Review

Malignant pleural effusion management: keeping the flood

gates shut
Steven Walker*, Rachel Mercer*, Nick Maskell, Najib M Rahman

With no cure for malignant pleural effusion, efforts are focused on symptomatic management. Historically, this Lancet Respir Med 2020;
symptomatic management was achieved with the instillation of a sclerosant agent into the pleural space to achieve 8: 609–18

pleurodesis. The development of the tunnelled indwelling pleural catheter and ambulatory pleural drainage changed Published Online
October 25, 2019
the management of malignant pleural effusion, not solely by offering an alternative management pathway, but by https://doi.org/10.1016/
challenging how health-care providers view success in a palliative condition. Furthermore, with additional treatment S2213-2600(19)30373-X
options available, increased imperative exists to better characterise patients to enable a personalised approach to their *Contributed equally as first
care. We have done a review of the scientific literature and clinical trial registries to provide an overview of the current authors
and ground-breaking research published in the past 10 years. Academic Respiratory Unit,
University of Bristol, Bristol,
Introduction This Review outlines seminal practice changing UK (S Walker MBChB,
Prof N Maskell DM); Oxford
Malignant pleural effusion (MPE) is a common and publications addressing prognostication, inpatient Respiratory Trials Unit,
disabling complication of cancer, with a sixth of patients manage­­ment, and outpatient pathways for patients with Churchill Hospital, Oxford, UK
with malignancy developing an effusion during their symptomatic MPE. (R Mercer MBChB); and Oxford
NIHR Biomedical Research
disease, and an estimated annual incidence of over
Centre, Oxford, UK
150 000 in the USA.1 Until 2010, the management pathway Optimising pleural thoracentesis role of (Prof N M Rahman DPhil)
was linear, non-personalised, and with little supporting manometry Correspondence to:
research. The British Thoracic Society Pleural Disease The first-line approach to an MPE is typically therapeutic Prof Najib M Rahman, Oxford
Guidelines,2 published in 2010, recommended recurrent aspiration with a cannula or bespoke aspiration kit. This Respiratory Trials Unit, Churchill
Hospital, Oxford OX3 7LE, UK
therapeutic aspirations in patients with MPE and a life
najib.rahman@ndm.ox.ac.uk
expectancy of less than 1 month, but recognised the
absence of validated predictors of prognosis. Pleurodesis Key messages
with a small-bore tube avoiding concurrent use of non- • The evidence base for the management of a malignant
steroidal anti-inflammatory (NSAID) drugs when a tube is pleural effusion (MPE) has increased substantially over the
inserted was advocated in all patients who had expandable past decade and the guidelines need to be updated to
lung. Indwelling pleural catheter (IPC) use was in its reflect this increase
infancy and was only recommended as second-line • Manometry is not used in routine therapeutic aspirations
treatment, or in those with non-expandable (ie, trapped) but might be helpful in identifying patients with
lung. The guidelines were based on the available evidence non-expandable lung
at the time, but over the past decade the data have increased • Prognostication for patients with MPE has improved with
substantially, leading to large changes in practice. the introduction of new prognostic scores but the role in
Several factors lead to this increased evidence base. The routine clinical practice is unclear
recognition that thoracic ultrasound improved the safety of • Sterile talc is the most effective pleurodesis agent;
pleural procedures and its subsequent near universal previous randomised controlled trials comparing slurry
adoption led to increased interest in the speciality and with poudrage have been inconclusive because of
improved understanding of the underlying disease methodological issues; the TAPPS study should provide
processes. The introduction of the FDA-approved, silicone- additional robust insight to this question
coated IPC offered an alternative approach to managing • Smaller bore chest drains might not be as effective as
refractory pleural effusions. The IPC also signalled the larger bore drains in delivering pleurodesis, but this
arrival of symptom-directed outcomes, in which success difference might be because of tube blockage or
was measured on the basis of patient-orientated para­ displacement, rather than the absolute diameter
meters, and not the conventional measure­ment of success • The option of indwelling pleural catheter (IPC) or chest
by an arbitrary, radiological definition of pleurodesis drain and pleurodesis should be presented as equal
success, which was largely used in old surgical studies.3 treatments in patients with fully expandable lung, with
Symptom directed outcomes are reflected in pleural the final decision decided by patient preference
clinical trial designs from the past decade, which have • Outpatient talc pleurodesis via an IPC is safe and increases
moved away from radiographical outcomes to patient- rates of pleurodesis compared with IPC alone
centred end­ points. Invariably, with additional ways of • IPCs can be used as a vehicle for other treatments, either
approaching the same problem, an increased interest to promote pleurodesis or address the underlying
exists in how to best phenotype and endotype MPE, with disease process and its capacity in this area has yet to be
several studies published since 2014 examining scoring fully recognised
systems to evaluate pleurodesis success and prognosis.

