What is the optimal management of malignant pleural effusions?

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What is the optimal management of malignant pleural effusions?

Introduction

Malignant pleural effusion (MPE) is a common problem for patients with metastatic cancer. Symptoms may include dyspnoea and cough. Effective palliation of symptoms with the least morbidity is the goal of management..[1] The mechanisms that underpin the breathlessness are not well defined but are likely to extend beyond the effect of lung compression/deflation. Imbalance between respiratory effort and diaphragm motion may contribute to the complex sensation that is breathlessness.[2][3] Therefore, symptomatic benefit from draining effusions with apparently minimal lung expansion can be seen.

Management options include recurrent needle drainage, drainage by long term catheter, pleurodesis via instilling of sclerosant either by bedside (blind or ultrasound guided) insertion of chest tube or at VATS, and pleurectomy by VATS or an open approach. In cases of incomplete re expansion, options include long term catheter drainage and pleurectomy / decortication by VATS or an open approach.

Prevention of fluid re-accumulation

Repeated simple aspiration should be reserved for patients with very poor prospects for survival but in whom aspiration produces a clinical benefit. The evidence that fluid recurs and that interventions are effective is based on clinical experience and before-after comparisons of fluid accumulation in patients in many intervention studies. However, randomised comparisons of simple aspiration with other interventions are lacking. In patients with better performance status, repeated simple aspiration may lead to adhesion formation that can in the future make lung expansion and pleural adhesions more difficult or less effective. Insertion of an indwelling intercostal catheter alone, without any attempt at pleurodesis, is not recommended.[4] The success rate of pleurodesis varies with the clinical characteristics of patients and the techniques used. Where the lung does not expand and therefore apposition of the visceral and parietal pleura does not develop, pleurodesis cannot be achieved. At a 3 month analysis, repeat aspirations are cheaper than tunnelled pleural catheters, followed by bedside pleurodesis and thoracoscopic pleurodesis. At 12 months, bedside pleurodesis is cheaper than tunnelled pleural catheter followed by thoracoscopic pleurodesis and repeated aspirations.[5]

Long-term tunnelled catheter

Tunnelled pleural catheters (TPCs) are designed to allow ambulatory or home care. The catheter consists of an intrathoracic end, a segment that is tunneled under the skin to the insertion site and a port to which a suction bottle is attached to facilitate intermittent drainage.[6] It is generally applied in cases where lung re-expansion has not been achieved, or is not expected, but a benefit of drainage has still been apparent. They can be used after failed pleurodesis.[7] Even in cases where re-expansion is not anticipated, there is a small but significant rate of spontaneous pleurodesis.[8][9][10] They can be used as a means to instil talc and achieve pleurodesis.[11] Advantages of this option include: insertion under local anaesthetic, early ambulation and short hospital stay. Disadvantages include: ongoing cost of drainage bottles (presently met most often by the patient) and the requirement of longterm foreign body protruding from the chest with respect to infectious risk and patient preference. Overall, cost effectiveness is greater in patients with shorter life expectancy,[12] but the cost transfer from hospital to individual patients is problematic.

Compared to bedside talc pleurodesis, tunnelled pleural catheters have a higher success of reliable drainage/pleurodesis of unilateral malignant pleural effusions (62% vs 46%, p=0.064), lower 30 day mortality (8.7 vs 5.9, p-0.036) and longer survival with effusion control (83% vs 52%, p=0.024).[13] Median hospital stay is less with a tunnelled pleural catheter, with a significant improvement in quality of life (p=0.02).[14] Dyspnoea scores and quality of life scores are improved post insertion of tunnelled pleural catheters.[15]

Pleuroscopic pleurodesis with insertion of a tunnelled pleural catheter minimises hospital length of stay. There is an improvement in dyspnoea scores and performance indexes post procedure.[16][17] Freeman et al also found a shorter length of stay with tunnelled pleural catheter compared to traditional talc poudrage (6 days vs 3 days, p<0.0017). There was a shorter time from surgery to systemic therapy with a tunnelled pleural catheter compared to talc poudrage (17 days vs 9 days, p<0.0001).[18]

