Non-small cell lung cancer

Risk Factors:

• People who carry a common variation in the gene for alpha1-antitrypsin -- a substance that normally protects the walls of the alveoli in the lungs -- are 70% more likely to develop lung cancer than those without the mutation, whether or not they smoke.
• Vitamins C, E, and folate supplements do not reduce the risk of lung cancer, and vitamin E supplements may actually slightly increase the risk.

Diagnosis:

• Positron emission tomography (PET) scans can diagnose lung tumors as small as 1 centimeter with very high accuracy, and may reduce the need for unnecessary surgical procedures. Research is also finding that PET scans are more accurate than computed tomography (CT) scans for staging lung cancer.
• A blood test based on four proteins in the blood (carcinoembryonic antigen, retinol binding protein, alpha1-antitrypsin, and squamous cell carcinoma antigen) appears to be very sensitive for diagnosing lung cancer. Researchers say the test, which is still experimental, may help determine whether patients with suspicious lung lesions seen on x-rays need biopsies.

Treatment:

• Radiofrequency ablation, which uses an x-ray guided electrode to deliver heat to tissues, may benefit lung cancer patients who aren't eligible for surgery, radiation, or chemotherapy. In one study, 70% of patients treated with this method survived for at least one year.

Although lung cancer accounts for only 15% of all cancers, it is among the most lethal, accounting for about 29% of all cancer deaths. It is more deadly than colon, breast, and prostate cancers combined. An estimated 161,840 people will die from lung cancer in 2008. Death rates have been declining in men over the past decade, and they have about stabilized in women.

The Lungs

The lungs are two spongy organs surrounded by a thin moist membrane called the pleura. Each lung is composed of smooth, shiny lobes: the right lung has three lobes, and the left has two. About 90% of the lung is filled with air. Only 10% is solid tissue.

• Air is carried from the trachea (the windpipe) into the lung through flexible airways called bronchi.
• Like the branches of a tree, the bronchi in turn divide into over a million smaller airways called bronchioles.
• The bronchioles lead to grape-like clusters of microscopic sacs called alveoli.
• In each adult lung, there are about 300 million of these tiny alveoli. A thin membrane makes up the alveoli sacs. Oxygen and carbon dioxide pass through this membrane to and from capillaries.
• Capillaries, the smallest of our blood vessels, carry blood throughout the body.

Lung Cancer

Lung cancer develops when genetic mutations (changes) occur in a normal cell within the lung. As a result, the cell becomes abnormal in shape and behavior, and reproduces endlessly. The abnormal cells form a tumor that, if not surgically removed, invades neighboring blood vessels and lymph nodes and spreads to nearby sites. Eventually, the cancer can spread (metastasize) to locations throughout the body.

The two major categories of lung cancer are small cell lung cancer and non-small cell lung cancer. Most lung cancers are non-small cell cancer, the subject of this report. Less common cancers of the lung are known as carcinoids, cylindromas, and certain sarcomas (cancer in soft tissues).

Some experts believe all primary lung cancers come from a single common cancerous (malignant) stem cell. As it copies itself, that stem cell can develop into any one of these cancer types in different people.

In addition, cancers in the lung may have spread from other sites, such as the breast, thyroid, or colon. In these cases, doctors name the cancer after its original location, such as "breast cancer with lung metastases."

Non-Small Cell Lung Cancers

Non-small cell lung cancers are categorized into three types:

• Squamous cell carcinoma (also called epidermoid carcinoma)
• Adenocarcinoma
• Large cell carcinoma

These separate types are grouped together because, in the early stages before the cancers have spread, they all can be treated with surgery.

Squamous Cell Carcinoma. Squamous cells are formed from reserve cells. These are round cells that replace injured or damaged cells in the lining (the epithelium) of the bronchi, the major airways. Tumors formed from squamous cells are usually found in the center of the lung, either in a major lobe or in one of the main airway branches. They may grow to large sizes and form cavities in the lungs.

Click the icon to see an image of squamous cell carcinoma.

When squamous cell cancer spreads, it may travel to the bone, adrenal glands, liver, small intestine, and brain.

Squamous cell carcinoma is nearly always caused by smoking and it used to be the most common cancer. It still makes up 25 - 30% of all lung cancers.