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 Review

approach allows assessment of symptom benefit after were only taken during brief interruptions in the
aspiration, assessment of fluid recurrence, and the drainages, and acute changes in pleural pressures might
identification of non-expandable lung on chest have been missed during these periods. Even with digital
radiograph after the procedure. The 2010 British Thoracic manometers, capturing true end-expiratory pressures,
Society guidelines suggest a maximum volume of which change multiple times during the respiratory
drainage of 1·5 L, as higher drainage volumes were cycle, is not easy and might confer inaccurate end-
suspected of increasing the risk of re-expansion expiratory pressures.6
pulmonary oedema, and this volume was felt adequate to Despite Lentz and colleagues4 finding no benefit in the
identify most non-expandable lung and be associated routine use of pleural manometry in predicting pain and
with symptom benefit. Many centres undertake a large complications during thoracentesis, mano­ metry might
volume aspiration, stopping if the patient develops still have value in predicting non-expandable lung and
symptoms of chest pain or cough. The presence of non- directing the clinician to an appropriate management
expandable lung considerably alters the management pathway. A study addressing whether pleural elastance
pathway, and accurate detection at time of aspiration assessment during thera­peutic aspiration can successfully
would expedite definitive management. Unfortunately, triage patients to either IPC or talc pleurodesis manage­
no methods of accurately predicting who will develop ment is currently recruiting.7 A change in pleural elastance
non-expandable lung or to identify its presence before of over 14·5 cm H20 per litre is used to denote negative
aspiration exist. Pleural manometry allows a greater pleural pressure and therefore non-expandable lung,
appreciation of the pressure changes in the pleural space which indicates that pleurodesis is less likely to be
during aspiration than observation alone and was felt by successful than in those with expandable lung and
physicians to be a potential solution for identifying and insertion of an IPC would be recommended. If
characterising non-expandable lung more accurately identification of non-expandable lung can be established
than radiology or patient symptomatology alone. while enough fluid is in the chest to allow for tube
Lentz and colleagues4 produced the first randomised placement, this information would allow for triage to IPC
study to address the clinical utility of pleural manometry or pleurodesis at the time of initial aspiration and has the
during routine thoracentesis, comparing manometry potential to direct future treatment.
with symptom-guided aspiration in 128 patients. The main clinical importance of non-expandable lung
The primary outcome was unique and directly addressed is related to pleurodesis failure. Manometry might
a patient-centred outcome (ie, chest discomfort during identify a cohort of patients who have a change in pleural
pleural aspiration), with secondary outcomes including elastance suggestive of non-expandable lung but with a
volume drained, procedure duration, lung re-expansion, subsequent normal chest radiograph. That this group
and radiograph appearance after procedure. The trial could still be at high-risk of pleurodesis failure is
found no significant differences in outcomes between plausible as the lung recoils away from the chest wall, in
groups, apart from a higher rate of radiological evidence small degrees, which may not be evident radiographically.
of pneumothorax without a persisting air leak in the This insufficient pleural apposition could be a driver for
control group (p=0·012) compared with the intervention pleurodesis failure, which has, until now, not been
group. These findings supported previous observational identified. This use of pleural elastance to direct
data that manometry could not predict re-expansion treatments might allow for informed patient choices,
pulmonary oedema, and represents the highest quality but additional directed work is needed to fully define the
study to date to directly address the clinical utility of area.
pleural manometry with patient-focussed outcomes; on
the basis of this data, no clear role exists for pleural Pleurodesis—challenging the dogma
manometry in routine pleural aspiration. However, to Chemical pleurodesis with instillation of a chemical
appreciate that determining and interpreting pleural sclerosant via a chest tube at the bedside has been the
pressure is difficult is important, and care needs to be long-established management of refractory MPE, but its
taken in establishing whether these results represent a practice has been based on long-standing canon in the
genuine non-difference between symptom and absence of scientific rigour. The choice of sclerosant was
manometry guided thoracentesis, or whether these mainly based on where physicians practiced, size of
results reflect physicians’ inability to accurately assess drain was based predominately on personal experience,
the changes of pleural pressures. Plausible physiological and NSAIDs were universally avoided because of
reasons exist for why measuring pleural pressures might concerns that their anti-inflammatory action would
not decrease the risk of chest pain, with previous studies impede pleurodesis. Over the past 10 years, a series of
showing an inconsistent relationship between pleural large randomised controlled trials (RCTs) and robust
pressures and chest pain,5 and pressure thresholds for meta-analyses have created a clearer picture of the
chest discomfort might vary between patients.4 However, definition of optimal pleurodesis.
concerns that these measurements do not truly reflect The choice of sclerosant available is wide, with no clear
the pressures in the pleural cavity exist. The pressures consensus and practice on the basis of regional

