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 • 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

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: 3-4x– 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

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

In dim light, the anisocoria is accentuated with the right pupil more miotic. The right upper lid is ptotic by 1.5 mm.

PtosisMiosisAnhidrosis

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 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

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

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

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 diagnosisa. 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 anearly stage

• Three distinct types of NSCLC

• Treatments are the same

Staging and Treatment of NSCLC-Simplified

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

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

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

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

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 (N3)– Contralateral mediastinal lymph nodes (N2)– 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 p53: 50% in NSCLC, in almost all with

SCLC– Dominant oncogene overexpression (c-mys, k-

ras, erb-B2): poor prognosis

Survival

Stage 5-year Survival

I 60-80%

II 40-50%

IIIa 25-30%

IIIb 5-10%

IV <1%

SCLC

• Most aggressive type of lung cancer

• Responds to chemotherapy and radiation

• Recurrence rates are high

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.

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, bisphosphonates

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

ErlotinibGefitinib

Bevacizumab

Chemotherapy

Inhibition of programmed cell death (apoptosis)

Tumor cell proliferation

Tumor cell invasion

metastasis

Development of tumor vasculature

(angiogenesis)

Cetuximab

PI3K

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