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Lung Cancer

• Lung cancer is the number one cause of cancer deaths in both men and women in the U.S. and worldwide.
• Cigarette smoking is the principal risk factor for the development of lung cancer.
• Passive exposure to tobacco smoke (passive smoking) also can cause lung cancer in nonsmokers.
• The two types of lung cancer, which grow and spread differently, are small-cell lung cancers (SCLC) and non-small-cell lung cancers (NSCLC). Medical professionals also refer to them as small-cell lung carcinoma and non-small-cell lung carcinoma.
• The stage of lung cancer refers to the extent to which cancer has spread in the body.
• Treatment of lung cancer can involve a combination of surgery, chemotherapy, targeted therapy, immunotherapy, radiation therapy, and newer experimental methods.
• The general prognosis of lung cancer is poor because doctors tend not to find the disease until it is at an advanced stage. Five-year survival is around 61% for early-stage lung cancer patients with a tumor localized to the lungs, but only about 6% in those with advanced, inoperable lung cancer.
• Smoking cessation is the most important measure that can prevent the development of lung cancer.

Treatment of Stage IV Lung Cancer With ALK Rearrangement

Identification of an ALK gene rearrangement in lung cancer is essential for deciding the optimal treatment course. The ALK rearrangement means that drugs that specifically act against the abnormal fusion protein can be used. Three drugs, crizotinib (Xalkori), ceritinib (Zykadia), and alectinib (Alecensa), have been developed to target the activity of the abnormal fusion protein, and additional agents are under development. For patients with advanced or metastatic ALK-positive NSCLC who do not have metastases to the brain, the ALK inhibitor crizotinib is the recommended therapy. Ceritinib or alectinib is typically given if cancer becomes resistant to crizotinib or if the patient is unable to tolerate crizotinib.

Lung Cancer

Cancer of the lung, like all cancers, results from an abnormality in the body’s basic unit of life, the cell. Usually, the body maintains checks and balances on cell growth so that cells divide to produce new cells only when new cells are needed. Disruption of this system of checks and balances on cell growth results in an uncontrolled division and proliferation of cells that eventually forms a mass known as a tumor.

Tumors can be benign or malignant; when we speak of “cancer,” we refer to malignant tumors. Medical professionals can usually remove benign tumors, and these tumors do not spread to other parts of the body. 

Malignant tumors, on the other hand, often grow aggressively locally where they start. Still, tumor cells also can enter into the bloodstream or lymphatic system and then spread to other sites in the body. This spreading process is termed metastasis; tumor growth areas at these distant sites are called metastases. Since lung cancer tends to spread or metastasize very early after it forms, it is a very life-threatening cancer and one of the most difficult cancers to treat. While lung cancer can spread to any organ in the body, certain locations — particularly the adrenal glands, liver, brain, and bones — are the most common sites for lung cancer metastasis.

The lung also is a general site for metastasis from malignant tumors in other parts of the body. The same types of cells as the original (primary) tumor make up tumor metastases. For example, suppose prostate cancer spreads via the bloodstream to the lungs. In that case, it is metastatic prostate cancer in the lung and is not lung cancer.

The principal function of the lungs is to exchange gases between the air we breathe and the blood. Through the lung, carbon dioxide is removed from the bloodstream, and oxygen enters the bloodstream. The right lung has three lobes, while the left lung has two lobes and a small structure called the lingula that is the equivalent of the middle lobe on the right. The major airways entering the lungs are the bronchi, which arise from the trachea outside the lungs. The bronchi branch into progressively smaller airways called bronchioles end in tiny sacs known as alveoli, where gas exchange occurs. A thin layer of tissue called the pleura covers the lungs and chest wall.

Lung cancers can arise in any part of the lung, but 90%-95% of lung cancers arise from the epithelial cells, the cells lining the larger and smaller airways (bronchi and bronchioles); for this reason, lung cancers are sometimes called bronchogenic cancers of bronchogenic carcinomas. (Carcinoma is another term for cancer.) Cancers can also arise from the pleura (called mesotheliomas) or rarely from supporting tissues within the lungs, such as the blood vessels.

