Lung cancer
O. Bílek, S. Bořilová, P. Grell
Lung cancer/Lung carcinoma
 Malignant tumor of lung tissue and bronchi of diverse
molecular character
 Incidence in Czech republic: 42,9/100,000 females,
86,2/100,000 males
 The most common age at diagnosis is between 50 – 80
years
 In Czechia
 6,700 new cases of lung cancer per year
 5,300 deaths per year
 The deadliest cancer worldwide in both genders
 accounting for 24% in males and 15% in females
 !AND THERE IS STILL NO SCREENING PROGRAME!
Incidence and mortality of lung cancer
in Czech republic
Incidence: males females
Mortality: males females
Source: National
oncological register
Siegel R, Ma J, Zou Z, Jemal A. Cancer
statistics, 2014. CA Cancer J Clin. 2014
Jan;64(1):9-29
Ten leading cancer types, USA, 2014
Histopathological types of lung cancer
Small cell lung
cancer (SCLC) 15%
Squamous cell
carcinoma 35% Adenocarcinoma
45%
Large cell
carcinoma 15%
Others 15%
• mixed (adenosquamous)
• sarcomatoid carcinoma
Non-small cell lung
cancer (NSCLC) 85%
Lung cancer
NSCLC is still mostly diagnosed in advanced stage
Incidence of histological types according
to sex
Risk factors
 Endogenous
 Genetic (p53), ⇡P450, ⇣ glutathione S transferase
 Exogenous
 Tobacco smoking
 by far the leading risk factor for lung cancer
 Others
 Asbestos
 Arsenic
 Ionizing radiation
 Nickel
Signs and symptoms
 Patients are often diagnosed in advanced stage of disease
 Symptoms not present in early stage
 Symptoms due to primary tumor
 Cough in 80 % patients (patient with 3 weeks lasting cough should
be checked for lung cancer)
 Dyspnea
 Hemoptysis
 Chest pain
 Pneumonia
 ! ALWAYS PERFORM A CONTROL CHEST X-RAY AFTER PNEUMONIA !
Signs and symptoms
 Symptoms due to thoracic extension of tumor
 Hoarseness (recurrent laryngeal nerve paralysis)
 Dysphagia
 Chest pain
 Vena cava superior syndrome
 cyanosis
 fixed raised internal jugular veins
 swollen face, arms
 prominent superficial veins throughout the chest wall
 Symptoms due to metastases
 lymph nodes enlargement, bone pain, neurologic deficit (often brain metastases)
 Systemic symptoms
 anorexia, weakness, weight loss
 paraneoplastic symptoms: fever, SIADH, hypercalcemia, gynecomastia, hypoglycemia
How is lung cancer diagnosed?
Imaging tests
Small cell lung
cancer of
right lung
Adenocarcinoma of
upper right lobe,
pleural infiltration,
massive pleural
effusion
Chest X-ray
CT scan (HRCT)
Lung cancer of the right lung.
Patient underwent surgery.
PET/CT
Adenocarcinoma of left hilum.
Pathological mediastinal lymph nodes
Bone scan
Lung adenocarcinoma
Bone metastases of ilium bone
Bronchoscopy
 Rigid/Flexible
 Diagnostic
 Description of tumor macroscopic morphology
 Biopsy
 Enough biological material for mutational analysis
 Cytology (brushing) is not enough!
 Therapeutic
 clearing the obstruction of bronchi
 laser resection
 stent insertion
 acute treatment: bleeding, foreign object
NO! YES!
Tissue collection for histology analysis
and molecular testing
 Bronchoscopy
 collect enough material
 cytology is not enough!
