Lung Cancer – Bawa – Flashcards

- Lung cancer is the leading cause of cancer-related deaths in North America and Europe - Kills over 3x as many men as prostate cancer and 2x as many women as breast cancer - More people die from lung cancer than the next 3 leading causes of cancer deaths combined: breast, colon, and prostate - Although one year survival has improved over the past few decades, 5 year survival has remained relatively unchanged at 12-16% over the past 30 yrs - One of the most preventable of all major malignancies

- Most common cause of cancer deaths among american men and women - Though ranked 2nd in cancer incidence in both sexes - Estimated total of about 225,000 new lung cancer cases and 150,000 deaths in 2013 - The age adjusted incidence rate of lung cancer is 62/100,00 men and women in USA, with incidence higher in men than in women - Current 5 yr survival rate in US for lung cancer is 17% - Globally is the most common cancer since 1985 both in incidence and in mortality rate - In males, most commonly dx cancer and leading cause of death - In females, 4th most commonly dx cancer and 2nd leading cause of death - Incidence and mortality highest in USA and developed countries and relatively lower in central america and most of africa - Incidence and mortality has increased worldwide since 1985 (51% increased incidence) - This is largely due to increase in global tobacco use, esp. in Asia - Incidence in males in USA has been decreasing since early 1980s - Decrease in death rate in men by 2%/yr from 1994-2006 - In women, lung cancer death increased by 0.3% from 1995-2005, recent data show decline of 0.9%/yr - Reason for difference is cigarette smoking peaked 2 decades later in women - In males age adjusted incidence rates varies by ethnicity with highest in African Americans - lowest incidence and mortality rates in hispanics, native americans, and asians c/w whites - Median age at dx: 71 yo - Rare below 40 yrs, with rates increasing until 80 yrs and then taper off (basically 40-85yo = most prevalent) - 2 broad categories: NSCLC (85%), SCLC (15%) - NSCLC => adenocarcinoma (38%), squamous cell carcinoma (20%), Large cell carcinoma (3%) - 5 yr survival is 17%, while in Europe, China, and developing countries it's 8.9% - Oftentimes advanced at dx [30-40% of NSCLC and 60% of SCLC is stage 4] - 50% 5 yr survival for stage 1 VS 1-2% for stage 4 at time of dx **This argues for better screening methods to detect early stage cancer**

Men - Prostate > lung/bronchus > colorectum Women - Breast > lung/bronchus > colorectum

Men - Lung/bronchus > prostate > colorectum Women - Lung/bronchus > Breast > colorectum

- Tobacco smoking is most important modifiable risk factor - 20% of all death worldwide could be prevented by eliminated tobacco smoking - 80% of lung cancers develop in smokers - 1 in 9 smokers develop lung cancer compared with lifetime risk of <1% in nonsmokers - The first report linking cigarettes smoking with premature death reported in 1938 - The tar (total particulate material in cigarette smoke after removing nicotine and water) when applied to skin of animals produced skin cancer - 1950 epidemiological studies est. the casual role of tobacco smoking with bronchogenic carcinoma - Lung cancer risk is proportional to: 1. number of packs per day of smoking 2. age of onset of smoking 3. degree of inhalation 4. the tar and nicotine content of cigarettes - Cigar and pipe smoking is associated with increased risk of lung cancer - Smoking 5 cigars/day on avg is equivalent to smoking 1 pack of cigarettes - Cigar smoking has relative risk of cancer of 2.1 to 5.1 compared to non smokers - Never smokers are defined as people who have smoked less than 100 cigarettes in their lifetime or nonsmokers - 15% lung cancers in men and up to 53% women worldwide occurs in nonsmokers, accounting for 25% of all lung cancer cases - In US, a study est. 19% of lung cancer in women and 9% in men occur in nonsmokers - Lung cancer arising in a lifetime never smoker is more common in younger, women, and east Asians - If smoke and are exposed to asbestos, even greater risk of getting lung cancer

- In 1964 US surgeon general issues landmark report on smoking and its health effect - 70% increase in age specific death rates of men - Smoking casually related to lung cancer in men - Since this report the yearly per capita consumption of cigarettes has declined - Still, 19.5% of American adults habitually smoke in 2009 - Prevalence much higher in: 1. men 2. People below federal poverty line 3. Education status < high school diploma 4. Regional differences: most in midwest and southern states, lowest in western states)

