1 lung cancer edit csada md 08.10.2014.. 2 epidemiology globocan 2012. lung cancer is the most...
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Lung cancerLung cancer
Edit Csada MDEdit Csada MD
08.10.2014.08.10.2014.
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EpidemiologyEpidemiology
Globocan 2012. Lung cancer is the most frequent malignant disease
New cases: 1,82 million/year (13%)Mortality: 1,59 million/yearMost frequent cause of death amoung malignant diseases>colon+prostate+breast
Europe:~1000 death/day
Lung cancer fatality: 159/1852 = 0,87breast cancer fatality: 0,35
Male/female: 2,4/1
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New diseases according to agesNew diseases according to ages
Until 40 years :Until 40 years : 1%1%↓↓ 40-49 years:40-49 years: 10%10%↓↓ 50-59 years:50-59 years: ~~30%30% 60-69 years:60-69 years: ~~30%30% Above 70 years:Above 70 years: 30%30%↓↓
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Etiologic factorsEtiologic factors
Smoking Smoking Athmospheric pollution Athmospheric pollution Ionisation Ionisation Occupational factorsOccupational factors
asbestos, radon, etcasbestos, radon, etcOther lung diseasesOther lung diseases
tb, COPD, ILDtb, COPD, ILDGenetic eventsGenetic events
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SmokingSmoking
400 chemical materials400 chemical materials 60 carcinogens60 carcinogens Gas and particulate phaseGas and particulate phase
Nitrosamines, aromatic amines, Nitrosamines, aromatic amines, benzopyrene, CO, CO2, aldehids, nicotin, benzopyrene, CO, CO2, aldehids, nicotin, free radicalsfree radicals
Pack-yearPack-year
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Smoking and Lung CancerSmoking and Lung Cancer
85-90% of lung cancer patients are 85-90% of lung cancer patients are smokerssmokers
Damages of 10-15 gens have role in the Damages of 10-15 gens have role in the development of lung cancerdevelopment of lung cancer
86% of smokers have damages of these 86% of smokers have damages of these gens gens
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Molecular biology of lung cancerMolecular biology of lung cancer Genetic damagesGenetic damages
DeletionDeletion MutationsMutations AmplificationsAmplificationsTumor suppressor gen injury (p53, RB1)Tumor suppressor gen injury (p53, RB1)
Inhibation of proliferationInhibation of proliferation
Repair mechanismRepair mechanismInduction of apoptosisInduction of apoptosis
Protooncogen abnormalitiesProtooncogen abnormalitiesAutocrine growth factorsAutocrine growth factorsmembran receptorsmembran receptorstranscription factorstranscription factors
A tüdőrák molekulárisA tüdőrák molekuláris biológiájabiológiájaSQCLC AC SCLC
Proliferáció/onkogen
EGFR/TK mutáció Amplifikáció(?) 30%
HER2ampl./mut. <5% <5%
KRAS mut. 5% 20%
CMYC ampl. 20% 20% LMYC
Proliferáció/suppr.
p53 mut. 50% 50% 90%
Rb(vesztés, metil.) 20% 20% 90%
P16(vesztés, metil.) 50%(?) 50%(?) <10%
Apoptosis
FHIT(vesztés) 80% 80% 80%
BCL2 fokozott 30% 30% 80%
Kszpáz8(metil) 80%
DAPK(vesztés) 50% 50%
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Genetic defects in lung cancerGenetic defects in lung cancer
SCLC (%)SCLC (%) NSCLC (%)NSCLC (%)
3p deletion3p deletion 9090 50-8050-80
3p14.23p14.2 8080 4040
RbRb 80-9080-90 15-3015-30
P16 (promoter P16 (promoter metilation)metilation)
77 1616
P53 (mutation)P53 (mutation) 8080 50-6050-60
C-MycC-Myc 10-4010-40 5-105-10
RasRas (H,K,N) (H,K,N) 00 20-3020-30
HER2/neuHER2/neu ?? 2525
Bcl-2 expressionBcl-2 expression 75-9075-90 25-3025-30
Procaspase-8 Procaspase-8 decreasedecrease
8080 ??
