1. 1 Lung cancer Edit Csada MD 08.10.2014.

2. 2 Epidemiology Globocan 2012.   Lung cancer is the most frequent malignant disease New cases:1,82 million/year (13%) Mortality:1,59 million/year Most frequent cause of death amoung malignant diseases>colon+prostate+breast Europe:~1000 death/day Lung cancer fatality: 159/1852 = 0,87 breast cancer fatality:0,35 Male/female: 2,4/1

3. 3 New diseases according to ages  Until 40 years :1%↓  40-49 years:10%↓  50-59 years:~30%  60-69 years:~30%  Above 70 years:30%↓

4. 4 Etiologic factors Smoking Athmospheric pollution Ionisation Occupational factors Smoking Athmospheric pollution Ionisation Occupational factors asbestos, radon, etc Other lung diseases tb, COPD, ILD Genetic events

5. 5 Smoking  400 chemical materials  60 carcinogens  Gas and particulate phase  Nitrosamines, aromatic amines, benzopyrene, CO, CO2, aldehids, nicotin, free radicals  Pack-year

6. 6 Smoking and Lung Cancer  85-90% of lung cancer patients are smokers  Damages of 10-15 gens have role in the development of lung cancer  86% of smokers have damages of these gens

7. 7 Molecular biology of lung cancer  Genetic damages  Deletion  Mutations  Amplifications Tumor suppressor gen injury (p53, RB1) Inhibation of proliferation Repair mechanism Induction of apoptosis Protooncogen abnormalities Autocrine growth factors membran receptors transcription factors

8. A tüdőrák molekuláris biológiája SQCLCACSCLC Proliferáció/onkogen EGFR/TK mutációAmplifikáció(?)30% HER2ampl./mut.<5% KRAS mut.5%20% CMYC ampl.20% LMYC Proliferáció/suppr. p53 mut.50% 90% Rb(vesztés, metil.)20% 90% P16(vesztés, metil.)50%(?) <10% Apoptosis FHIT(vesztés)80% BCL2 fokozott30% 80% Kszpáz8(metil)80% DAPK(vesztés)50%

9. 9 Genetic defects in lung cancer SCLC (%) NSCLC (%) 3p deletion 9050-80 3p14.28040 Rb80-9015-30 P16 (promoter metilation) 716 P53 (mutation) 8050-60 C-Myc10-405-10 Ras (H,K,N) 020-30 HER2/neu?25 Bcl-2 expression 75-9025-30 Procaspase-8 decrease 80? Telomerase10080

10. 10 Prevention  Primary  Smoking sessation  Secundary  Screening  X-ray  LDCT

11. 11 Histology of lung cancer Non small cell lung cancer Squamous cell carcinoma (30%) Well, or less differentiated, with or without keratinisation Adenocancer (45%) acinarpapillarybronchioloalveolar with mucus formation Large cell carcinoma (10%↓) clear cell giant cell

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13. 13 Histology of lung cancer Small cell lung cancer (15%) Oat cell Intermediate cell type Combined type Carcinoid tumor Bronchial gland carcinomas Adenoid cystic carcinoma Mucoepidermoid carcinoma

14. 14

15. Hitology in Hungary Korányi Bulletin 2012 152015. 06. 09.2015. 06. 09.2015. 06. 09.

16. Molecular types of adenoc. 2015. 06. 09.2015. 06. 09.2015. 06. 09.16 Tímár József, Magyar Onkológia 57:26-32, 2013.03.

17. 17 Pathological prognostic factors  TNM  Histology  Histological differentiation  Invading vessels  Necrosis  Proliferation activity  Prognostic proteins

18. 18 Symptoms Frequency (%) Cough 45 - 75 % Dyspnoe 37 - 58 % Haemopthysis 27 – 57 % Weight loss 8 – 68 % Chest pain 27 – 49 % Hoarsness 2 – 18 %

19. 19 Symptoms of lung cancer  Regional spread  Superior vena caval sy  Recurrent laryngeal nerve paralysis (hoarsness)  Phrenic nerve paralysis elevated hemidiaphragm  Horner’s sy  Pancoast’s sy  Trachea obstruction  Oesophagus obstruction  Pleural effusion  Lymphatic tumor spread