Commonality of Lung Cancer

Lung cancer is the most common cause of death due to cancer in both men and women worldwide. Statistics from the American Cancer Society estimated that in 2019 there would be about 228,000 new cases of lung cancer in the U.S. occurred, and over 142,000 deaths were due to the disease. According to the U.S. National Cancer Institute, approximately 6.5% of men and women in the U.S. will be diagnosed with cancer of the lung at some point in their lifetime, based on data from 2011-2013.

Lung cancer is predominantly a disease of the elderly; almost 70% of people diagnosed with lung cancer are over 65 years of age, while less than 3% of lung cancers occur in people under 45. The median age at diagnosis is 70 years.

Lung cancer was not common before the 1930s but increased dramatically over the following decades as tobacco smoking increased. In many developing countries, lung cancer incidence is beginning to fall following public education about the dangers of cigarette smoking and the introduction of effective smoking-cessation programs. Nevertheless, lung cancer remains among the most common types of cancers in both men and women worldwide. In the U.S., lung cancer has surpassed breast cancer as the most common cause of cancer-related deaths in women.

Causes and Risk Factors of Lung Cancer

The incidence of lung cancer is strongly correlated with cigarette smoking, with about 90% of lung cancers from tobacco use. The risk of lung cancer increases with the number of cigarettes smoked and the time over which smoking has occurred; doctors refer to this risk in terms of pack-years of smoking history (the number of cigarettes smoked per day multiplied by the number of years smoked). For example, a person who has smoked two packs of cigarettes per day for ten years has a 20 pack-year smoking history. While the risk of lung cancer increases with even a 10-pack-year smoking history, those with 30-pack-year histories or more are considered to have the most significant chance of developing lung cancer. Among those who smoke two or more packs of cigarettes per day, one in seven will die of lung cancer.

Pipe and cigar smoking can also cause lung cancer, although the risk is not as high as cigarette smoking. Thus, while someone who smokes one pack of cigarettes per day has a chance to develop lung cancer that is 25 times higher than a nonsmoker, pipe and cigar smokers have a risk of lung cancer that is about five times that of a nonsmoker.

Tobacco smoke contains over 4,000 chemical compounds, many of which are cancer-causing or carcinogenic. The two primary carcinogens in tobacco smoke are chemicals known as nitrosamines and polycyclic aromatic hydrocarbons. The risk of developing lung cancer decreases each year following smoking cessation as normal cells grow and replace damaged cells in the lung. In former smokers, the risk of developing lung cancer begins to approach a nonsmoker about 15 years after smoking cessation.

In recent years, vaping (or “e-cigs”) has gained popularity as an alternative to cigarette smoking. Experts agree that vaping is harmful to the lungs. Still, there is not enough history to know definitively if vaping can cause lung cancer. Like cigarette smoking, vaping does introduce chemicals deep into the lung tissue, which can pose a cancer risk in theory.

Although marijuana has not been definitively linked to lung cancer, marijuana smoke also contains levels of chemicals and tar that are similar to those found in tobacco smoke. This causes concerns about a potential risk for cancer and lung disease.

Passive smoking
Passive smoking or the inhalation of tobacco smoke by nonsmokers who share living or working quarters with smokers is also an established risk factor for lung cancer development. Research has shown that nonsmokers who reside with a smoker have a 24% increase in risk for developing lung cancer than nonsmokers who do not live with a smoker. The risk appears to increase with the degree of exposure (number of years exposed and number of cigarettes smoked by the household partner) to secondhand smoke. Over 7,000 lung cancer deaths occur each year in the U.S. that are attributable to passive smoking.

Exposure to asbestos fibers
Asbestos fibers are silicate fibers that can persist for a lifetime in lung tissue following asbestos exposure. The workplace was a common source of exposure to asbestos fibers. Asbestos was widely used in the past as both thermal and acoustic insulation. Today, asbestos use is limited or banned in many countries, including the U.S. Both lung cancer and mesothelioma (cancer of the lung’s pleura and the lining of the abdominal cavity called the peritoneum) are associated with asbestos exposure. 

Cigarette smoking drastically increases the chance of developing asbestos-related lung cancer in workers exposed to asbestos; asbestos workers who do not smoke have a fivefold more significant risk of developing lung cancer than nonsmokers. Still, asbestos workers who smoke have a chance that is 50- to 90-fold greater than nonsmokers.

