Malignant Pleural Effusion: Prevalence
•
~ 200,000 MPE / year in USA
1:4 Lung Cancer pt; 1:3 Breast; 9:10 Mesothelioma
•
~ 100,000 MPE from Lung Cancer / yr in Europe
•
Pleural effusion is the first sign of cancer in 25%
of patients with MPE
Light RW & Lee YCG. Textbook of Pleural Disease, 2nd ed. 2008
Malignant Pleural Effusions
•
95% MPM pts suffer from a pleural effusion
•
Dyspnea most common presenting symptom
•
Fear of ‘drowning to death’
Malignant Effusion: significant burden
~8,000 inpatient bed days
(population
million):
per2year
10000
Total Bed Days
9500
9000
8500
8000
7500
7000
6500
2003 2004 2005 2006 2007 2008
Year
Western Australia
US$10 million inpatient cost
per year
Myths in Malignant Effusions
Although MPE common recent advances in
knowledge has shed light on many myths in
-
Why symptoms develop
-
Diagnostic workup and limitations
-
Pleurodesis and its limitations
-
Indwelling pleural catheters: pros and cons
Myth:
Patients with malignant effusions are breathless
because the fluid compresses on the lung,
restricting its expansion.
Why are patients breathless?
Effects on Lung Function: For 1 L fluid
drained: FEV1 or FVC  0.2 L; TLC  0.4 L
Lung Compression not the key factor
Effects on Diaphragm:
 Weight of the effusion profoundly affects the diaphragm

Dyspnea related to effect on the diaphragm:
- No dyspnea if diaphragm domed and moves normally
- Severe dyspnea if diaphragm inverted and not move
with respiration
Lee YCG & Light RW. in Encyclopedia of Respiratory Disease 2006
Why are patients breathless?
The pleural cavity expands to accommodate the fluid.
Altered respiratory mechanics contribute to
breathlessness
Why are patients breathless?
Drainage of effusion remove weight from
hemidiaphragm and restore respiratory mechanics
Small effusion
Diaphragm normal
Large effusion
Diaphragm inverted
Courtesy: Dr Naj Rahman
Sofia Lee born Sept 09
3L effusion
2.93kg
3kg
Myth:
Drainage of effusion in patients with a trapped
lung is not useful.
Drainage of effusion in patients with a trapped
lung can still improve symptoms
70/M
Metastatic Thyroid Cancer
Myth:
The more fluid sent for cytology, the more likely
you can make a malignant diagnosis.
Pleural fluid for Cytology Analyses
‘More likely to make a malignant diagnosis on
cytology if you send more fluid?’ True or False
No significant increase in sensitivity of cytology
when >50mL of fluid is sent:
Swiderek J et al
Abouzgheib W et al
Sallach SM et al
Anderson CB et al
Chest 2010
Chest 2009
Chest 2002
Cancer 1974
Indication: Diagnosis of Pleural Malignancy
Cytology diagnostic sensitivity 20-60% depends on:
type of tumor (adeno >> mesothelioma)
Benign
MPM
TTF-1
experience of cytologists
tumor load
Light RW & Lee YCG.
Textbook of Pleural Disease, 2nd ed. 2008
Myth:
Pleuroscopy or Thoracoscopy biopsy can safely
exclude malignant pleural disease.
Pleuroscopy / Medical Thoracoscopy
Jacobaeus performing
thoracoscopy
Tassi GF. International Pleural
Newsletter 2004
Felice Cova
• Thoracoscopy is not gold standard
• 142 Medical Thoracoscopy / Pleuroscopy
• Negative Predictive Value 90%
• False negative occurs – all mesothelioma
• Similar rate to previous papers
- despite advances in immunohist/thoracoscopy
Mesothelioma: nodular lesions
Mesothelioma: diffuse thickening
biopsy often fibrous tissue only
false negative possible
Myth:
FDG PET is not useful in management of
malignant pleural diseases.
PET
Limited diagnostic value:
•
•
Malignancy vs benign pleural diseases
Mesothelioma vs metastatic carcinoma
West SD & Lee YCG.
Clin Pulm Med 2006
Percutaneous biopsy guided by PET/CT
Evolving option. In selected patients can be useful.
Semiquantitative FDG PET using volume-based
parameter of TGV
Prognosis
Nowak et al. Clin Cancer Res; 2010, 16(8); 2409–17.
