International Lung Symposium on Pleural Diseases, Manila 2019. Practice changing clinical trials in pleural diseases from 2017 to 2019 by Dr. Gary Lee.

1. Professor, University of Western Australia
Director, Pleural Services, Sir Charles Gairdner Hospital
Head, Pleural Medicine Unit, Institute for Respiratory Health
National Health & MRC Career Development Fellow
Y C Gary Lee
MBChB PhD FCCP FRCP FRACP
What are new in Pleural Diseases?
Practice Changing Clinical Trials 2017-19

2. Pleural diseases are common

3. Hippocratic Succussion:
Shake the patient by shoulders
to identify sound of fluid in
the pleural space
Hippocrates: the most iconic pleural researcher
Published extensive amount of landmark papers in
460-377 BC

4. Pleural research was neglected for subsequent
25 centuries… until the last 25 years
Bielsa & Porcel. The Pleura 2016

5. Last 12 years have seen a significant number of
high quality clinical studies that changed our
practice.

6. Highlighted papers on
• General Approaches
• Malignant Pleural Effusions
• Mesothelioma
• Pleural Infection
• Pneumothorax

7. General approach to pleural diseases

8. Key Points:
A good summary of existing literature and overall of
current common clinical practice in pleural medicine.
Key Points:
A good summary of existing literature and overall of
current common clinical practice in pleural medicine.
N Engl J Med. 2018 Feb 22;378(8):740-751

9. • RCT; 2 centres in USA. N=128 with >0.5L pleural
effusion undergoing thoracentesis
• Randomized to stopping drainage based on symptoms vs
based on manometry pressure + symptoms
• Patients rated their discomfort before, during and after
drainage with a Visual Analog Scale (0-100mm)
• 1 endpoint: Chest discomfort from beginning to 5 min
after thoracentesis

11. Breathlessness
Start to 5 min
post-tap
Chest discomfort
Start to 15 min
post-tap
Start to 15 min
post-tap

12. Key Points:
No benefits of using manometry in minimizing chest
discomfort or breathlessness during/after thoracentesis.
Key Points:
No benefits of using manometry in minimizing chest
discomfort or breathlessness during/after thoracentesis.

13. Key Points:
Many pleural abnormalities (eg nodules) visualized
during pleuroscopy/VATS were not detected on
conventional CT.
Proof of concept case series showing presence of pleural
air can show up many pleural abnormalities.
Key Points:
Many pleural abnormalities (eg nodules) visualized
during pleuroscopy/VATS were not detected on
conventional CT.
Proof of concept case series showing presence of pleural
air can show up many pleural abnormalities.

15. Malignant Pleural Effusions

16. Most recent large conferences have a dedicated
symposium on MPE - well attended
Unprecedented amount of high profile papers published
on Malignant Pleural Effusion (MPE) in the past 18
months: NEJM, JAMA x2, AJRCCM, Lancet RM x2 etc
Many guidelines on MPE – difficult to keep up!
American Thoracic Soc MPE Guidelines (published)
European Resp Soc/EACTS MPE Guidelines (published)
Am Assoc of Bronchology/Interventional Pulmonology
IPC Guidelines (in progress)
NSW IPC Use: Positional Statement (just released)

18. 1st Eur Respir Soc & Eur Assoc for Cardiothoracic Surg
joint statement on pleural topics. More planned.
Listed 6 questions by consensus. Summarized literature on
the topic. Not a guideline: No recommendations.

19. Q1: What is the best definitive treatment for pts with
symptomatic MPE?
Q2: What optimal management for MPE with trapped lung?
Q3: How should septated and loculated MPE be managed?
Q4: What factors predict prognosis in MPE?
Q5: Should patients with MPE and cancer that is sensitive to
oncological treatment receive treatment prior to definitive
management of their MPE? If so, which cancers?
Q6: In order to determine treatment in MPE, is a histological
diagnosis always required or is cytology sufficient?

20.  7 PICO questions. Considerable debate on some topics.
 Tried to incorporate latest data up to time of publication.