TelomeraseTelomerase 100100 8080
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PreventionPrevention
PrimaryPrimary Smoking sessationSmoking sessation
SecundarySecundary ScreeningScreening
X-rayX-ray LDCTLDCT
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Histology of lung cancerHistology of lung cancerNon small cell lung cancerNon small cell lung cancer
Squamous cell carcinoma (30%)Squamous cell carcinoma (30%)Well, or less differentiated, with or without keratinisationWell, or less differentiated, with or without keratinisation
Adenocancer (45%)Adenocancer (45%)acinaracinarpapillarypapillarybronchioloalveolarbronchioloalveolarwith mucus formationwith mucus formation
Large cell carcinoma (10%↓)Large cell carcinoma (10%↓)clear cellclear cellgiant cellgiant cell
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Histology of lung cancerHistology of lung cancer
Small cell lung cancer (15%)Small cell lung cancer (15%)Oat cellOat cellIntermediate cell typeIntermediate cell typeCombined typeCombined type
Carcinoid tumorCarcinoid tumorBronchial gland carcinomasBronchial gland carcinomas
Adenoid cystic carcinomaAdenoid cystic carcinomaMucoepidermoid carcinomaMucoepidermoid carcinoma
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Hitology in HungaryHitology in Hungary
Korányi Bulletin 2012151523.04.18.23.04.18.
Molecular types of adenoc. Molecular types of adenoc.
23.04.18.23.04.18. 1616Tímár József, Magyar Onkológia 57:26-32, 2013.03.
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Pathological prognostic Pathological prognostic factorsfactors
TNMTNM HistologyHistology Histological differentiationHistological differentiation Invading vesselsInvading vessels NecrosisNecrosis Proliferation activityProliferation activity Prognostic proteinsPrognostic proteins
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SymptomsSymptoms Frequency (%)Frequency (%)
CoughCough 45 - 75 %45 - 75 %
DyspnoeDyspnoe 37 - 58 %37 - 58 %
HaemopthysisHaemopthysis 27 27 –– 57 % 57 %
Weight lossWeight loss 8 8 –– 68 % 68 %
Chest painChest pain 27 27 –– 49 % 49 %
HoarsnessHoarsness 2 2 –– 18 % 18 %
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Symptoms of lung cancerSymptoms of lung cancer
Regional spreadRegional spread Superior vena caval sySuperior vena caval sy Recurrent laryngeal nerve paralysis (hoarsness)Recurrent laryngeal nerve paralysis (hoarsness) Phrenic nerve paralysis elevated Phrenic nerve paralysis elevated
hemidiaphragmhemidiaphragm Horner’s syHorner’s sy Pancoast’s syPancoast’s sy Trachea obstructionTrachea obstruction Oesophagus obstructionOesophagus obstruction Pleural effusionPleural effusion Lymphatic tumor spreadLymphatic tumor spread
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Vena cava superior syVena cava superior sy
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Sárosi Veronika anyaga
Pálföldi Regina anyaga
Pancoast tumor
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Squamous cellSquamous cellcancercancer
Adeno-Adeno-cancercancer
Small cell Small cell cancercancer
Large cell Large cell cancercancer
Ectopic parathormon Ectopic parathormon productin, productin, hypercalcaemiahypercalcaemia
++ -- ++ --
Ectopic ACTH Ectopic ACTH production, production, Cushing-syndromCushing-syndrom
++ ++ ++ --
Osteoarthropathy, Osteoarthropathy, digital clubbingdigital clubbing
++ ++++ ++ ++
Eaton - Lambert Eaton - Lambert syndromsyndrom
-- -- ++++++ --
Peripherial neuropathy, Peripherial neuropathy, subacut cerebellar subacut cerebellar degenerationdegeneration
++ ++ ++ ++
Polymyositis, Polymyositis, dermatomyositisdermatomyositis
++ ++ ++ ++
Thrombophlebitis Thrombophlebitis migrans, DICmigrans, DIC
-- ++++++ ++ ++
Nephrosis syndromNephrosis syndrom ++ ++ ++ ++
Inappropriate ADH Inappropriate ADH production production (SIADH)(SIADH)
-- -- ++ --
Dobverő ujj, óraüveg Dobverő ujj, óraüveg körömköröm
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Sárosi Veronika anyaga
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Diagnostic proceduresDiagnostic procedures
Imaging technicsImaging technics EndoscopyEndoscopy PathologyPathology Laboratory tests (?)Laboratory tests (?)
