Screening, early referral and treatment for asbestos related cancer

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1 Screening, early referral and treatment for asbestos related cancer Marc de Perrot, MD, MSc, FRCSC Toronto Mesothelioma Research Program University of Toronto

2 Asbestos related diseases Mesothelioma Lung cancer Asbestosis and interstitial lung disease Pleural plaques Autoimmune diseases (lupus, rheumatoid arthritis, scleroderma) Gastro-intestinal malignancy (Colon cancer, gastroesophageal cancer) etc

3 Mesothelioma: Tumor of the Pleura (lining of the lung)

4 Asbestos Induced Mesothelioma About 80% of mesothelioma are related to asbestos exposure Mostly from workplace exposure (M>F) ~400 new cases in Canada per year Incidence of mesothelioma is rising Long latent period (20-40 years) between exposure and diagnosis of mesothelioma

5 Mesothelioma characteristics Rapid progression Late diagnosis Invasion of local structures (heart, chest wall) Symptoms are Chest pain Shortness of breath Weight loss Fatigue

6 Outcome after diagnosis Median survival 6 to12 months Prognostic factors Performance status Histology Stage Edwards et al Thorax 2000;55:731-5.

7 Chemotherapy for mesothelioma Survival improves by less than 3 months Symptoms improve in 40%- 45% of patients Cisplatin-pemetrexed is the only approved therapy for patients with advanced mesothelioma Vogelzang et al. J Clin Oncol 2003;21:

8 Current issues in mesothelioma Diagnosis of mesothelioma is typically made at an advanced stage Referral to a specialized center is often delayed by several months Management is disparate across the province/country New and better treatment are needed

9 University Health Network We started a screening program for individuals exposed to asbestos We are developing a rapid assessment and diagnosis program with direct referrals for patients with suspicion of asbestos related lung disease We are conducting clinical trials to assess response to new treatments and impact on quality of life We are performing basic science and translational research to develop new therapy Brenda O Sullivan: Research and clinical coordinator

10 Screening program for early detection Low dose chest CT for patients with previous exposure to asbestos or with pleural plaques

11 Screening program Program started in March 2005 Currently enrolled over 1,000 individuals Median age of participants is 61 yo (32-85 yo) Smoking history: 73% of participants Blood sample collected at each visit to analyze tumors markers (mesothelin, osteopontin) Principal investigator: Demetris Patsios Radiology fellow: George Dong

12 Role of serum markers for early detection of mesothelioma Mesothelin Osteopontin Lancet 2003;362: NEJM 2005;353:

13 SMRP and OPN (Classification) Tumor markers in screening individuals Time Time (years) Kat Rey-McIntyre (manuscript in revision)

14 Refinement in screening program Annual low dose CT chest is not sufficient to detect early stage mesothelioma Development of new tumor markers and identification of genetic mutations will potentially allow us to screen individuals at higher risk of developing mesothelioma Low dose CT scan should potentially be done more frequently than annually in this population at risk

15 Cursus of patients with diagnosis of mesothelioma Symptoms Initial evaluation Referrals to respirology/thoracic surgeon Diagnosis Referral to oncologist Referral to specialized center ~ 6 months (2 to >12 months)

16 Rapid assessment and diagnosis program Assessment by nurse practitioner and clinical coordinator 1 to 2 days visit High resolution CT chest and pulmonary function tests Medical consultation with Thoracic surgeon and/or Respirologist Interventional Thoracic Surgery Suite (drainage, biopsy, scope, EBUS) Follow-up

17 Interventional Thoracic Surgery Suite Provide immediate: Evaluation Intervention Diagnosis Director ITSS: Kazuhiro Yasufuku

18 VATS pleuroscopy capabilities Semi-rigid Pleuroscope Diagnostic pleuroscopy Management of pleural effusion

19 EBUS-TBNA for staging in mesothelioma Thoracic Surgery Interventional Suite Toronto General Hospital

20 Sites of mediastinal node metastasis de Perrot et al JTCVS 2007;133:111-6

21 Tri-modality therapy Chemotherapy (Cisplatin and pemetrexed) Surgery (Extrapleural Pneumonectomy) Radiation (50-60 Gy Hemithoracic) PI: Ronald Feld

22 Surgery (extrapleural pneumonectomy)

23 Intensity Modulated Radiation Therapy

24 Survival after tri-modality therapy de Perrot et al J Clin Oncol March 2009

25 Factors affecting outcome Gender Nodal status Histology (epithelial vs other) Hemithoracic radiation

26 Impact of radiation on mesothelioma Case 1 Pre-radiation Post-radiation Case 2 Jenkins et al Eur J Cancer 2011;47:2143

27 New world first trial with accelerated hemithoracic radiation and surgery MPM ct1-3 cn0 M0 Hemithoracic radiation IMRT 25Gy in 5 fractions over 1 week 5 Gy boost to area at risk based on PET and CT Extrapleural pneumonectomy pn0-1 pn2 Observation Adjuvant chemotherapy PI: John Cho

28 Rational Optimal delivery of radiation to the primary tumor based on PET and CT findings Sterilization of the edges of the tumor before surgery with less risk of seeding Shorter treatment Better tolerated than adjuvant radiation Pleuroscopy site

29 IMRT planning based on CT and PET findings Green contour: baseline 25 Gy Red contour: boost to 30 Gy

30 IMRT covers entire hemithorax

31 Impact of surgery on tumor markers Wheatley-Price/ Liu et al. J Clin Oncol 2010;28:

32 Survival High levels of CD8+ tumor infiltrating lymphocytes is associated with better survival in MPM Cytotoxic (CD8+) Counts and Survival 1.0 High level Cytotoxic CD8 + T cells in mesothelioma Low level P = Months after Surgery Anraku/ de Perrot et al J Thorac Cardiovasc Surg. 2008

33 Total number of TILs Cultures of tumor infiltrating lymphocytes After 4 weeks in culture (x 10 8 ) x 10 7 cells for clinical use before RT after RT 1.0 0

34 CD8+ TIL expansion and cell sorting for adoptive cell transfer Expansion of lymphocytes in vitro Selection of lymphocytes with CliniMACS system Director Immunotherapy Lab PMH: Pam Ohashi

35 Intrathoracic murine model of mesothelioma Associate Scientist: Licun Wu

36 In vivo evaluation of intrathoracic tumor in mice Mice are intrapleurally injected with mesenchymal stromal cell (MSC) transduced with lentivirus luciferase (0.5x10 6 to 4x10 6 )

37 Impact of CTLA-4 blockade on tumor growth at early stage of tumor development Wu/ de Perrot et al Mol Cancer Ther Aug;11(8):

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39 Acknowledgement John Cho Ron Feld Natasha Leighl Ming Tsao Pam Ohashi Linh Nguyen Heidi Roberts Demetris Patsios Brenda O Sullivan Kazu Yasufuku John Thenganatt Jakov Moric Li Zhang Licun Wu Hanna Zhu Masaki Anraku Tetsuzo Tagawa Department of Radiation Oncology Department of Medical Oncology Department of Surgical Oncology Department of Pathology Department of Immunology Department of Radiology Division of Thoracic Surgery Division of Respirology Thoracic Surgery Research Laboratory Mesothelioma Applied Research Foundation Canadian Mesothelioma Foundation Princess Margaret Hospital Foundation Toronto General Hospital Foundation Imperial Oil Foundation

40 Thank you