Use of intrapleural streptokinase for multiloculated malignant pleural effusions

Saydam et al, in a randomised controlled trial, found a significant improvement in mean drainage in patients receiving streptokinase compared to control. There was no significant difference in recurrence rate of pleural fluid.[19]


Intercostal catheter drainage plus sclerosant instillation

To achieve pleurodesis using the catheter/sclerosant approach, a catheter is inserted under LA into the pleural space and fluid is drained. After drainage, a mixture of sclerosant and local anesthetic is injected into the pleural space. Pleural fluid drainage beyond 24-48 hours may not increase the chance of successful pleurodesis[20] and the practice of leaving the catheter in situ until daily drainage has fallen below a certain volume is not evidence based. Success rate, measured by failure of fluid re-accumulation requiring any further procedure is over 70%[1][21][22][23] Procedural risks should be low if the procedure is performed following current guidelines that include the use of bedside ultrasound.[24]

The drainage of pleural fluid does not need to be below 300ml per day prior to attempting pleurodesis. The success rate of pleurodesis is not significantly different if pleurodesis is attempted when all fluid has been drained (as per chest radiography) or when daily drainage is less than 300ml per day. This significantly reduces hospital length of stay.[25]

Patients receiving treatment for their malignancy have a significantly longer survival time than those not receiving treatment in conjunction with pleurodesis.[26]

Recommended catheter size to achieve pleurodesis using an intercostal catheter

Historically, large bore ( >20F) catheters were used for pleurodesis. One justification for their continued use after smaller, tube over guide-wire, catheter systems became available was that smaller tubes might become blocked by the talc slurry or viscous pleural drainage. Talc slurry will pass through 12F catheters and the blockage rate of size 8F-12F tubes even when used for drainage of empyema was 8% and even lower in non-infected effusions.[27] Intercostal catheters larger than 20F, as traditionally used, may not increase the success rate but may increase complications and pain. Catheters in the range 12-14F may be as effective as larger tubes.[28][29][30][26]

Pigtail Catheter versus intercostal tube for pleurodesis of malignant pleural effusions

Ghoneim at al compared pigtail catheters versus intercostal tubes for pleurodesis of malignant pleural effusions. 66% of patients in the pigtail catheter arm compared to 54% of patients in the intercostal catheter arm achieved pleurodesis, p=0.22). There was a significantly higher complication rate in the intercostal tube arm compared to the pigtail catheter arms (86% vs 44%, p<0.0004).[31] Srour et al found a significant improvement in pleural effusion control (OR 2.1 95% CI 1.2-3.7), as well as significant improvement in survival time and effusion free time.[32]

VATS talc pleurodesis versus bedside intercostal catheter pleurodesis

Terra et al[33] randomised 60 patients with recurrent MPE (17 with NSCLC), >90% expansion after thoracentesis and KPS > 70% to VATS talc poudrage under general anesthesia versus bedside chest tube and talc slurry. Patients who underwent VATS talc poudrage more often had complete postoperative lung expansion than those who received talc slurry administered through a chest tube (60% versus 30%, [p = 0.027]). Whilst the authors emphasise that no difference was found in quality of life or requirement of re intervention between the groups, no power calculation was reported with regard to these outcomes and as such a negative result is difficult to interpret. There was a trend toward incomplete initial re expansion being associated with both clinical recurrence (2/27 versus 7/33 [p=0.15]) and complication (5/27 versus 11/33 [p=0.20]).

Yim et al[34] randomised 57 patients (33 with NSCLC) to VATS talc insufflation under general anesthesia versus talc slurry at the bedside. There was no statistically significant difference between the two groups of patients with respect to chest drainage duration, post procedural hospital stay, parenteral narcotic requirement, complications, or recurrence (1/28 versus 3/29 [NS]). No power calculation was reported.

Dressler et al[22] randomised 482 patients (182 with NSCLC) to VATS with talc insufflation under general anesthesia (TTI) versus bedside chest tube and talc slurry. Thirty day freedom from radiographic recurrence among surviving patients whose lungs initially re-expanded > 90% favoured VATS, but did not reach significance (78% versus 71% [NS]). Patients with primary lung or breast cancer had statistically significantly higher success with TTI than with TS (82% versus 67% [p = 0.022]). Respiratory complications were more common after TTI (13.5% versus 5.6% [p = 0.007]). There was no difference in mortality. Patient perceptions of pain control (p = 0.07), comfort (p = 0.019) and medical safety (p = 0.013) favoured TTI. Fatigue was significantly better after TTI (p = 0.016).

