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Rare Solid Cancers: An Introduction - Slide 16 - R.A. Stahel - Rare thoracic cancers

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  • Thymome und Thymuskarzinome sind epitheliale Tumoren, die von dem feinen Netzwerk an epithelialen Zellen des Thymus ausgehen. Dies ist eine immunhistochemische Färbung für Zytokeratin, die das Netzwerk von epithelialen Zellen des Thymus darstellt. In der Vergangenheit hat es zwei Klassifikationen von Thymomen gegeben, die seit 1999 durch die WHO Klassifikation der Thymome ersetzt ist.
  • A ersetzt das wort medullär, b das wort Kortikal und C das Karzinom im offensichtlich malignen Thymuskarzinom

Rare Solid Cancers: An Introduction - Slide 16 - R.A. Stahel - Rare thoracic cancers Rare Solid Cancers: An Introduction - Slide 16 - R.A. Stahel - Rare thoracic cancers Presentation Transcript

  • Rare thoracic cancers Rolf Stahel, MD University Hospital Zurich, Switzerland Stresa, April 1 st 2011
  • Rare thoracic tumors
    • Pulmonary carcinoid
    • Pleural mesothelioma
    • Thymic tumors
    • Molecularly defined subtypes of „non-small cell lung cancer“
  • Pulmonary carcinoids Typical carcinoid Atypical carcinoid defined by 2-10 mitoses/HPH and/or presenced of necrosis Rekhtman, Arch Pathol Lab Med 2010
  • Ki-67 IHC to distinguish typical and atypical carcinoid H&E Ki-61 typical carcinoid atypical carcinoid Rekhtman, Arch Pathol Lab Med 2010
  • Arrray comparative genomic hypridization-based characterization of pulmonary neuroendocrine tumors Voortman, PNAS 2010 High degree CNAs in SCLC but not in bronchial carinoids Common CNAs in neuroendocrine tumors
  • Clinical presentation of pulmonary carcinoids
    • Symptoms:
    • One third incidental finding
    • Cough, recurrent pneumonia, and hemoptysis
    • Carcinoid syndrome exceedingly rare
    • Location:
    • Central > peripheral
    • Nodal involvement:
    • Associated with atypical carcinoid
    Detterbeck, Ann Thorac Surg 2010
  • Treatment: Surgical resection (and mediastinal lymph node dissection) Typical carcinoid: OAS Atypical carcinoid: OAS Garcia-Yuste, Europ J Cardiothoracic Surg 2007
    • Pleural plaques
    Pleural plaques Asbestosis Pleural mesothelioma
  • Mesothelioma in Europe
    • Peak incidence around 2020
    • British mesothelioma register and male death rates for cancer of the pleura from 6 European countries
    • Statistical modeling taking into account asbestos legislation and the long latency period
    • Peto, BJC 1999
    • Peak leveling off between 2010 and 2015
    • Perlucchi, BJC 2004; Hodgson BJC 2005
  • Latency period in pleural mesothelioma after asbestos-exposure
    • Data collected by the Italian mesothelioma registry in the period 1993-2000: median latency 44.6 years
    Marinaccio, EJC 2007
  • Asbestos in the developing world
  • Alterations of NF2 and LATS
    • Mutations in NF2 have been described in 40% of mesothelioma Bianchi, PNAS 1995; Sekido, CR 1995; Deguen, IJC 1998
    • In tumors without NF2 truncation, NF2 activity is inhibited by phosphorylation, for example by increased expression of CPI-17 Thurneysen, Lung Cancer 2009
    • Loss of NF2 (merlin) correlates with activation of PI3K/mTORC1 signalling and sensitivity to rapamycin Lopez-Lago, MCB 2009
    • LATS (large tumor suppressor homolog 2) is a tumor supressor gene in mesothelioma Murakami, Mol Cell Pathol; 2011
  • NF2 is a „gatekeeper “ during tissue repair Sonic hedgehog signaling
    • NF2
    • Mst
    • WW45
    • Mob
    • Lats
    • YAP
    • YAP
    • YAP
    • X
    • NF2
    • Mst
    • WW45
    • Mob
    • Lats
    • YAP
    • YAP
    • X
    • survivin
    • amphiregulin
    Stimulation of repair in NF2-deficientcancer cells Sonic hedgehog signaling
    • NF2
    Normal tissue repair Hippo pathway
    • survivin
    • amphiregulin
    • Ser127P
    • P
    • P
    • P
    • P
  • Soluble mesothelin-related peptide
    • Mesothelin is a cell surface glycoprotein, expressed on normal mesothelial cells and > 90% of mesotheliomas (binds to CA125)
    • Soluble mesothelin-related proteins in serum
    • Target for antibody therapy
    Robinson, Lancet 2003 Cristaudo, Clin Cancer Res 2007 Pass, ATS 2008
  • Systemic therapy
    • Chemotherapy provides symptom relief
    • Based on a landmark study of Vogelzang et al., the combination of cisplatin and pemetrexed has become the preferred chemotherapy regimen
    • Most current studies examining neoadjuvant chemotherapy followed by extrapleural pneumonectomy include combined cisplatin and pemetrexed chemotherapy
    • Optimal second line chemotherapy is not defined, vinorelbine might be a good choice
    • Novel and targeting agents: so far no or very limited success
  • Pemetrexed + Cisplatin vs Cisplatin: Tumor Response Rates and Survival Vogelzang , JCO 2003
  • Surgery and multimodality therapy
    • The role of surgery continues to be a matter of debate
      • Radical resectability?
