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Lung Cancer

The Merck Manual Home Edition
" Cigarette smoking is the most common cause of lung cancer. One common symptom is a persistent cough or a change in the character of a chronic cough. Chest x-rays can detect most lung cancers, but other additional imaging tests and biopsies are needed. Surgery, chemotherapy, targeted agents, and radiation therapy may all be used to treat lung cancer. Lung cancer is the leading cause of cancer death in both men and women. It occurs most commonly between the ages of 45 and 70 and has become more prevalent in women in the last few decades because more women started smoking cigarettes in years past. Cancer that originates from lung cells is called a primary lung cancer. Primary lung cancer can start in the airways that branch off the trachea to supply the lungs (the bronchi) or in the small air sacs of the lung (the alveoli). Cancer may also spread (metastasize) to the lung from other parts of the body (most commonly from the breasts, colon, prostate, kidneys, thyroid gland, stomach, cervix, rectum, testes, bones, or skin). There are two main categories of primary lung cancer:

Non–small cell lung carcinoma:
About 85 to 87% of lung cancers are in this category. This cancer grows more slowly than small cell lung carcinoma. Nevertheless, by the time about 40% of people are diagnosed, the cancer has spread to other parts of the body outside of the chest. The most common types of non–small cell lung carcinoma are squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Small cell lung carcinoma:
Sometimes called oat cell carcinoma, this cancer accounts for about 13 to 15% of all lung cancers. It is very aggressive and spreads quickly. By the time that most people are diagnosed, the cancer has metastasized to other parts of the body.

Rare lung cancers include
*Bronchial carcinoid tumors (which may also be noncancerous)
*Bronchial gland carcinomas
*Lymphomas (cancers of the lymphatic system)

Deaths Due to Lung Cancer:
Among cancers, lung cancer is the most common cause of death in men and women. The number of deaths due to lung cancer has been decreasing in men and appears to be leveling off or decreasing in women after increasing for several decades. These trends reflect a decrease in the number of smokers over the last 30 years. In 2013, more than 159,480 people are expected to have died of lung cancer—about 87,260 men and 72,220 women. This number represents about 28% of all deaths due to cancer.

Cigarette smoking is the leading cause of cancer, accounting for about 85% of all lung cancer cases. About 10% of all smokers (former or current) eventually develop lung cancer, and both the number of cigarettes smoked and number of years of smoking seem to correlate with the increased risk. In people who quit smoking, the risk of developing lung cancer decreases, but former smokers will still always have a higher risk of developing lung cancer than people who never smoked.

About 15 to 20% of people who develop lung cancer have never smoked or have smoked only minimally. In these people, the reason why they develop lung cancer is unknown, but certain genetic mutations may be responsible.

Other possible risk factors include air pollution, exposure to cigar smoke and secondhand cigarette smoke and exposure to carcinogens such as asbestos, radiation, radon, arsenic, chromates, nickel, chloromethyl ethers, polycyclic aromatic hydrocarbons, mustard gas, or coke-oven emissions, encountered or breathed in at work, and exclusively using open fires for cooking and heating. The risk of contracting lung cancer is greater in people who are exposed to these substances and who also smoke cigarettes. In rare incidences, lung cancers, especially adenocarcinoma and bronchioloalveolar cell carcinoma (a type of adenocarcinoma), develop in people whose lungs have been scarred by other lung disorders, such as tuberculosis. Also, smokers who take beta-carotene supplements may have an increased risk of developing lung cancer.

Although smoking causes most cases, people who have never smoked may still get lung cancer.

The symptoms of lung cancer depend on its type, its location, and the way it spreads. One of the more common symptoms is a persistent cough or, in people who have a chronic cough, a change in the character of the cough. Some people cough up blood or sputum streaked with blood (hemoptysis). Rarely, lung cancer grows into an underlying blood vessel and causes severe bleeding. Additional nonspecific symptoms of lung cancer include loss of appetite, weight loss, fatigue, chest pain, and weakness.

Lung cancer may cause wheezing by narrowing the airway. Blockage of an airway by a tumor may lead to the collapse of the part of the lung that the airway supplies, a condition called atelectasis. Other consequences of a blocked airway are shortness of breath and pneumonia, which may result in coughing, fever, and chest pain. If the tumor grows into the chest wall, it may cause persistent, unrelenting chest pain. Fluid containing cancerous cells can accumulate in the space between the lung and the chest wall (pleural effusion). Large amounts of fluid can lead to shortness of breath. If the cancer spreads throughout the lungs, the levels of oxygen in the blood become low, causing shortness of breath and eventually enlargement of the right side of the heart and possible heart failure (cor pulmonale).

