Download - LUNG CANCER Dr. Başak Oyan-Uluç Yeditepe University Hospital Department of Medical Oncology
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LUNG CANCER
Dr. Başak Oyan-Uluç Yeditepe University Hospital
Department of Medical Oncology
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Lung Cancer
• Uncontrolled growth of malignant cells in one or both lungs and tracheo-bronchial tree
• A result of repeated carcinogenic irritation causing increased rates of cell replication
• Proliferation of abnormal cells leads to hyperplasia, dysplasia or carcinoma in situ
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Epidemiology
• Second most common tumor • 1st cause of cancer deaths• In USA: Decreasing incidence and deaths in
men; continued increase in women
• Women are more prone to tobacco effects 1.5 times more likely to develop lung cancer than men with same smoking habits
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Etiology
• Smoking– Cause of 90% of lung cancers– Increase risk 30 times – Cumulative dose important (pack-years) – Cigars, pipes: increase risk 2 times – Chewing tobacco– >20 packs-year: 1/7 die from lung cancer– Incidence diverge from nonsmoking population at 10 packs-year.– Passive smoking: increases risk 2 fold, cause in 17% of lung
cancers in non-smokers
– Other tumors caused by smoking: Oral cavity, esophagus, larynx, bladder, renal, pancreas, cervical
• Radiation exposure: – Increase risk of small cell lung cancer (SCLC)– Radon: assosiated with 6% of lung cancer
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Etiology• Asbestos:
– crocidolite and amosite: Most carcinogenic– Risk: 3-4x– Isolation, pipe fitters, mining– Asbestos and smoking: synergistic, risk 80-90x
• Other substances: Arsenic, nickel, chromium, chlomethyl ether, air pollutants
• Lung cancer: – Increased risk of a second lung cancer– Other cancers of upper aerodigestive tract also increased FIELD
CANCERIZATION
• Other lung diseases– Lung scars: tuberculosis, Scleroderma- bronchoalveolar cancer
• Genetic factors: – High metabolizers of debrisoquine– Lack of µ class phenotype of glutathione transferase
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Smoking Facts
• Risk related to:– age of smoking onset– amount smoked – gender– product smoked – depth of inhalation
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Pathology
• Small cell lung cancer (SCLC) (15%)– 95% central or hilar– Widespread disease at diagnosis– Hematogenous metastasis: brain, bone
marrow, liver– Pleural effusions common
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Pathology
• Non-small cell lung cancer (NSCLC) (85%)– Adenocarcinoma (50-60 % of NSCLC)
• Most common cell type occurring in non-smokers• Spread widely outside thorax by hematogenous dissemination• Bronchoalveolar carcinoma:
– Spreading pattern within bronchioles without evidence of invasion– Radiology: Infiltrative, frequently multicentric– More frequently in young, female nonsmokers
– Squamous cell (20-25% of NSCLC)• Central location• Most likely to be localized early in disease
– Large cell – Mix type
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Uncommon tumors of the lung
• Bronchial carcinoids• Cystic adenoid carcinomas• Carcinosarcomas• Mesotheliomas
– Caused by exposure of asbestosis– Occur in lung, pleura, peritoneum, tunica
vaginalis or albeuginea of testis– Spreads rapidly over pleura, encases lung
parenchyma
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Where does it spread?
• Lymph Nodes• Brain• Bones• Liver• Lung/Pleura• Adrenal Gland
• 40% of metastasis occurs in the Adrenal Gland
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Symptoms
• Cough• Dyspnea• Hemoptysis• Recurrent infections• Chest pain
• Symptoms related to distant metastases– Pain– Organ-related
• General Symptoms– Weight loss– Fatigue
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Syndromes/Symptoms secondary to regional metastases
• Esophageal compression Dysphagia
• Laryngeal nerve paralysis Hoarseness
• Symptomatic nerve paralysis Horner’s syndrome
• Cervical/thoracic nerve invasion Pancoast syndrome
• Lymphatic obstruction Pleural effusion
• Vascular obstruction SVC syndrome
• Pericardial/cardiac extension Effusion, tamponade
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Sympathetic pathway for pupillary innervation
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Horner’s syndrome
In dim light, the anisocoria is accentuated with the right pupil more miotic. The right upper lid is ptotic by 1.5 mm.
