response to initial thoracentesis is necessary, because nonresponders do not benefit from TPC. In a survey-based study of TPCs for MPE with trapped lung, nearly half of patients reported moderate symptomatic and functional improvement [85]. In another cohort, 94 % had symptomatic relief from TPC placement upon trapped lung discovery during VATS [86]. TPCs also have been successfully utilized for recurrent MPE following failed chemical pleurodesis [87]. More recently, prospective trials have directly compared TPCs to other palliative modalities. The 2012 TIME2 trial randomized 106 patients to outpatient TPC placement or chest tube talc pleurodesis and importantly had a patient-centered primary outcome measure (daily dyspnea during initial 6 weeks) [88••]. No difference was seen in primary outcome, but TPC patients had less dyspnea at 6 months, shorter index hospitalization (0 vs. 4 days), fewer hospital days in first year for treatment-related complications (1 vs. 4.5 days), and less follow-up pleural procedures (6 % vs. 22 %). An Australian RCT also compared TPC insertion to talc pleurodesis (poudrage or slurry) for the primary outcome of hospital days from procedure to death [89•]. TPCs favorably reduced hospitalization: 7 vs. 18 overall days, 3 vs. 10 effusion-related days, and 8 % vs. 11.2 % spent of remaining life. Moreover, fewer TPC patients required additional pleural procedure (14 % vs. 32 %), and no difference in rate of pleural infection or albumin loss was observed between groups. In another

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study, TPC insertion outperformed talc slurry pleurodesis for symptomatic improvement and combined 30-day outcome success with measures including survival, effusion recurrence, lung reexpansion, and achieving criteria to remove chest tube in talc arm or functioning TPC [90]. Drawbacks of in-dwelling catheters relate to outpatient self-care and delayed complications. Some patients are averse to the aesthetic presence and responsibility of a TPC. Those lacking the social support and diligence required for TPC care are suboptimal candidates. Outpatient physician follow-up after TPC insertion remains important, and institutional resources are necessary to prevent and manage complications. Despite relative safety and minimal invasiveness, delayed TPC complications include empyema (0.5-3.2 %), local cellulitis (1.1-3.4 %), and catheter obstruction (2.0-4.8 %) or dislodgement (0.6-2.2 %) [80–83]. Overall, 87.5 % of TPCs remain complication-free, but 68 % of those with complications require removal [83]. The TPC-related infection rate is less than that of in-dwelling dialysis access [91]. Concurrent chemotherapy does not heighten the risk of infection [92]. In general, cellulitis is managed using oral antibiotics without catheter removal. Empyema usually requires intravenous antibiotics, continuous drainage from the TPC or another nontunneled catheter for source control, and potentially TPC removal [93]. Because TPC presence causes excess fibrin deposition, catheter obstruction or loculations can occur. Clogged catheters often are cleared with saline or fibrinolytic flushes, whereas induced loculation is challenging and may necessitate TPC removal. TPCs have been integrated to novel combined modality approaches, which simultaneously exploit benefits of TPCs and standard pleurodesis. Strategies are intended to minimize hospitalization associated with chemical pleurodesis and reduce delayed TPC complications. Small studies have evaluated the effects of instilled sclerosant through TPCs, simultaneous TPCs placements at the time of thoracoscopic talc pleurodesis [94], as well as experimental sclerosant-eluting TPCs [95]. The cost-effectiveness of TPCs relative to other MPE therapies has been questioned. TPCs are initially less expensive than bedside or thoracoscopic pleurodesis, because hospitalization is avoided, but disposable drainage bottles and ongoing care increase cost later. According to two decision analysis models, TPCs are cheaper than pleurodesis for patients surviving less than 6 weeks to 3 months, but cost-effectiveness is comparable later [96, 97]. Similarly, resource data from the TIME2 trial found no difference in overall cost between groups, but TPCs were cost-saving in patients who died before 14 weeks [98].