      • Extrapleural pneumonectomy or pleurectomy and decortication?
      • Impact on survival?
      • Lack of prospective randomized data
    • However:
      • Longest median survival and long term survivors reported in series with multimodality therapy including EPP
      • Surgical mortality in experienced centers dropped to around 3%
  • Multimodality therapy including extrapleural pneumonectomy (EPP)
    • Boston: EPP with adjuvant chemotherapy and radiotherapy:
    • Retrospective series on 176/183 pts surviving EPP
    • MST 19 months, periop. mortality 3.8%, 35% local failure Sugarbaker JTCVS 1999; Baldini, ATS 1997
    • Zürich/SAKK: Neoadjuvant chemotherapy and EPP (± radiotherapy):
    • Prospective phase II study on 61 pts
    • MST by intent to treat 19.8 months, operative mortality 2%
    • EPP 45 pts (74%), MST 23.8 months Weder and Stahel, Ann Oncol 2007
  • Neoadjuvant chemotherapy, EPP and radiotherapy in MPM Number of patients Survival (months) Author Stage Chemoth. EPP Radioth. ITT EPP Weder, JCO 2004 T1-3, N0-2 19 16 (84%) 13 (68%) 23 n/a Weder, AO 2007 T1-3, N0-2 61 45 (74%) 36 (59%) 19.8 23 Rea, LC 2007 T1-3, N0-2 21 17 (81%) 15 (71%) 25.5 27.5 Batirel, JTO 2008 T1-3, N0-2 20 16 (80%) 12 (60%) 17 19.6 Krug, JCO 2009 T1-3, N0-2 77 57 (74%) 44 (57%) 16.8 21.9 Van Schil, ERJ 2010 T1-3, N0-1 59 42 (73%) 38 (64%) 18.4 n/a 257 193 (75%) 158 (61%)
  • Well-differentiated papillary mesothelioma of the pleura
    • 24 cases
    • Equal proportion of man and women, mean age 60 years, less than half h h/o asbestos exposure
    • Dysnpnea and recurrent pleural effusion
    • Thorocoscopy demonstread multipe millimeter nodues on the parieal and or visceral pleura
    • 2/6 with no treatment survived 73 and 83 months
    • 17 pts alive with disease, including 11 longer than 2 years and 2 with a f/u of 5 and 10 years
    • Galateau-Sallé, J Surg Pathol 2004
  • Classification of Thymic Tumors
    • Thymic tumors are epithelial tumors, often admixed with lymphocytes (mostly T-cells)
    • Incidence: 1-5/million/year
    • Morphology: very heterogeneous
      • „ American “ Classification
      • Marino/Müller-Hermelink Classifikation
      • WHO-Classification (1999)
  • WHO-Einteilung
    • WHO types
      • A = medullary, B = cortical, C = carcinoma
    WHO-Classifikation of Thymic Tumors A: « atrophic », the thymic cells of adult life B: « bioactive » biologically active organ of the fetus / infant C: « carcinoma »
    • WHO types: Morphology and behaviour
      • A = medullary, B = cortical, C = carcinoma
      • A Medullary thymoma
      • AB Mixed thymoma
      • B1 Predominant cortical thymoma
      • B2 Cortical thymoma
      • B3 Well-differentiated thymic ca.