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Diagnostic proceduresDiagnostic procedures
Imaging technicsImaging technics Chest x-raysChest x-rays CTCT MRIMRI Isotope scanningIsotope scanning PET/CTPET/CT UltrasoundUltrasound
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Bronchoscopy: sample taking, Bronchoscopy: sample taking, stagingstaging
BiopsyBiopsy BrushingBrushing Transbronchial biopsyTransbronchial biopsy Transbronchial needle aspiration Transbronchial needle aspiration
(TBNA, EBUS)(TBNA, EBUS) WashingWashing BALBAL
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Other sample takingsOther sample takings
TTB, x-ray or CT supervisionTTB, x-ray or CT supervision Percutan pleura biopsyPercutan pleura biopsy Lymphnode aspiration biopsyLymphnode aspiration biopsy Surgical biopsySurgical biopsy
MediastinoscopyMediastinoscopy Parasternal mediastinotomy Parasternal mediastinotomy
(Stemmer)(Stemmer) VATSVATS Thoracotomy (10%Thoracotomy (10%↓↓))
Staging 1Staging 1
T1a = Tumor ≤2 cm in greatest dimension, T1a = Tumor ≤2 cm in greatest dimension, surrounded by lung or visceral pleura, without surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in proximal than the lobar bronchus (i.e., not in the main bronchus).the main bronchus).
T1b = Tumor >2 cm but ≤3 cm in greatest T1b = Tumor >2 cm but ≤3 cm in greatest dimensiondimension
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Staging 2Staging 2
T2a = Tumor >3 cm but ≤5 cm in greatest T2a = Tumor >3 cm but ≤5 cm in greatest dimension, dimension, oror tumor with any of the following tumor with any of the following features: involves main bronchus, ≥2 cm distal to features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2); the carina; invades visceral pleura (PL1 or PL2); oror is associated with atelectasis or obstructive is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but pneumonitis that extends to the hilar region but does not involve the entire lung.does not involve the entire lung.
T2b = Tumor >5 cm but ≤7 cm or less in greatest T2b = Tumor >5 cm but ≤7 cm or less in greatest dimensiondimension
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Staging 3Staging 3
T3 = Tumor >7 cm T3 = Tumor >7 cm oror one that directly invades one that directly invades any of the following: parietal pleural (PL3) any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium or parietal pericardium oror tumor in the main tumor in the main bronchus (<2 cm distal to the carinabronchus (<2 cm distal to the carinabb but but without involvement of the carina) without involvement of the carina) oror associated atelectasis or obstructive associated atelectasis or obstructive pneumonitis of the entire lung or separate pneumonitis of the entire lung or separate tumor nodule(s) in the same lobetumor nodule(s) in the same lobe
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Staging 4Staging 4
T4 = Tumor of any size that invades any of the T4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe.nodule(s) in a different ipsilateral lobe.
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Staging 5Staging 5
N0 = No regional lymph node metastasis.N0 = No regional lymph node metastasis. N1 = Metastasis in ipsilateral peribronchial and/or N1 = Metastasis in ipsilateral peribronchial and/or
ipsilateral hilar lymph nodes and intrapulmonary ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.nodes, including involvement by direct extension.
N2 = Metastasis in ipsilateral mediastinal and/or N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).subcarinal lymph node(s).
N3 = Metastasis in contralateral mediastinal, N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).scalene, or supraclavicular lymph node(s).
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Staging 6Staging 6
M0 = No distant metastasis.M0 = No distant metastasis. M1a = Separate tumor nodule(s) in a M1a = Separate tumor nodule(s) in a
contralateral lobe tumor with pleural nodules or contralateral lobe tumor with pleural nodules or malignant pleural (or pericardial) effusionmalignant pleural (or pericardial) effusion
M1b = Distant metastasis (in extrathoracic M1b = Distant metastasis (in extrathoracic organs).organs).