20. 20

21. Vena cava superior sy 2015. 06. 09.2015. 06. 09.2015. 06. 09.21 Sárosi Veronika anyaga

22. Pálföldi Regina anyaga Pancoast tumor 2015. 06. 09.2015. 06. 09.2015. 06. 09.22

23. 23 Squamous cell cancerAdeno-cancer Small cell cancer Large cell cancer Ectopic parathormon productin, hypercalcaemia +-+- Ectopic ACTH production, Cushing-syndrom +++- Osteoarthropathy, digital clubbing +++++ Eaton - Lambert syndrom --+++- Peripherial neuropathy, subacut cerebellar degeneration ++++ Polymyositis, dermatomyositis ++++ Thrombophlebitis migrans, DIC -+++++ Nephrosis syndrom ++++ Inappropriate ADH production (SIADH) --+-

24. Dobverő ujj, óraüveg köröm 2015. 06. 09.2015. 06. 09.2015. 06. 09.24 Sárosi Veronika anyaga

25. 25 Diagnostic procedures  Imaging technics  Endoscopy  Pathology  Laboratory tests (?)

26. 26 Diagnostic procedures  Imaging technics  Chest x-rays  CT  MRI  Isotope scanning  PET/CT  Ultrasound

27. 27 Bronchoscopy: sample taking, staging  Biopsy  Brushing  Transbronchial biopsy  Transbronchial needle aspiration (TBNA, EBUS)  Washing  BAL

28. 28 Other sample takings  TTB, x-ray or CT supervision  Percutan pleura biopsy  Lymphnode aspiration biopsy  Surgical biopsy  Mediastinoscopy  Parasternal mediastinotomy (Stemmer) (Stemmer)  VATS  Thoracotomy (10%↓)

29. Staging 1  T1a = Tumor ≤2 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).  T1b = Tumor >2 cm but ≤3 cm in greatest dimension 29

30. Staging 2  T2a = Tumor >3 cm but ≤5 cm in greatest dimension, or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2); or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.  T2b = Tumor >5 cm but ≤7 cm or less in greatest dimension 30

31. Staging 3  T3 = Tumor >7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium or tumor in the main bronchus ( 7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium or tumor in the main bronchus (<2 cm distal to the carina b but without involvement of the carina) or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe 31

32. Staging 4  T4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe. 32

33. Staging 5  N0 = No regional lymph node metastasis.  N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.  N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).  N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s). 33

34. Staging 6  M0 = No distant metastasis.  M1a = Separate tumor nodule(s) in a contralateral lobe tumor with pleural nodules or malignant pleural (or pericardial) effusion  M1b = Distant metastasis (in extrathoracic organs). 34

36. 36 Metastases  Liver: CT, ultrasound, PET/CT  Bones: scintigraphy, CT, PET/CT  Adrenals: CT, ultrasound, PET/CT  Brain: MRI, CT

37. 37 Prognostic factors  Poor performance status  Karnofsky, WHO ECOG  Weight loss, more than 10%  Elevated LDH  Elevated tumormarker (CEA, NSE, SCC)  Old age

38. Performance status GradeECOG 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 5 Dead 38

39. Performance status Karnofsky scaleDescription 100Normal; no complaints; no evidence of disease 90 Able to carry out normal activity; minor signs or symptoms of disease 80 Normal activity with effort; some signs or symptoms of disease 70 Cares for self; unable to carry on normal activity or do active work 60 Requires occasional assistance, but is able to care for most of his/her needs 50Requires considerable assistance and frequent medical care 40Disabled; requires special care and assistance 30 Severely disabled; hospitalization is indicated although death not imminent 20 Very sick; hospitalization necessary, active supportive treatment necessary 10Moribund; fatal processes progressing rapidly 0Dead 39

40. 40 Therapy of lung cancer  Surgery  Radiotherapy  Radiochemotherapy  Chemotherapy  Molecular target therapy  Supportive treatment

41. Surgery   The type of surgical procedure depends on staging, the patient’s performance status, cardiopulmonal function and comorbidities.   The aim is radical resection   Sublobar resection may have a role in very early diseases.   Thoracotomy   Video assisted thoracoscopy (VATS) 41

42. Surgery   Absolute contraindications:   haematogen metastases in the lungs   pleuritis carcinomatosa   III.b stage disease   multiplex distanti metastases   Relative contraindications 42

43. 43 Surgery (20-25%)  NSCLC IIIA stage  Lobectomy, pulmonectomy, sleeve lobectomy, extensive resection – radical  Segmentectomy, wedge resection – mostly non radical  Early stage SCLC, as part of combined therapy  Carina resection?  Before surgery: lung function, Ecg, functional evaluation

44. 44 Radiation therapy  NSCLC: III.A, III.B stage  SCLC: combined with chemotherapy  Inoperable patient with resecable disease  Resected N2 disease, in combined treatment  Metastasis palliation  Pancoast’s tu  Brain metastasis (stereotactic, whole brain)  PCI  Brachytherapy Radiochemotherapy!