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 Review

preference. The trial data reflects this absence of they were shown in be non-inferior in terms of
consensus, with numerous small studies examining pleurodesis success.
differing agents. A review by Clive and colleagues8 The recommended practice for timing of talc
proposed to combine these data, reviewing 62 studies instillation and chest tube removal on the basis of the
involving 3428 patients to assess the effectiveness of volume of fluid output is based on little evidence. With
different methods of pleurodesis. They concluded that increasing use of thoracic ultrasound, it has been
instillation of sterile talc via thoracoscopy (ie, poudrage) proposed that a superior method might be to examine for
was more effective than many of the commonly used satisfactory apposition of the parietal and visceral pleura,
methods, although because of high heterogeneity and and sonographically assess fibrin deposition in the
risk of bias, the analysis could not definitively state its pleural space. The use of thoracic ultrasound to
superiority over other methods (such as talc slurry via determine pleurodesis success has been shown in animal
chest drain). This question of the optimal method of models of chemical pleurodesis, in which a thoracic
administrating talc, either at thoracoscopy (ie, poudrage) ultrasound score showing absence of lung sliding (ie, the
or via chest drain (ie, slurry) has not yet been convincingly movement between visceral and parietal pleura) has
answered; however, the TAPPS trial,9 which directly been associated with the development of a successful
addresses this question, has recently completed recruit­ pleurodesis.11 A small prospective obser­ vational study
ment and follow up of 330 patients, and this study should tested the hypothesis in 20 patients, concluding that
provide definitive information. pleural adhesion was shown on ultra­ sound in 13 of
The TIME1 trial10 sought to answer two important 20 patients after 24 h, and to remove drains earlier on the
questions concerning talc pleurodesis by way of a basis of ultrasound findings might therefore be possible.12
2 × 2 factorial phase 3 randomised clinical trial. The first A currently recruiting RCT (SIMPLE, ISRCTN16441661)
question addressed optimal chest drain size, comparing was designed to investigate whether using this ultra­
small-bore (ie, 12Fr) with large-bore (ie, 24Fr) drains. sound score would allow a reduction in hospital length of
Secondly, the trial addressed for the first time in humans stay and is near the end of recruitment.
whether NSAID administration impaired pleurodesis, These trials8,10,11,12 have challenged accepted dogmas and
compared with opiate use.10 A total of 320 patients with filled knowledge gaps. The TIME1 trial10 was the first,
MPE requiring pleurodesis were enrolled, with co- multicentre randomised trial in malignant pleural
primary outcomes of pain during admission (superiority disease addressing the pleurodesis method. The hypo­
comparison) and pleuro­ desis at 3 months (non- thesis that NSAID analgesia reduces pleurodesis success
inferiority com­parison with a pre-specified threshold of was disproven and that small chest drains cannot be
15%). No significant difference was found in pain scores considered equivalent to large-bore drains for pleurodesis
between the analgesia groups, but the NSAID group was shown. A Cochrane review8 could not determine the
received a modestly higher number of rescue doses of most effective method of pleurodesis but the authors did
analgesia (median one per patient). NSAIDs were shown agree that sterile talc was the most effective agent.
to be non-inferior in terms of pleurodesis success at Advances in practice have allowed the use of thoracic
3 months. The large-bore 24Fr chest drains (26 mm ultrasound in identifying pleural adhesions and might
visual analogue scale score) were on average more revolutionise the way clinicians deliver pleurodesis care.
painful than the small-bore 12Fr drains (22 mm visual
analogue scale score), although the absolute difference The surgical option
on average in pain scores were small. However, for the Surgical pleurectomy is not recommended in the
pleurodesis outcome, 12 (24%) of 50 patients with 24Fr treatment of MPE,2 but some doubt exists as to whether
drains had pleurodesis failure compared with 15 (30%) surgery might offer a better option to selected patients
of 50 with 12F drains, and 12F drains did not meet the with MPE than medical pleurodesis methods. The largest
15% criteria for non-inferiority. Smaller drains were and only randomised study assessing this theory was
associated with a high rate of early fall out, patients with done in patients with mesothelioma. The MesoVATS
small-bore chest were at higher risk of not receiving trial13 was a randomised study directly comparing surgical
talc and were associated with modestly increased treatment using video-assisted partial pleur­ ectomy
complications at insertion. These results imply that (VATS-PP) with physician talc pleurodesis, either by talc
small-bore chest drains are not as effective as large-bore slurry or poudrage. The study showed no significant
chest drain in achieving pleurodesis; however, the difference in the primary outcome of survival at 1 year
number of patients in the pleurodesis analysis was (52% [95% CI 41–62] in the VAT-PP group compared with
smaller than intended because of the inclusion of 57% [46–66] in the talc pleurodesis group, hazard ratio
patients undergoing thora­ coscopy in this study, and [HR] 1·04 [95% CI 0·76–1·42]; p=0·81). No significant
therefore further confirmatory studies are proposed to differences were found in measures of fluid control,
understand this signal fully. Nonetheless, the study measured in this study by chest radiography alone.
results challenge the current trend of small-bore drain Complications and the length of stay were both higher in
use for all indications and the avoidance of NSAIDS if the VATS-PP group (median hospital stay in the VATS-PP

