LUNG CANCER Dr Baak OyanUlu Yeditepe University Hospital

LUNG CANCER Dr. Başak Oyan-Uluç Yeditepe University Hospital Department of Medical Oncology

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

Epidemiology • Second most common tumor • 1 st 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

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

Etiology • Asbestos: – – crocidolite and amosite: Most carcinogenic Risk: 3 -4 x Isolation, pipe fitters, mining Asbestos and smoking: synergistic, risk 80 -90 x • 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

Smoking Facts • Risk related to: – age of smoking onset – amount smoked – gender – product smoked – depth of inhalation

Pathology • Small cell lung cancer (SCLC) (15%) – 95% central or hilar – Widespread disease at diagnosis – Hematogenous metastasis: brain, bone marrow, liver – Pleural effusions common

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

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

Where does it spread? • • • Lymph Nodes Brain Bones Liver Lung/Pleura Adrenal Gland • 40% of metastasis occurs in the Adrenal Gland

Symptoms • • • Cough Dyspnea Hemoptysis Recurrent infections Chest pain • Symptoms related to distant metastases – Pain – Organ-related • General Symptoms – Weight loss – Fatigue

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

Sympathetic pathway for pupillary innervation

Horner’s syndrome Ptosis Miosis Anhidrosis In dim light, the anisocoria is accentuated with the right pupil more miotic. The right upper lid is ptotic by 1. 5 mm.

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

Bronchoscopy

Bronchoscopy

Biopsy

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?

Evaluation of solitary pulmonary nodule Diagnostic strategy: 1. Maximize chance of detecting cancer 2. Minimize chance of performing a unnecessary thoracotomy if the nodule is benign Characteristics that define a solitary pulmonary nodule 1. 2. 3. 4. A peripheral lung mass <3 -4 cm Asymptomatic Physical examination: normal CBC, LFT: normal

Likelihood that a nodule is malignant - Clinical Features • Age: Risk increases with age <35 years 35 -39 years 40 -49 years 50 -59 years ≥ 60 years • Smoking history 2% 3% 15% 43% ≥ 50%

Likelihood that a nodule is malignant - Radiographic Features • Size (risk increases with size) < 3 mm 4 -7 mm 8 -20 mm >20 mm • 0. 2% 0. 9% 18% 50% Border Growth (Volume doubling time) <20 days 20 -400 days >400 days • <1% 30 -50% <1% Ground glass appearance – – Malignant: <147 Hounsfield units (HU) – Benign: >167 HU • Calcification Malignant: More irregular and spiculated borders • • Density Frequently malignant (40 -60%) – Eccentric: carcinoma arising in an old granulomatous lesion (ie, a "scar" carcinoma) – Benign calcifications • “Popcorn" calcification • Laminated (concentric) calcification • Central calcification • Diffuse, homogeneous calcification

Evaluation of solitary pulmonary nodule • Serial CT scans • Metabolic imaging (PET/CT) • Nodule sampling – Bronchoscopy – Percutaneous needle aspiration

SPN algorithm

Management of lung cancer 1. Accurate diagnosis a. SCLC b. NSCLC 2. Staging 3. Selection of treatment modality

Staging • • • Bone scan Spinal MRI Brain CT or MRI Mediastinoscopy PET, PET/CT Bone marrow aspiration and biopsy

NSCLC • 80% of all lung cancers are NSCLC • Survival is improved when found at an early stage • Three distinct types of NSCLC • Treatments are the same

Staging and Treatment of NSCLC -Simplified

NSCLC Stage I 2 cm T 1 Ia N 0 M 0 T 2 Ib N 0 M 0 Any of the following: T > 3 cm T 3 cm No lobar bronchus involvement N 0: no lymph node involvement M 0: no distant metastasis T= main bronchial involvement 2 cm distal to carina T + visceral pleural involvement T + distal atelectasis

NSCLC 2 cm Stage II IIa T 1 N 1 M 0 T 2 IIb N 1 M 0 T 3 N 0 M 0 Any of the following: T+ main bronchial involvement < 2 cm distal to carina T (any size) invading chest wall, diaphragm, mediastinal pleura, or pericardium T + total atelectasis N 1: ipsilateral peribronchial and/or ipsilateral hilar nodes involved M 0: no distant metastasis

NSCLC 2 cm Stage IIIa <2 cm T 3 N 1 N 2 M 0 T 2 T 1 T 2 N 2 M 0 T 3 cm OR T chest wall (or diaphragm) OR T + visceral pleura involved OR T mediastinal pleura (or pericardium) OR T + atelectasis T 3 cm No lobar-bronchus involvement N 1: ipsilateral peribronchial and/or ipsilateral hilar nodes involved N 2: ipsilateral mediastinal and/or subcarinal nodes involved M 0: no distant metastasis

NSCLC - Stages at Presentation 7% Stage II 31% Stage III 24% Stage I 38% Stage IV Fry WA, et al. Cancer. 1996; 77: 1949 -1995.

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)

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)

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 (N 3) Contralateral mediastinal lymph nodes (N 2) Recurrent laryngel nerve Tracheal wall Main stem bronchus <2 cm from carina (resectable by sleeve resection technique)

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

Prognosis • TNM staging • Performance status • Weight loss • Tumor histology: not influence prognosis • Molecular prognostic factors – Supressor oncogene alterations: poor prognosis – Mutated p 53: 50% in NSCLC, in almost all with SCLC – Dominant oncogene overexpression (c-mys, k-ras, erb-B 2): poor prognosis

Survival Stage I II IIIa IIIb IV 5 -year Survival 60 -80% 40 -50% 25 -30% 5 -10% <1%

SCLC • Most aggressive type of lung cancer • Responds to chemotherapy and radiation • Recurrence rates are high

Staging of SCLC • Limited Stage Tumor is in one lung, the mediastinum and lymph nodes that can be radiated using a single radiation port. • Extensive Stage Tumor 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.

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

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%

Complications • Treatment related: – Chemotherapy – Radiotherapy – Infection • Disease related – – Superior vena cava syndrome Brain metastasis Carcinomatosis leptomeningitis Paraneoplastic syndromes

What are Paraneoplastic Syndromes? • Heterogeneous group of disorders • Cause symptoms independent of: – Tumor invasion/metastasis – Infection – Ischemia – Metabolic/nutritional deficits – Tumor treatment

Mechanism

Paraneoplastic Syndromes • • • Cancer cachexia Fatigue Electrolyte dysfunction Endocrine dysfunction Neurological dysfunction* Cutaneous lesions* Hematological dysfunction Coagulation dysfunction Fever Hepatic dysfunction Renal dysfunction

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, bisphonates

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.

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

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

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

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

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

Targeted Therapies in NSCLC • EGFR Inhibitors – Gefitinib (Iressa) – Erlotinib (Tarceva) • EGFR Monoclonal antibodies – Cetuximab (Erbitux) • VEGF Monoclonal antibodies – Bevacizumab (Avastin, Altuzan)

Targeted Therapies Bevacizumab Cetuximab PI 3 K Erlotinib Gefitinib Chemotherapy Inhibition of programmed cell death (apoptosis) Tumor cell proliferation Tumor cell invasion metastasis Development of tumor vasculature (angiogenesis)

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