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!