45. Combination of radio/chemotherapy  Sequential ChT  RT(ChT  RT  ChT) ChT  RT(ChT  RT  ChT)  Concomitant ChT/RT ChT/RT  Timing - Induction: ChT  ChT/RT - Induction: ChT  ChT/RT - Consolidation: ChT/RT  ChT - Consolidation: ChT/RT  ChT 45

46. Chemotherapy  Neoadjuvant treatment  Before surgery IIIa stage  Adjuvant treatment  After surgery II-IIIa stage  First-, second-, thirdline…..  IIIb, IV stage 46

47. 47 First line treatment of NSCLC  Chemotherapy  Cis-, carboplatin-gemcitabin  Cis-, carboplatin-paclitaxel  Cisplatin-docetaxel  Cisplatin-vinorelbin  Cisplatin-pemeterexed (non squamous c)  Doublet+bevacizumab(adenoc)  Adenoc.: EGFR mutácio pozitivitás  Erlotinib, gefitinib, afatinib

48. 48 Second line treatment of NSCLC  Chemotherapy  Docetaxel monoterapy  Pemetrexed monoterapy  Adenoc.: EGFR mutation positivity/KRAS negativity  gefinitib, erlotinib

49. Diagnózis CR/PR/SD PD PD-ig eltelt idő megnyúlik Klasszikus kezelés Új megközelítés Diagnózis CR/PR/SD PD Fenntartó kezelés Maintenance treatment Elsővonalbeli kezelés Platina-alapú kettős kombináció (4–6 ciklus) Kezelési szünet Másod- és többedvonalbeli kezelés Bevacizumab Pemetrexed ellotinib

50. Surgery in SCLC  I/A-I/B: resection  Postoperative chemotherapy  Adjuvant irradiation in positive node status  Induction chemohterapy

51. Chemoterapy in SCLC  Absoute indication  Cisplatin/carboplatin-Vepesid  ECO (epirubicin-cyclophoscphamid-vincristin)  Topotecan (Hycamtin) (2. line)  Progression:  Within 3 months (resistant disease): new combination  Over 3 months (senzitive disease): reinduction therapy with the original drugs

52. Radiotherapy in SCLC  LD: radio-chemotherapy  PCI: preventíve cerebral irradiation  In LD and ED  Remission after treatment  Dose: 25-30 Gy  Possible impairment of neurocognitive functions

53. 53 Molecular target therapy  EGFR tirosin kinase inhibitors  Erlotinib (Tarceva)  Gefinitib (Iressa)  afatinib  Angiogenesis inhibitors (VEGF)  Bevacizumab (Avastin)  Alk-EML4 fusion gen inhibitor  Crizotinib (Xalkori)

54. 54 Supportive treatment  Pain control  WHO suggestion  Adverse events control  Thrombosis prophylaxis  Malignant pleural fluid treatment  Bone metastases treatment  Endobronchial palliation  Nutrition

55. 55 WHO’s pain stairs (1986) III. I. II. Non opioid ± adjuvant Weak opioid ± non opioid ± adjuvant Strong opioid ± non opioid ± adjuvant 24 h 24 h 24 h

56. 56 Supportive treatment  Pain control  Adverse events control  febrile neutopenia  Anaemia (erythropoetin)  Nausea, vomiting  Thrombosis prophylaxis  Malignant pleural fluid treatment  pleurodesis  Bone metastases treatment  bisphosphonat  Endobronchial palliation  Nutrition

57. 57 Prognosis  I. stage:55-80%  II. stage:30-50%  III.a stage:10-30%  III.b stage:4%  IV. stage:1%  Five year survival: 15-17%

58. 58 Thank you for your attention!