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 Review

group was 7 days [IQR 5–11] compared with 3 days [2–5] and fewer pleural procedures (odd ratio [OR] 0·21; 95% CI
in the talc pleurodesis group [p<0·0001]) and the cost of 0·04 to 0·86; p=0·03) than the instillation of talc slurry
VATS-PP was higher than talc pleurodesis without any via a test tube. Adverse events were, however, higher in
significant improvement in survival or quality of life—a the IPC cohort (OR 4·70; 95% CI 1·75 to 12·60; p=0·002).
single quality-of-life measure was in favour of VATS-PP The adverse events were predominately related to
in those that survived 6 months. This important trial infection (eg, pleural and cellulitis).
showed that surgery has no advantage over medical The AMPLE study15 examined whether IPCs were more
treatment in mesothelioma in terms of survival, fluid effective than talc pleurodesis in reducing the total number
control, or quality of life, but higher complications and of days treated in hospital in patients with MPE. IPCs were
costs than talc pleurodesis. The method for measuring inserted as a day case, with subsequent drainages in the
fluid control (ie, chest radiograph only with no community guided by symptoms. The talc group were
information on requirement for further pleural admitted for chest tube insertion, followed by talc slurry
procedures) is not considered robust, as pleural instillation. Of the 146 patients randomised, the total all-
malignancy is difficult to differentiate from fluid on cause median hospital stay was shorter in the IPC group
plain chest radiograph. Although a single quality-of-life (10 days) when compared with the talc pleurodesis group
measurement was in favour of VATS-PP, this result only (12 days; estimate of difference 2·92 days, 95% CI
occurred at 6 months at which time a substantial attrition 0·43–5·84; p=0·030), with the reduction mainly attributed
of patients had occurred. to a decrease in effusion-related days when treated in
hospital. Only four patients randomised to IPC required
Indwelling pleural catheter—changing the further ipsilateral pleural procedures compared with
framework 22 patients in the talc cohort (p=0·001). Serious adverse
Insertion of an IPC to facilitate long-term drainage of a rates were one (1%) of 73 in the IPC group and three (4%)
refractory MPE has been traditionally recommended in of 71 in the talc group. Overall adverse rates were higher in
guidelines2 as a second-line approach, when the patient the IPC cohort (22 [30%] of 73) than in the talc group (13
has developed fluid recurrence after conventional [18%] of 71).
pleurodesis with a sclerosing agent or for patients with The ASAP trial16 examined whether aggressive daily
non-expandable lung. However, over the past decade a drainages of the IPC were superior to the current standard
wealth of robust RCT evidence has been published, of alternate day drainages in achieving autopleurodesis. In
showing IPCs as an effective first-line method for the 149 patients who were randomly assigned, the rate of
controlling dyspnoea.14,15 These trials14,15 have also moved autopleurodesis, defined as complete or partial response
beyond the passive use of the IPC as a simple drainage on the basis of symptomatic and radiographical changes,
system, to an active role, with regimens incor­porating was greater in the aggressive drainage group (34 [47%] of
aggressive drainage or instillation of sclerosants aimed at 73) than in the standard group (18 [24%] of 76; p=0·003).
inducing rapid pleurodesis. Additionally, during this time Additionally, median time to autopleurodesis was shorter
the design of pleural clinical trials has matured, moving in the aggressive group (54 days; 95% CI 34–83) than in
away from radio­ graphical outcomes to patient-centred the standard group (90 days; 70 to non-estimable). Adverse
endpoints. The following five clinical trials are the events rate, quality of life, and patient satisfaction scores
seminal studies that have established IPC’s position in were similar between the two groups.
the management pathway of MPE and expanded its role The AMPLE-2 trial17 examined whether aggressive
beyond a simple ambulatory chest drain. (ie, daily) drainages of IPC compared with drainages
The TIME2 trial14 was the first to directly examine when symptomatic were superior in providing
whether using an IPC or the instillation of talc slurry via a breathlessness control. In the 87 patients who were
chest tube was effective at relieving dyspnoea, as assessed randomly assigned, there was no difference in mean
with a visual analogue scale dyspnoea score. Patients with daily breathlessness scores between the aggressive
MPE without preceding pleurodesis were randomised to drainage group (geometric mean 13·1 mm; 95% CI
either IPC insertion or chest drain with talc instillation. 9·8–117·4) and the symptomatic drainage group
IPCs were inserted as an outpatient, with subsequent (17·3 mm; 13·0–22·0; p=0·18) during the first 60 days.
home drainage 3 times weekly or as required for the relief More patients in the aggressive drainage group achieved
of dyspnoea. The talc group were admitted with chest spontaneous pleurodesis (16 [37·2%] of 43) than the
tube insertion and subsequent talc slurry pleurodesis. symptom-guided group (five [11·4%] of 44) at 60 days
Dyspnoea improved in both groups, although no (HR 3·287; 95% CI 1·360–7·740; p=0·0065). Quality-of-
significant difference was found in the mean visual life measures reported by patients were better in the
analogue scale dyspnoea for the first 42 days comparing aggressive group (estimated difference in mean 0·112;
the IPC and talc groups (difference of 0·16 mm; 95% CI 95% CI 0·0198–0·204; p=0·0174)
–6·82 to 7·15; p=0·96). IPC insertion was associated with The IPC Plus trial examined whether talc admin­
significantly shorter length of treatment in hospital istration through an IPC was more effective at inducing
(difference –3·5 days; 95% CI –4·8 to 1·5 days; p<0·001) pleurodesis than the use of IPC alone.18 Patients with