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MetastasesMetastases
Liver: Liver: CT, ultrasound, PET/CT CT, ultrasound, PET/CT Bones: Bones: scintigraphy, CT, PET/CTscintigraphy, CT, PET/CT Adrenals: Adrenals: CT, ultrasound, PET/CTCT, ultrasound, PET/CT Brain: Brain: MRI, CTMRI, CT
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Prognostic factorsPrognostic factors
Poor performance statusPoor performance status Karnofsky, WHO ECOGKarnofsky, WHO ECOG
Weight loss, more than 10%Weight loss, more than 10% Elevated LDHElevated LDH Elevated tumormarker (CEA, NSE, SCC)Elevated tumormarker (CEA, NSE, SCC) Old ageOld age
Performance statusPerformance 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
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Performance statusPerformance statusKarnofsky 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 Severely disabled; hospitalization is indicated although death not imminent
20 Very sick; hospitalization necessary, active supportive treatment necessary
10 Moribund; fatal processes progressing rapidly
0 Dead3939
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Therapy of lung cancerTherapy of lung cancer
SurgerySurgery RadiotherapyRadiotherapy RadiochemotherapyRadiochemotherapy ChemotherapyChemotherapy Molecular target therapyMolecular target therapy Supportive treatmentSupportive treatment
SurgerySurgery
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)
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SurgerySurgery
Absolute contraindications: haematogen metastases in the lungs pleuritis carcinomatosa III.b stage disease multiplex distanti metastases
Relative contraindications
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Surgery (20-25%)Surgery (20-25%)
NSCLC IIIA stageNSCLC IIIA stage Lobectomy, pulmonectomy, sleeve Lobectomy, pulmonectomy, sleeve
lobectomy, extensive resection – radicallobectomy, extensive resection – radical Segmentectomy, wedge resection – mostly Segmentectomy, wedge resection – mostly
non radicalnon radical Early stage SCLC, as part of combined Early stage SCLC, as part of combined
therapytherapy Carina resection?Carina resection? Before surgery: lung function, Ecg, functional Before surgery: lung function, Ecg, functional
evaluationevaluation
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Radiation therapyRadiation therapy
NSCLC: III.A, III.B stageNSCLC: III.A, III.B stage SCLC: combined with chemotherapySCLC: combined with chemotherapy Inoperable patient with resecable diseaseInoperable patient with resecable disease Resected N2 disease, in combined treatmentResected N2 disease, in combined treatment Metastasis palliationMetastasis palliation Pancoast’s tuPancoast’s tu Brain metastasis (stereotactic, whole brain)Brain metastasis (stereotactic, whole brain) PCIPCI BrachytherapyBrachytherapy
Radiochemotherapy!Radiochemotherapy!
Combination of Combination of radio/chemotherapyradio/chemotherapy
SequentialSequential
ChTChTRTRT (ChT(ChTRTRTChT)ChT) ConcomitantConcomitant
ChT/RT ChT/RT Timing Timing
- Induction: ChT - Induction: ChT ChT/RTChT/RT
- Consolidation: ChT/RT - Consolidation: ChT/RT ChTChT
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ChemotherapyChemotherapy
Neoadjuvant treatmentNeoadjuvant treatment Before surgery IIIa stage Before surgery IIIa stage
Adjuvant treatmentAdjuvant treatment After surgery II-IIIa stageAfter surgery II-IIIa stage
First-, second-, thirdline…..First-, second-, thirdline….. IIIb, IV stageIIIb, IV stage
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First line treatment of NSCLCFirst line treatment of NSCLC
ChemotherapyChemotherapy Cis-, carboplatin-gemcitabinCis-, carboplatin-gemcitabin Cis-, carboplatin-paclitaxelCis-, carboplatin-paclitaxel Cisplatin-docetaxelCisplatin-docetaxel Cisplatin-vinorelbinCisplatin-vinorelbin Cisplatin-pemeterexed (non squamous c)Cisplatin-pemeterexed (non squamous c) Doublet+bevacizumab(adenoc)Doublet+bevacizumab(adenoc)
