Post on 07-Jan-2020
Lung Tumors
Internal Medicine - Pneumology Lecture #3 General Medicine ELP
Assoc. Prof. Robert Vyšehradský, M.D., PhD. Clinicic of Pneumology & Phthisiology
Simplified Classification of Lung Tumors
• Epithelial tumors – Adenocarcinoma
– Squamous cell carcinoma
– Neuroendocrine tumors • Small cell carcinoma
• Carcinoid (typical, atypical, tumourlets)
– Large cell carcinoma
– Adenosquamous carcinoma
– Sarcomatoid carcinomas
– Salivary gland-type tumors • Papillomas
• Adenomas
• Mesenchymal tumors – Hamartoma – Chondroma – Perivascular epithelioid cell
tumors • Lymphangioleiomyomatosis
– Sarcomas • Lymphohistiocytic tumors
– Lymphomas – Lymphomatoid
granulomatosis – Pulmonary Langerhans cell
histiocytosis • Tumors of ectopic origin • Metastatic tumors
Lung Cancer
• the most common cancer in men
• the third most common cancer in women
• one of the most aggressive cancers
• 5-year overall survival of 10–15%
Burdens of Lung Cancer Estimated world cancer incidence proportions, 2012
Lung 17%
Prostate 15%
Colorectum 10% Stomach
9%
Liver 7%
Bladder 4%
Oesophagus 4%
NHL 3%
Kidney 3%
Other 28%
Men
Breast 25%
Colorectum 9%
Lung 9%
Cervix uteri 8%
Stomach 5%
Corpus uteri 5%
Ovary 4%
Thyroid 3%
Liver 3%
Other 29%
Women
Epidemiology
• 1.8 mil. new cases annually = 13% of total cancer incidence
• 1.6 mil. deaths annually = 20% of total cancer mortality
Global distribution of estimated age-standardized incidence rates (ASR) per 100 000, 2012. men women
Epidemiology - trends Age-standardized incidence rates per 100 000 by year in selected populations, 1975–2012. men women
Etiology
Exogenous risk factors • tobacco smoking – 90%
• arsenic, metals, fibres, dusts
• organic compounds (painters, rubber industry)
• radon
• household combustion of coal
• β-carotene supplements, fruits and foods containing carotenoids
Exogenous risk factors 2
Factor Relative risk
Environmental tobacco smoke 1.2
Asbestos (risk proportional to dose) 1.0–5.0
Radon gas (granite rock) 1.2
Diesel fumes (occupational) 1.3
Silicosis 2.5–3.2
Family history (especially women) <50 yr 2–4
Gender (women at greater risk) 1.2–1.7
COPD 2.7–5.0
Radon Level World
Endogenous risk factors
• 5p15
• 6p21
• 15q25 (14% attributable risk)
genes regulating NACCHr and telomerase production
Micromorphological types
SCLC 15-20%
Adeno 40-50%
Squamous 25-40%
Large cell 3-5%
NOS <5%
NSCLC 80-85%
Driver mutations
mutation molecularly targeted drug
Adenocarcinoma EGFR, HER2 (ERBB2), KRAS, ALK, BRAF, PIK3CA, and ROS1
available
Small cell carcinoma
TP53 and RB1 (100%) no
Squamous cell carcinoma
without specific molecular abnormalities but 50% have genetic alterations that are potential molecular targets: TP53, CDKN2A (P16), PTEN, PIK3CA, KEAP1, and MLL2
in development
Driver mutations in adenocarcinoma smokers vs nonsmokers
smokers never-smokers
EGFR mutation 14% 38%
ALK translocation 2% 12%
Clinical symptoms Vague, non-specific, late onset
Symptoms and signs Range of frequency (%) Cough 8–75 Weight loss 0–68 Dyspnoea 3–60 Chest pain 20–49 Haemoptysis 6–35 Bone pain 6–25 Clubbing 0–20 Fever 0–20 Weakness 0–10 Superior cava vein sy. 0–4 Dysphagia 0–2 Wheezing and stridor 0–2
Physical findings
• Non-specific!
• Signs of complications (airways obstruction, pneumonia, pleural effusion, lung collapse).
• General cancer symptoms (cachexia, anemia...)
• Signs of extrathoracic spread (extrathoracic lymphadenomegaly, Bernard-Horner sy., SCV sy., intracranial hypertension, neurological symptoms, hepatomegaly, bone fracture, skin metastasis).
• Paraneoplastic syndromes.
Paraneoplastic syndromes Secreted peptide or hormone
Mechanism Clinical presentation
Vasopressin antidiuretic hormone, ADH)
Low serum sodium
Weakness, blackouts
Adrenocorticotrophin (ACTH)
High cortisol Cushing’s syndrome
Atrial natriuretic peptide (ANP)
Low serum sodium
Weakness, blackouts
Granulocyte colony stimulating factor (G-CSF)
High WBC Asymptomatic
Paraneoplastic encephalomyelitis /sensory neuropathy
Anti-Hu antibodies
Sensory neuropathy, cerebellar ataxia, pseudo-obstruction
Lambert Eaton myasthenic syndrome (LEMS)
Voltage-gated calcium channel antibodies
Proximal muscle weakness, autonomic symptoms
Physical findings
Work-up
• Micromorphology
• Staging
• Biomarkers
• Assessment of fitness for surgery
• Investigation for CHT, RT
Micromorphology • Bronchoscopy: Narrow Band Imaging (NBI),
brushig, forceps biopsy, perbronchial needle aspiration, kryobiopsy, endobronchial ultrasound (EBUS).
• Perthoracic needle biopsy (CT-guided, ultrasound-guided).
• Sputum cytology.
• Pleural fluid cytology.
• Surgical biopsy (resection).