Intrapleural fibrinolytics for loculated MPE The use of fibrinolytics for multiloculated MPEs remains poorly researched. Intrapleural fibrinolytics appear to be a safe salvage option in poor surgical candidates, but the efficacy and reversible degree of loculation remain unclear. In a series evaluating multiloculated MPEs (n=48), intrapleural streptokinase and urokinase produced an increase in fluid volume drained, improved lung expansion, and subjective benefit without noted adverse events [99]. Another trial randomized patients with loculated MPE (extent not delineated) to intrapleural streptokinase

• Single procedure offers pleurodesis and diagnostic capability • May be more efficacious than tubethoracostomy in lung and breast Ca • Lung expansion and sclerosant distribution is directly visualized • Option for lysis of adhesions and minimally-invasive decortication • Less invasive than VATS, with reduced morbidity and mortality • Single procedure offers pleurodesis and diagnostic capability • Lung expansion and sclerosant distribution is directly visualized • Same-day outpatient placement • Good patient-centered symptom control with self-drainage • Spontaneous pleurodesis is possible (~50 %) without sclerosant • Minimally-invasive palliative option in setting of trapped lung • Cost-saving compared to pleurodesis if survivalG3 months

VATS pleurodesis

Tunneled pleural catheter

• Addressing trapped lung and loculation is not feasible • Requires inpatient hospitalization (but fewer days than VATS) • High cost • Available in very few institutions • Requires adequate support system and diligence for catheter self-care • Aesthetic drawback of indwelling device • Delayed complications (cellulitis, empyema, obstruction, loculations) may require catheter removal • Pleurodesis rate is lower than traditional modalities • Increasing cost over time (supplies)

• High pleurodesis efficacy rate • Less invasive than alternate pleurodesis modalities

Tube thoracostomy pleurodesis

Medical thoracoscopy pleurodesis

• Advanced malignancy, predicted survival of weeks to a few months • Poor functional status • Slowly reaccumulating effusion • A chemotherapy responsive effusion

• Requires repeated pleural needle sticks, which may lead to adhesions • Requires multiple hospital visits • Not effective for long-term palliation • Risk of reexpansion pulmonary edema for large drainage sessions • Requires inpatient hospitalization (5-7 days) • Unable to address pleural adhesions and loculations • Sclerosant-related morbidity (pain, fever, pneumonitis, etc.) • Requires general anesthesia and single-lung ventilation • Requires protracted inpatient hospitalization (5-10 days) • More frequent respiratory complications than tube thoracostomy pleurodesis • Higher cost than alternate modalities

• Avoids morbidity associated with more invasive procedures • Prompt relief of dyspnea

Serial thoracentesis

• Initial lung reexpansion is not required (as long as palliation is achieved with pleural aspiration) • Any predicted survival91 month, though oftenG3 months • Suboptimal thoracoscopy candidate • Capacity and available resources for catheter self-care

• Near complete lung reexpansion • Predicted survival93 months • Suboptimal candidate for VATS • Tissue diagnosis needed

• Near complete lung re-expansion, though trapped lung or non-extensive loculation may be addressed • Predicted survival93 months • Good candidate for general anesthesia and single-lung ventilation • Tissue diagnosis needed

• Near-complete lung reexpansion • Predicted survival91-3 months • Relatively poor functional status and sub-optimal VATS candidate

Appropriate candidates

Disadvantages

Advantages

Treatment modality

Table 2. Major treatment modalities for symptomatic malignant pleural effusion. Advantages, disadvantages, and appropriate patient candidates

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versus chest tube drainage alone, with fibrinolysis producing significantly more fluid drainage and adequate lung expansion to permit successful talc pleurodesis (96 % vs. 74 %) [100•].

Summary: Choosing a management modality for MPE Current evidence does not clearly support a particular MPE treatment modality. Optimal management is multidisciplinary and individually tailored on a caseby-case basis, while a generic algorithmic approach should be avoided. The advantages, disadvantages, and appropriate patient candidates for each therapeutic option are summarized in Table 2. When choosing a strategy it is important to consider patient values, their social support network, and local institution resources and expertise. Key clinical factors to take into account include baseline functional status, predicted survival, surgical candidacy, and potential chemotherapy response, as well as the extent of lung reexpansion achieved with initial fluid drainage, presence of pleural loculations, and whether a tissue diagnosis is needed. Future research is necessary to establish optimal MPE management, with a focus on specific patient subgroups and patient-centered outcome measures.

Compliance with Ethics Guidelines Conflict of Interest Andrew J. Sweatt and Arthur Sung declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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