Adenoc.: EGFR mutácio pozitivitásAdenoc.: EGFR mutácio pozitivitás Erlotinib, gefitinib, afatinibErlotinib, gefitinib, afatinib
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Second line treatment of NSCLCSecond line treatment of NSCLC
ChemotherapyChemotherapy Docetaxel monoterapyDocetaxel monoterapy Pemetrexed monoterapyPemetrexed monoterapy
Adenoc.: EGFR mutation positivity/KRAS Adenoc.: EGFR mutation positivity/KRAS negativitynegativity gefinitib, erlotinibgefinitib, erlotinib
Diagnózis CR/PR/SD PD PD
PD-ig eltelt idő megnyúlik
Klasszikuskezelés
Újmegközelítés
Diagnózis CR/PR/SD PD PD
Fenntartó kezelés
Maintenance treatmentMaintenance treatmentElsővonalbeli kezelésPlatina-alapú kettős kombináció(4–6 ciklus)
Kezelésiszünet
Másod- és többedvonalbeli kezelés
BevacizumabPemetrexedellotinib
Surgery in SCLCSurgery in SCLC
I/A-I/B: resectionI/A-I/B: resection
Postoperative chemotherapyPostoperative chemotherapy
Adjuvant irradiation in positive node statusAdjuvant irradiation in positive node status
Induction chemohterapyInduction chemohterapy
Chemoterapy in SCLCChemoterapy in SCLC
Absoute indicationAbsoute indication
Cisplatin/carboplatin-VepesidCisplatin/carboplatin-Vepesid ECO (epirubicin-cyclophoscphamid-vincristin)ECO (epirubicin-cyclophoscphamid-vincristin) Topotecan (Hycamtin) (2. line)Topotecan (Hycamtin) (2. line)
Progression:Progression: Within 3 months (resistant disease): new Within 3 months (resistant disease): new
combinationcombination Over 3 months (senzitive disease): Over 3 months (senzitive disease):
reinduction therapy with the original drugsreinduction therapy with the original drugs
Radiotherapy in SCLCRadiotherapy in SCLC
LD: radio-chemotherapyLD: radio-chemotherapy
PCI: PCI: preventíve cerebral irradiationpreventíve cerebral irradiation In LD and EDIn LD and ED Remission after treatmentRemission after treatment Dose: 25-30 GyDose: 25-30 Gy Possible impairment of neurocognitive Possible impairment of neurocognitive
functionsfunctions
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Molecular target therapyMolecular target therapy
EGFR tirosin kinase inhibitorsEGFR tirosin kinase inhibitors Erlotinib (Tarceva)Erlotinib (Tarceva) Gefinitib (Iressa)Gefinitib (Iressa) afatinibafatinib
Angiogenesis inhibitors (VEGF)Angiogenesis inhibitors (VEGF) Bevacizumab (Avastin)Bevacizumab (Avastin)
Alk-EML4 fusion gen inhibitorAlk-EML4 fusion gen inhibitor Crizotinib (Xalkori)Crizotinib (Xalkori)
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Supportive treatmentSupportive treatment
Pain controlPain control WHO suggestionWHO suggestion
Adverse events controlAdverse events control Thrombosis prophylaxisThrombosis prophylaxis Malignant pleural fluid treatmentMalignant pleural fluid treatment Bone metastases treatmentBone metastases treatment Endobronchial palliationEndobronchial palliation NutritionNutrition
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WHO’s pain stairs (1986)
III.
I.
II.
Non opioid ± adjuvant
Weak opioid ± non opioid ± adjuvant
Strong opioid ± non opioid ± adjuvant
24h 24h 24h
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Supportive treatmentSupportive treatment Pain controlPain control Adverse events controlAdverse events control
febrile neutopeniafebrile neutopenia Anaemia (erythropoetin)Anaemia (erythropoetin) Nausea, vomitingNausea, vomiting
Thrombosis prophylaxisThrombosis prophylaxis Malignant pleural fluid treatmentMalignant pleural fluid treatment
pleurodesispleurodesis Bone metastases treatmentBone metastases treatment
bisphosphonatbisphosphonat Endobronchial palliationEndobronchial palliation NutritionNutrition
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PrognosisPrognosis
I. stage:I. stage: 55-80%55-80% II. stage:II. stage: 30-50%30-50% III.a stage:III.a stage: 10-30%10-30% III.b stage:III.b stage: 4%4% IV. stage:IV. stage: 1%1%
Five year survival: 15-17%Five year survival: 15-17%
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Thank you for your attention!