 Endobronchial ultrasound (EBUS)
 biopsy through bronchial wall under ultrasound control
 Percutaneous biopsy under CT control
 fine needle biopsy
 Surgery
 Endoscopic surgery
 mediastinoscopy
 video-assisted thoracoscopic surgery (VATS)
 Open thoracotomy
EBUS
VATS
Fine needle
biopsy
Laboratory examination
 Tumor tissue
 Morphology - cytology, histology
 Immunohistochemistry (IHC) – specific antibodies
 Molecular testing
 Blood samples
 Tumor markers
 CEA: adenocarcinoma
 NSE: small cell carcinoma
 SCC, CYFRA 21-1: squamous cell carcinoma
 Liquid biopsy
 blood samples, mutation analysis of extracellular DNA (cfDNA)
FISHHE
IHC
How to manage an excellent staging?
 Chest X-ray
 mostly negative! insufficient for staging!
 CT scan
 Spiral chest CT or HRCT better for interstitial lung disease or small lung lesions
 Abdominal CT - to complete staging and to rule out metastases
 PET/CT
 To rule out metastases and to determinate malignant lymph nodes before surgery!
 Bone scan
 To determinate bone lesions, mainly useful in adenocarcinomas
 Brain scans
 consider CT, MRI or PET/CT if curative treatment is planned or patient is symptomatic
 Bronchoscopy
 in centrally situated tumors
Non – small cell lung cancer
(NSCLC)
Staging of NSCLC – TNM classification
 Tumor
 Tumor size
 Endobronchial location
 Atelectasis/pneumonitis
 Visceral pleura invasion
 Invasion of peripheral/central structures
 Nodus lymfaticus
 Metastasis
 M1a thoracic metastases,
pericardial/pleural effusion
 M1b solitary extrathoracic metastasis
 M1c multiple extrathoracic metastases
Treatment according to clinical stage
 Stage I–IIIA: local + systemic treatment
 Surgery
 Video-assisted thoracoscopic surgery (VATS)
 Open thoracotomy
 Adjuvant chemotherapy (from stage IB)
 Radiotherapy+/-chemotherapy
 when surgery is not indicated
 studies with immunotherapy in adjuvant setting
 Stage IIIB–IV – systemic treatment
 Chemotherapy
 Tyrosine kinase inhibitors
 Immunotherapy
 Radiotherapy
 definitive radiotherapy in IIIB stage
 palliative radiotherapy on metastatic lesion
Types of
resection
Odpověď na
single- agent
chemoterapii
Gemcitabin
Taxans
Vinorelbin
Cisplatin
prolonged OS in
advanced NSCLC
Evolution of systemic treatment of NSCLC
Docetaxel for
2. line of
treatment
Target therapy
Gefitinib in EGFR
mutation
Pemetrexed
for 2.line of
treatment
Erlotinib for
2. line of
treatment
Bevacizumab
(anti VEGF),
combination with
chemotherapy
Discovery of
EML4-ALK
translocation
Gefininib for 1.
line treatment
NSCLC EGFR+
Crizotinib for
ALK+ NSCLC
Immunotherapy
anti-PD-1, anti-PDL-1, anti
CTLA4 antibodies
Afatinib a
Erlotinib for 1.
line of treatment
NSCLC
Nivolumab,
pembrolizumab
for 2. line of
treatment
Pembrolizu
mab for 1.