Lung cancer may grow into certain nerves in the neck, causing a droopy eyelid, small pupil, and reduced perspiration on one side of the face—together these symptoms are called Horner syndrome. Cancers at the top of the lung may grow into the nerves that supply the arm, making the arm or shoulder painful, numb, and weak. Tumors in this location are often called Pancoast tumors. When the tumor grows into nerves in the center of the chest, the nerve to the voice box may become damaged, making the voice hoarse.

Lung cancer may grow into or near the esophagus, leading to difficulty swallowing or pain with swallowing.

Lung cancer may grow into the heart or in the midchest (mediastinal) region, causing abnormal heart rhythms, blockage of blood flow through the heart, or fluid in the sac surrounding the heart (pericardial sac).

The cancer may grow into or compress one of the large veins in the chest (the superior vena cava); this condition is called superior vena cava syndrome. Obstruction of the superior vena cava causes blood to back up in other veins of the upper body. The veins in the chest wall enlarge. The face, neck, and upper chest wall—including the breasts—can swell, causing pain, and become flushed. The condition can also cause shortness of breath, headache, distorted vision, dizziness, and drowsiness. These symptoms usually worsen when the person bends forward or lies down.

Lung cancer may also spread through the bloodstream to other parts of the body, most commonly the liver, brain, adrenal glands, spinal cord, or bones. The spread of lung cancer may occur early in the course of disease, especially with small cell lung cancer. Symptoms—such as headache, confusion, seizures, and bone pain—may develop before any lung problems become evident, making an early diagnosis more complicated.

Paraneoplastic syndromes consist of effects that are caused by cancer but occur far from the cancer itself, such as in nerves and muscles. These syndromes are not related to the size or location of the lung cancer and do not necessarily indicate that the cancer has spread outside the chest. These syndromes are caused by substances secreted by the cancer (such as hormones, cytokines, and various other proteins).

Doctors explore the possibility of lung cancer when a person, especially a smoker, has a persistent or worsening cough or other lung symptoms (such as shortness of breath or coughed-up sputum tinged with blood), or weight loss. Usually, the first test is a chest x-ray, which can detect most lung tumors, although it may miss small ones. Sometimes a shadow detected on a chest x-ray done for other reasons (such as before surgery) provides doctors with the first clue, although such a shadow is not proof of cancer.

Computed tomography (CT) may be done next. CT can show characteristic patterns that help doctors make the diagnosis. They also can show small tumors that are not visible on chest x-rays and reveal whether the lymph nodes inside the chest are enlarged. Newer techniques, such as positron emission tomography (PET—see see Chest Imaging) and a certain type of CT called helical (spiral) CT, are improving the ability to detect small cancers. Oncologists (doctors who specialize in treating people with cancer) frequently use PET-CT scanners, which combine the PET and CT technology in one machine, to evaluate patients with suspected cancer. Magnetic resonance imaging (MRI) can also be used if the CT or PET-CT scans do not give doctors sufficient information.

A microscopic examination of lung tissue from the area that may be cancerous is usually needed to confirm the diagnosis. Occasionally, a sample of coughed-up sputum can provide enough material for an examination (called sputum cytology). If the cancer has caused a pleural effusion, removing and testing that fluid may be enough. Usually, however, doctors need to obtain a sample of tissue directly from the tumor. One common way to obtain the tissue sample is with bronchoscopy. The person's airway is directly observed and samples of the tumor can be obtained (see see Bronchoscopy). If the cancer is too far away from the major airways to be reached with a bronchoscope, doctors can usually obtain a specimen by inserting an instrument through the skin. This procedure is called a percutaneous biopsy. Sometimes, a specimen can only be obtained by a surgical procedure called a thoracotomy. Doctors may also do a mediastinoscopy, in which they take and examine samples of enlarged lymph nodes (a biopsy) from the center of the chest to determine if inflammation or cancer is responsible for the enlargement.

Doctors do genetic tests on the tissue sample to see whether the person's cancer is caused by a mutation that can be treated with drugs that target the mutation's effects.

