Malignant Neoplasm of Lung Dr Edit Csada 13

Malignant Neoplasm of Lung Dr Edit Csada 13. 09. 2017. 1

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: breast cancer fatality: Male/female: 2, 4/1 1, 59/1, 82 = 0, 87 0, 35 2

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

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

Smoking • 400 chemical materials • 60 carcinogens • Gas and particulate phase – Nitrosamines, aromatic amines, benzopyrene, CO 2, aldehids, nicotin, free radicals • Pack-year 5

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 6

Molecular biology of lung cancer • Genetic damages – Deletion – Mutations – Amplifications Tumor suppressor gen injury (p 53, RB 1) Inhibation of proliferation Repair mechanism Induction of apoptosis Protooncogen abnormalities Autocrine growth factors membran receptors transcription factors 7

Lung Cancer Mutation Consortium Mutations frequency M G Kris ASCO Annual Meeting 2011, June 3– 7, Chicago

Histology of lung cancer Non small cell lung cancer Squamous cell carcinoma (30%) Well, or less differentiated, with or without keratinisation Adenocancer (45%) acinar papillary bronchioloalveolar with mucus formation Large cell carcinoma (10%↓) clear cell giant cell 9

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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 11

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Histology in Hungary 2018. 03. 15. 13 Korányi Bulletin 2014

Pathological prognostic factors • • TNM Histology Histological differentiation Invading vessels Necrosis Proliferation activity Prognostic proteins 14

Symptoms Frequency (%) Cough 45 - 75 % Dyspnoe 37 - 58 % Haemopthysis 27 – 57 % Weight loss 8 – 68 % Chest pain 27 – 49 % Hoarsness 2 – 18 % 15

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 16

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Vena cava superior sy 2018. 03. 15. 18 Sárosi Veronika anyaga

Pancoast tumor 2018. 03. 15. 19 Pálföldi Regina anyaga

Squamous cell cancer Adenocancer 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) - - + 20 -

Digital clubbing 2018. 03. 15. 21 Sárosi Veronika anyaga

Diagnostic procedures • • Imaging technics Endoscopy Pathology Laboratory tests 22

Diagnostic procedures • Imaging technics – Chest x-rays – CT – MRI – Isotope scanning – PET/CT – Ultrasound 23

Bronchoscopy: sampling • • Biopsy Brushing Transbronchial biopsy Transbronchial needle aspiration (TBNA, EBUS) • Washing • BAL 24

Other samplings • • TTB, x-ray or CT supervision Percutan pleura biopsy Lymphnode aspiration biopsy Surgical biopsy – Mediastinoscopy – Parasternal mediastinotomy (Stemmer) – VATS – Thoracotomy (10%↓) 25

Metastases • • Liver: Bones: Adrenals: Brain: CT, ultrasound, PET/CT scintigraphy, CT, PET/CT CT, ultrasound, PET/CT MRI, CT 34

Prognostic factors • Poor performance status – Karnofsky, WHO ECOG • • Weight loss, more than 10% Elevated LDH Elevated tumormarker (CEA, NSE, SCC) Old age 35

Performance status Grade ECOG 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 36

Performance status Karnofsky scale Description 100 Normal; 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 50 Requires considerable assistance and frequent medical care 40 Disabled; requires special care and assistance 30 20 Severely disabled; hospitalization is indicated although death not imminent Very sick; hospitalization necessary, active supportive treatment necessary 10 Moribund; fatal processes progressing rapidly 0 Dead 37

Defining treatment • Tumor specific factors – TNM stage – Histology – Molecular features • Patient specific factors – Age – Performance status – Concomitant diseases – gender, etnicity, smoking Based on these factors multidisciplinary tumour board decides on curative-palliative therapy

Multimodality treatment Surgery Radiotherapy Chemotherapy Molecular target therapy Immunoncology! Supportive therapy

Surgery • Type of surgical procedure depends on – – Staging patient’s performance status cardiopulmonal function comorbidities. • Aim is radical resection • Sublobar resection may have a role in very early diseases. • Thoracotomy • Video assisted thoracoscopy (VATS) 40

Surgery • Absolute contraindications: – haematogen metastases in the lungs – pleuritis carcinomatosa – III. b stage disease – multiplex distant metastases • Relative contraindications 41