Exposure to radon gas
Radon gas is a radioactive natural gas that is a natural decay product of uranium that emits ionizing radiation. Radon gas is a known cause of lung cancer, with an estimated 12% of lung cancer deaths attributable to radon gas, or about 21,000 lung-cancer-related deaths annually in the U.S., making radon the second leading cause of lung cancer in the U.S. after smoking. As with asbestos exposure, concomitant smoking dramatically increases the risk of lung cancer with radon exposure. Radon gas can travel up through the soil and enter homes through gaps in the foundation, pipes, drains, or other openings. The U.S. Environmental Protection Agency estimates that one out of every 15 homes in the U.S. contains dangerous radon gas levels. Though radon gas is invisible and odorless, simple test kits can detect it.

Familial predisposition
While most lung cancers are associated with tobacco smoking, the fact that not all smokers eventually develop lung cancer suggests that other factors, such as individual genetic susceptibility, may play a role in the causation of lung cancer. Numerous studies have shown that lung cancer is more likely to occur in smoking and nonsmoking relatives of those who have had lung cancer than in the general population. It is unclear how much of this risk is due to shared environmental factors (like a smoking household) and how much is related to genetic risk. Like genes that interfere with DNA repair, people who inherit certain genes may be at greater risk for several types of cancer. Tests to identify people at increased genetic risk of lung cancer are not yet available for routine use.

Lung diseases
The presence of certain diseases of the lung, notably chronic obstructive pulmonary disease (COPD), is associated with an increased risk (four- to sixfold the risk of a nonsmoker) to develop lung cancer even after the effects of concomitant cigarette smoking are excluded. Pulmonary fibrosis (scarring of the lung) increases the risk about sevenfold. This risk is not related to smoking.

Prior history of lung cancer
Survivors of lung cancer have a greater risk of developing second lung cancer than the general population in creating first lung cancer. Survivors of non-small-cell lung cancers (NSCLCs, see below) have an additive risk of 1%-2% per year for developing second lung cancer. In survivors of small-cell lung cancers (SCLCs, see below), the risk of developing second lung cancers approaches 6% per year.

Air pollution
Air pollution from vehicles, industry, and power plants can raise the likelihood of developing lung cancer in exposed individuals. Up to 1%-2% of lung cancer deaths are attributable to breathing polluted air, and experts believe that prolonged exposure to highly polluted air can carry a risk for developing lung cancer similar to that of passive smoking.

Exposure to diesel exhaust
Exhaust from diesel engines contains gases and soot (particulate matter). Many occupations, such as truck drivers, toll booth workers, forklift and other heavy machinery operators, railroad and dock workers, miners, garage workers and mechanics, and some farmworkers, are frequently exposed to diesel exhaust. Studies of workers exposed to diesel exhaust have shown a small but significant increase in the risk of developing lung cancer.

Types of Lung Cancer

Health care professionals broadly classify lung cancers, also known as bronchogenic carcinomas, because they arise from the bronchi within the lungs, into two types: small-cell lung cancers (SCLC) and non-small-cell lung cancers (NSCLC). This classification depends upon the microscopic appearance of the tumor cells themselves, precisely the cells’ size. These two types of cancers grow and spread differently and may have different treatment options, so distinguishing these two types is essential.

SCLC comprises about 20% of lung cancers and is the most aggressive and rapidly growing of all lung cancers. SCLC is related to cigarette smoking, with only 1% of these tumors occurring in nonsmokers. SCLC metastasizes quickly to many sites within the body and is most often discovered after spreading extensively. Referring to a specific cell appearance often seen when examining SCLC samples under the microscope, these cancers are sometimes called oat cell carcinomas.

NSCLC is the most common lung cancer, accounting for about 80% of all lung cancers. NSCLC can be divided into several main types that are named based upon the type of cells found in the tumor:

• Adenocarcinomas are the most commonly seen type of NSCLC in the U.S. and comprise up to 50% of NSCLC. While adenocarcinomas are associated with smoking like other lung cancers, physicians see this type in nonsmokers who develop lung cancer. Most adenocarcinomas arise in the outer or peripheral areas of the lungs.