      • C Thymic carcinoma
    WHO-Einteilung Mostly en- capsulated Mostly invasive Often metastatic WHO-Classifikation of Thymic Tumors
    • WHO type C: No longer suggested, but replaced by descriptive terms
      • Squamous cell carcinoma (most common)
      • Basaloid carcinoma
      • Mucoepidermoid carcinoma
      • Lymphoepithelioma-like carcinoma
      • Sarcomatoid carcinoma
      • Clear cell carcinoma
      • Papillary adenocarcinoma
      • Non-palliary adenocarcinoma
      • Undifferentiated carcinoma of the thymus
      • Thymic neuroendocrine tumors
    WHO-Einteilung WHO-Classification of Thymic Tumors
  • Staging Masaoka, Cancer 1981
  • WHO-Einteilung Relationship between WHO and Stage Rena, Lung Cancer 2005
    • Heterogeneous disease, in particular thymoma vs thymic carcinoma
    • No randomized studies
    • Very little prospective studies, mostly single center experience (retrospective analysis)
    • Many review articles, recent reviews include:
    Treatment recommendatons
    • Tomaszek, Ann Thorac Surg 2009 (Mayo Clinic)
    • Girard, JTO 2009 (European)
    • Falkson, JTO 2009 (Cancer Care Ontario)
    Treatment recommendations
    • Stage I: Surgery
    • Stage II: Surgery, postoperative radiotherapy recommended after incomplete resection
    • Stage III/IVA: Multimodality therapy, mostly neoadjuvant chemotherapy followed by surgery with our without radiotherapy
    • Stage IVB: Chemotherapy
    Treatment recommendations
  • Completeness of surgical resection Strobel, JCO 2004
  • Recommendation on postoperative radiotherapy for stage II
    • European:
      • Incomplete resection
      • Radiation dose 60-65 Gy in case of incomplete resection
      • Otherwise controversial
    • Ontario:
      • Routine XRT not recommended
      • Restricted to “ high risk ” : Capsular invasion, close margins, WHO type B, adherence to pericardium
    • Mayo:
      • Controversial for completely resected tumors
      • Consider for WHO B2, B3 or C
      • Increase in dose or extension in field does not improve outcome
  • Reommendation on potentially resectable disease
    • European:
      • Surgery and postoperative radiotherapy
    • Ontario:
      • Evaluation for multimodality therapy
      • Neoadjuvant chemo(radio)therapy and surgery, considering volume
    • Mayo:
      • Multimodality therapy
  • Neoadjuvant Chemotherapy, Surgery, and Radiotherapy in Advanced Thymoma Importance of surgery for survival! Publication Regimen Pts RR (%) Complete resection Survival Berrutti, BJC 1999 PAC 16 81% 56% 25% 5-y Kim, Lung Cancer 2007 PAC 22 77% 73% 79% 7-y Lucchi, JTO 2006 PEA 30 73% 77% 82% 10-y Yokio, JTO 2007 CAMP 17 92% 18% 81% 10-y Yokio, JTO 2007 CAMP 17 92% 18% 81% 10-y Lemma, ASCO 2008 CP 23 35% ? ~ 80? 5-y Wright, Ann Thorac Surg 2008 PE 10 40% 80% 69% 5-y
    • Basis for treatment decision for the individual patient:
    • Evidence-based guidelines: N/A
    • Prospective randomized studies: N/A
    • Few prospective phase II studies, mostly retrospective single center experience:
      • RR ≈ 70% with cyclophosphamide, doxorubicine and cisplatin combinations
      • RR ≈ 40% with etoposide and cisplatin combinations
    • Review articles
    Chemotherapy of Thymic Tumors
  • WHO-Einteilung Survival Thymoma vs Thymic Carcinoma Lemma, ASCO 2008 ALIVE DEAD MEDIAN TOTAL Stratum Thymoma 23 4 19 6+years Thymic Carcinoma 21 16 5 15.1 Probability Log Rank Test p<0.001 Overall Survival: Thymoma vs. Thymic Carcinoma 0.0 0.2 0.4 0.6 0.8 1.0 Months 0 6 12 18 24 30 36 42 48 54 60 66
  • The future development of systemic therapy of non-small cell lung cancer will be based on molecular tumor characteristics
    • Advanced adenocarcinoma: Evolving molecular determinants
    | Pao & Girard, Lancet Oncol, 2011 ETOP | Zürich, March 17, 2011
  • Translational research in lung cancer: The advances over the last years
    • Advanced adenocarcinoma: Molecular targets
    • EGFR mutation First line TKIs
    • ALK fusion gene product
    | ETOP | Zürich, March 17, 2011
  • Translational research in lung cancer: Evolving targets
    • Advanced adenocarcinoma: Evolving targets
    • EGFR mutation: Overcoming TKI resistance
    • MET amplification
    • Targeting HER mutations
    • Targeting BRAF mutations
    | ETOP | Zürich, March 17, 2011
  • Translational research in lung cancer: Evolving targets
    • Advanced squamous cell carcinoma: Evolving targets
