Lung cancer

Source:  Lung cancer    Tag:  fluoroscopic operating table definition
Author: Dr Jessica Donington New York University 2008-07-28

Lung Cancer: Lung cancer is a disease of uncontrolled cell growth in tissues of the lung. A malignant tumor arising from the cells of the respiratory epithelium. By definition, tumors arising from non epithelial cells (sarcoma and lymphoma) or from mesothelial lining (mesothelioma) of the lung are excluded. This uncontrolled cell growth may lead to metastasis, invasion of adjacent tissue and infiltration beyond the lungs.

GLOSSARY


Adenocarcinoma
-a tumor arising from cells that have glandular or secretory properties.
Adjuvant therapy- the use of chemotherapy or radiation therapy after the primary therapy. It is additional therapy performed to decrease the risk for recurrence.
Current Smoker- a person with a lifetime smoking exposure of >100 cigarettes and whose last cigarette was less than one year prior.
Environmental tobacco smoke (ETS)- A form of indoor air pollution which results from a combination of the smoke from burning tobacco product and the mainstream smoke which is exhaled by the smoker, formerly known as second hand smoke.
Former Smoker- a person with a lifetime smoking exposure to greater than 100 cigarettes and whose last cigarette was at least one year prior.
Hilum-wedge-shaped depression on mediastinal surface of the lung where the bronchus, blood vessels, nerves, and lymphatics enter and leave the lung.
Mainstream tobacco smoke- that smoke directly inhaled by the smoker from the tobacco product.
Mediastinum-center portion of the chest cavity, between the lungs, containing the structures of the chest, except the lungs.
Neoadjuvant therapy- chemotherapy or radiation therapy given prior to surgery to decrease the size of the tumor and/or to eradicate micro metastatic disease.
Never Smoker- a person with a lifetime smoking exposure to less than 100 cigarettes.
Polycyclic aromatic hydrocarbons (PAH) - a major class of carcinogens present in the tar component of mainstream cigarette smoke. They lead to the formation of DNA adducts, which cause mutagenic events including DNA strand breaks, chromosomal aberrations, activation of oncogenes, and tumor suppressor gene inactivation.
Small cell lung cancer - A highly malignant type of lung tumor consisting of small cells expressing neuroendocrine features. It occurs almost exclusively in smokers, current or former.
Squamous cell carcinoma- a tumor arising from multilayered squamous lining cells.

INTRODUCTION

Lung cancer is the world’s leading cause of preventable death. There are over 1,200,000 new cases of lung cancer diagnosed world-wide each year. In the United States there are over 170,000 new cases of lung cancer and greater than 160,000 deaths, each year. The cure rate for lung cancer in this country is currently 14%.  Lung cancer is the third most common malignancy in the United States, but the most frequent cause of cancer death for both men and women in the United States. Lung cancer accounts for 29% of all cancer deaths in this country. More patients die from lung cancer each year than from the three next most frequent causes of cancer death (colon, breast, and prostate) combined. Lung cancer is a major health issue both in this country and worldwide.

Cancers begin as an error or mutation in the DNA of a cell. DNA mutations can result from normal aging, genetic predisposition, or through environmental factors such as tobacco smoke. Normal lung cells require a series of DNA mutations in order for them to become cancerous.

An important differentiation exits between primary lung cancers which originate in the lung, from tissues of the lung and airway, and metastatic (secondary cancers) which spread to the lung from other sites. Primary lung cancers all start in the lung but have the potential to spread to other sites. Cancers from almost every site in the body have the potential to spread to the lungs, and the lung is also the most common site for metastatic spread from other tissues. This distinction is important because staging, treatment, and prognosis are all based upon the primary site of disease. This Knol focuses on bronchogenic carcinomas, those cancers which begin in the tissues of the lung and the airway.

RISK FACTORS

Primary lung cancer is rare in children and young adults. The median age at diagnosis is 69. It is estimated that between 85-90% of all lung caners occur in current or former smokers. The risk for lung cancer with smoking varies with the type, duration, and amount of tobacco smoked. Because of its strong association with tobacco smoke, the epidemiology and incidence of lung cancer closely mimics and lags approximately 20 years behind smoking patterns. Prior to the 20th century lung cancer was much less common. At the turn of the century the mass production of cigarettes greatly increased tobacco consumption and the incidence of lung cancer began to rise steadily.  It was almost entirely a disease of men for much of the 20th century, but with the onset of World War II and the introduction of women to the workplace in the 1940s, women began to smoke in greater numbers and 20 years later the incidence of lung cancer in women also began to rise. In 1964 the US Surgeon General released the first report connecting tobacco smoke to lung cancer. Men in America heeded  that report, and smoking rates, which were greater than 50% at that point, began to steadily decrease, to the current rate of approximately 25% of adult males. Lung cancer incidence and death rates have been steadily declining in men since the late 1980s. Lung cancer is still responsible for nearly 98,000 deaths per year in American men. Unfortunately, in the 1960s American women were in the midst of the sexual revolution, and smoking was heavily linked to an image of independence and power. Smoking incidence in American women continued to rise through the 1960s and 70s. It was not until the 1980s that smoking incidence began to decrease in American women. The incidence and death rates from lung cancer in American women have been rising steadily since the 1960s and, has increased by over 600% in that time period. We are just beginning to see the incidence numbers level off each year, reflecting the change in smoking patterns from the 1980s. Lung cancer kills over 65,000 women each year in the United States.

