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Slide 1: Progress in Mesothelioma Michael R. Johnston, MD, FRCSC Professor of Surgery, Dalhousie University Adjunct Professor of Surgery, University of Toronto Affiliate Scientist, Ontario Cancer Institute
Slide 2: Mesothelioma Research Program • – Early Detection Study LDCT scan, questionnaire, biomarkers, spirometry • – – – Treatment Protocols Trimodality therapy Neo-adjuvant IMRT Advanced disease chemo studies • – – – Basic R B i Research Studies h S di Genetic profiling of tumours Immunomodulation in mesothelioma Screening new therapies • – Epidemiology Studies Asbestos l t d l A b t related lung disease di
Slide 3: Mesothelioma Research Program Michael R. Johnston, MD Heidi Roberts, MD Marc de Perrot, MD Ming Tsao, MD Ron F ld R Feld, MD Brenda O’Sullivan Li Zhang, PhD Masaki Anraku, MD John Cho, MD Geofrey Liu, MD, PhD Martin Tammamagi, PhD Demetris Patsios, MD Gregory Pond Albert Ebidia Thoracic Surgeon Radiologist Thoracic Surgeon Pathologist Medical O l i t M di l Oncologist Coordinator Immunologist Thoracic Oncology Fellow Radiation Oncologist Molecular Epidemiologist Epidemiologist Radiologist Statistician Database support
Slide 4: Survival by Stage in Adjuvant Trials Brigham (Sugarbaker) EPP+chemo+rads+chemo Memorial (Rusch) EPP+rads
Slide 5: “Early” Mesothelioma Early 21 year old student
Slide 7: First Sites of Relapse after EPP and 54 Gy Rad Tx Locoregional only y Distant only Locoregional and distant Locoregional Pleural Nodal Distant Peritoneal P it l Intralateral visceral Contralateral pleural Contralateral lung Bone Central nervous system Other 2 30 5 7 3 4 30 17 5 13 8 7 0 5 p p Some patients had more than one site of recurrent disease at relapse. Rusch. J Thorac Cardiovasc Surg 2001
Slide 8: Treatment Protocol Malignant pleural Mesothelioma pathology review pleurodesis staging Cisplatin b Ci l ti based chemotherapy dh th re-stage Extrapleural pneumonectomy Hemithoracic radiation
Slide 9: Chemotherapy Toxicities (N=19) 14 Num mber of patients p 12 10 8 6 4 2 0 No compl. Nausea Paresth. Fever PE
Slide 10: Extrapleural Pneumonectomy
Slide 11: Major Post operative Complications Post-operative 57 consecutive patients undergoing EPP Deaths Technical* Esophageal perf BPF/Empyema ARDS/pneumonia Pulm emboli Cardiac arrest Atrial Fib Total Complic 0 5 10 15 20 25 % of patients 30 35 40
Slide 12: Risk Factors for Major Complications p-value p-value* Univariate • Right sided EPP • RBC transf >4 units • Age (> 60 yo) • Ind ction chemo Induction 0.01 0.03 0.06 0.5 05 Multivariate 0.02 0.03 0.1 0.5 05
Slide 13: Impact of Induction Chemotherapy No induction therapy py Induction chemotherapy 16 14 12 10 8 6 4 2 0 Preop Hb (g/l) Blood transf. (units) Hosp stay (days)
Slide 14: HemiHemi-thoracic Radiation
Slide 16: Hemithoracic Radiation (N=12) 7 6 5 4 3 2 1 0 Grade 1 Grade 2 Grade 3 Skin Fatigue erythema Nausea Esophagitis Vertigo
Slide 17: Toronto Trimodality Therapy Update • 2001 - December, 2007: 60 patients – Induction chemotherapy: 50 • Cisplatin + vinorelbine 26; pemetrexed 24; other 10 – No resection: 15 • Progressive disease: • Unresectable: • P iti mediastinoscopy: Positive di ti 4 6 5 3 (7%) – EPP: 45 • Operative mortality: – Adjuvant hemi-thoracic radiation: 30 • 3-D conformal (54 Gy in 30 fractions) • IMRT (50 Gy in 25 fractions) ( y ) dePerrot, JCO; in press