21. PICO 1: In patients with known or suspected malignant
pleural effusion (MPE), we suggest that ultrasound imaging be
used to guide pleural interventions.
PICO 2: In patients with known or suspected MPE who are
asymptomatic, we suggest that therapeutic pleural interventions
should not be performed.
PICO 3: In patients with symptomatic MPE, we suggest
large-volume thoracentesis if it is uncertain whether the patient's
symptoms are related to the effusion and/or if the lung is
expandable (the latter if pleurodesis is contemplated), to assess
lung expansion.
PICO 4: In patients with symptomatic MPE with known (or
likely) suspected expandable lung, and no prior definitive
therapy, we suggest that either an indwelling pleural catheter
(IPC) or chemical pleurodesis be used as first-line definitive
pleural intervention for management of dyspnea.

22. PICO 5: In patients with symptomatic MPE and expandable
lung undergoing talc pleurodesis, we suggest the use of either
talc poudrage or talc slurry.
PICO 6: In patients with symptomatic malignant pleural
effusions with nonexpandable lung, failed pleurodesis, or
loculated effusion, we suggest the use of IPCs over chemical
pleurodesis.
PICO 7: In patients with IPC-associated infections, treating
through the infection without catheter removal is usually
adequate. We suggest catheter removal if the infection fails to
improve.

23. Critique:
• An excellent overview. A lot of effort put into it.
• Useful as a reference point and/or starting point for
clinicians.
• In a rapid changing field, guidelines are outdated even
before published.
• Recommend keeping abreast of original research papers to
establish most up-to-date knowledge.
Critique:
• An excellent overview. A lot of effort put into it.
• Useful as a reference point and/or starting point for
clinicians.
• In a rapid changing field, guidelines are outdated even
before published.
• Recommend keeping abreast of original research papers to
establish most up-to-date knowledge.

25. J Thorac Surg 1935;4:251-261
Standard Rx in most countries remains talc pleurodesis
Widespread belief: talc is more effective if delivered
thoracoscopically as a dry powder ‘poudrage’ vs as a slurry
via chest tube
No proof at all.
Surgeons and some pulmonologists remain strong
believers of poudrage

26. Thoracoscopic poudrage v Bedside pleurodesis
Dresler et al.
Chest 2005
Poudrage
n=242
Slurry
n=240
Successful Pleurodesis (30 d) 78% 71% p=NS
Yim AP et al.
Ann Thorac Surg 1996
Poudrage
n=28
Slurry
n=29
No recurrence 27 26 p=NS
Terra RM et al.
Chest 2009
Poudrage
n=30
Slurry
n=30
No symptomatic recurrence 25 26 p=NS
Mohsen et al.
Eur J Cardiothorac Surg 2010
Poudrage
n=22
Iodine
n=20
No further intervention 20 17 p=NS

27. • Multicentre RCT (UK): just completed analysis
• Talc poudrage (medical thoracoscopy) vs chest tube talc
slurry (n=330 MPE patients)
• Hypothesis: thoracoscopic poudrage more efficacious
• 1° Endpoint: Pleurodesis failure (need of re-intervention)
at 3 months

28. Key Points:
4 RCTs of ~1000 patients from UK, USA, Asia & S
America all failed to show any significant differences
in success rates of thoracoscopic poudrage (surgical
VATS or pleuroscopy) vs bedside chest tube talc slurry.
Please… no more trials!
Key Points:
4 RCTs of ~1000 patients from UK, USA, Asia & S
America all failed to show any significant differences
in success rates of thoracoscopic poudrage (surgical
VATS or pleuroscopy) vs bedside chest tube talc slurry.
Please… no more trials!

29. Why is thoracoscopic poudrage not superior?
TALC IS NOT GLUE!!!
Even spread over pleura not essential

31. TALCIPC
Talc pleurodesis and indwelling pleural
catheter (IPC) are the focus of many recent
clinical trials

32. N= Talc Success Rate
Dresler et al 484
Slurry or
Poudrage 75% (1 month)
Rahman et al 57 Slurry 76% (3 months)
Davies et al 54 Slurry 77% (6 months)
Thomas et al 73 Slurry 77% (12 months)
Talc pleurodesis success rate in
recent RCTs
Dresler CM: CHEST 2005; Rahman HE: JAMA 2015
Davies HE: JAMA 2012; Thomas R: JAMA 2017

33. Limitations of talc pleurodesis
Trapped lung
Talc pleurodesis are not suitable / not ideal for
patients with
• Trapped lung
• Failed prior talc pleurodesis
• Significant hypoxemia
Most of these patients are excluded
in RCTs for MPE so the ‘real life’
application of talc pleurodesis
may be more limited.