Although tobacco smoke is recognized as the largest risk factor for the development of lung cancer, not all lung cancers occur in smokers. Approximately 10-15% of lung cancers occur in never smokers. Other risk factors for the development of lung cancer include environmental tobacco smoke (ETS), radon, other air pollutants, and genetics.

ETS is also known as “second hand smoke.” It is a combination of the smoke from the burning tip of the cigarette and the mainstream smoke exhaled by the smoker. It contains the same carcinogens as the mainstream smoke, but at a much lower concentration. Several spousal and work place studies have identified a 20-25% increase in risk of lung cancer from exposure to environmental tobacco smoke.

Other air pollutants, specifically oil vapors from cooking over very high heat and indoor coal burning without adequate ventilation, have highly concentrated polycyclic aromatic hydrocarbons which are the same carcinogens in tobacco smoke and which increase the risk for developing lung cancer. This is not a major risk factor or health issue in the United States, but remains a large issue throughout Asia, and possibly in Asian immigrants to the United States where much of the cooking is still done under these conditions.
Radon is a naturally occurring radioactive gas product from uranium in the soil. It can collect indoors. Epidemiologic studies in mine workers have established a causal relationship between exposure to very high levels radon and lung cancer.

Genetic factors also play a large role. Only 10-20% of smokers develop lung cancer, suggesting that certain individuals may have a different genetic susceptibility to the same environmental risk factors. A family history of lung cancer is associated with a 1.5-fold increased risk of developing lung cancer. There are numerous genes whose expression appear to be tied to the risk of developing lung cancer. The two most widely recognized are cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase (GSTM1). These genes produce proteins that are important in the disposal of the carcinogens in tobacco smoke. Altered expression of these genes will place individuals at increased risk for DNA damage from tobacco and to the subsequent development of lung cancer. These two genetic alterations are more common in women than men. There is evidence that women may therefore be more sensitive to the effects of carcinogenic effects of tobacco than are men.

SYMPTOMS

Lung cancers can produce a wide variety of symptoms. Some of the most frequent pulmonary symptoms include a new or increased cough, persistent chest, back, or shoulder pain, increased volume of sputum, blood in the sputum, wheezing, and repeated episodes of pneumonia. These symptoms are usually the result of a tumor blocking or narrowing the airway or invading into the boney and muscular portions of the chest. Patients can also present with systemic symptoms such as fatigue, anorexia, weight loss, headache, neurologic symptoms, bone pain, or fractures. These symptoms are typically the result of spread of the cancer outside of the lung. On rare occasion, patients can present with unusual symptoms such as leg pain or clubbing of the fingernails or rash. Lung cancers can causes a conglomeration of changes due to proteins in the blood as a result of the cancer, which is known as a para-neoplastic syndrome. The most frequently seen example of this syndrome causes very wide, thickened ends of the fingers (clubbing), sometime with pain in the joints, known as hypertrophic pulmonary osteoarthropathy. Unfortunately many lung cancers are quite large or metastatic by the time they produce symptoms. Many patients with early stage disease have no symptoms and the tumor is found on  a chest x-ray or CT scan performed for another reason. Cure rates are higher for those patients without symptoms at the time of diagnosis than those with symptoms.

SCREENING EFFORTS

Lung cancer screening is very controversial. Intuitively, lung cancer screening makes sense; if lung cancers are usually advanced by the time they produce symptoms then a screening test that would allow for earlier diagnosis should improve the chance for cure. Unfortunately, cancer screening is not that simple. For a screening test to be useful it has to: 1) detect lung cancer at a time when its course can be altered by therapy: 2) be specific for lung cancer and not create the need for numerous of additional tests; and 3) the test has to be cost effective so that it can be accessible to the large population at risk. Examples of successful cancer screening tools include prostate specific antigen (PSA) for prostate cancer, mammography for breast cancer, and colonoscopy for the detection of colon cancer. Investigators are in search of biomarkers in the blood for the early detection of lung cancer, but to date none are reliable enough for clinical use. The current areas of screening interest include chest-x-ray, low-dose helical computerized tomography (CT) scanning of the chest and sputum cytology (the examination of sputum for cancer cells). Most screening efforts have focused on high risk patients with extensive smoking history. The National Cancer Institute (NCI) is conducting a large lung cancer screening trial using chest x-ray compared with CT, however  data will not be available for 2-3 years.  Sputum studies are difficult because the yield for analysis is low, it can only detect central tumors, and when abnormal cells are found, it is not always easy to find the corresponding location in the airway. Low- dose (of radiation) helical CT scanning appears to be the most promising screening technology for lung cancer. Numerous large CT screening trials have been performed in high risk patients and the results have been mixed. The largest trials are from the Mayo Clinic and the International Early Lung Cancer Action Project (IELCAP). In these trials asymptomatic early lung cancers were found in about 2.5% of the patients enrolled. Numerous other small non-cancerous nodules were found at a greater frequency then cancer. These required further work up and removal in many cases. Although, the vast majority of cancers found in most studies were early stage, not all of them were early stage and therefore not all were curable. The controversy continues because we know that CT scans will detect a small number of early stage lung cancers in a population at risk, but at what cost, and to what benefit is not fully defined. Lung cancer screening is not paid for by insurance companies, so individuals interested in being screened will need to pay out of pocket, and should only participate in screening at centers with the expertise of the IELCAP where the screening is performed according to a protocol.