    • FGFR1 amplification
    • Independent of histology
    • EGFR IHC revisited
    | ETOP | Zürich, March 17, 2011 Weiss, Sci Transl Med 2010
  • LUNGSCAPE is a translational research project designed by ETOP (www.lungscape.org) Lugano, April 12, 2011
    • Austria
    • CECOG – Central European Cooperative Oncology Group
    • Belgium
    • ELCWP – European Lung Cancer Working Party
    • EORTC Lung Cancer
    • Leuven Lung Cancer Group
    • TOGA – Thoracale Oncologie Groep Antwerpen
    • Czech Republic
    • Czech Lung Cancer Cooperative Group
    • Denmark
    • DLCG – Danish Lung Cancer Group
    • DOLG – Danish Oncological Lungcancer Group
    • France
    • GFPC – Groupe Français de Pneumo-Cancérologie
    • IFCT – Intergroupe francophone de Cancérologie thoracique
    • IGR – Institut Gustave Roussy
    • Germany
    • AOT – Arbeitsgemeinschaft Onkologische Thoraxchirurgie
    • Arbeitsgruppe Thorakale Onkologie der Arbeitsgemeinschaft Internistische Onkologie der Deutschen Krebsgesellschaft
    • Lung Cancer Group Cologne
    • Greece
    • HeCOG – Hellenic Co-operative Oncology Group
    • HORG – Hellenic Oncology Research Group
    • Hungary
    • Thoracic Oncology Program
    • Italy
    • AIOT – Associazione Italiana di Oncologia Toracica
    • Poland
    • Polish Lung Cancer Group
    • Medical University of Gdansk TOP Group
    • Portugal
    • GECP – Grupo de estudos do cancro do pulmão
    • Spain
    • SLCG – Spanish Lung Cancer Group
    • Sweden
    • Swedish Lung Cancer Study Group
    • Switzerland
    • SAKK – Schweizerische Arbeitsgemeinschaft fuer Klinische Krebsforschung
    • The Netherlands
    • NVALT – Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
    • ROTS – Rotterdam Thoracic Oncology Study Group
    • United Kingdom/Ireland
    • Birmingham Group
    • BTOG – British Thoracic Oncology Group
    • London Lung Cancer Group
    • Manchester Lung Cancer Group
    • National Cancer Research Institute – Lung Cancer Clinical Study Group
    Participating groups and institutions
  • Molecular based clinical trials in lung cancer: Issues
    • Molecular pathology both at diagnosis and at relapse for definition or stratification of study population mandatory
    • Centralized analysis or standardization of methodologies between sites
    • Availability of integrated services at sites
    • Rarity of molecular subgroups
    • Large networks of sites necessary to detect eligible patients
    • Optimal number or sites for a given trial
    • Emphasis on early decision in molecularly-driven trials
    • New models of collaboration with diagnostic and pharmaceutical companies
    |
    • ETOP | LUNGSCAPE | Malta, April 10, 2011
  • About LUNGSCAPE
    • The LUNGSCAPE addresses the challenges of studying the molecular epidemiology of lung cancer
      • by coordinating and harmonizing the procedures of of lung cancer specialists in translational research across Europe
      • by facilitating analysis of larger series of cases.
    • Specifically, LUNGSCAPE will:
      • Establish a virtual NSCLC bank with (anonymized) patient specific information including molecular pathology as resource for research and hypotheses generation for future diagnostic platforms and biomarker driven clinical trials
      • Samples will be analyzed at the sites of origin according to SOPs
      • Web-based electronic data base (lungscape.org)
    | ETOP | LUNGSCAPE | Zürich, March 17, 2011
  • Web-based data bank: Comprehensive clinical data capture |
    • ETOP | LUNGSCAPE | Malta, April 10, 2011
  • Stepwise evolution
    • Step 1: Retrospective analysis of 1500 completely resected NSCLC from a limited number sites: Mutation testing, immunohistochemistry, selected FISH on formalin-fixed, paraffin-embedded tumor tissue
    • Step 2: Expansion to biopsies from advanced disease and a phased approach increasing to the number of participating sites with the aim to have participation from at least one site from all countries represented in ETOP
    • Further steps and issues under considerations: Enlargement of biobank, exon sequencing (selected frozen tissue), circulating biomarkers, technology platforms, resource utilization and health economics research
    | ETOP | LUNGSCAPE | EMCTO | Lugano, February 24, 2011
  • ETOP | European Thoracic Oncology Platform | c/o IBCSG | Effingerstrasse 40 | 3008 Bern | www.etop.ch Visit us at www.etop.ch