34. IPC: increasingly used
in MPE management
Last decade, rapid rise in IPC use esp Nth America
>40,000/year in USA
>2000 IPC inserted over 4 years in Ontario, Canada
20% increase in IPC use each year in the UK
The shortcomings of talc pleurodesis raise
the need of alternatives

35. IPCs
offer similar
improvement in
QoL vs talc
Key Points: IPC as effective as Talc
• Neither Rx superior in QoL
Key Points: IPC as effective as Talc
• Neither Rx superior in QoL

36. A Multicentre Randomized Study of
IPC vs Talc Pleurodesis in Malignant Pleural Effusion
MPE (n=146)
Talc pleurodesis
n = 72
IPC
n = 74
Minimization: mesothelioma, trapped lung and region
JAMA Nov. 2017

37. P = 0.026
Primary endpoint:
All cause
Hospital Days
IPC Pleurodesis
Mean 12.7 16.3
Median 10.0 12.0

38. P = 0.01
Percentage of Remaining
Lifespan spent in Hospital
IPC Pleurodesis
Mean 6.2 % 11.1 %
IQR (13.8) (33.7)

39. P=0.001
RR=0.18
95%CI 0.06-0.60 IPC Pleurodesis
0
10
20
30
%Patientsrequiringfurther
pleuralprocedures
2 Endpoint
Need for further pleural
procedures in remaining life
IPC Pleurodesis
4.1 % 22.5 %

40. Key Points:
The advantages IPC offers in reducing
life-time hospitalization days and
need for pleural re-interventions
are not off-set by any ‘penalties’ in
symptom relief, QoL, survival or adverse events.
In Australia 8000 MPEs/year: translate to saving 14,400
bed days a year
Key Points:
The advantages IPC offers in reducing
life-time hospitalization days and
need for pleural re-interventions
are not off-set by any ‘penalties’ in
symptom relief, QoL, survival or adverse events.
In Australia 8000 MPEs/year: translate to saving 14,400
bed days a year

41. TALC
IPC
Including latest data: IPC should be 1st
line management option
Including latest data: IPC should be 1st
line management option

42. To optimize
• Use of IPC and maximize benefits
– Drainage regime
– Adding pleurodesis to IPC
Where from now?

43. AJRCCM 2017
• Single-blinded randomized phase IV trial
12 centers in USA 2009-2013
• MPE patients (n=162) block randomized to
Daily vs Alternate Day IPC drainages
• 1° endpoint: Autopleurodesis and alive at 12 wks
“Autopleurodesis” referred to patent IPC and no fluid drainage.
That included patients with loculated fluid and/or cessation of
fluid formation.

44. Daily arm (median time to
autopleurodesis 54 days)
Alternate Day arm (90 days)

45. • Imbalance of patients who withdrew / died before 12 wks
• QoL scores were not different despite the advantages in
early IPC removal in the Daily drainage arm.
To note:
Daily
(n=73)
Alternate
Day (n=76)
p =
Success (Alive + No drainage) 47% 24% 0.003
Died before 12 wks 25% 34%
“Unable to complete study” 12%
(n=9)
29%
(n=22)

46. International multi-center RCT to determine if daily or
symptom-based drainage best improves breathlessness

47. IPC Drainage: Optimal Approach Unknown
Aggressive (Daily)
Drainage
2 approaches worldwide
Symptom-guided
Drainage
Pros
• Better symptom control?
• Increased spontaneous
pleurodesis
Cons
• Increased infection risk?
• More resources?
Pros
• More convenient?
• Less cost?
Cons
• Sub-optimal symptom
control?