Once cancer has been identified under the microscope, doctors usually do tests to determine whether it has spread. A PET-CT scan and head imaging (brain CT or MRI) may be done to determine if lung cancer has spread, especially to the liver, adrenal glands, or brain. If a PET-CT is not available, CT scans of the chest, abdomen, and pelvis and a bone scan are done. A bone scan may show that cancer has spread to the bones.

Cancers are categorized on how large the tumor is, whether it has spread to nearby lymph nodes, and whether it has spread to distant organs. The different categories are used to determine the stage of the cancer. The stage of a cancer suggests the most appropriate treatment and enables doctors to estimate the person's prognosis.

Clinical trials are underway to determine the value of screening tests to detect lung cancer in people who do not have any symptoms. These trials use chest x-rays, CT, sputum examinations, or all these methods to try to detect cancer when it is at an early stage.

Screening of all people, has not been shown to improve lung cancer survival, and therefore screening is not recommended for people who have no risk factors. Tests can be expensive and cause people undue worry if they produce false-positive results that incorrectly imply that a cancer is present. The opposite is also true. A screening test can give a negative result when a cancer really does exist.

Screening of high-risk people, however, may be effective. For these reasons, it is important for doctors to try to accurately determine a person's risk for a particular cancer before screening tests are done (see see Screening). People who may benefit from screening include middle-aged and older people who smoke heavily or have done so for many years. Yearly CT with a technique that uses lower-than-normal amounts of radiation seems to find enough cancers that can be cured to save lives.

Prevention and Treatment:
Prevention of lung cancer includes quitting smoking (see see Smoking) and avoiding exposure to potentially cancer-causing substances.

Doctors use various treatments for both small cell and non–small cell lung cancer. Surgery, chemotherapy, and radiation therapy can be used individually or in combination. The precise combination of treatments depends on the type, location, and severity of the cancer, whether the cancer has spread, and the person's overall health. For example, in some people with advanced non–small cell lung cancer, treatment includes chemotherapy and radiation therapy before, after, or instead of surgical removal. Some people with non–small cell lung cancer survive significantly longer when treated with chemotherapy, radiation therapy, or some of the newer targeted therapies. Targeted therapies include drugs, such as biologic agents that specifically target lung tumors.

Recent studies have identified proteins within cancer cells and the blood vessels that nourish the cancer cells. These proteins may be involved in regulating and promoting cancer growth and metastasis. Drugs have been designed to specifically affect the abnormal protein expression and potentially kill the cancer cells or inhibit their growth. Drugs that target such abnormalities include bevacizumab, gefitinib, erlotinib, crizotinib, vemurafenib, and dabrafenib. These drugs may be used instead of the usual chemotherapy drugs, in combination with them, or after the conventional chemotherapy drugs have been tried and have not worked.

Laser therapy, in which a laser is used to remove or reduce the size of lung tumors, is sometimes used. A high-energy current (radiofrequency ablation) or cold (cryoablation) can sometimes be used to destroy tumor cells in people who have small tumors or are unable to undergo surgery.

Surgery is the treatment of choice for non–small cell lung cancer that has not spread beyond the lung (early-stage disease). In general, surgery is not used for early-stage small cell lung cancer, because this aggressive cancer requires chemotherapy and radiation therapy. Surgery may not be possible if the cancer has spread beyond the lungs, if the cancer is too close to the windpipe, or if the person has other serious conditions (such as severe heart or lung disease).

Before surgery, doctors do pulmonary function tests (see see Pulmonary Function Testing (PFT)) to determine whether the amount of lung remaining after surgery will be able to provide enough oxygen and breathing function. If the test results indicate that removing the cancerous part of the lung will result in inadequate lung function, surgery is not possible. The amount of lung to be removed is decided by the surgeon, with the amount varying from a small part of a lung segment to an entire lung.

Although non–small cell lung cancers can be removed surgically, removal does not always result in a cure. Supplemental (adjuvant) chemotherapy after surgery can help increase the survival rate and is done for all but the smallest cancers.

Occasionally, cancer that begins elsewhere (for example, in the colon) and spreads to the lungs is removed from the lungs after being removed at the source. This procedure is recommended rarely, and tests must show that the cancer has not spread to any site outside of the lungs.