Response – 1 cycle chemo
Francis et al J Nucl Med 2007;48:1449-1458
Novel Tracers in mesothelioma




FLT – Fluorothymidine
Thymidine is a pyrimidine analogue
incorporated into DNA
CELL PROLIFERATION tracer
Not influenced by pleural inflammation,
infection or pleurodesis
Courtesy Prof Ros Francis (Australia)
FLT PET response assessment
baseline
post chemo
Courtesy Prof Ros Francis (Australia)
Hypoxia imaging in mesothelioma
FMISO PET-CT
FDG PET-CT
18F-Annexin Phase I: apoptosis marker
Scan before vs after chemotherapy to assess response
Myth:
Pleurodesis is the standard first choice for
management of malignant pleural effusions.
Pleural Effusion: Management
•
This approach is now strongly challenged
i) Pleurodesis (talc) is less efficacious as often
reported and can induce significant complications
ii) Aim for management is relief of Dyspnea and QoL:
Drainage is the key
Light RW & Lee YCG. Textbook of Pleural Diseases 2nd ed 2008
Courtesy
Dr Rodriguez Panadero
Controversy: Is talc better delivered via
•
thoracoscopy (poudrage) or chest tube (slurry)
‘Talc poudrage is superior:
Distribute talc over
entire pleural surface’
Fact or Myth?
Courtesy Dr Carla Lamb
TALC IS NOT GLUE !!!
Even spread over pleura not essential
Dresler CM. Chest 2005: Multicenter phase III study
talc poudrage (n=242) vs slurry (n=240)
at 6 months
< 50%
Thoracoscopic poudrage v Bedside pleurodesis
Dresler et al.
Chest 2005
Poudrage
n=242
Slurry
n=240
Successful Pleurodesis (30 d)
78%
71%
Yim AP et al.
Ann Thorac Surg 1996
Poudrage
n=28
Slurry
n=29
No recurrence
27
26
Terra RM et al.
Chest 2009
Poudrage
n=30
Slurry
n=30
No symptomatic recurrence
25
26
Mohsen et al.
Eur J Cardiothorac Surg 2010
Poudrage
n=22
Iodine
n=20
No further intervention
20
17
p=NS
p=NS
p=NS
p=NS
Failed VATS Pleurodesis
Complications of Talc Pleurodesis
Dresler CM. Chest 2005: CALGB phase III study

More side effects from thoracoscopic (VATS) poudrage
Thoracoscopic Chest Tube
Slurry
Poudrage
(n=223)
(n=196)
Pneumonia (antibiotics)
21 (9%)
7 (4%)
p=0.03
Respiratory Failure
18 (8%)
8 (4%)
p=0.007
Fatal Resp Failure
5 (2%)
6 (3%)
p=NS

2.3% patients died from ARDS
Talc Pleurodesis
Significant shortcomings:
• Success rate low (70%) even in
selected patients
•
Unsuitable in trapped lung
Overall <50% pts benefit
•
Side effects common: can be lethal
Do we really need to create pleurodesis?
Relieve symptoms without pleurodesis using
Ambulatory Small Bore Catheter Drainage
Tunnelled Indwelling Pleural Catheter
• Ambulatory drainage outside hospital
• Patient controlled drainage whenever breathless
Tunnelled Indwelling Pleural Catheter
• 39,000 units sold in USA alone each year
• 1st choice for malignant effusion in many centers
Malignant Pleural Effusion
Indwelling
Pleural Catheter
Talc
Pleurodesis
Cost Economics: Bed days; Inpatient costs
IPC significantly reduce hospital days for patients
with malignant effusions over talc pleurodesis
Effusion-Related Bed Days
60
50
p<0.001
Days
40
30
p<0.001
20
10
0
IPC
N:
34
Median: 3.0
IQR: 1.75-8.25
Pleurodesis
31
10.0
6.0-18.0
Fysh E et al. Chest 2012
JAMA 2012 in press
Randomized Trial on Management of Malignant
Effusion using Indwelling Pleural Catheters
(British Lung Foundation)
Malignant Pleural Effusions
n=110
randomize
Ambulatory indwelling
catheter drainage
Standard care & inpatient talc pleurodesis
Visual Analog Score for breathlessness (daily)
QoL: Wks 1, 2, 4, 6, 10, 14, 18, 22, 26, 39, 52
Indwelling Pleural Catheters offer the same
improvement in QoL as talc pleurodesis
From: Effect of an Indwelling Pleural Catheter vs Chest Tube and Talc Pleurodesis for Relieving Dyspnea in
Patients With Malignant Pleural Effusion: The TIME2 Randomized Controlled Trial
JAMA. 2012;307:2383-9
Cost-Effectiveness
Puri V et al. Ann Thorac Surg.2012
Treatment of Malignant Pleural Effusion:
A Cost-Effectiveness Analysis
The most cost-effective treatment for a malignant
pleural effusion (in USA setting):
•
•
Indwelling Pleural Catheter if survival short (3 mths)
Bedside Pleurodesis if survival > 12 mths
• Define place of IPC in
management algorithm
of MPE
• Define optimal
management and
aftercare
• Significant potential to
grow in its use in both
malignant and nonmalignant effusions
Fysh E and Lee YCG. J Thorac Oncol 2011
Myth:
Indwelling pleural catheters are associated with
significant and serious complications
eg infection, protein loss.