Three meta analyses have addressed rate of recurrence of MPE after VATS talc pleurodesis versus bedside chest tube and talc slurry. Two found in favour of VATS and one found no difference between the two groups. Tan et al[35] found a relative risk (RR) of 0.21 (95% CI 0.05 – 0.93) if VATS was employed and Shaw et al[1] a RR of 1.19 (95% CI 1.04 to 1.36) if bedside chest tube and talc slurry were employed. Shaw also reported data for mortality based on four studies and 127 patients comparing thoracoscopic versus bedside instillation of various sclerosant. There was no difference in mortality amongst the participants with RR = 1.36 (95% CI 0.88 to 2.10). Unfortunately neither meta analysis included the results of the largest RCT to date.[23]

Mummadi et al had a RR of 1.06 (95% CI 0.99 to 1.14) when comparing talc slurry to talc insufflation. Respiratory complications were less in the talc insufflation groups with a RR of 1.91 (95% CI 1.24 to 2.93).[36] VATS has the advantage of assessing the likelihood of adequate re expansion to achieve talc pleurodesis and failing this may facilitate the intra operative decision to decorticate or more likely place a long term catheter. The procedure is performed under sterile conditions, with general anaesthesia and peri operative pain service support. This compares favourably from the patient’s perspective to bedside insertion of tube under local anaesthetic.[34] Further, tissue biopsy provides histological confirmation and potentially molecular information, which may be important to ongoing management.

Likely increased cost (though no study has addressed the impact of repeat procedures in failed pleurodesis), pressure on operating theatre time and requirement of admission are disadvantages when compared to long term indwelling catheters, which may be inserted in an outpatient setting. Disadvantages of long term indwelling catheters include patient preference, long term consumable expense and requirement for long term nursing support.

Basso et al studied 46 patients undergoing Videoassisted thoracoscopic talc pleurodesis to assess improvement in quality of life in symptomatic malignant pleural effusions. Karnofsky Index and MRC dyspnoea score were both significantly improved post-operateively, p=0.014 and p<0.001 respectively.[37]

VATS decortication versus VATS pleurodesis

VATS decortication has not been the subject of a RCT, but mortality has been as high as 13% and prolonged air leak 20% in case series.[35]

Use of single incision thoracoscopic pleurectomy

A case series involving 19 patients undergoing single incision pleurectomy demonstrated a success rate of 91.4%. Median chest tube removal time was 2 days.{{Cite footnote|Citation:Kara M, Alzafer S, Okur E, Halezeroglu S 2013}

Intubated vs nonintubated VATS pleurodesis

There is no difference in pleurodesis success rate between intubated nonintubtaed VATS pleurodesis. Operating time, postoperative hospital stay, postoperative mortality, costs and quality of life were all better in the nonintubated VATS pleurodesis group. There is no difference in effusion free and overall survival.[38]

VATS talc pleurodesis versus tunnelled pleural catheter

Tunnelled pleural catheter has a significantly shorter mean length of stay (7 days vs 8 days, p=0.006), post procedure length of stay (3 days vs 6 days, p<0.0001) and less reinterventions required (1 vs 8, p=0.01) compared to VATS talc pleurodesis. There is no difference in complications, readmission for ipsilateral effusion or in-hospital mortality.[39]