Radiation therapy:
Radiation therapy is used in both non-small cell and small cell lung cancers. It may be given to people who do not want to undergo surgery, who cannot undergo surgery because they have another condition (such as severe coronary artery disease), or whose cancer has spread to nearby structures, such as the lymph nodes. Although radiation therapy is used to treat the cancer, in some people, it may only partially shrink the cancer or slow its growth. Combining chemotherapy with radiation therapy improves survival in these people. Some people with small cell lung cancer who have been responding well to chemotherapy may benefit from radiation therapy to the head to prevent spread of cancer to the brain. If the cancer has already spread to the brain, radiation therapy of the brain is commonly used to reduce symptoms such as headache, confusion, and seizures. Radiation therapy is also useful for controlling the complications of lung cancer, such as coughing up of blood, bone pain, superior vena cava syndrome, and spinal cord compression.

Chemotherapy is used in both non-small cell and small cell lung cancers. In small cell lung cancer, chemotherapy, sometimes coupled with radiation therapy, is the main treatment. This approach is preferred because small cell lung cancer is aggressive and has often spread to distant parts of the body by the time of diagnosis. Chemotherapy can prolong survival in people who have advanced disease. Without treatment, the median survival is only 6 to 12 weeks.

In non–small cell lung cancer, chemotherapy usually also prolongs survival and treats symptoms. In people with non–small cell lung cancer that has spread to other parts of the body, the median survival increases to 9 months with treatment. Targeted therapies may also improve cancer patient survival.

Other treatments:
Other treatments are often needed for people who have lung cancer. Many such treatments, called palliative treatments, aim to relieve symptoms rather than cure cancer.

Because many people who have lung cancer have a substantial decrease in lung function whether or not they undergo treatment, oxygen therapy (see see Oxygen Therapy) and bronchodilators (drugs that widen the airways) may aid breathing.

Pain often requires treatment. Opioids are often used to relieve pain but can cause side effects, such as constipation, that also require treatment.

Lung cancer has a poor prognosis. On average, people with untreated advanced non–small cell lung cancer survive 6 months. Even with treatment, people with extensive small cell lung cancer or advanced non–small cell lung cancer do especially poorly, with a 5-year survival rate of less than 1%. Early diagnosis improves survival. People with early non–small cell lung cancer have a 5-year survival of 60 to 70%. However, people who are treated definitively for an earlier stage lung cancer and survive but continue to smoke are at high risk of developing another lung cancer.

Survivors must have regular checkups, including periodic chest x-rays and CT scans to ensure that the cancer has not returned. Usually, if the cancer returns, it occurs within the first 2 years. However, frequent monitoring is recommended for 5 years after lung cancer treatment, and then people are monitored yearly for the rest of their lives.

Because many people die of lung cancer, planning for terminal care is usually necessary. Advances in end-of-life care, particularly the recognition that anxiety and pain are common in people with incurable lung cancer and that these symptoms can be relieved by appropriate drugs, have led to an increasing number of people being able to die comfortably at home, with or without hospice services (see see Choices to Make Before Death)."

Medications Used in Treatment:
1. Antifolates: Rheumatrex® Trexall®/methotrexate, Alimta®/pemetrexed
2. EGFR Inhibitors: Tarceva®/erlotinib
3. Kinases Inhibitors: Xalkori®/crizotinib, Gilotrif®/afatinib
4. Topoisomerase Inhibitors: etoposide, Hycamtin®/topotecan
5. RANKL Inhibitor: Xgeva®/denosumab
6. Microtubule Inhibitors: Taxotere®/docetaxel, Abraxane®/nano-particle albumin-bound paclitaxel, paclitaxel, Docefrez®/docetaxel
7. Nucleoside Metabolic Inhibitors: Gemar®/gemcitabine
8. VEGF Antibodies: Avastin®/bevaciumab
9. Antrhracyclines: doxorubicin
10. Vinca Alkaloids: Navelbine®/vinorelbine

Suggested Links:
*Medscape/ Small cell lung cancer
*Medscape/ Non-small cell lung cancer
*American Cancer Society
*American Lung Association

*[Editor]The newest research in lung cancer has focused on the estrogen and progesterone receptors present in normal and malignant lung tissue. Estrogen receptor-beta (ER-B) not ER-alpha (ER-a) is present in both men and women. Male-derived lung tumors respond to estrogens. Both express CYP19 (aromatase) which converts testosterone to estrone and Beta-estradiol. Thus testosterone acts a a precursor for local estrogen production within lung tumors. The Editor hypothesizes that blocking the ER with a non-aromatizable androgen might have a rate limiting effect on the lung cancer just as this methodology has a rate limiting effect on the ER for endometriosis.

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