48. Recruitment Centres
Study Sites: 4 countries, 11 centres
Sir Charles Gairdner
Royal Perth
St George & The Sutherland
Wesley & St Andrew’s
Middlemore
Malaysia
Fiona Stanley
Bunbury
Hong Kong
Nambour General
Royal Adelaide
AUSTRALIA
Western Aus: Sir Charles Gairdner
Royal Perth
Fiona Stanley
St John of God, Bunbury
NSW: St George
The Sutherland
Queensland: Wesley & St Andrew’s
Sunshine University General
South Aus: Royal Adelaide
NEW ZEALAND - Middlemore
HONG KONG - Queen Mary
Hospital
MALAYSIA - Queen Elizabeth Hospital

49. *MCID (19 mm)
VASSOB
Aggressive Symptom
-guided
P = 0.18
Geometric mean
(95% CI)
13·1 mm
(9·8-17·4)
17·3 mm
(13·0-22·0)
Primary outcome
– VAS breathlessness at 60 days

50. More patients developed
spontaneous pleurodesis in
the Aggressive arm
by 6 months
19 (44·2%) vs 7 (15·9%)
p=0·004
Secondary outcome
– Spontaneous pleurodesis at 6 months

51. Secondary outcome:
*MCID (0.09)
Pickard et al. Health Qual Life Outcomes 2007
EQ-5D-5L (index value)
VAS QoL
Aggressive Symptom-guided
Mean (95% CI)
0.713
(0.647-0.779)
0·601
(0·536-0·667)
Estimated differences in
means (95% CI)
0.112 (0.0198 – 0.204)
P= 0.0174
Ratio of geometric
means (95% CI)
1.22 (0.871 – 1.709)
P= 0.25
• A non-significant trend favouring Aggressive drainage

52. Key Points:
Patients managed with daily drainage of IPC and those who
drained only when symptomatic did not differ in their
• breathlessness control
• pain scores, days spent in hospital, SAE or mortality.
Daily IPC drainage is more effective in promoting
spontaneous pleurodesis and may improve QoL.
Key Points:
Patients managed with daily drainage of IPC and those who
drained only when symptomatic did not differ in their
• breathlessness control
• pain scores, days spent in hospital, SAE or mortality.
Daily IPC drainage is more effective in promoting
spontaneous pleurodesis and may improve QoL.

53. TALCIPC IPC + TALC
Where are we heading?
• IPC and Talc Pleurodesis have different pros and
cons and are not mutually exclusive.
• Combining IPC with Pleurodesis can potentially
increase likelihood of removal of catheter (early),
thus reduce inconvenience and costs.

54. IPC-Plus Trial
IPC alone vs
IPC + talc in patients
with MPEs managed
as out-patients

55. Key Point: Talc slurry instillation via IPC in an outpatient
setting is feasible, safe and enhances pleurodesis.
Key Point: Talc slurry instillation via IPC in an outpatient
setting is feasible, safe and enhances pleurodesis.
Discussion Point:
Successful pleurodesis rate
(43%) was lower than
expected for talc slurry
Discussion Point:
Successful pleurodesis rate
(43%) was lower than
expected for talc slurry
Whether related to IPC
drainage performed 2-
3x/week post-talc?
Whether applying aggressive (daily) drainage increases
likelihood of talc pleurodesis via IPC?

56. ⸱ Pilot study: First drug eluted pleural catheter
⸱ IPC coated with silver nitrate (pleurodesing agent often used
in South America)
⸱ Aim: Drug dissolves
in pleural fluid and
facilitate pleurodesis
and potentially early
IPC removal
⸱ Promising pilot data
on animals

57. • N=10 MPE patients without significant trapped lung
• 8/10: successfully pleurodesis median 4 days (IQR 2-6)
with no recurrence up to 60 days
• Significant improvements in Breathlessness (VAS) and
overall QoL (EQ5D) scores
• 1 had significant pain necessitating IPC removal
AJRCCM 2017

58. A PIVOTAL, MULTI-CENTER, RANDOMIZED, CONTROLLED,
SINGLE-BLINDED STUDY COMPARING THE SILVER NITRATE-
COATED TO UNCOATED IPC FOR THE MANAGEMENT OF
SYMPTOMATIC, RECURRENT, MPEs (SWIFT)
⸱ N=119 with MPE randomized to silver nitrate-coated vs
Uncoated IPCs to determine safety and effectiveness
⸱ Exclusion: Significant trapped lung ( >20% hemithorax or
ipsilateral mediastinal shift); ECOG ≥3; bilateral effusions
⸱ 1° Endpoint: Pleurodesis with no recurrence D30 post IPC
⸱ 2° Endpoint: Pleurodesis success in pts without trapped lung D90
Success rate by cancer type (lung, breast and others).
Incidence of IPC occlusion, empyema and cellulitis
Pain using 100 mm visual analog scale (VAS)