PROCEDURES FOR DIAGNOSIS AND STAGING

When a new pulmonary nodule or mass suspicious for lung cancer is found on a chest x-ray or a CT scan, there are a number of tests which are routinely performed to make the correct diagnosis and to establish the stage of the disease prior to the initiation of therapy. One of the initial tests is a chest x-ray of the front and the side of the chest. This is a simple, painless, and inexpensive test which provides valuable information on the lung fields, size and location of a nodule, contour of tissue spaces (mediastinum) and presence or absence of fluid (effusion). When a suspicious nodule is detected, old chest x-rays, if available, should always be inspected for comparison to see if the abnormality was present years ago.
A computer tomography (CT) scan is essential in the accurate staging of a lung cancer. The CT scan is a radiographic study in which two dimensional thin slices of the body are produced, similar to slices of bread. They can be visualized individually in a series, or the images can be reconstructed by computer to form three-dimensional images. CT scans are now very fast and can scan the entire chest in one breath hold (less than 10 seconds).  This decreases motion artifact and delivers a very small dose of radiation. CT scans provide the most accurate visualization of the lung anatomy and the most accurate information on a nodule’s size, shape, location, and proximity to other structures. A complete CT scan of the chest for the work up of a suspicious pulmonary nodule should have thin cuts (< 5mm), extend from the mouth through the bottom of the liver, and be viewed as both pulmonary (lung) and mediastinal (soft tissue) windows. Pulmonary windows provide the most accurate view of the lung parenchyma while mediastinal windows allow for accurate evaluation of mediastinal lymph nodes and associated structures (Fig.1).


Figure1. CT scans of the chest of patients with lung cancer which demonstrate a tumor in the lung parenchyma on pulmonary windows and mediastinal lymph nodes involved with cancer on mediastinal windows.
 
Positron emission tomography (PET) is a nuclear medicine scan using radioactivity in tracers, which was introduced in 1984. It has become an invaluable tool in the staging of many malignancies, including lung cancer. PET scanning uses a radio-labeled sugar to detect metabolically active tissue throughout the body. Areas suspicious for malignancy will have greater uptake of the sugar tracer, which leads to a brighter signal on PET, compared to the surrounding normal tissue (Fig.2). PET activity is measured in standardized uptake values (SUVs). The pictures produced by the PET scan are anatomically non-specific, but when paired or fused with CT scans can provide a very accurate location for metabolically active tissue. The labeled sugar in a PET scan will be taken up by any metabolically active tissue and therefore PET scans cannot differentiate active infection or wound healing from the presence of a cancer, since all of these entities are metabolically more active than normal tissue. PET scanning is a very sensitive tool in the staging of lung cancer. The majority of lung cancers are positive on PET scan, and when the primary tumor is positive on PET scan any metastatic deposits will also be positive. PET scanning is unreliable for lesions less than 1 cm in size, therefore tumors or metastatic deposits less then 1 cm may not be recognized. PET scanning is more sensitive than CT scanning for the detection of metastatic spread from lung cancer to the mediastinum or distant sites. The brain is an area of the body where PET scanning is not as useful for the detection of metastatic disease because of its continuous metabolic activity.
 
Figure 2 .These are  PET images from a patient with lung cancer, which demonstrate increased activity in the tumor and in an adjacent mediastinal lymph node.
 
Magnetic Resonance imaging (MRI) is the diagnostic modality of choice for evaluation of metastatic spread to the brain . Lung cancer has a strong predilection for spread to the brain. In all patients with significant disease burden in the chest (locally advanced) or metastatic disease, spread to the brain should be evaluated with MRI or CT of the brain, even in the absence of symptoms.
 
A tissue diagnosis is an important aspect of staging and diagnosis. There are numerous techniques which can be used to obtain tissue from the primary tumor or metastatic sites. These include percutaneous (sticking through the skin into the chest) needles, endoscopic  biopsies (using a lighted tube to look in the breathing tubes or chest), and surgical biopsies.
 
CT or ultrasound-guided needle biopsies are a relatively noninvasive way to obtain tissue for diagnosis. The success rates for percutaneous needle biopsies are dependent on the size and location of the mass in question, and the expertise of both the radiologist obtaining the tissue and the cytologist interpreting the results. Percutaneous biopsies can be fine needle aspirations (22-gauge), which are interpreted by cytology, or larger core needle biopsies (12-gauge), which provide enough tissue for standard pathologic examination. Complications from percutaneous biopsies of the lung include self-limited coughing up of blood (hemoptysis) in 10% of patients, and pneumothorax (air in the chest possibly leading to a collapsed lung) in up to 24% of patients. Only 10% of patients require a chest tube after a percutaneous biopsy.

Bronchoscopy is another technique for acquiring tissue for diagnosis without a formal operation. A bronchoscopy is an examination of the inside of the airway using a lighted tube with or without a series of lenses or cameras. Almost all patients with an early stage lung cancer will undergo bronchoscopy prior to resection to establish the endobronchial anatomy and rule out endobronchial spread of tumor prior to resection. Bronchoscopy can be performed either with a rigid or flexible scope. Rigid scopes require general anesthesia and provide a view of only a limited portion of the airway. They are used frequently for airway obstruction, relief of airway bleeding, and retrieval of foreign bodies, but are now rarely used in the staging and diagnosis of lung cancer. The flexible bronchoscope is a very small scope that can fit through the mouth or nostrils. It can be used under general anesthesia or just with topical anesthesia. The small size of the scope and video-optics provide an excellent view of the airway down through the segmental bronchi. The flexible endoscope can obtain lung tissue for diagnosis by: 1) direct biopsy of, or brushing visualized endobronchial mass, 2) by fluoroscopic guided biopsy of mass beyond the area of visualization, or 3) by washing fluid through the effected segment and saving the cells to be viewed under a microscope. The bronchoscope can also be used to biopsy mediastinal lymph nodes through the wall of the wind pipe. This technique is referred to as a Wang biopsy. It is a blind biopsy with the biopsy site being approximated by examination of the CT scan. The greatest yield is for biopsies of the lymph nodes in the subcarinal space because of ease of both location and advancing the needle, as compared with the left and right paratracheal sites.