- At least 50 carcinogens identified in tobacco smoke - Tobacco specific N-nitrosamine (TSNA) formed by nitrosation of nicotine are important inducer of lung cancer - Polycyclic Aromatic Hydrocarbons (PAH) - They get activated and bind to DNA and form DNA adducts which mediate signaling pathway activation that induces modulation of critical oncogenes and tumor suppressive genes - This promotes uncontrolled cellular proliferation and tumor-genesis

- 1st degree relatives of lung cancer probands have 2-3x excess risk of lung cancer and other cancers, many of which are not related to smoking - However very few genes identified that contribute to lung cancer susceptibility - Individuals with mutation in RB and p53 genes may develop lung cancer - Rare germ-line mutation in epidermal growth factor receptor (EGFR) is linked to lung cancer susceptibility in non smokers

- COPD has the strongest association with lung. Both have smoking as an etiology - Pulmonary fibrosis even after adjustment for smoking is associated with increased risk of lung cancer - Other fibrosing diseases associated with lung cancer is Scleroderma related ILD and asbestosis - Pulmonary TB in one study had increased risk of lung cancer with hazard ratio of 3.3 after adjusting for COPD and smoking.

- Increased risk of lung cancer - Is dose dependent - 17% of lung cancers in non smokers are thought to be attributed to ETS exposure during childhood and adolescence - Increased risk of lung cancer in non smoking women married to smoker men

- IARC has identified arsenic, asbestos, beryllium, cadmium, chloromethyl ethers, nickle, radon, silica, and vinyl chloride as carcinogens - 10% lung cancer deaths worldwide in men and 5% in women attributed to above carcinogens - Asbestos is the most common occupational cause of lung cancer with relative risk of 3.5 after adjusting for age, smoking (if smoke and have asbestos exposure, your chances are even greater)

- Outdoor air pollution especially fine particulate (less than 2.5 micro mm in diameters) and sulfur oxide related pollution - Fossil fuel combustion - Diesel exhaust **This is more pertinent in 3rd world countries**

- In lung cancers clinical outcome related to stage at dx - Early detection of occult cancer will lead to improved survival - RCT 1960-1980 screened with CXR with or without sputum cytology - Reported no impact on lung cancer specific mortality in high risk pts (male, age>45 yo with a smoking hx) - PLCO Screening trial was initiated in 1993. Pt either received annual CXR for 4 yrs VS no intervention - Included 155k individuals between age of 55-74 yo. Also included women and non smokers - Through 13 yrs of follow up, no difference in lung cancer incidence rate and mortality - Confirms previous recommendation against CXR for lung cancer screening - Low dose CT chest scans (LDCT) shown to detect more lung nodules and cancer than standard CXR in high risk selected population - In national lung screening trial, LDCT compared to CXR in high risk population - Included individual age of 55-74 yo with hx of >30 pack yrs cigarettes smoking; former smokers must have quit in last 15 yrs - Excluded if they had hemoptysis, prior lung cancer, unexplained weight loss >15 lbs, CT chest in last 18 mo. - 53k pts enrolled and randomized to annual screening yearly for 3 yrs - Positive = any noncalcified nodule equal or greater than 4 mm or mass - 39% in LDCT and 16% in CXR group had at least 1 positive result - False positive rate was 96.4% in LDCT and 94.5% in CXR - Nearly 2x more early cancer (stage 1a) detected with LDCT - 40% VS 21% - Lower rates of cancer deaths in LDCT with 20% reduction in cancer mortality in this group - In 2013, the US preventive Services Task Force released a recommendation in factor of annual screening for adults 55-80 yrs old with 30 pack year smoking hx who either currently smoke or quit smoking within the past 15 yrs --> a grade B recommendation representing "moderate certainty that screening is of moderate net benefit"

- Had more false alarms - These false alarms sometimes led to invasive procedures and some had major complications from invasive procedures ** So although cuts down mortality, it also causes increased incidence complications and increases the amt of procedures that you do