Complications of Indwelling Catheters
n=
Incidence
Mild Pain after insertion
20/56
35.7%
Symptomatic loculation
44/621
7.0%
Pain during drainage
8/147
5.4%
Catheter Occlusion
29/624
4.6%
Pneumothorax
15/438
3.4%
Tumour Seeding
20/596
3.4%
Empyema
29/1091
2.7%
Skin infection/ Cellulitis
22/832
2.6%
Wrightson J, Fysh E, Maskell N, Lee YCG. Curr Opin Pulm Med 2010
Catheter Tract Metastases
•
Incidence 0-6%
•
Response to radiotherapy
•
IPCs withstand irradiation
Janes SM, Lee YCG et al. Chest 2007
IPC Removal
Auto-pleurodese: No drainage 4-6 wk. No fluid on CXR
Pleural infection: Only if uncontrolled sepsis
No symptom improvement with drainage
•
Removal as outpatient
•
Careful dissection around the cuff. PULL HARD!
•
Fracture of IPC during removal a risk
IPC Fracture
Pro-fibrotic cuff to secure
IPC in place
•
Dense subcut adhesions
develop over time
•
Can be difficult/impossible
to free adhesions to remove
•
Fracture can occur, often
at cuff level
•
IPC Fracture
Safe to leave fractured IPC in situ
• No increased infection risk
• No need to retreive
•
Fysh et al. Chest 2012
Myth:
Pleural effusion is always the cause of the
breathlessness in patients with a malignant
pleural effusion.
Myth:
Malignant pleural mesothelioma seldom
metastasize.
Breathlessness
Always consider other concomitant
causes of dyspnea
-
-
-
-
Lung parenchymal causes
Consolidation, Trapped lung, Asbestosis
Lung vascular and lymphatic causes
Emboli, Lymphangitis
Cardiac causes
Myocardial and Pericardial diseases; Arrhythmia
Deconditioning
Mesothelioma in Western Australia & Bristol:
A two-centre post-mortem study
• Largest post-mortem series in MPM (n=318)
• Mesothelioma not a local disease:
Metastatic spread common
• Extra-pleural metastases
• Nodal metastases
• Extra-thoracic metastases
85.2%
57.1%
59.7%
Known (L) MPM with loculated effusion
Presented acute dyspnea
Results: Mesothelioma metastasizes
Intra-thoracic Sites
Ipsilateral parenchyma
56.8%
Pericardium
44.7%
Diaphragm
39.5%
Contralateral parenchyma
35.7%
Contralatateral pleura
31.8%
Chest wall invasion
29.6%
Myocardium
12.5%
Results: Mesothelioma metastasizes
Extra-thoracic Sites
Liver
Peritonium
Bone
29.1%
24.2%
15.0%
Adrenals
Spleen
Kidneys
11.7%
11.3%
9.5%
G I tract
Thyroid
Brain
8.0%
7.3%
2.9%
Known (R) MPM with loculated effusion
Presented acute dyspnea
Pulmonary emboli 6%;
Cause of death in 4% of MPM
Median age of MPM (UK) 75 yrs old
Co-morbidity common
70% of asbestos workers were heavy smokers
COPD common
Summary
•
Weight of malignant effusion contributes
significantly to dyspnea.
•
Pleural fluid cytology is useful but large volume
beyond 60mL adds little diagnostic sensitivity.
•
Pleuroscopy biopsy can be false negative (~10%).
Imaging guided biopsy useful alternatives.
•
Indwelling pleural catheter and talc pleurodesis
offer different advantages.
•
Talc poudrage has no advantages over slurry.
The incidences of mesothelioma and
malignant pleural effusion are likely to
continue to rise…
Respirology 2011
Courtesy Prof Bai (Shanghai)
Courtesy Prof Bai (Shanghai)
Pleural Effusions and Vienna
Percussion (stony) dullness
described 1808 by a Prof of
Medicine at Vienna University
Prof Josef Leopold
Auenbrugger
Son of innkeeper; used to watch
his father tapping on wine
barrels for level of wine left
If only we are elephants…
West J. International Pleural Newsletter 2004
Elephant are auto-pleurodesed and live happily
without a pleural cavity, and never have to worry
about effusions!