• Distant metastasis biopsy.
• Liquid biopsy?
Staging procedures
T – Bronchoscopy: localization in the bronchial tree. – CT: size, localization, involvement of the adjacent
structures.
– CT: localization and size of intrathoracic LN – EBUS: micromorphology – Mediastinoscopy/thoracoscopy: micromorphology – PET/CT – specificity of 85%
N
Abdominal ultrasound + according to symptoms
M
NSCLC
Abdominal ultrasound Bone scintigraphy Brain imaging? + according to symptoms
NSCLC
Simplified TNM
T
Tis In situ carcinoma
T1 ≤3 cm, no more proximal than the lobar bronchus
T2 >3 cm ≤7 cm or: involves main bronchus, ≥2 cm distal to the carina; visceral pleura; atelectasis or obstructive pneumonitis
T3 >7 cm or invades: parietal pleura, chest wall, diaphragm, phrenic nerve, mediastinal pleura, pericardium; main bronchus <2 cm distal to the carina; nodule in the same lobe
T4 any size + mediastinal organs, vertebral body, carina, nodule(s) in a ipsilateral lobe
N
N0 No regional lymph nodes
N1 Ipsilateral peribronchial and/or hilar LN
N2 Ipsilateral mediastinal and/or subcarinal LN
N3 Contralateral mediastinal or hilar, scalene, or supraclav. LN
M M0 No distant metastasis
M1 Distant metastasis
Simplified staging Occult TX N0 M0
0 Tis N0 M0
IA T1 N0 M0
IB T2a N0 M0
IIA T2b N0 M0
T1-2a N1 M0
IIB T2b N1 M0
T3 N0 M0
IIIA T1-3 N2 M0
T3-4 N1 M0
T4 N0-1 M0
IIIB T1-3 N3 M0
T4 N2-3 M0
IV Any T Any N M1
Lung cancer metastasis distribution autopsy data
Biomarkers
• SCCAg
• CYFRA21-1
• CEA
• NSE
Operability assessment
• Resecability – CT scan
– screening for distant metastasis (PET/CT? 20% of metastasis not detecable by CT).
• Operability: – overall status performance,
– comorbidities,
– lung function (spirometry, BGA, lung diffusion capacity, ergospirometry),
– cardiovascular ability (echocardiography, possibly ergometry, coronarography).
Investigation for CHT, RT
• BUN, creatinine clearance, CBC, liver enzymes
• EGFR, ALK, ROS1,
Treatment NSCLC
I, II N0 lobectomy
+ evaluation of LN
II N1(p)
IIIa N2a lobectomy, pneumonectomy
+ complete homolateral lymphadenectomy
IIIa N2b neoadjuvant
CHT
lobectomy + complete homolateral
lymphadenectomy
lobectomy, pneumonectomy + complete homolateral
lymphadenectomy ERT
ERT
concomitantCHT Pt+ERT
ERT
IIIb
induction CHT Pt
induction CHT Pt
ERT
IV CHT Pt+
biological treatment
adjuvant CHT
adjuvant CHT
adjuvant CHT
Treatment SCLC
LD
ED
lobectomy/pneumonectomy + complete
lymphadenectomy
concomitant CHT Pt+Etoposide, CAV
+ ERT
CHT Pt+Etoposide, CAV
adjuvant CHT
ERT
prophylactic brain irradiation
neoadjuvant CHT
T1,2 N0,1
Molecular targeted therapies Gene Histological type Therapy
EGFR mutation
Advanced adenocarcinoma
EGFR tyrosine kinase inhibitor Erlotinib, gefitinib
ALK fusion Adenocarcinoma Crizotinib
ROS1 fusion Advanced adenocarcinoma
Crizotinib
HER2 Adenocarcinoma Afatinib (BIBW 2992)
PI3KCA NSCLC Trastuzumab, PI3K inhibitor
BRAF NSCLC Sorafenib?
MET NSCLC Phase 2: rilotumumab (AMG 102), MetMAb
RAS Adenocarcinoma PI3K + MEK inhibitors
Immunotherapy
• checkpoint inhibitors - “taking the brakes off” the immune system: – PD-1/PD-L1 checkpoint inhibitors: nivolumab,
pembrolizumab, atezolizumab, durvalumab, (NSCLC) – CTLA-4 checkpoint inhibitors : ipilimumab, Ipilimumab
• monoclonal antibodies: bevacizumab, ramucirumab • therapeutic vaccines: to elicit an immune response
against tumor-specific antigens (MAGE-3 – 42%; NY-ESO-1 – 30%; p53 – 50%; survivin, MUC1).
• adoptive cell therapy: T cells removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient.
Supportive Care
• nausea
• pain
• fatigue
• shortness of breath
• cough
• nourishment
• emotional and spiritual problems
Prevention
• Low-dose CT
• Healthy individuals aged 55–79 years with at least a 30 pack-year history of smoking and who have smoked within the past 15 years
• Mortality reduction by 20%.
• Smoking cessation.
Smoking cessation
• 70% of smokers want to quit!
• Quit programmes cost € 890 per life-year saved (1998 data); lung cancer CHT is 25 times as expensive.
• Simple advice by a doctor = quit rate of 1–3%.
• Nicotine replacement = quit rate of 6–8%.
• Bupropion – improvement by 36%.
‘quitting smoking is the easiest thing in the world to do; I have done it several times.’
Prognosis
• Lung cancer accounts for 13% of all cancers and 20% of all cancer deaths.
• 5-year survival of 10–15%.
• 80% diagnosed with metastatic disease.
• >50% distant metastases.
Overall and five-year survival and median survival by stage for NSCLC
The impact of small-cell lung cancer (SCLC) treatment on survival