Sx: Cough, weight loss, dyspnea, chest pain, hemoptysis, bone pain...., fever, weakness, superior vena cava obstruction, dysphagia, wheezing - Over 1/2 of all pts dx with lung cancer present with locally advanced or metastatic disease at the time of dx (38% IV, 28% III, 26% I, 8% II) - Signs and sx are attributed to location of primary lesion, local tumor growth, invasion/obstruction of adjacent structures, growth at distant metastatic sites or a paraneoplastic syndrome - Central or endobronchial growth of the primary tumor may present with cough, hemoptysis, wheeze, stridor, dyspnea, or postobstructive pneumonitis - Peripheral growth of the primary tumor may cause pain from pleural or chest wall involvement, dyspnea on a restrictive basis, and sx of a lung abscess resulting from tumor cavitation Regional spread of tumor in the thorax: - Either by contiguous growth or by metastasis to regional lymph nodes - Can cause tracheal obstruction and esophageal compression with dysphagia - A regional spread of tumor in the thorax can lead o recurrent laryngeal paralysis with hoarseness, phrenic nerve palsy with elevation of the hemidiaphragm and dyspnea - Can also lead to malignant pleural effusions (causing cough, dyspnea, or pain)

- 1/3 of pts presented with sx related to primary tumor onlly - Another 1/3 presented with nonspecific sx concerning for metastatic disease - The first 1/3 presented with sx attributable to a distant metastatic site - Only 6% were asymptomatic

- Result from local extension of a tumor growing in the apex of the lung with involvement of the 8th cervical and 1st/2nd thoracic nerves - Presents with shoulder pain that radiates in the ulnar distribution of the arm, often with radiologic destruction of the 1st and 2nd ribs

- Sympathetic nerve paralysis (enophthalmos, ptosis, miosis, and anhydrosis) ** often pancoast and horner's syndrome co-exist**

- Obstruction of blood flow through the superior vena cava - Sx: edema of the face and arms and development of swollen collateral veins on the front chest wall. SOB and coughing are common sx. Additionally: difficulty swallowing, headache, and stridor.

- Found on autopsy in more than 50% of pts with squamous carcinoma, 80% of pts with adenocarcinoma and large cell carcinoma, and greater than 95% of pts with SCLC - 1 study listed a standard set of clinical features found to be associated with metastatic disease - Systematic review suggests that absence of all of these features makes metastatic disease highly unlikely with a negative predictive value exceeding 90% Evaluation for Metastatic Disease - Sx: weight loss >10lbs, focal skeletal pain, neurological sx (headaches, syncope, seizures, focal extremity weakness, altered mentation) - Signs: palpable LAD, hoarseness or SVC syndrome, bone tenderness, hepatomegaly, focal neuro signs, soft tissue mass - Labs: Hematocrit (<40% in men or <35% in women) and elevated alkaline phosphatase, liver function function tests

Endocrine - Hypercalcemia - Cushing Syndrome - Gynecomastia - Hypercalcitoninemia - Elevated LH/FSH - Hyperthyroidism - Carcinoid syndrome Neuro - Subacute sensory neuropathy - Encephalyomyelitis - Lambert-Eaton Myasthenic Syndrome - Envephalomyelitis - Necrotizing myelopathy - Cancer associated retinopathy Skeletal - Hypertrophic osteoarthropathy - Clubbing **Refer to slide for others**

- Resulting from ectopic production of PTH or more commonly PTH-related peptide - most common life-threatening metabolic complication of malignancy, primarily occurring with squamous cell carcinomas of the lung - Sx: nausea, vomiting, abdominal pain, constipation, polyuria, thirst, and altered mental status "Stones, cystic bones, and abdominal groans"

- May be caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or possibly atrial natriuretic peptide (ANP). SIADH resolves within 1-4 wks of initiating chemo in the vast majority of cases - Ectopic secretion of ACTH by SCLC and pulmonary carcinoids usually results in additional electrolyte disturbances, esp. hypokalemia, rather than the changes in body habitus that occur in Cushing's Syndrome from a pituitary adenoma - Rheumatological and neurological paraneoplastic syndromes are seen in SCLC. They are due to formation of auto antibodies.

- Include clubbing in 30% of cases (usually NSCLCs) and hypertrophic primary osteoarthropathy in 1-10% of cases (usually adenocarcinomas) - Pts develop periostitis, causing pain, tenderness, and swelling over the affected bones and a positive bone scan

- CXR - CT scan chest (all pts should get with contrast) - PET scan (helps staging) - Ultrasound Chest - MRI brain

- PET with 18-fluoro-2-deoxyglucose (FDG) commonly used in the initial noninvasive evaluation of the patient with suspected lung cancer - Metabolically active tissues take up FDG, a glucose analog, avidly and appear bright on PET scan - Strongly hypermetabolic activity raises suspicion of malignancy - False positive - seen in inflammatory processes related to infections or recent surgery - False negatives - can occur with low grade malignancies or small foci of malignancy. Lesions less than 0.8-1.0cm may be too small for accurate assessment. - High level physiologic uptake within the brain, heart, GI, or GU tracts may compromise precise evaluation of tumor invasion in these areas - Hyperglycemia can interfere with the uptake of FDG and thus increase the likelihood of false negatives - PET scan is more sensitive and specific than CT in regional lymph node assessment with a pooled sensitivity of 74% and a specificity of 85% in the ID of mediatstinal lymph node metastases - PET scanning can disclose unsuspected metastatic disease (M1) in 6%-37% of cases