• Squamous cell carcinomas were formerly more common than adenocarcinomas; at present, they account for about 30% of NSCLC. Also known as epidermoid carcinomas, squamous cell cancers arise most frequently in the bronchi’s central chest area.

• Large cell carcinomas sometimes referred to as undifferentiated carcinomas, are the least common type of NSCLC.

• Mixtures of different types of NSCLC also are seen.

Other types of cancers can arise in the lung; these types are much less common than NSCLC and SCLC and together comprise only 5%-10% of lung cancers:
• Bronchial carcinoids account for up to 5% of lung cancers. Physicians sometimes refer to these tumors as neuroendocrine lung tumors. They are generally small (3 cm-4 cm or less) when diagnosed and occur most commonly in people under 40. Unrelated to cigarette smoking, carcinoid tumors can metastasize. A small proportion of these tumors secrete hormone-like substances that may cause specific symptoms related to the hormone produced. Carcinoids generally grow and spread more slowly than bronchogenic cancers. Medical professionals detect many early enough to be amenable to surgical resection.

• Cancers of supporting lung tissue such as smooth muscle, blood vessels, or cells involved in the immune response can rarely occur in the lung.
Metastatic cancers from other primary tumors in the body often appear in the lung. Tumors from anywhere in the body may spread to the lungs through the bloodstream, through the lymphatic system, or directly from nearby organs. Metastatic tumors are often multiple, scattered throughout the lung, and concentrated in the peripheral rather than the lung’s central areas.

Symptoms and Signs of Lung Cancer

Symptoms of lung cancer are varied depending upon where and how widespread the tumor is. Warning signs of lung cancer are not always present or easy to identify. Lung cancer may not cause pain or other symptoms in some cases.

A person with lung cancer may have the following kinds of symptoms:
• No symptoms: In up to 25% of people who get lung cancer, the cancer is first discovered on a routine chest X-ray or CT scan as a small solitary mass sometimes called a coin lesion, since, on a two-dimensional X-ray or CT scan, the round tumor looks like a coin. These patients with small, single masses often report no symptoms at the time of the cancer discovery.

• Symptoms related to cancer: The growth of the tumor and invasion of lung tissues and surrounding tissue may interfere with breathing, leading to cough, shortness of breath, wheezing, chest pain, and coughing up blood (hemoptysis). Suppose cancer has invaded nerves, for example. In that case, it may cause shoulder pain that travels down the outside of the arm (called Pancoast syndrome) or paralysis of the vocal cords leading to hoarseness. Invasion of the esophagus may lead to difficulty swallowing (dysphagia). If there is an obstruction of a large airway, collapse of a portion of the lung may occur and cause infections (abscesses, pneumonia) in the obstructed area.

• Symptoms related to metastasis: Lung cancer that has spread to the bones may produce excruciating pain at bone involvement sites. Cancer that has spread to the brain may cause several neurologic symptoms that may include blurred vision, headaches, seizures, or signs of stroke such as weakness or loss of sensation in parts of the body.

• Paraneoplastic symptoms: Symptoms that result from the production of hormone-like substances by the tumor cells frequently accompany lung cancers. These paraneoplastic syndromes occur most commonly with SCLC but may occur with any tumor type. A common paraneoplastic syndrome associated with SCLC is producing a hormone called adrenocorticotrophic hormone (ACTH) by the cancer cells, leading to oversecretion of the hormone cortisol by the adrenal glands (Cushing’s syndrome). The most frequent paraneoplastic syndrome seen with NSCLC is producing a substance similar to parathyroid hormone, resulting in elevated levels of calcium in the bloodstream.

• Nonspecific symptoms: Nonspecific symptoms are seen with many cancers, including lung cancers, include weight loss, weakness, and fatigue. Psychological symptoms such as depression and mood changes also are common.

When to Consult a Doctor:
One should consult a health care professional if he or she develops the symptoms associated with lung cancer, in particular, if they have
• new persistent cough or worsening of an existing chronic cough,
• blood in the sputum,
• persistent bronchitis or repeated respiratory infections,
• chest pain,
• unexplained weight loss and or fatigue, and
• Breathing difficulties such as shortness of breath or wheezing.


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