Optimal choice of sclerosant

Over time, a large number of sclerosants have been used to achieve pleurodesis. Those commonly used in Australia have included formulations of bleomycin and tetracycline (that are no longer available) and talc. Success rates with bleomycin and tetracycline were 50-60%.[40] A 2013 study in Japan, demonstrated the efficacy of thoracocsocpic talc poudrage to be 100% at 180 days post procedure, and 71.1% in patients having talc slurry pleurodesis.[41] Graded talc is used in almost all pleurodesis procedures in Australia whether by VATS or talc slurry. Only talc that is graded so that fine particles are excluded should be used as ungraded talc is associated with acute respiratory events that can be severe.[42] Justification for the use of talc as preferred sclerosant is derived from a meta-analysis that compared the relative efficacy of six sclerosants (talc, bleomycin, tetracyclines, corynebacterium parvum, mitozantrone, mepacrine) for pleurodesis. Particular emphasis was placed on talc, bleomycin and tetracycline as these sclerosants are most frequently used in clinical practice and were also the most extensively evaluated in these RCTs. The meta-analysis demonstrated that talc was the most effective sclerosant, with a relative risk for success of pleurodesis of 1.34 (95%CI 1.16 to 1.55). The efficacy of talc relative to bleomycin and tetracycline favoured talc as the sclerosant for successful pleurodesis (RR 1.23, 95%CI 1.00 to 1.50). Talc, compared with all other sclerosants as controls, had a number needed to benefit (NNTB) of 5 (95% CI 3.31 to 9.71).[1]

A meta-analysis of talc pleurodesis demonstrated a RR of 1.21 (95% CI 1.01 to 1.45) for talc pleurodesis compared to control. For thoracoscopic talc poudrage versus control the RR was 1.74 (95% CI 1.11 to 2.73) and talc slurry versus control the RR was 1.05 (95% CI 0.87 to 1.27). Talc was superior to bleomycin for pleurodesis (RR 1.25, 95% CI 1.06 to 1.46).[43]

A systematic review of six observational trials supports Iodopovidone as a safe and effective pleurodesis agent with the success rate of pleurodesis varying from 64.2% to 100%.The summary success rate of all the studies was 90.6% (95% confidence intervals [CI], 86.4–93.8). The only significant complication reported was chest pain of varying degree.[44] A randomised controlled trial consisting of 60 patients, investigating the adverse events of Iodopovidone demonstrated 47 serious events in 34 patients. These were mainly chest pain and hypertension.[45] In a case series by Godazandeh et al, pleurodesis success with povidone-iodone was 72.2%, with pain being the most common adverse event (35.9%).[46] In other parts of the world, small volume solutions of povidone-iodine have been used and achieve success rates similar to talc.[44][47][48] Iodopovidone is effective when administered via thoracoscopy or intercostal catheter. Only small volumes of iodine as reported in published papers should be used, as iodine toxicity can occur with larger instillations (up to 500mls).[44]

A randomised controlled trial comparing autologous blood pleurodeis to tetracycline pleurodesis in malignant pleural effusion demonstrated equivalent efficacy (83.4% vs 87.5%, p=0.37). Autologous blood pleurodesis had fewer complications (pain score p<0.01 and fever p<0.01). Total hospital stay was shorter in the autologous blood pleurodesis group (8.2 days vs 9.8 days, p=0.04).[49]

Gaafar et al performed a randomised controlled trial compared mistletoe preparation to Bleomycin as palliative treatment for malignant pleural effusion. There was no difference in clinical response (61.5% vs 30%, p=0.2138) or toxicities.([50]

A case series by Menna et al using silver nitrate as a sclerosant following failed thoracoscopic talc poudrage showed a significant reduction in fluid drainage with no difference in hospital stay.[51] Adverse events are predominantly metabolic and hypoxia.[52]

Vandetanib, a vascular endothelial growth factor inhibitor, was combined with an intrapleural catheter by Massarelli et al to determine whether this reduces time to pleurodesis.[53] They did not find any significant reduction to time in pleurodesis.

Intrapleural hyperthermic perfusion chemotherapy versus talc pleurodesis or pleurectomy/decortication

The median survival is longer in patients undergoing Intrapleural hyperthermic perfusion chemotherapy compared to talc pleurodesis and pleurectomy/decortication (median survival 15 months vs 6 months vs 8 months). There was no significant difference in adverse events.[54] Back to top


Evidence summary Level References
Talc slurry or povidone-iodone solution may be instilled using a small bore 12-14F catheter. There may be no benefit from larger catheters.


Last reviewed December 2015

II, III-1, III-3 [28], [29], [30], [26]
Evidence-based recommendationQuestion mark transparent.png Grade
Smaller-bore, 12-14F, intercostal catheters may be used for bedside pleurodesis in patients with malignant pleural effusions.


Last reviewed December 2015

C


Evidence summary Level References
Indwelling pleural catheters reduce hospital length of stay, improve quality of life and provide superior effusion control to bedside pleurodesis.