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 42

Radiation therapy • NSCLC: III. A, III. B stage • SCLC: combined with chemotherapy • Inoperable patient with resecable disease • Resected N 2 disease, in combined treatment • Metastasis palliation • Pancoast’s tu • Brain metastasis (stereotactic, whole brain) • PCI • Brachytherapy Radiochemotherapy! 43

Combination of radio/chemotherapy • Aim – local control – Prevention of toxic side effects – Decreasing of distant metastases • Sequential Ch. T RT (Ch. T RT Ch. T) • Concomitant Ch. T/RT • Timing - Induction: Ch. T/RT - Consolidation: Ch. T/RT Ch. T 44

Chemotherapy • Neoadjuvant treatment – Before surgery IIIa stage • Adjuvant treatment – After surgery II-IIIa stage • First-, second-, thirdline…. . – IIIb, IV stage 45

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ESMO guideline: first-line treatment of nonsquamous NSCLC Előrehaladott, nem laphám NSCLC Diagnózis EGFR mut + Driver mut – /ismeretlen ALK fúzió Rossz általános állapot (ECOG PS ≥ 2) Jó általános állapot (ECOG PS 0 -1) EGFR TKI (erlotinib, gefitinib, afatinib) (I, A) crizotinib (I, A) Platina-alapú kombináció Cis + gem/taxán (I, B) Átvéve: NSCLC ESMO Guidelines, Reck, et al. Ann Oncol 2014 Pem + cis (II, B) Bev + Platina-kettős (I, A) Monoterápia Platina-alapú kombináció Gemcitabin, vinorelbin, taxán (I, B) Carbo+pac vagy Pem (II, B) BSC

Chemotherapy of NSCLC • First-line – – – Cis-, carboplatin-gemcitabin Cis-, carboplatin-paclitaxel Cisplatin-docetaxel Cisplatin-vinorelbin Cisplatin-pemeterexed (non squamous c) Doublet+bevacizumab(adenoc) • Second-line – Pemetrexed – docetaxel 48

Molecular target therapy • EGFR tirosin kinase inhibitors – erlotinib (Tarceva) – gefinitib (Iressa) – Afatinib (Giotrif) • Angiogenesis inhibitor – bevacizumab (Avastin) • Alk-EML 4 fusion gene inhibitor – Crizotinib (Xalkori) – Ceritinib – alectinib 49

EGFR-TKI treatment • EGRF activating mutation – first or second line (also PS 3 -4!) – Erlotinib (Tarceva) – Gefitinib (Iressa) – Afatinib (Giotrif) • Erlotinib is a potential second line treatment option in pretreated patients with undetermined or wild type EGFR status. (In Hungary KRAS negativity) • Resistence: T 790 M mutation – osimertinib 50

Maintenance treatment Bevacizumab Pemetrexed erlotinib

Immuntherapy • Immun check point inhibitors – PD-1 and PDL-1 inhibitors • Nivolumab: Opdivo – 2. and 3. line • Pembrolizumab: Keytruda – (1. ) and 2. line 52

Surgery in SCLC • I/A-I/B: resection • Postoperative chemotherapy • Adjuvant irradiation in positive node status • Induction chemotherapy

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

Radiotherapy in SCLC • LD: radio-chemotherapy • PCI: prophylactic cerebral irradiation – In LD and ED – Remission after treatment – Dose: 25 -30 Gy – Possible impairment of neurocognitive functions

Supportive treatment • Pain control – WHO suggestion • Adverse events control • Thrombosis prophylaxis • Malignant pleural fluid treatment • Bone metastases treatment • Endobronchial palliation • Nutrition 56

WHO’s pain stairs (1986) Strong opioid ± non opioid ± adjuvant III. Weak opioid ± non opioid ± adjuvant II. Non opioid ± adjuvant I. 24 h 24 h 57

Supportive treatment • Pain control • Adverse events control – febrile neutopenia – Anaemia (erythropoetin) – Nausea, vomiting • Thrombosis prophylaxis • Malignant pleural fluid treatment – pleurodesis • Bone metastases treatment – bisphonat • Endobronchial palliation 58

Prognosis • • • I. stage: III. a stage: III. b stage: IV. stage: 55 -80% 30 -50% 10 -30% 4% 1% • Five year survival: 15 -17% 59

Prevention • Primary – Smoking sessation • Secundary – Screening • X-ray • LDCT 60

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