Endobronchial ultrasound (EBUS) is a very new technology, where along with video-optics and a needle biopsy chamber, scopes are equipped with an ultrasound probe at the tip. This probe can examine the tissues just outside of the windpipe. Lymph nodes involved with cancer have a very characteristic appearance, they are large, round, with sharp borders and dark centers. Once a suspicious lymph node is visualized by EBUS, a 22-gauge needle can be passed through the tracheal wall and into the lymph node under real-time ultrasound guidance.

Some patients require a surgical biopsy in order to make a diagnosis. Frequently used procedures include mediastinoscopy, anterior mediastinotomy (Chamberlain procedure), or video assisted thoracoscopic surgery (VATS) biopsy of the lung or mediastinum.

Mediastinoscopy is a small surgical procedure done under general anesthesia for the evaluation of mediastinal lymph nodes. A small incision is made at the top of the sternum and the soft tissues are divided down to the trachea. At that point a plane can be developed along the trachea into the mediastinum. A small rigid scope can be slid along side the windpipe to biopsy lymph nodes on either side of the windpipe and in the subcarinal space. Only lymph nodes adjacent to the trachea can be biopsied with this technique. The only significant complications from mediastinoscopy include bleeding, which is rare, but can be life threatening and requires median sternotomy or thoracotomy for control, and possibly hoarseness from interference with the nerves to the vocal cords.  A Chamberlain’s procedure (anterior mediastinotomy) is very similar to a mediastinoscopy in that it is a relatively simpler outpatient operation, done under general anesthesia, for the evaluation of mediastinal lymph nodes. It provides access to the lymph nodes on the left side that are sheltered by the aorta and thus cannot be biopsied by mediastinoscopy. These lymph nodes are not directly adjacent to the trachea and therefore are not accessible through cervical mediastinoscopy. Chamberlain’s procedure is classically performed through the resected bed of the third costal cartilage just to the left of the sternum. The chest cavity in the majority of cases need not be entered.

VATS can also be used to biopsy mediastinal lymph nodes, pleural surfaces or nodules in the parenchyma of the lung. VATS requires general anesthesia and single lung ventilation (collapsing of the lung on the side being operated on) and most lung procedures require placement of a chest tube, making this a more invasive biopsy technique. Many patients with suspected early stage lung cancer will complete all of their other staging prior to a planned VATS biopsy, so that they can proceed on to a definitive resection at the same operative setting, based upon frozen section evaluation of the tissue while the patient is asleep.

TYPES OF LUNG CANCER

There are many different subtypes of lung cancer, but they all fall into two broad categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). The names derive from the appearance of the cells under the microscope.

Small Cell Lung Cancer

SCLCs account for about 15-20% of all lung cancers. They are often referred to as oat cell cancers, based on their microscopic appearance, with numerous small round cells. SCLC is very strongly associated with smoking. These are aggressive tumors which grow quickly and metastasize to distant sites very early. The majority of patients have widely metastatic disease at the time of diagnosis. Because of the predilection for early spread, SCLC is generally staged as either limited-stage disease (LD) or extensive disease (ED). Limited-stage disease is defined as tumors limited to one hemithorax and regional lymph nodes that can be encompassed in one radiation port.

Non-Small Cell Lung Cancer

NSCLC comprises 80-85% of lung cancers in this country. The major histological subtypes within this group include adenocarcinoma, squamous cell carcinoma, and large cell undifferentiated carcinoma. All three histologic types are staged and treated the same, and carry similar prognoses.

Squamous cell carcinoma is a malignant epithelial tumor. . Squamous cell histology is the most common in men and in smokers. The tumors tend to be more central in location and have a greater tendency to cavitate and cause symptoms.

Adenocarcinomas are glandular malignancies. They have a tubular, papillary, or acinar growth pattern or can be solid with mucin production. These tumors tend to be in peripheral locations. This is the most common histology in women and in non-smokers. Bronchoalveolar carcinoma (BAC) is a subset of adenocarcinomas in which the tumor cells spread and grow against the preexisting alveolar walls. The key feature of this tumor type is the preservation of the underlying alveolar architecture. BAC come in mucinous and nonmucinous varieties. These tumors rarely metastasize out of the lung, but tend to occur at multiple locations within the lung.

Large cell undifferentiated carcinoma is a subset of NSCLC and is a category of exclusion. It compromises malignant epithelial tumors with large nuclei and without the characteristic features of squamous cell carcinoma, adenocarcinoma, or SCLC.