PtosisMiosisAnhidrosis
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Diagnosis
• History and Physical exam• Diagnostic tests
– Chest x-ray– Pathological evaluation by:
• Sputum cytology• Flexible fiberoptic bronchoscopy• Percutanous and transbronchial needle biopsy• Lymph node metastases
• Staging tests– CT chest/abdomen– Bone scan– Bone marrow aspiration– PET scan
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Bronchoscopy
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Bronchoscopy
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Biopsy
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Solitary pulmonary nodule (SPN)
• A lesion that is both within and surrounded by pulmonary parenchyma
• Size: < 3-4 cm
• The major question that follows detection of a SPN: Whether the lesion may be malignant?
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Evaluation of solitary pulmonary nodule
Diagnostic strategy: 1. Maximize chance of detecting cancer2. Minimize chance of performing a unnecessary
thoracotomy if the nodule is benign
Characteristics that define a solitary pulmonary nodule
1. A peripheral lung mass <3-4 cm2. Asymptomatic3. Physical examination: normal4. CBC, LFT: normal
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Likelihood that a nodule is malignant
- Clinical Features -
• Age: Risk increases with age<35 years 2%
35-39 years 3%
40-49 years 15%
50-59 years 43%
≥ 60 years ≥50%
• Smoking history
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Likelihood that a nodule is malignant- Radiographic Features -
• Size (risk increases with size)< 3 mm 0.2%4-7 mm 0.9%8-20 mm 18%>20 mm 50%
• BorderMalignant: More irregular and
spiculated borders
• Growth (Volume doubling time)<20 days <1%20-400 days 30-50%>400 days <1%
• Ground glass appearance – Frequently malignant (40-60%)
• Density– Malignant: <147 Hounsfield
units (HU)
– Benign: >167 HU
• Calcification– Eccentric: carcinoma arising
in an old granulomatous lesion (ie, a "scar" carcinoma)
– Benign calcifications• “Popcorn" calcification • Laminated (concentric)
calcification• Central calcification• Diffuse, homogeneous
calcification
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Evaluation of solitary pulmonary nodule
• Serial CT scans
• Metabolic imaging (PET/CT)
• Nodule sampling – Bronchoscopy – Percutaneous needle aspiration
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SPN algorithm
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Management of lung cancer
1. Accurate diagnosisa. SCLC
b. NSCLC
2. Staging
3. Selection of treatment modality
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Staging
• Bone scan
• Spinal MRI
• Brain CT or MRI
• Mediastinoscopy
• PET, PET/CT
• Bone marrow aspiration and biopsy
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NSCLC
• 80% of all lung cancers are NSCLC
• Survival is improved when found at anearly stage
• Three distinct types of NSCLC
• Treatments are the same
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Staging and Treatment of NSCLC-Simplified
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NSCLC Stage I
2 cm
N0: no lymph node involvementN0: no lymph node involvementM0: no distant metastasisM0: no distant metastasis
No lobarbronchusinvolvement
T 3 cm
IaIaT1T1 N0N0 M0M0
IbIbT2T2 N0N0 M0M0
T >3 cm
T + visceral pleuralinvolvement
T + distal atelectasis
Any of the following:
T= main bronchial involvement
2 cm distal to carina
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2 cmNSCLCStage II
N1: ipsilateral peribronchial and/or ipsilateral hilar nodes involvedN1: ipsilateral peribronchial and/or ipsilateral hilar nodes involvedM0: no distant metastasisM0: no distant metastasis
IIaIIa
T1T1 N1N1 M0M0
IIbIIbT2T2 N1N1 M0M0
T + total atelectasis
T3 N0 M0
Any of the following:
T+ main bronchial involvement < 2 cm distal to carina
T (any size) invading chest wall, diaphragm, mediastinal pleura, or pericardium
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NSCLC Stage IIIa
T3T3 N1N1 M0M0T3T3 N2N2 M0M0
T1 T1 N2N2 M0M0T2T2 N2N2 M0M0
N1: ipsilateral peribronchial and/or ipsilateral hilar nodes involvedN1: ipsilateral peribronchial and/or ipsilateral hilar nodes involved
N2: ipsilateral mediastinal and/or subcarinal nodes involvedN2: ipsilateral mediastinal and/or subcarinal nodes involved
M0: no distant metastasisM0: no distant metastasis
<2 cm 2 cm
OR
OR
OR
OR
T2
T chest wall(or diaphragm)
T mediastinal pleura (or pericardium)
T 3 cm
T + visceral pleura involved
T + atelectasis
T 3 cmNo lobar-bronchus involvement
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Fry WA, et al. Cancer. 1996;77:1949-1995.