line of
treatment
Crizotinib for ROS-1
mutation
Alectinib for ALK+
NSCLC
Osimertinib
for T790M+
Cisplatin/pemetrexed
for 1. linie of
treatment (adenoca)
Single- agent
chemotherapy
Systemic treatment of NSCLC
Chemotherapy for NSCLC
 Platinum - based chemotherapy
 The foundation of systemic treatment for lung cancer
 Cisplatin, carboplatin
 Other chemotherapies
 Used in monotherapy or in combination with platinum based
chemotherapy
 Taxanes - paclitaxel, docetaxel
 Antimetabolites – gemcitabin, pemetrexed
 Vinca alkaloids - vinorelbine
Target therapy for NSCLC
Personalised medicine
Prognostic markersMolecular profiling
EGFR mutation and its inhibition
• Tyrosine kinase domain
• Therapeutic target of
tyrosine kinase inhibitors
Transcription
Proliferation
Metastasize
AngiogenesisCell survival
 Responsible for approximately
15 % of NSCLC (adenocarcinoma)
 Investigated also from liquid
biopsy
 Treatment - Tyrosine kinase
inhibitors (TKI)
 1st generation of TKI
 Gefinitib
 Erlotinib
 2nd generation of TKI
 Afatinib
 3rd generation of TKI
 Osimertinib
ALK (anaplastic lymphoma kinase)
mutation
 EML-4/ALK fusion gene
 Responsible for approximately
3-5 % of NSCLC
 Therapy of ALK+ NSCLC
(Tyrosine kinase inhibitors)
 1st generation
 Crizotinib
 2nd generation
 Ceritinib
 Alectinib
 3rd generation
 Lorlatinib
Similar consequences like
EGFR mutation
Other target therapy
 1. ROS-1 mutation
 Occurs in 1-2 % of lung
adenocarcinoma
 Treatment – Tyrosine kinase inhibitors
(TKI)
 similar to treatment of ALK+ tumors
 crizotinib, lorlatinib
 2. Anti-VEGF therapy (Bevacizumab)
 monoclonal antibody
 inhibition of vascular endothelial
factor (VEGF)
 combination with first-line palliative
chemotherapy
VEGF
Immunotherapy – checkpoint inhibitors
 Immune checkpoints
 key regulators of the immune system
 stimulation of checkpoints can diminish the immune
response to an immunologic stimulus
 Inhibition of PD-1/PDL-1
 restores T- lymphocytes antitumor immunity
 Anti PD-1/PDL-1 antibodies
 anti PD-1 monoclonal antibody
 pembrolizumab, nivolumab
 – standard treatment in Czech republic
 durvalumab
 anti PDL-1 monoclonal antibody
 atezolizumab/avelumab
Immunotherapy – checkpoint inhibitors
 Benefits
 New unique mechanism of action
 Great therapeutic potential
 Pitfalls
 Does not work in every cancer and every
patient
 predictive biomarkers are needed
 Immune-related adverse effects
 similar to autoimmune diseases
 can affect any organ
Small cell lung cancer
 Highly aggressive cancer type
 Median overall survival without treatment is 3 months
 for extensive disease 7 weeks
 The etiology is strongly linked with smoking
 TNM classification is identical with TNM for NSCLC in
early stages
 ! BUT early stages are rare!
 Therefore we used a different classification
 Limited disease: tumor limited to lungs and mediastinum with
radiotherapy treatment possibility
 Extensive disease (70 %): does not fulfill the conditions for
limited disease
Small cell lung cancer - treatment
 Surgery
 only exceptions, really rare
 Chemotherapy
 platinum – based chemotherapy + etoposide
 Radiotherapy
 for limited disease
 palliative radiotherapy for symptomatic metastases (bones, brain)
 more than 50 % patients have brain metastases
 prophylactic cranial radiotherapy
 Immunotherapy
 only within studies
BUT!!!
• not always is our
treatment this
effective
• majority of patients
are not fit enough to
start treatment
• only 50 % of patients
will start oncological
treatment
Miraculous improvement with target
therapy Before
treatment
After 6 weeks of
EGFR TKI
After 4 weeks of
ALK TKI
Take home message
 Highly heterogenous disease with various biological characteristics
 Efforts for early diagnosis
 KEEP THAT IN MIND in differential diagnosis!
 Reduction of risk factors – mainly smoking!
 Introduction of screening programe for smokers?
 There are new therapeutic aims (EGFR, ALK, ROS-1, PD-1)
 fundamentally changed therapeutic results and patient's quality of life
 in every NSCLC (mainly adenocarcinoma) we should automatically investigate EGFR,
ROS1, ALK, PDL-1
 Challenges
 To overcome resistance to target therapy
 New therapeutic targets (RET, MET and others)
 Search for predictive markers for immunotherapy
Thank you for your
attention!