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

Western Australia (population 2 million):

Year

2004

Tot

al B

ed D

ays

6500

7000

7500

8000

8500

9000

9500

10000

2005 2006 2007 2008 2003

~8,000 inpatient bed days per year

US$10 million inpatient costper year

Myths in Malignant EffusionsAlthough 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 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

Effects on Lung Function: For 1 L fluid drained: FEV1 or FVC 0.2 L; TLC 0.4 LLung Compression not the key factor

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

Courtesy: Dr Naj Rahman

Small effusion Diaphragm normal

Large effusion Diaphragm inverted

2.93kg

Sofia Lee born Sept 09

3kg

3L effusion

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 Chest 2010 Abouzgheib W et al Chest 2009Sallach SM et al Chest 2002Anderson CB et al Cancer 1974

Cytology diagnostic sensitivity 20-60% depends on: type of tumor (adeno >> mesothelioma)

experience of cytologiststumor load

Benign MPM TTF-1

Light RW & Lee YCG. Textbook of Pleural Disease, 2nd ed. 2008

Indication: Diagnosis of Pleural Malignancy

Myth:

Pleuroscopy or Thoracoscopy biopsy can safely

exclude malignant pleural disease.

Pleuroscopy / Medical Thoracoscopy

Jacobaeus performing thoracoscopy

Felice Cova

Tassi GF. International Pleural Newsletter 2004

• 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 thickeningbiopsy often fibrous tissue onlyfalse negative possible

Myth:

FDG PET is not useful in management of

malignant pleural diseases.

PETLimited diagnostic value:

• Malignancy vs benign pleural diseases• Mesothelioma vs metastatic carcinoma

West SD & Lee YCG. Clin Pulm Med 2006

Percutaneous biopsy guided by PET/CTEvolving option. In selected patients can be useful.

Response – 1 cycle chemo

Francis et al J Nucl Med 2007;48:1449-1458

Prognosis

Nowak et al. Clin Cancer Res; 2010, 16(8); 2409–17.

Semiquantitative FDG PET using volume-based parameter of TGV

Novel Tracers in mesothelioma

FLT – FluorothymidineThymidine is a pyrimidine analogue incorporated into DNA CELL PROLIFERATION tracerNot influenced by pleural inflammation, infection or pleurodesis

Courtesy Prof Ros Francis (Australia)

baseline

post chemo

FLT PET response assessment

Courtesy Prof Ros Francis (Australia)

Hypoxia imaging in mesothelioma

FMISO PET-CT

FDG PET-CT

18F-Annexin Phase I: apoptosis markerScan before vs after chemotherapy to assess response

Myth:

Pleurodesis is the standard first choice for

management of malignant pleural effusions.

• 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

Pleural Effusion: Management

Light RW & Lee YCG. Textbook of Pleural Diseases 2nd ed 2008

Cou

rtes

y D

r R

odri

guez

Pan

ader

o

Courtesy Dr Carla Lamb

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?

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 pleurodesisDresler et al.Chest 2005

Poudrage n=242

Slurryn=240

Successful Pleurodesis (30 d) 78% 71% p=NS

Yim AP et al. Ann Thorac Surg 1996

Poudragen=28

Slurryn=29

No recurrence 27 26 p=NS

Terra RM et al. Chest 2009

Poudragen=30

Slurryn=30

No symptomatic recurrence 25 26 p=NS

Mohsen et al. Eur J Cardiothorac Surg 2010

Poudragen=22

Iodinen=20

No further intervention 20 17 p=NS

Failed VATS Pleurodesis

Dresler CM. Chest 2005: CALGB phase III study

More side effects from thoracoscopic (VATS) poudrage

2.3% patients died from ARDS

Complications of Talc Pleurodesis

Thoracoscopic Poudrage

(n=223)

Chest Tube Slurry (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

Significant shortcomings: • Success rate low (70%) even in selected patients

• Unsuitable in trapped lung

Overall <50% pts benefit

• Side effects common: can be lethal

Talc Pleurodesis

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

Talc Pleurodesis

Indwelling Pleural Catheter

Cost Economics: Bed days; Inpatient costs

IPC significantly reduce hospital days for patients with malignant effusions over talc pleurodesis

p<0.001

Effusion-Related Bed Days

IPC Pleurodesis

Day

s

0

10

20

30

40

50

60

p<0.001

N: 34 31Median: 3.0 10.0 IQR: 1.75-8.25 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 Effusionsn=110

Visual Analog Score for breathlessness (daily)QoL: Wks 1, 2, 4, 6, 10, 14, 18, 22, 26, 39, 52

Ambulatory indwelling catheter drainage

Standard care & in-patient talc pleurodesis

randomize

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

Indwelling Pleural Catheters offer the same improvement in QoL as talc pleurodesis

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

Cost-Effectiveness

• 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 non-malignant 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.

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%

Complications of Indwelling Catheters

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

• 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 causesConsolidation, 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 85.2%• Nodal metastases 57.1% • Extra-thoracic metastases 59.7%

Known (L) MPM with loculated effusionPresented 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 SitesLiver 29.1%Peritonium 24.2%Bone 15.0%Adrenals 11.7%Spleen 11.3%Kidneys 9.5%G I tract 8.0%Thyroid 7.3%Brain 2.9%

Known (R) MPM with loculated effusionPresented acute dyspnea

Pulmonary emboli 6%; Cause of death in 4% of MPM

Median age of MPM (UK) 75 yrs oldCo-morbidity common

70% of asbestos workers were heavy smokersCOPD 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) dullnessdescribed 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…

Elephant are auto-pleurodesed and live happily without a pleural cavity, and never have to worry about effusions!

West J. International Pleural Newsletter 2004