STAGING

Lung cancer like other solid tumors, is staged based upon the TNM classification. This staging system is used routinely in NSCLC, but rarely applied to SCLC which is typically classified as extensive (ED) or limited (LD) as discussed above.  In the TNM system for NSCLC  the “T” status ranges from 0-4 and describes the primary tumor, based upon size, distance from the carina, presence of associated collapsed lung and invasion into surrounding structures. The “N” status describes involved lymph nodes and ranges from 0-3. Nodal stations for lung cancer have been organized on a staging map developed by Naruke (fig 3). Stations 1-9 represent the mediastinal lymph nodes (N2) and stations 10-14 represent hilar and intra-pulmonary nodes. These nodes have an N1 designation if they occur on the same side as the primary tumor. Any lymph node that occurs on the side opposite from the tumor carries a very poor prognosis and has N3 designation.  The “M” status denotes the presence (M1) or absence (M0) of distant metastatic disease. Each tumor is given a clinical TNM classification and then placed into a cancer stage. Stages range from I-IV and help us to predict survival in an individual patient, based upon the behavior of a group of similar patients.  
Figure3. These diagrams depict the Naruke lymph node map used in the staging of lung cancer.
The staging system for NSCLC was recently revised by the International Association for the Study of Lung Cancer (IASLC). It reviewed over 67,000 cases of NSCLC world-wide, from 1990-2000 . The current IASLC TNM sub-groups appear in Table 1. Significant changes from the old staging system include dividing tumors <3cm into two groups, T1a and T1b based on a 2cm cutoff, dividing tumors >3cm into a and b categories based on a 5cm cutoff. This was done because in node negative patients size significantly effects survival. Tumors >7cm and tumors with satellite nodules in the same lobe were moved to T3. Tumors with satellite nodules in other lobes of the same lung were reclassified from M1 to T4. Pleural dissemination of disease was moved from T4 to M1a and metastatic disease was sub-classified to M1a and M1b.
Table 1.
Stage
TNM subsets
Description
5-year survival
0
TisN0M0
Carcinoma in situ

IA
T1aN0M0
Tumor <2cm, surrounded by lung, no nodes, no mets
73%
T1bN0M0
Tumor >2cm and <3cm, surrounded by lung, no nodes, no mets
IB
T2aN0M0
Tumor >3cm and <5cm, tumors within 2cm of trachea or invading pleura or causing lobar collapse, no nodes, no mets
58%
IIA
T1aN1M0

Tumor <2cm, surrounded by lung, ipsilateral hilar or intrapulmonary nodes, no mets
46%
T1bN1M0
Tumor >2cm and <3cm, surrounded by lung, ipsilateral hilar or intrapulmonary nodes, no mets
T2aN1M0


Tumor >3cm and <5cm, or tumors including tumors invading the main bronchus >2cm from the carina or invading pleura or causing lobar collapse, ipsilateral hilar or intrapulmonary nodes, no mets
T2bN0M0

Tumor >5cm and <7cm including tumors including tumors invading the main bronchus >2cm from the carina or invading pleura or causing lobar collapse, no nodes, no mets
T2bN1M0
Tumor >5cm and <7cm including tumors including tumors invading the main bronchus >2cm from the carina or invading pleura or causing lobar collapse, no nodes, no mets
IIB
T2bN1M0
Tumor >5cm and <7cm including tumors invading the main bronchus >2cm from the carina or invading visceral pleura or causing lobar collapse; ipsilateral hilar or intrapulmonary nodes; no mets
36%
T3N0M0
Tumor >7cm or directly invading chest wall, diaphragm, phrenic nerve, pericardium, mediastinal pleura, or invading the main bronchus <2cm from the carina, or causing collapse of entire lung, or with separate nodule in the same lobe; no nodes; no mets
IIIA
T1N2M0
Tumor <3cm, surrounded by lung, ipsilateral mediastinal or subcarinal nodes; no mets
24%
T2N2M0
Tumor >3cm and <7cm including tumors including tumors invading the main bronchus >2cm from the carina or invading pleura or causing lobar collapse, ipsilateral mediastinal or subcarinal nodes, no mets
T3N1M0
Tumor >7cm or directly invading chest wall, diaphragm, phrenic nerve, pericardium, mediastinal pleura, or invading the main bronchus <2cm from the carina, or causing collapse of entire lung, or with separate nodule in the same lobe; ipsilateral hilar or intrapulmonary nodes; no mets
T3N2M0
Tumor >7cm or directly invading chest wall, diaphragm, phrenic nerve, pericardium, mediastinal pleura, or invading the main bronchus <2cm from the carina, or causing collapse of entire lung, or with separate nodule in the same lobe; ipsilateral mediastinal or subcarinal nodes; no mets
T4N0M0
Tumor of any size that invades mediastinum, heart, great vessels, spine, trachea, recurrent laryngeal nerve, esophagus, carina or separate tumor nodules in a different lobe of the same lung; no nodes ; no mets
T4N1M0
Tumor of any size that invades mediastinum, heart, great vessels, spine, trachea, recurrent laryngeal nerve, esophagus, carina or separate tumor nodules in a different lobe of the same lung ; ipsilateral hilar or intrapulmonary nodes; no mets
IIIB
T4N2M0
Tumor of any size that invades mediastinum, heart, great vessels, spine, trachea, recurrent laryngeal nerve, esophagus, carina or separate tumor nodules in a different lobe of the same lung; ipsilateral mediastinal or subcarinal nodes; no mets
9%
AnyTN3M0
Any tumor; contralateral mediastinal or hilar or scalene or supraclavicular lymph nodes; no mets
IV
AnyTAnyNM1a
Any tumor: any nodes; mets to opposite lung, pleural nodules, or malignant pleural or pericardial effusion
13%
AnyTAnyNM1b
Any tumor; any nodes; distant mets
Tumor, primary tumor; nodes, lymph nodes: mets, metastases
 
