Transcript 06. Malignant neoplasm of lung

Lung cancer
Edit Csada MD
08.10.2014.
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
159/1852 = 0,87
0,35
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New diseases according to ages
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Until 40 years :
40-49 years:
50-59 years:
60-69 years:
Above 70 years:
1%↓
10%↓
~30%
~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, CO2, aldehids, nicotin,
free radicals
 Pack-year
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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
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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
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A tüdőrák molekuláris biológiája
SQCLC
AC
SCLC
EGFR/TK mutáció
Amplifikáció(?)
30%
HER2ampl./mut.
<5%
<5%
KRAS mut.
5%
20%
CMYC ampl.
20%
20%
LMYC
p53 mut.
50%
50%
90%
Rb(vesztés, metil.)
20%
20%
90%
P16(vesztés, metil.)
50%(?)
50%(?)
<10%
FHIT(vesztés)
80%
80%
80%
BCL2 fokozott
30%
30%
80%
Proliferáció/onkogen
Proliferáció/suppr.
Apoptosis
Kszpáz8(metil)
DAPK(vesztés)
80%
50%
50%
Genetic defects in lung
cancer
SCLC (%)
NSCLC (%)
3p deletion
90
50-80
3p14.2
80
40
Rb
80-90
15-30
P16 (promoter
metilation)
7
16
P53 (mutation)
80
50-60
C-Myc
10-40
5-10
Ras (H,K,N)
0
20-30
HER2/neu
?
25
Bcl-2 expression
75-90
25-30
Procaspase-8
decrease
80
?
Telomerase
100
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80
Prevention
 Primary
 Smoking sessation
 Secundary
 Screening
 X-ray
 LDCT
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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
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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
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Hitology in Hungary
2015.04.13.
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Korányi Bulletin 2012
Molecular types of adenoc.
2015.04.13.
Tímár József, Magyar Onkológia 57:26-32,16
2013.03.
Pathological prognostic
factors
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TNM
Histology
Histological differentiation
Invading vessels
Necrosis
Proliferation activity
Prognostic proteins
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Symptoms
Frequency (%)
Cough
45 - 75 %
Dyspnoe
37 - 58 %
Haemopthysis
27 – 57 %
Weight loss
8 – 68 %
Chest pain
27 – 49 %
Hoarsness
2 – 18 %
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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
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Vena cava superior sy
2015.04.13.
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Sárosi Veronika anyaga
Pancoast tumor
2015.04.13.
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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
syndrom
-
-
+++
-
Peripherial neuropathy,
subacut cerebellar
degeneration
+
+
+
+
Polymyositis,
dermatomyositis
+
+
+
+
Thrombophlebitis
migrans, DIC
-
+++
+
+
Nephrosis syndrom
+
+
+
+
Inappropriate
production
(SIADH)
-
-
+
- 23
Lambert
ADH
Dobverő ujj, óraüveg
köröm
2015.04.13.
24
Sárosi Veronika anyaga
Diagnostic procedures
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Imaging technics
Endoscopy
Pathology
Laboratory tests (?)
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Diagnostic procedures
 Imaging technics
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Chest x-rays
CT
MRI
Isotope scanning
PET/CT
Ultrasound
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Bronchoscopy: sample taking,
staging
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Biopsy
Brushing
Transbronchial biopsy
Transbronchial needle aspiration
(TBNA, EBUS)
 Washing
 BAL
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Other sample takings
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TTB, x-ray or CT supervision
Percutan pleura biopsy
Lymphnode aspiration biopsy
Surgical biopsy
 Mediastinoscopy
 Parasternal mediastinotomy
(Stemmer)
 VATS
 Thoracotomy (10%↓)
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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
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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
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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 (<2 cm distal to the carinab 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
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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.
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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).
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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).
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Metastases
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Liver:
Bones:
Adrenals:
Brain:
CT, ultrasound, PET/CT
scintigraphy, CT, PET/CT
CT, ultrasound, PET/CT
MRI, CT
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Prognostic factors
 Poor performance status
 Karnofsky, WHO ECOG
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Weight loss, more than 10%
Elevated LDH
Elevated tumormarker (CEA, NSE, SCC)
Old age
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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
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Performance status
Karnofsky scale
100
90
80
70
Description
Normal; no complaints; no evidence of disease
Able to carry out normal activity; minor signs or symptoms
of disease
Normal activity with effort; some signs or symptoms of
disease
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
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Therapy of lung cancer
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Surgery
Radiotherapy
Radiochemotherapy
Chemotherapy
Molecular target therapy
Supportive treatment
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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)
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Surgery
 Absolute contraindications:
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haematogen metastases in the lungs
pleuritis carcinomatosa
III.b stage disease
multiplex distanti metastases
 Relative contraindications
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Surgery (20-25%)
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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
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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!
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Combination of
radio/chemotherapy
 Sequential
ChTRT
(ChTRTChT)
 Concomitant
ChT/RT
 Timing
- Induction: ChT ChT/RT
- Consolidation: ChT/RT ChT
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Chemotherapy
 Neoadjuvant treatment
 Before surgery IIIa stage
 Adjuvant treatment
 After surgery II-IIIa stage
 First-, second-, thirdline…..
 IIIb, IV stage
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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
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Second line treatment of NSCLC
 Chemotherapy
 Docetaxel monoterapy
 Pemetrexed monoterapy
 Adenoc.: EGFR mutation positivity/KRAS
negativity
 gefinitib, erlotinib
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Maintenance treatment
Klasszikus
kezelés
Elsővonalbeli
kezelés
Kezelési
szünet
Platina-alapú kettős
kombináció
(4–6 ciklus)
Diagnózis
CR/PR/SD
Új
megközelítés
Bevacizumab
Pemetrexed
ellotinib
Másod- és
többedvonalbeli
kezelés
PD
PD
PD-ig eltelt idő
megnyúlik
Fenntartó kezelés
Diagnózis
CR/PR/SD
PD
PD
Surgery in SCLC
 I/A-I/B: resection
 Postoperative chemotherapy
 Adjuvant irradiation in positive node status
 Induction chemohterapy
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
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
Molecular target therapy
 EGFR tirosin kinase inhibitors
 Erlotinib (Tarceva)
 Gefinitib (Iressa)
 afatinib
 Angiogenesis inhibitors (VEGF)
 Bevacizumab (Avastin)
 Alk-EML4 fusion gen inhibitor
 Crizotinib (Xalkori)
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Supportive treatment
 Pain control
 WHO suggestion
 Adverse events control
 Thrombosis prophylaxis
 Malignant pleural fluid treatment
 Bone metastases treatment
 Endobronchial palliation
 Nutrition
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WHO’s pain stairs (1986)
Strong opioid ± non opioid ± adjuvant
III.
Weak opioid ± non opioid ± adjuvant
II.
Non opioid ± adjuvant
I.
24h
24h
24h
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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
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Prognosis
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I. stage:
II. stage:
III.a stage:
III.b stage:
IV. stage:
55-80%
30-50%
10-30%
4%
1%
 Five year survival: 15-17%
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Thank you for your attention!