Last reviewed December 2015

II, III-2, IV [10], [13], [18], [14], [39], [15], [32]
Evidence-based recommendationQuestion mark transparent.png Grade
Indwelling pleural catheters might be effective in the outpatient management of malignant pleural effusion.


Last reviewed December 2015

C


Evidence summary Level References
In patients with NSCLC, VATS talc pleurodesis under general anesthesia is superior to bed side chest tube talc pleurodesis in terms of radiological recurrence.


Last reviewed December 2015

I, II [1], [22], [35]
VATS talc pleurodesis under general anesthesia is superior to bed side chest tube talc pleurodesis in terms of patient perception of pain, comfort and safety.


Last reviewed December 2015

II [22]
Evidence-based recommendationQuestion mark transparent.png Grade
VATS talc pleurodesis is recommended in fit (ECOG 0-2) patients with NSCLC with an expected survival of >2 months who have >90% lung expansion after needle thoracocentesis.


Last reviewed December 2015

A
Evidence-based recommendationQuestion mark transparent.png Grade
VATS talc pleurodesis may be considered in fit (ECOG 0-2) patients with NSCLC with an expected survival of >2 months who have <90% lung expansion after needle thoracocentesis.

VATS with biopsy and subsequent talc pleurodesis may be considered in patients who require pathological confirmation of their cancer to determine management.
Last reviewed December 2015

C


Evidence summary Level References
Cytoreductive therapy with intrapleural hyperthermic perfusion chemotherapy improves survival in patients with malignant pleural effusions.


Last reviewed December 2015

II [1], [20], [21], [22], [23], [47], [54]
Evidence-based recommendationQuestion mark transparent.png Grade
Intrapleural Hyperthermic Perfusion Chemotherapy (HIPEC) could be used in the treatment of malignant pleural effusions.


Last reviewed December 2015

C


Evidence summary Level References
Pleurodesis using an intercostal catheter and injection of sclerosant is an effective and safe alternative to VATS procedures albeit with a somewhat lower success rate.


Last reviewed December 2015

I, II, III-3, IV [11], [45], [36], [43], [1], [20], [21], [22], [23], [47]
Evidence-based recommendationQuestion mark transparent.png Grade
Intercostal catheter (ICC) pleurodesis should be performed in patients unfit for more aggressive interventions and is an acceptable alternative where access to VATS without delay is problematic.


Last reviewed December 2015

A



Practice pointQuestion mark transparent.png

For fit patients, with an established diagnosis, an attempt to reduce pleural fluid re-accumulation by pleurodesis can be made at the first opportunity.
Last reviewed December 2015


Practice pointQuestion mark transparent.png

Initial drainage of MPE to dryness is a reasonable approach, as it may stratify patients to further treatment based on: a. radiological evidence of re expansion versus trapped lung, b. symptomatic improvement, and c. cytological confirmation of the diagnosis.
Last reviewed December 2015


Practice pointQuestion mark transparent.png

Tunnelled pleural catheters (TPC) may be preferred where lung reinflation is not achieved, but consideration of the practicalities of ongoing care should be made before their use.
Last reviewed December 2015


Practice pointQuestion mark transparent.png

Tunnelled pleural catheters may be considered in patients well enough for only a minor procedure where issues of disposable equipment costs can be addressed and ongoing clinical care is available.
Last reviewed December 2015


Practice pointQuestion mark transparent.png

Long term pleural catheter may be an option in those patients who prefer this.
Last reviewed December 2015


Practice pointQuestion mark transparent.png

In highly selected cases where re expansion is poor and patients adamantly refuse long term drainage, or alternatively have minimal symptomatic relief with drainage, it may be reasonable to attempt VATS decortication.
Last reviewed December 2015


Practice pointQuestion mark transparent.png

VATS decortication cannot be justified in patients with symptomatic relief from long term catheter drainage despite poor lung expansion.
Last reviewed December 2015


Practice pointQuestion mark transparent.png

Insertion of a small intercostal catheter is not without risk. In particular, standard dilators are long enough to damage major mediastinal structures if inserted an unnecessary distance into the thoracic cavity.
Last reviewed December 2015

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