Mediastinal lymph node involvement plays a key role in the staging and subsequent treatment and prognosis in NSCLC. Therefore, careful staging of the mediastinal lymph nodes is essential prior to starting treatment. For small peripheral tumors, a normal PET and normal CT of the mediastinum are adequate to rule out lymph node involvement. In patients with enlarged lymph nodes on CT, or increased activity on PET, or with large tumors, central tumors, or bilateral tumors, tissue biopsy of the mediastinal lymph nodes is warranted. In patients with very suspicious lymphadenopathy by clinical evaluation it is equally important to verify tumor involvement prior to treatment and to not commit the patient to a higher stage disease without pathologic verification. The primary techniques for obtaining tissue from mediastinal lymph nodes are: Wang biopsy (transbronchial needle biopsy), EBUS guided transbronchial needle biopsy, endoscopic ultrasound (EUS), guided biopsy, and cervical mediastinoscopy.

TREATMENT

Lung cancer treatment, like that of other solid tumors, incorporates the use of surgery, radiation therapy, and chemotherapy. The use of the three treatment arms is based upon the stage of disease and the overall health of the patient . In general, early-stage disease is treated with surgery, disease with regional involvement is treated with combination therapy, and patients with advanced or metastatic disease are treated with chemotherapy alone.

Chemotherapy

Chemotherapy, or systemic therapy, is an arm of treatment that uses medications to treat cancer throughout the entire body. These medications are frequently given intravenously, but many oral agents are now available. Chemotherapy is the primary treatment modality for SCLC and for stage IIIB and IV NSCLC. Cisplatin has been the backbone of systemic treatment for NSCLC since the mid 1990s, with significant scientific evidence of its benefit over other agents. Cisplatin is associated with numerous side effects, including nausea, vomiting, renal toxicity, neuropathy, ototoxicity, and fatigue. Carboplatin is a similar medication with fewer side effects, and is, in general, better tolerated, but lacks the wealth of evidence of superiority enjoyed by cisplatin. Numerous trials comparing these two agents would suggest that cisplatin is more efficacious, but carboplatin is better tolerated. The decision between the two is individualized based upon the patient’s overall health and treatment goals, but one of those two agents is usually included in standard first-line chemotherapy for NSCLC. The “platinum” agent is typically paired with a second chemotherapy agent for the treatment of lung cancer. There are numerous other agents that can be used, including gemcitabine, vinorelbine, docetaxel, and paclitaxel. These are all newer, “third-generation” agents and despite numerous trials comparing different combinations, no one of them has been proven to be better than the others. Ideally, in the treatment of NSCLC patients receive “doublet therapy,” two agents with one of them being cisplatin or carboplatin. Lung cancer patients generally receive three to four cycles of this type of therapy over three to four months, rather than a prolonged course. The majority of patients who are going to respond to treatment will do so in the first three to four cycles and additional cycles only exposes patients to additional toxicities. In patients whose cancer progresses following the completion of chemotherapy, docetaxel is the standard agent for second-line therapy.

Many of the new chemotherapeutic agents are specifically designed to interfere with a specific molecular or biochemical pathway that is abnormally activated in cancer cells. Most of these “targeted agents” are given orally and are very well tolerated. Gefitinib and erlotinib are both inhibitors of tyrosine kinase, which disrupts the activity of the epidermal growth factor receptor (EGFR), and is frequently over expressed on the surface of lung cancer cells. These agents have demonstrated striking responses in women, Asians, never smokers, and patients with adenocarcinomas. EGFR gene mutations are common in that same population and there is a strong correlation between EGFR gene mutations and response to the EGFR-TK inhibitors. Because of the dramatic responses that may be obtained with these agents in this specific population, they are now being introduced as part of first-line therapy for this population.

Small cell lung cancer is treated somewhat different from NSCLC. Cisplatin is still the backbone of therapy, but it is typically paired with. As in NSCLC, doublet therapy is the rule here. The majority of patients will respond to first-line chemotherapy, but most relapse within 8 months. Topotecan either orally or intravenously is a common second-line therapy in SCLC. Numerous targeted agents are also being investigated.

Radiation Therapy

Radiation therapy involves the delivery of highly selective and focused x-ray beams to kill cancer cells. It is a form of local therapy, similar in that sense to surgery. It is usually administered as an outpatient. It can be given as a single dose, but is more frequently given as several doses over many consecutive days. Because of the very precise delivery of treatment, radiation therapy requires extensive planning and very exact positioning of the patient prior to each treatment. In the treatment of lung cancer, radiation therapy is used in many different ways. It is used alone to treat early stage NSCLC in patients who cannot tolerate surgery. It is used in combination with chemotherapy as a primary treatment for locally advanced NSCLC and limited stage SCLC.  It is used after surgery if residual disease is left in the chest. It is used to treat symptomatic metastatic disease. It is used to both treat metastatic lesions to the brain and to protect the brain against metastasis. The dosing and associated complications are very specific to each use.

Stereotactic radiotherapy is a very precise and specialized form of radiation therapy where a very large dose of radiation is given to a very precise treatment volume in very few treatment fractions. It is used extensively for tumors in the brain and is now being used to treat lung cancer with encouraging early results.