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 Review

MPE had an IPC inserted, with maximal drainage at the AMPLE study15 might not be important for the
catheter placement and then a minimal of four further individual patient but have financial implications when
drainages before having a chest radiograph at day 10 to extrapolated across a health system. Similarly, the
rule out substantial lung entrapment. Patients were then reduced median time until pleurodesis with accelerated
randomly assigned to receive either 4 g of talc slurry or IPCs regimens has cost implications. The drainage
placebo via the IPC as an outpatient, with patients masked bottles are expensive and, if there is a high volume of
to the intervention. In the talc group, 30 (43%) of drainage over a long period of time, this long-term
69 patients had successful pleurodesis at day 35, drainage might negate any cost saving from the
compared with 16 (23%) of 70 patients in the placebo avoidance of an inpatient admission. Any cost analysis
group (HR 2·20, 95% CI 1·23–3·92; p=0·008). No needs to be clear about the relative costs of inpatient
significant increase was found in IPC blockages rates or stays compared with the care and equipment in the
adverse events in the talc group. community in different health-care systems with
The TIME2 trial14 and AMPLE study15 compared IPC different funding models. A cost analysis of patients in
directly with talc slurry pleurodesis. The TIME2 trial14 the TIME2 trial14 compared patients managed with IPCs
showed similar relief in dyspnoea whereas the (US$4993) to patients managed with talc pleurodesis
AMPLE study15 showed a significant reduction of total ($4581), finding no difference in overall mean cost
time treated in hospital for patients with an MPE who are (95% CI –1387 to $2261).19 The cost associated with IPCs
managed with an IPC compared with talc slurry management increased with time, with survival of less
pleurodesis. The TIME2 trial14 showed a higher adverse than 14 weeks skewing the cost-benefit towards the IPCs
event rate in the IPC group compared with the talc pathway. These health economic assessments were
pleurodesis group and whether a reduction from primarily derived from the UK and Australia and might
12 to 10 days total inpatient stay in the AMPLE-2 trial17 not be applicable to all health-care services depending
represents a clinically significant difference for the on the relative costs of homecare services, inpatient
patient is not clear. Nevertheless, these findings, stays, and equipment costs.
combined with fewer ipsilateral pleural procedures in the Current and future research aims include developing
IPC cohort compared with the talc pleurodesis group effective strategies of inducing pleurodesis to facilitate
helped to further define its role in this population. By IPC removal, both for patient comfort and to reduce the
highlighting the potential benefits of IPCs (eg, shorter cost and potential complications of long-term drainage.
hospital stays than for talc pleurodesis) and potential The rate of successful pleurodesis with IPCs is appreciably
draw-backs (eg, higher adverse event rates than for talc lower than that of chest drain and talc pleurodesis, even
pleurodesis), these studies helped to inform patient when talc was instilled via an IPC in an expandable lung.18
choice on the available options. This difference could be related to the inability to
The ASAP trial,16 AMPLE-2 trial,17 and IPC Plus18 maintain a dry pleural space after pleurodesis, compared
focussed on achieving pleurodesis with an IPC, either via with when a chest drain is connected to an underwater
autopleurodesis or by the introduction of a sclerosing seal for patients undergoing an inpatient pleurodesis.
agent, to allow the removal of the catheter. The ASAP This differ­ence might also reflect the thrice weekly
trial16 showed that a more aggressive drainage regimen standard drainage regimen taken during this trial, rather
resulted in higher rates of pleurodesis, although many than more aggressive drainage. The encouraging results
patients in both groups dropped out or died before achieved by the aggressive daily drainages of the ASAP
the primary endpoint timeline was reached. No trial16 and the AMPLE-2 trial17 reinforces that keeping the
evidence of quality-of-life improvement was found. The pleural space dry is key to prompting autopleurodesis and
AMPLE-2 trial17 showed both regimens were equally further studies are required to examine whether
effective in improving breathlessness, but that aggressive combining talc and aggressive drainages would achieve
drainage increased autopleurodesis rates and for the first higher pleurodesis rates than either talc or regular
time showed an improvement in quality of life. The IPC drainage alone. A summary of the trials since 2014 is
Plus trial18 showed that talc instillation doubled the provided in figure 1. Future work on whether the IPC can
chances of pleurodesis, without increased rates of adverse be used as more than just a drainage catheter, or
events, supporting its use as part of an ambulatory conversely research into whether persistent exposure to
pathway. Of importance was the absence of increased risk pleural fluid is associated with poor prognosis, might
of development of a symptomatic loculated effusion after help to crystallise the place of the IPC in the management
talc instillation. algorithm of MPE.
The permutations in IPC management and their
associated outcomes of number of days treated as an The septated malignant pleural space
inpatient in hospital and time until pleurodesis have Patients with a septated MPE are difficult to manage.
health-care cost impli­cations, in addition to implications The British Thoracic Society guidelines recommended
on the individual. The reduction of length of hospital intrapleural fibrinolytics in patients with a non-draining,
stay from 12 to 10 days in patients managed with IPCs in septated pleural space, although the recommendation

