11

Lung cancerLung cancer

Edit Csada MDEdit Csada MD

08.10.2014.08.10.2014.

22

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

33

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%↓↓

44

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

55

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

66

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

1010

PreventionPrevention

PrimaryPrimary Smoking sessationSmoking sessation

SecundarySecundary ScreeningScreening

X-rayX-ray LDCTLDCT

1111

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

1414

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 %

1919

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

2020

Vena cava superior syVena cava superior sy

23.04.18.23.04.18. 2121

Sárosi Veronika anyaga

Pálföldi Regina anyaga

Pancoast tumor

23.04.18.23.04.18. 2222

2323

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

23.04.18.23.04.18. 2424

Sárosi Veronika anyaga

2525

Diagnostic proceduresDiagnostic procedures

Imaging technicsImaging technics EndoscopyEndoscopy PathologyPathology Laboratory tests (?)Laboratory tests (?)

2626

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

5 Dead 3838

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)

4141

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

5656

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

5757

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!