31%31%Stage IIIStage III
31%31%Stage IIIStage III
38%38%Stage IVStage IV
38%38%Stage IVStage IV
24%24%Stage IStage I
24%24%Stage IStage I
7%7%Stage IIStage II
7%7%Stage IIStage II
NSCLC - Stages at Presentation
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Management of NSCLC
• Staging to determine resectability (tumor can be surgically removed with clear margins)
• Patient evaluation for operability (patient is capable of withstanding such a procedure)
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Management of NSCLC
• Surgery: Mainstay of treatment– Primary mode of therapy in stage I and II– Resectability: determined by extent of tumor– Operability: Overall medical condition of patient
– ½ of NSCLC patients: operable– ½ of tumors in operable patients are resectable (25%
of all patients)– ½ of patients with resectable tumors survive 5 years
(12% of all patients, 25% of operable patients)
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Determinants of resectable disease: Signs of unresectable NSCLC
• Distant metastases, including metastases to opposite lung
• Persistant pleural effussions with malignant cells– Cytological examination: positive for malgnant cells in 65%
• Superior vena cava obstruction
• Involvement of following structures:– Supraclavicular and neck lymph nodes (N3)– Contralateral mediastinal lymph nodes (N2)– Recurrent laryngel nerve– Tracheal wall– Main stem bronchus <2 cm from carina (resectable by sleeve
resection technique)
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Determinants of operability: Signs of inoperability
• Age and mental status: not factors
• Cardiac status– Uncontrolled cardiac failure– Uncontrolled arrhytmia– Recent myocardial infarction (within 6 months)
• Pulmonary status: the patients ability to tolerate resection of part of or all of a lung must be determined – Pulmonary hypertension– Inadequate pulmonary reserve
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Prognosis
• TNM staging• Performance status
• Weight loss• Tumor histology: not influence prognosis• Molecular prognostic factors
– Supressor oncogene alterations: poor prognosis – Mutated p53: 50% in NSCLC, in almost all with
SCLC– Dominant oncogene overexpression (c-mys, k-
ras, erb-B2): poor prognosis
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Survival
Stage 5-year Survival
I 60-80%
II 40-50%
IIIa 25-30%
IIIb 5-10%
IV <1%
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SCLC
• Most aggressive type of lung cancer
• Responds to chemotherapy and radiation
• Recurrence rates are high
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Staging of SCLC
• Limited StageTumor is in one lung, the mediastinum and lymph nodes that can be radiated using a single radiation port.
• Extensive StageTumor has spread beyond one lung, the mediastinum and local lymph nodes.
Common distant sites of metastases are the adrenals, bone, liver, bone marrow, and brain.
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Management of SCLC
Limited stage: • Radiotherapy and concomitant chemotherapy• Prophylactic brain irradiation• Rarely: Surgery
• <5%: Stage I, II• 30%: stage IIIA, IIIB
Extensive stage: Chemotherapy
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SCLC: Survival
• Limited Disease:– Median survival 18-20 months– 5-year survival 10%
• Extensive Disease:– Median survival 10-12 months– 5-year survival 1-2%
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Complications
• Treatment related:– Chemotherapy– Radiotherapy– Infection
• Disease related– Superior vena cava syndrome– Brain metastasis– Carcinomatosis leptomeningitis– Paraneoplastic syndromes
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What are Paraneoplastic Syndromes?