- MRI scanning is the test of choice when assessing for intracranal metastatic disease - It is more sensitivity than CT scan of the brain - Staging brain MRI should be considered in pts who present with locally advanced or advanced NSCLC on chest CT or PET scanning, pts with neurological sx, pts presenting with nonspecific constitutional sx of fevers, weight loss, anorexia and weakness and in all pts with SCLC

- Sputum Cytology - sensitivity range between 42-97%, dx yield is higher in pts with central tumors, tumors >2.4 cm, squamous cell histopathology, and those with hemopytsis - Bronchoscopy - BAL, Brushing, Biopsy --> higher yield in central lesion) - Transthoracic CT Guided Biopsy (higher yield in peripheral lesion) - Thoracentesis (repeat tap increase sensitivity, not much role of pleural biopsy) - VATS (video-assisted thoroscopic surgery) biopsy

- EGFR mutation seen in 10-15% of north american pts with NSCLC - EGFR seen more in adenocarcinoma, younger age, asian, women, and light/non-smokers - EGFR tyrosine kinase inhibitors like Erlotinib are first line - Another mutations ALK and ROS1 has been recognized in 7% and 2% in pt with adenocarcinoma. Tx with crizotinib has shown significant improvement.

Anatomical Staging = determination of the location of the tumor and possible metastatic sites Physiological Staging = assessment of a pt's ability to withstand various antitumor tx

T = primary tumor M = distant metastases N = Regional lymph nodes **See slides for more detailed view**

- Lung cancer pts have co-morbid conditions related to smoking including cardiovascular disease and COPD - Pts with FEV > 2L or greater than 80% of predicted can tolerate a pneumonectomy, and those with a FEV >1.5L have adequate reserve for a lobectomy - Borderline lung function but a resectable tumor, CPET (cardiopulmonary exercise testing) could be performed as part of the physiologic evaluation - A maximal O2 consumption <15mL predicts for a higher risk of postoperative complications - Recent MI in last 3 mo. is absilute contraindication for thoracic surgery as associated with 20% mortality

- Surgery (tx of choice as potentially curable) - Chemo - Radiation - Palliative - Combination

Stage I - surgery as first line (lobectomy or pneumonectomy with mediastinal LN sampling). Radiotherapy as 2nd line Stage IIA and IIB - surgery with adjuvant chemo is first line. Radioteherapy second line. Stage IIIA - surgery firstline with adjuvant chemo in resectable tumors. Chemoradiation therapy (concurrent) is first line for unresectable tumors. Stage IIIB - is unresectable, concurrent chemoradiation therapy first line Stage IV - chemo is first line. Radiotherapy is used for pallitative only. All should have mutational analysis (incl EGFR, ALF, and KRAS)

- VA staging is used for SCLC - Pts are classified as having limited or extensive disease Limited disease = disease limited to one hemithorax, although it can include ipsilateral supraclavicular and mediastinal LAD Extensive Disease = any disease outside of the hemithorax - LD tx with chemo and radiotherapy - ED is tx with chemo alone - Malignant pleural effusion can technically be categorized as LD. However they have the same characteristics as those with ED, hence are treated like them - The TMN staging is most helpful in potentially resectable pts with T1-2N0 disease

- Single radiographic opacity completely surrounded by normal aerated lung with well circumscribed margins, of any shape up to 3cm in greatest diameter - Greater than 3cm in diameter are called lung masses and are presumed to be bronchogenic carcinoma until proven otherwise - Approach is based on estimate of probability of cancer - Determined by pts smoking hx, age, and characteristics on imaging - Only 2 radiographic criteria are thought to predict the benign nature of a SPN 1. lack of growth over 2 yrs 2. Certain pattern of calcification (ie: popcorn in hemartoma, central bull's eye in granuloma) - Radiological characteristics considered as a predictor of malignancy are: 1. irregular/spiculated margin 2. size of nodule 3. upper lobe location

Benign - Central - Laminated - Diffuse - Popcorn Malignant - Stippled - Eccentric