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 Review

Personalising MPE management—

prognostication
With the increasing management options for MPE a
need exists for better stratification to enable selection of
an optimal management strategy. Prediction of survival
in MPE would be of value in triaging patients with good
prognosis to more aggressive pleural and oncological
Small-bore versus interventions, whereas patients with a poor prognosis
wide-bore Drug-eluting would be managed with less invasive procedures aimed
TIME1 catheter
Swift* at symptom control. Since 2014, two publications have
Talc poudrage versus
Ag developed and prospectively validated prognostic scores
talc slurry
TAPPS* in MPE.21,22
The pleural fluid Lactate dehydrogenase, Eastern
Cooperative Oncology Group performance score,
Neutrophil-to-lymphocyte ratio, and Tumour type (LENT)
IPC versus talc
TIME2
score was derived using three prospectively collected
AMPLE Aggressive drainage datasets, assessing for factors predictive of survival in
regimens patients with MPE.21 Effusion size, Eastern Cooperative
Pleurodesis timing ASAP Talc Oncology Group performance score, pleural fluid lactate
(drainage volume versus TUS) AMPLE2
SIMPLE* Talc instillation dehydrogenase, serum neutrophil to lymphocyte ratio,
IPC plus serum NT-proBNP, and malignant cell type were all
AMPLE3*
OPTIMUM*
independently associated with survival in this model. Four
of the most clinically applicable variables were selected
Figure 1: Recruited and recruiting trials in management of malignant pleural effusion (pleural fluid Lactate dehydrogenase, Eastern Cooperative
Ag=silver. TUS=thoracic ultrasound. *Recruiting trials. Oncology Group performance score, serum neutrophil-to-
lymphocyte ratio, and tumour type) to produce the LENT
was based on radiological rather than patient-reported score. This score separated the patients into low-risk,
outcomes. moderate-risk, and high-risk groups. Median survival for
The TIME3 study20 assessed the effects of intrapleural the cohorts were 319 days (IQR 228–549) for the 43 patients
fibrinolytics (ie, urokinase) on dyspnoea and pleurodesis in the low-risk group, 130 days (47–467) for the 129 patients
success in patients with septated MPE with a double- in the moderate-risk group, and 44 days (22–77) for the
blind, placebo-controlled trial. Dyspnoea was measured 31 patients in the high-risk group. In the validation cohort,
with the 100 mm visual analogue scale for breathlessness the LENT score was significantly better than the Eastern
with an established clinically significant difference of Cooperative Oncology Group performance score alone in
19 mm. The secondary endpoints were chest radiograph predicting survival at 3 months (p=0·002) and 6 months
change, survival, length of stay, adverse events, and (p<0·001) but the difference was not significant at 1 month
blood parameters. The study showed no significant (p=0·360).
difference in mean dyspnoea between groups (mean The PROMISE study22 aimed to develop a clinical
difference 3·8 mm; 95% CI –12 to 4·4; p=0·36) or prognostic score for MPE and to discover and validate
pleurodesis success (urokinase group 13 [37%] of new biological markers using cutting edge techniques in
35 patients, placebo group 11 [32%] of 34 patients; translational medicine. The PROMISE study22 used
adjusted HR 1·2; p=0·65). However, patients treated five patient cohorts for discovery, validation, and pro­
with urokinase showed statistically significant improve­ spective assessment.10,14,20,23 Patients were stratified into
ment in chest radiograph appearance, reduced length of poor (<3 months) and good survival (>3 months) and
hospital stay, and appeared to have improved survival. pleurodesis success or failure. From 1250 proteins, only
Although this trial did not show significant improvement four proteins were statistically significantly associated
in dyspnoea or pleurodesis success, the unexpected very with survival and none for pleurodesis success. R­gression
poor survival (median of 2 months) might mean that the analysis from the dataset produced seven variables for
time was insufficient for these outcomes to change. The the clinical score with the addition of pleural fluid tissue
change in radiographical appearance suggests biological inhibitor of metalloproteinases 1 (TIMP 1) levels for the
activity of intrapleural urokinase and no significant biological score. The clinical factors were the Eastern
urokinase related adverse events was found, and Cooperative Oncology Group performance score,
importantly, no bleeding related adverse events. This previous chemo­therapy and radiotherapy, cancer type,
result suggests that urokinase should not be used white blood cell count, c-reactive protein, and haemo­
routinely in such patients but might have a role in those globin. Stratifying into four PROMISE survival categories
with longer potential survival and septated effusions by PROMISE score showed that the lowest risk group
with substantial sized collections on chest radiograph. had a less than 25% risk of death at 3 months, compared