• Heterogeneous group of disorders
• Cause symptoms independent of:– Tumor invasion/metastasis– Infection– Ischemia– Metabolic/nutritional deficits– Tumor treatment
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Mechanism
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Paraneoplastic Syndromes
• Cancer cachexia• Fatigue• Electrolyte dysfunction• Endocrine dysfunction• Neurological dysfunction*• Cutaneous lesions*• Hematological dysfunction• Coagulation dysfunction• Fever• Hepatic dysfunction• Renal dysfunction
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Most common paraneoplastic syndromes in lung cancer-1
• Hypercalcemia– Mostly in squamous cell carcinoma
• Hypertrophic osteoartropathy– Clubbing + periosteal proliferation of tubular bones– Associated with lung cancer and other lung disease– Clinically:
• Symmetrical painful arthropathy• Usually involves ankles, wrists and elbows• Metacarpal, metatarsal and phalangeal bones may also be
involved
– Tx: If inoperable tm NSAID, bisphosphonates
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Hypertrophic osteoartropathy
A) Side and B) top view of nail bed hypertrophy causing a distal enlargement of the fingers in a patient with lung cancer.
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Hypertrophic osteoartropathy
Bone scan showing diffuse uptake by the long bones in a patient with painful arthropathy and lung cancer.
Normal bone scan for comparison
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Most common paraneoplastic syndromes in lung cancer-2
• SIADH secretion– Mostly in SCLC– 10% of SCLC have SIADH– SCLC accounts for 75% of all malignancy
associated SIADH
• Cushing syndrome– Ectopic secretion of ACTH– Most common in SCLC and carcinoid tumors of
lung and extrathoracic malignancies– If present, prognosis worse
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Most common paraneoplastic syndromes in lung cancer-3
• Hematologic– Anemia– Leukocytosis
• Due to overproduction of G-CSF (Granulocyte-colony stimulating factor
• Nearly all in NSCLC
– Thrombocytosis– Eosinophilia
• In large cell carcinoma
– Hypercoagulable disorders• Trousseau’s syndrome (migratory superficial thrombophlebitis)
• Deep vein thrombosis and thromboembolism
• Disseminated intravascular coagulopathy
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Most common paraneoplastic syndromes in lung cancer-4
• Neurologic– Lung cancer is the most common cancer associated with
paraneoplastic neurological syndromes
– Typically associated with SCLC
– Immune-mediated
– Lambert Eaton myasthenic syndrome• Most in SCLC• In >80%: precede diagnosis of SCLC often by months to years
Cerebellar ataxia
Sensory neuropathy
Limbic encephalitis
Autonomic neuropathy
Retinopathy
Opsoclonus
– Generally not improve with immunosuppressive treatment
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Most common paraneoplastic syndromes in lung cancer-5
• Dermatomyositis and polymyositis– Inflammatory myopathy– Clinically muscle weakness– Presenting symptom or develop later in the course of
disease– In lung cancer, also in ovary, cervix, pancreas, bladder,
stomach
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Targeted Therapies in NSCLC
• EGFR Inhibitors– Gefitinib (Iressa)– Erlotinib (Tarceva)
• EGFR Monoclonal antibodies– Cetuximab (Erbitux)
• VEGF Monoclonal antibodies– Bevacizumab (Avastin, Altuzan)
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Targeted Therapies
ErlotinibGefitinib
Bevacizumab
Chemotherapy
Inhibition of programmed cell death (apoptosis)
Tumor cell proliferation
Tumor cell invasion
metastasis
Development of tumor vasculature
(angiogenesis)
Cetuximab
PI3K
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Conclusion
• Lung cancer is the leading cause of cancer deaths.
• Only prevention: Not smoking
• Most diagnosed at advanced stage
• Overall 5-year survival rate: 15%
• Treatment depends on histology and stage