Surgery

Surgery is the primary treatment modality for stage I and II NSCLC. Surgery has a role in combination with other therapies for select patients with stage IIIA disease, but has a very limited role in the treatment of patients with stage IIIB or IV lung cancer.  Lobectomy, (resection of the entire lobe the tumor is in) or pneumonectomy (resection of the entire lung the tumor is in) are the recommended procedures for the treatment of lung cancer. Lesser resections, such as wedges or segmentectomy are thought to leave the patient at increased risk for local recurrence compared with the more anatomic resections. This is based on work from the Lung Cancer Study Group done in the 1990s. In a randomized trial, it noted a significant increase in local recurrence in stage I patients who underwent limited resection versus lobectomy. There is now increasing interest in sub-lobar resections, especially segmentectomy for the treatment of very small lung cancers. CT scanning technology has greatly improved over the past 20 years. The quality of the current scans allows for the detection of many more very small cancers (<1cm) and thus more accurate staging, especially with the addition of PET.

A mediastinal lymph node dissection or sampling is a standard part of a resection for lung cancer. Lymph nodes from stations #2R, 4R, 7, 9R, 10R are routinely sampled during right side resections and lymph nodes from stations #5, 6, 7, 9R, 10R are sampled during left side procedures (Fig.3).

The morbidity rate for resection of lung cancer in the United States is approximately 1.5%. The most common causes of death after surgery are pneumonia and respiratory failure. Complications occur n approximately 38% of patients. The most common complications include atrial arrhythmias (fast heart rhythm), prolonged air leak (>7 days), atelectasis, respiratory failure, and pneumonia. Transfusion rates are <3% and hospital stays average about 6 days. Lobectomies have been traditionally performed via a posterior lateral thoracotomy, a 10-12 inch incision that surrounds the tip of the scapula.  The chest is entered between the 5th and 6th rib and the ribs are spread to allow access to the chest cavity. With increasing frequency VATS techniques are being used for these resections. VATS lobectomy uses two to three working ports and a 4-5 inch access incision, through which the lobe is removed. There is no spreading of the ribs. The VATS lobectomy allows for an oncologic equivalent operation, but with fewer days in hospital, less pain, faster recovery, and greater ability to tolerate additional therapy. Not every tumor is amenable to VATS resection. Large central tumors and tumors with extension into the airway are notable exceptions.

Anesthesia for thoracic surgery is a specialized field. Lung resections require a significant amount of anesthesia care to be done safely. The majority of lung cancer operations are done with single lung ventilation. A double lumen endotracheal tube allows each lung to be ventilated independently. During the operation the operative side is left unventilated so that the surgeon can work in a quiet and still operative field. Many lung resections are also performed with an epidural catheter in place for postoperative pain management, continuous arterial blood pressure monitoring, and pulse-oximetry. Each of these technologies has significantly decreased the complications associated with major lung resections.

Preoperative evaluation

In addition to appropriately staging the lung cancer prior to surgery, it is essential to evaluate the overall health and pulmonary function of the patient to determine if they can tolerate the planned resection. Cardiovascular disease and lung cancer are both related to tobacco smoke and often coexist in the same patients. Thoracic surgery puts a patient at moderate risk for cardiac event and therefore thorough cardiac evaluation is warranted prior to a lung resection. This includes a meticulous history for cardiac risk factors and an EKG in all patients. In patients with known coronary artery disease or significant risk factors such as diabetes mellitus, hypertension, or hypercholesteremia, further work up is warranted prior to surgery.

Many patients who undergo thoracic surgery also have poor underlying pulmonary function, due in large part to long-term tobacco use. Preoperative pulmonary history should investigate tobacco usage, including current use, total number of pack years, and time since cessation. Prolonged tobacco exposure may also suggest significant parenchymal disease and occult chronic obstructive pulmonary disease (COPD). Other important pulmonary history includes prior thoracic surgery, history of lung disease, or active pulmonary infection. The patient’s preoperative activity level needs to be assessed.
Pulmonary function testing (PFTs) is a simple, inexpensive, and readily available means of evaluating pulmonary function. For the majority of patients, PFTs along with history and physical exam form an adequate preoperative pulmonary evaluation, and it should be the starting point for evaluation of all patients. Forced expiratory volume in one second (FEV1) is the most commonly used PFT parameter for the assessment of surgical risk. FEV1 greater than 1.5L is proposed as safe for a lobectomy; FEV1 greater than 2.0L is safe for a pneumonectomy. These absolute values provide a good, but crude set of selection criteria as they do not take into account gender or body size. Predicted postoperative values for FEV1 (ppoFEV1) should be calculated for any patient with FEV1 below that threshold. Predicted postoperative FEV1 historically needed to be greater than 800 ml (30). Recent studies indicate that ppoFEV1 less than 40% of predicted is associated with a significant increase in morbidity and mortality. The most common method of calculating ppoFEV1 involves accounting for the anticipated number of resected segments as a percentage of the total number of segments in both lungs. There are 19 segments, each accounting for roughly 5.26% of overall lung function.

Patients considered high risk for thoracic surgery based on PFTs and calculated ppoFEV1 should undergo exercise testing to identify those with marginal pulmonary function, but even these can still tolerate a resection. The simplest form of exercise testing is stair climbing. The height climbed is inversely related to the rate of postoperative complications. The old rule-of-thumb was that patients who could climb one flight could tolerate a lobectomy and those who could climb two flights could tolerate a pneumonectomy. More sophisticated exercise testing also exists; those that measure maximal oxygen consumption (maxV02) appear to be most useful. MaxV02< 10ml/min/kg being prohibitory for thoracic surgery.