Slide 18: Complications of Trimodality Therapy Table 2. Severe adverse events recorded during the tri-modality therapy* Chemotherapy Complications Pulmonary emboli Leukopenia Cardiac herniation Cardiac arrhythmia Bronchopleural fistula Esophageal perforation Gastric herniation Chylothorax Fatigue Nausea 10 1 1 1 1 5 1 1 1 1 1 Grade 3 Grade 4 3 Grade 5 Grade 3 Surgery Grade 4 1 Grade 5 Grade 3 Radiation Grade 4 Grade 5 * Severe adverse events defined by grade 3 to 5 toxicity according to the NCI CTCAE version 3.0 guidelines dePerrot, JCO; in press
Slide 19: Overall Survival 60 patients; median survival 14 months 100 90 80 70 60 50 40 30 20 10 0 Su urvival 0 12 24 36 48 60 72 Time (months) dePerrot, JCO; in press
Slide 20: Survival According to Nodal Status and Therapy dePerrot, JCO; in press
Slide 21: DiseaseDisease-free Survival in Patients Who Completed Trimodality Therapy N = 30 100 90 80 70 60 50 40 30 20 10 0 Disease-fr surviva ree al 0 12 24 36 48 60 72 Time (months)
Slide 22: Toronto Trimodality Therapy • Median survival – Epithelial vs biphasic: 18 vs. 12 mo (p=0.002) – N 0 disease • Completed trimodality therapy vs incomplete • 59 vs. 8 mo (p=0.0001) – Ch Chemo regimen: ns i • 5 year disease-free survival – 53% in all N0 patients • 75% in T1-2 • 45% in T3 4 T3-4
Slide 23: Recurrance Following Trimodality Therapy • Recurrences – 16/30 patients • • • • • Ipsilateral chest: ps ate a c est: 4 Pericardium: 1 Peritoneum: 5 Contralateral chest: 4 Chest and peritoneum: 2 local surgical seeding vs distant mets?
Slide 24: Tumour Seeding
Slide 25: NeoNeo-adjuvant IMRT for Mesothelioma Cho, dePerrot, Feld • Phase 2 study in 25 patients with cT1-2 N0 – Resectable patients only • 25 Gy in 5 fractions over 1 week – 5 Gy boost to gross disease • EPP 1 week following XRT • Pathologic node negative > no treatment • Pathologic node positive > adjuvant chemo
Slide 26: IMIG 2005 LowLow-dose Computed Tomography For The Early Diagnosis Of Mesothelioma And Lung l i i h li Ad Cancer In Prior Asbestos Workers: Preliminary Results P li i Rl Michael R. Johnston, MD, FRCSC Heidi Roberts, MD University of Toronto University Health Network Toronto, Ontario, Canada
Slide 27: Methods • Early detection study in a population at risk for y y pp pleural mesothelioma – Prevalence and incidence • Inclusion criteria – History of asbestos exposure at least 20 years ago – Asbestos exposure with pleural plaques on chest x-ray
Slide 28: Methods: follow up flow chart Baseline low-dose CT indeterminate nodules no or inconspicuous plaques or no or non-specific nodules (≥5 mm solid or ≥8 mm non-solid) or suspicious plaques lobulated, asymmetric, effusion endobronchial nodules suspicious nodules (≥15 mm) or mass-like plaques with effusion annual repeat 6 months f/u 3 months f/u immediate biopsy no change no change growth resolved (mucous) stable bi-annual repeat annual repeat biopsy etc. annual repeat bronchoscopy
Slide 29: Update on Early Detection Study (9/08) • 751 participants (98% male; average age 61)
 – 84% with lung nodule (20% > 4mm; 1% GGO) – 62% with pleural plaques – 2% with pleural effusion ith l l ff i • 14 cancers found – 6 meso 
(3 pleural, 3 peritoneal) (3 pleural – 8 lung cancers 
 • Mesothelin and osteopontin assays are in progress p y pg • Expanding endpoints to include asbestos related lung disease
Slide 30: Plasma markers in patients with MPM Prospective evaluation in patients with MPM (38) and asbestos exposed matched controls (64) Anraku, IMIG; 2008
Slide 31: Ketch Harbour, Nova Scotia