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 Review

with the highest risk group who had a greater than 75%
risk. A nomogram was derived associating individual Malignant pleural effusion
PROMISE score (from 0 to 43) and risk of death at
3 months. This score was externally validated with a
Therapeutic aspiration
separate cohort and produced C statistic values of
0·89 (95% CI 0·84–0·93) for the clinical score and
0·90 (0·84–0·93) for the biological score. The PROMISE Improvement in dyspnoea?
study22 has provided a wealth of much needed information
on pleural biomarkers, several of which might provide Consider repeated
No Yes therapeutic
targets for future treatment. However, despite identifying aspirations if
several thousand proteins, only four pleural biomarkers Investigate for other Lung re-expansion? expected survival
causes of dyspnoea <1 month and slow
(ie, TMP metalloproteinase inhibitor 1 [TIMP1], gelsolin,
reaccumulation
versican, and macrophage migration inhibitory factor)
were identified as predicting risk of death and no No Yes

biomarkers were useful in predicting pleurodesis Patient choice

IPC
success. Of these biomarkers, only the TIMP1 protein IPC Talc pleurodesis (either
formed part of the final scoring system, and this score poudrage or slurry)
derived from TIMP1 only accounted for a maximum of
two out of the total possible 43 points. The absence of
If patients prefer
success in identifying pleural biomarkers, particularly in accelerated pleurodesis,
determining pleurodesis success shows the challenges in offer either:
• Aggressive drainage
character­ising MPEs caused by a heterogenous group of regimens
primary malignancies.24 Moving forward, better personal­ • Talc installation
isation should aid biomarker identification.
The LENT score was the first validated score, showing Figure 2: Suggested management pathway for malignant pleural effusion (adapted from Feller-Kopman and
great promise in predicting survival in MPE. However, colleagues25)
Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society. The
over 60% of patients fell into the moderate-risk group,
American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
which also had the widest range of survival, potentially IPC=indwelling pleural catheter.
reducing clinical applicability. The PROMISE score
predicted mortality more effectively for the individual dyspnoea. Figure 2 provides an adapted version of this
patient than the LENT score and is the first study to show a pathway using trial evidence since its publication. These
robust pleural fluid protein signal associated with survival. official guidelines are echoed in the ERS and EACTS
As such, the study provides an improved understanding of statement on the management of malignant pleural
some of the pathways implicated in poor outcomes for effusions,26 which also highlight the absence of robust
MPE and might provide future treatment targets. However, evidence for the management of patients with loculated
the PROMISE score is relatively complex and might not be effusions or non-expandable lung.
as applicable in daily practice as the LENT score. The next 5 years will further explore accelerated auto-
Knowledge of probable prognosis is clearly beneficial to pleurodesis regimens, with two further recruiting studies
both the patient and treating physician, as such knowledge examining instillation of talc via the IPC (table). There
allows better discussions on optimal treatment pathways. are exciting possibilities with drug-eluting catheters,
However, that neither of these scoring systems have been including a silver-nitrate coated IPC that slowly elutes
implemented and shown to improve patient reported the pleurodesis agent over time and a 2015 pilot clinical
outcomes should be noted; further studies assessing their study showing no significant adverse events.27 This silver
effect on the clinical pathway and outcomes such as quality nitrate coated IPC is being investigated in a large
of life are required. phase 3 trial (NCT02649894). The possibility of using a
pleural pump, draining the pleural space directly into the
Future direction—controlling the flow urinary bladder, has also been explored.28
The research done over the past 10 years has challenged Important work has explored the experience of
the current or longstanding practices and provided patients with pleural malignancy and their carers.29,30
evidence for new techniques. The findings of these studies The first RCT examining the role of early specialist
are reflected in the Official ATS, STS, and STR Clinical palliative care on quality of life for malignant pleural
Practice Guidelines on the Management of Malignant mesothelioma was published in 2019.31 Although a
Pleural Effusions,25 which recommends that for patients difference in health-related quality-of-life outcomes
with suspected expandable lung and no previous definitive between early specialist palliative care and standard care
therapy, and whose symptoms are attributable to the was not shown, interest­ing insights into their holistic
effusion, either IPCs or chemical pleurodesis be used as care was provided. Further studies have looked at the
first-line definitive intervention for management of role of nutrition, exercise, and complementary medicine

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 Review

Intervention Comparator Trial design Single or Primary outcome Number of Status Date
multicentre objective participants complete
TAPPS (ISRCTN47845793) Medical Small-bore chest drain Randomised, Multicentre Rate of pleurodesis 330 Completed October 2017
thoracoscopy and and talc pleurodesis non-blinded failure
talc poudrage
SWIFT (NCT02649894) Sliver nitrate Standard IPC Randomised, Multicentre Pleurodesis rates 118 Completed April 2018
eluting catheter single blinded
OPTIMUM IPC and talc Chest drain (small bore) Randomised, Multicentre Health-related 142 Recruiting ··
(ISRCTN15503522) pleurodesis and talc pleurodesis non-blinded quality of life
MESOTRAP (NCT03412357) VAT-PD Standard IPC Randomised, Multicentre Breathlessness 38 Recruiting ··
non-blinded
AMPLE-3 IPC alone (no VATS pleurodesis Randomised, Multicentre Requirement for 160 Recruiting ··
(ACTRN12618001013257) pleurodesis) non-blinded ipsilateral pleural
procedure
RAPID (NCT03325192) IPC with IPC with placebo Randomised, Single centre Time to catheter 72 Recruiting ··
iodopovidone double blinded removal
SIMPLE (ISRCTN16441661) Thoracic ultrasound Talc pleurodesis with no Randomised, Multicentre Length of hospital 344 Recruiting ··
before and after talc thoracic ultrasound non-blinded stay
administration
TACTIC (Awaited) Thoracoscopy, talc Thoracoscopy and Randomised, Multicentre Need for further 150 Due to start ··
poudrage, and IPC poudrage with non-blinded pleural interventions 2019–2020
with outpatient admission for a chest over 3 months after
management drain randomisation
IPC=indwelling pleural catheter. VATS=video-assisted thoracoscopic surgery. VAT-PD=video-assisted thoracoscopic partial pleurectomy or decortication.