59. - In patients planning to undergo talc pleurodesis for MPE
but found loculated effusion after drainage
- Would intrapleural fibrinolytics to breakdown loculated
fluid before talc instillation provide any advantage?
- N=71 (12 UK ctrs) with loculated MPE randomized to
intrapleural urokinase (100,000 U x 3 doses) or placebo
- Co-1° Endpoints: Breathlessness control (VAS)
Pleurodesis success up to 1 year

60. Key Point: Pre-pleurodesis administration of intrapleural
urokinase offered no benefits in symptom control or
pleurodesis success in patients with loculated MPE.
Key Point: Pre-pleurodesis administration of intrapleural
urokinase offered no benefits in symptom control or
pleurodesis success in patients with loculated MPE.

61. Malignant Pleural Mesothelioma

63. - Does prophylactic
radiotherapy prevent needle
tract metastases in
mesothelioma patients?

64. Deferred Radiotherapy
No prophylactic radiotherapy
Immediate Radiotherapy
21Gy (3#) in 42 d of procedure
RANDOMISATION (1:1)
Minimising by: Histology (epithelioid or other)
IPC or other
Surgical procedure or other
FOLLOW UP
Clinic visits at 1,3, 6, 9, 12 months
Phone every month (unless seen in clinic)
MPM patients large bore pleural procedure within 35
days
N=203

65. Primary Outcome
Analysis
(number
developed PTM)
Treatment
n (%)
No RT
n (%)
Treatment effect
% (95% CI)
p
Intention to
Treat
9/102
(9%)
16/101
(16%)
7%
(95%CI: -2, 16)
0.141
Treatment No RT p
Number of painful PTM 2/102 (2%) 6/101 (6%) 0.170
Proportion of nodules
which were painful
2/9 (22%) 6/16 (38%) 0.661

66. Key Points:
Prophylactic radiotherapy appeared to likely have (small)
effects
The incidence of symptomatic Tract Metastases in MPM
appeared low vs with older trials (results of modern
chemotherpy?)
Subjecting all patients to prophylactic XRT not justified
Key Points:
Prophylactic radiotherapy appeared to likely have (small)
effects
The incidence of symptomatic Tract Metastases in MPM
appeared low vs with older trials (results of modern
chemotherpy?)
Subjecting all patients to prophylactic XRT not justified

67. Key Points:
Very detailed description of upcoming/ongoing trials in
MPM.
Worth reading.
Key Points:
Very detailed description of upcoming/ongoing trials in
MPM.
Worth reading.

69. Pleural Infection

72. Mesothelial Layer
PLEURALSPACE
BACTERIA
BACTERIA
If you are the bacteria,
where in the pleural cavity will you live?
Bacterial culture of pleural fluid notoriously low yield.
Are we looking at the wrong place?

73. A Pilot Feasibility Study in Establishing the Role of
Ultrasound-Guided Pleural Biopsies in Pleural Infection
(The AUDIO Study) Psallidas I et al. CHEST 2018
U/S guided biopsy (n=20) at time of chest tube provided high
yield of bacterial culture:
Blood (10%) vs Fluid (20%) vs Pleural Biopsy (45%)
75% of pts with +ve
pleural Bx were already
on antibiotics
• Bx still worthwhile on
antibiotics
• Antibiotics regime for
pleural infection needs
optimization

74. Pneumothorax

75. Key Points:
Lots of contentious points in routine management of
pneumothorax as everyone thinks differently and there
are no data to guide clinical decisions.
Key Points:
Lots of contentious points in routine management of
pneumothorax as everyone thinks differently and there
are no data to guide clinical decisions.

80. Key Points:
Largest RCT (n=342) on PSP and compares
conservative (no drainage) vs small chest tube drainage
Multicentre, non-inferiority randomized trial from
Australia/New Zealand
Recruitment and follow-up completed. Manuscript in
preparation.
Key Points:
Largest RCT (n=342) on PSP and compares
conservative (no drainage) vs small chest tube drainage
Multicentre, non-inferiority randomized trial from
Australia/New Zealand
Recruitment and follow-up completed. Manuscript in
preparation.

81. Pleural research: Very Exciting Time

82. pleura.com.au
THE PLEURAL MEDICINE UNIT
Sir Charles Gairdner Hospital,
Harry Perkins Institute of Medical Research, Perth, Australia
gary.lee@uwa.edu.au