SCLC TREATMENT BY STAGE

Limited Disease (LD)
Approximately 40% of SCLC patients have LD at the time of diagnosis. These patients are preferentially treated with two drug chemotherapy (cisplatin and etoposide) and concurrent twice-daily radiation therapy. Median survival with this type of treatment is 10-20 months; approximately 25% of patients will survive to two years. Most chemotherapies are not effective in the brain and there is a very high risk for metastatic spread from SCLC to the brain. Prophylactic cranial irradiation (PCI) decreases the risk for relapse in the brain and improves overall survival in those patients who have a good response to chemotherapy. Surgery has no significant role in the treatment of SCLC. Patients who undergo resection are typically those with very limited disease, which is mistaken for NSCLC.
Extensive disease (ED)
The majority of patients have ED at the time of diagnosis and are ideally treated with chemotherapy that combines a platinum agent with etoposide. Median survival for patients with ED is nine months and only 30% of patients survive to one year. 

NSCLC TREATMENT BY STAGE

Stage IA (T1aN0M0 and T1bN0M0)
For Stage IA NSCLC surgery alone is the treatment recommendation and 5-year survival is approximately 70-75%. The new staging system has separated out tumors <2cm from those between 2-3 cm because of the difference in survival observed in node-negative patients. Patients with significant medically co-morbidities who cannot undergo surgery are treated with external beam radiation and survival is approximately half that of surgery. 
Stage IB (T2aN0M0)
Surgery alone is the recommended treatment for stage IB tumors <4cm, but the addition of chemotherapy after surgery is recommended in select patients with tumors >4cm. This is based on a randomized trial comparing adjuvant (additional) chemotherapy to observation in a group of resected patients with stage IB NSCLC (CALGB 9633). Overall there was no survival benefit with the addition of chemotherapy, but in an analysis of patients with tumors >4cm, adding chemotherapy after surgery improved survival.

Stage IIA (T1aN1M0, T1bN1M0, T2aN1M0, T2bN0M0, T2bN1M0)
For many years surgery alone was the treatment of choice for patients with stage II NSCLC, despite survival rates <50%. There have recently been a series of large, randomized control trials comparing surgery alone to surgery followed by chemotherapy for patients with early stage lung cancer. No benefit was seen in IA disease and only select benefit was noted in stage IB (see above), but strong clinical evidence now exists supporting the use of adjuvant chemotherapy for those patients with completely resected stage II and IIIA NSCLC. In summary, resection followed by adjuvant doublet chemotherapy with a platinum agent is now the treatment of choice for stage IIA. It is recommended that adjuvant chemotherapy be started by 12 weeks after surgery. Cure rates for stage IIA are currently 46%.

Stage IIB (T2bN1M0, T3N0M0)
As in stage IIA NSCLC, resection plus adjuvant chemotherapy is the recommended treatment for stage IIB. Cure rates are approximately 36%. T3 tumors are generally those tumors that invade resectable structures within the chest. Those structures should be resected en-bloc with the lung at the time of surgery. Small defects in the pericardium or chest wall do not require reconstruction and larger defects are reconstructed with materials such as gortex or bovine pericardium.

Stage IIIA (T1N2M0, T2N2M0, T3N1M0, T3N2M0, T4N0M0, T4N1M0)
Stage IIIA encompasses what is referred to as locally advanced disease, and includes a very diverse group of patients. Cure rates for stage IIIA are 24%. Treatment options for stage IIIA vary significantly. Most patients are treated with curative intent and receive combination therapy. Almost all patients in this group receive chemotherapy because of the very high risk for distant disease following treatment. The addition of surgery or radiation, or both, is case specific. Patients with T3N1M0 tumors or resectable T4 tumors are typically treated with a combination of chemotherapy and surgery. Patients with N2 disease, mediastinal lymph node involvement, make up the largest proportion of patients in this stage and that can also be a very diverse group. The decision of how to use radiation and surgery is based on the extent of lymph node involvement, the resection necessary to remove all of the tumor, and health of the patient. There are several trials that report improved survival with the use of chemotherapy, radiation, and surgery in this population, but that treatment is also associated with an increase in complications, including death, and must be used selectively in those patients thought to deem the most benefit without excessive risk.

When chemotherapy and radiation are used to treat NSCLC it is better to give them at the same time (concurrently), rather than one after the other (sequentially). If surgery is used, it is usually performed two-four weeks following the last cycle of chemotherapy and four to six weeks following radiation therapy.

Stage IIIB (T4N2M0, AnyTN3M0)
Stage IIIB is also defined as locally advanced disease, but cure rates are significantly less than stage IIIA, at only 9% at five years. Patients are treated with a combination of chemotherapy and radiation. Surgery usually has no roll in the treatment of this stage.

Stage IV (AnyTAnyNM1a, AnyTAnyNM1b)
Stage IV disease is incurable, but was recently separated into two categories, a and b, based upon the site of metastatic spread. Involvement of the pleural space or contralateral lung has a median survival of 13 months, while spread to distant sites outside of the chest has a median survival <10 months. The most common sites of spread include the brain, bones, liver, and adrenal glands. Treatment for both groups is primarily chemotherapy, with radiation for symptomatic lesions or brain metastases. 

CONCLUSION

Lung cancer is the leading cause of cancer death in this country. Cure rates remain low -- at 14% overall. Research efforts are focused on screening techniques and biomarkers for early detection, new targeted chemotherapeutic agents, less invasive measures for the staging and resection of cancers, and better and safer ways to combine current agents. Because we are still a long way from a cure, prevention remains a large focus in the fight against lung cancer. Tobacco cessation remains one of the surest ways to decrease death rates from this aggressive and deadly form of cancer.

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