Table: Current trials investigating management of malignant pleural effusion

to mesothelioma compared with lung or breast cancer.36

Search strategy and selection criteria However, the pleural metastases tumours have been
An electronic search was made on PubMed for completed shown to be discordant from their primary carcinoma,
studies and published protocols in English published between with substantial difference in epidermal growth factor
April 1, 2009, and April 1, 2019 with the title and abstract receptor mutation status between primary tumours and
terms “malignant pleural”, “randomisation”, “prognosis”, and corresponding pleural metastases.37 Clearly, improved
“non-expandable”. The search identified 406 citations. understanding is required to facilitate targeted pleural
We used ClinicalTrials.gov to identify current recruiting trials therapies, and studies of intrapleural chemo­ therapy
in malignant pleural effusion, identifying 115 trials. have produced some positive and some negative
We evaluated studies that investigated recent advances in the results.38–40 Immunotherapies have provided great strides
prognostication or management in MPE and selected the in the management of cancer, with substantial progress
studies that were felt to be most relevant to the field. being made in the understanding of the molecular and
cellular bases of T-cell-mediated antitumour responses41
and an increasing interest in intrapleural immuno­
in patients with mesothelioma.32 Considering that therapies to promote the adaptive immune system
94% of these patients complain of fatigue and 87% of exists.38,42–45 As well as increased local effects, whether
appetite loss, future work should broaden its focus to intrapleural immune therapy will enable the dis­
address their entire symptoms burden.33 semination of memory T cells capable of controlling
The ultimate aim in MPE should be turning off pleural disease systemically is postulated.38
fluid formation.34 New translational research, such as the By enabling longitudinal evaluation of tumour and
PROMISE study,22 has identified possible biological immune cells during immunotherapy and chemotherapy,
markers as therapeutic targets. Early work has examined IPC might facilitate identification of clinically actionable
antiangiogenic agents to reduce vascular hyper­ per­ targets present within the tumour and immune cells,
meability and resultant pleural fluid formation.35 allowing for development of effective patient-specific
Exciting new work is being undertaken, not solely using treatments.38 This treatment and investigation framework
the IPC as a route to instil oncological therapies intra­ is a largely unassessed area of research and is probably
pleurally, but as a port to serially sample pleural fluid. an important direction for the future.
This work might elaborate on the understudied tumour In 10 years’ time, the scope of pleural disease will
microenvironment, which is not a simple reflection of probably be unrecognisable, and as our understanding of
its primary tumour. That the composition of the MPE is pleural formation increases, so does the potential for
influenced by the site of the primary cancer is clear, with directed intrapleural biological treatments that will
differing immune profiles of pleural effusions secondary reduce the need for symptomatic drainages.

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 Review

Contributors 17 Muruganandan S, Azzopardi M, Fitzgerald DB, et al. Aggressive

SW and RM were responsible for initial draft preparation and revision. versus symptom-guided drainage of malignant pleural effusion via
NM and NMR were responsible for reviewing and approving the final indwelling pleural catheters (AMPLE-2): an open-label randomised
manuscript. All authors are responsible for the overall content as trial. Lancet Respir Med 2018; 6: 671–80.
guarantors. 18 Bhatnagar R, Keenan EK, Morley AJ, et al. Outpatient talc
administration by indwelling pleural catheter for malignant
Declaration of interests effusion. N Engl J Med 2018; 378: 1313–22.
NM reports grants from Beckton Dickinson Medical and grants from 19 Penz ED, Mishra EK, Davies HE, Manns BJ, Miller RF, Rahman NM.
Rocket Medical, outside of the submitted work, and sat on an advisory Comparing cost of indwelling pleural catheter vs talc pleurodesis for
board for Beckton Dickinson Medical. NMR has received consultancy malignant pleural effusion. Chest 2014; 146: 991–1000.
fees and clinical trials support from Rocket Medical UK and Beckton 20 Mishra EK, Clive AO, Wills GH, et al. Randomised controlled trial
Dickinson Medical. RM and SW declare no competing interests. of urokinase versus placebo for non-draining malignant pleural
effusion. Am J Respir Crit Care Med 2018; 197: 502–08.
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