Adenocarcinoma. Adenocarcinomas usually start from the mucus-producing cells in the lung. About two-thirds of adenocarcinomas develop in the outer regions of the lung, while one-third develop in the center of the lung.

In 1965, 12% of lung cancers were adenocarcinomas. They are now estimated to account for 40% of all lung cancers and are the most common lung cancers in many countries. They are also the most common lung cancers in women. Adenocarcinoma is also increasing dramatically in men. Until recently, adenocarcinoma was only weakly linked to smoking. Experts now suggest, however, that the dramatic increase in this lung cancer type in recent decades may be due to low-tar, filtered cigarettes. People who smoke them draw tiny particles deeper into their lungs.

The course of this cancer varies widely. Most often, it develops slowly and causes few or no symptoms until it is far advanced. In some cases, however, it can be extremely aggressive and rapidly fatal. In 50% of cases in which this cancer spreads, it spreads only to the brain. It also can spread to the other lung, liver, adrenal glands, and bone.

Click the icon to see an image of adenocarcinoma.

Bronchoalveolar Lung Cancer. Bronchoalveolar lung cancer is actually a subtype of adenocarcinoma. It develops as a layer of column-like cells on the lung and spreads through the airways, causing great volumes of sputum. This cancer also is increasing in incidence.

Large Cell Carcinoma. Large cell carcinoma, which makes up about 10 - 15% of lung cancers, includes cancers that cannot be identified under the microscope as squamous cell cancers or adenocarcinomas.

Click the icon to see an image of large cell carcinoma.

Small Cell Lung Cancer

Small cell lung cancer may, like squamous cells, originate from reserve cells or other cells in the epithelium. It causes 10 - 15% of all lung cancers. Without chemotherapy, it is very aggressive and usually rapidly fatal. It requires a different treatment approach from non-small cell lung cancer, so it is not discussed in this report.

Click the icon to see an image of small cell carcinoma.

Cigarette Smoke. Smoking causes 87% of lung cancer deaths, accounting for 30% of all cancer-related deaths. Cigarettes, nicotine, or both may contribute to lung cancer in one or more of the following ways:

• The smoke is the most dangerous component of the cigarette. Chemicals formed during smoking trigger genetic mutations that lead to cancer. When people inhale cigarette smoke, they bring into their lungs tar that includes over 4,000 chemicals, some of which are carcinogenic (cancer-causing). Other inhaled chemicals in cigarette smoke that may increase the risk for cancer include cyanide, benzene, formaldehyde, methanol (wood alcohol), acetylene (the fuel used in torches), and ammonia. Smoke also contains nitrogen oxide and carbon monoxide, both harmful gases.
• Nicotine itself may be a hazard. Some studies indicate that nicotine has a role in causing cancer. Whether or not these studies apply to long-term use of nicotine replacement products (such as patches), or to cigarette smoking, is still unclear. The studies should certainly not discourage people from using nicotine replacement methods for quitting. However, these studies may indicate that people should not use these devices on a long-term basis.

Radon. Radon is a gas produced naturally by the breakdown of uranium. It is often present in the soil and in water and can seep into any dwelling. Radon is the second leading cause of lung cancer.

Other Contributors. Toxic particles leading to precancerous changes in the lung are also found in marijuana. In one study, 53.8% of cigarette smokers, 66.7% of marijuana smokers, and all of those subjects who smoked both substances showed evidence of precancerous changes in the lungs. Smoking just one marijuana cigarette may be as harmful to the lungs as smoking 20 tobacco cigarettes. One study found that people who smoked one joint a day for 10 years had a lung cancer risk 5.7 times higher than that of nonsmokers.

There is considerable debate over the lung cancer risk posed by depleted uranium used in military weapons (such as in the Gulf and Balkan conflicts).

Other lung carcinogens include asbestos, arsenic, certain petrochemicals (materials made from crude oil or natural gas), and other airborne (carried through the air) byproducts of various mining and manufacturing processes.

Click the icon to see an image of the tobacco plant.

Genetic Mutations

Genetic mutations that cause cancer generally occur in two types of genes:

• Tumor-suppressor genes, which prevent cells from endlessly copying themselves
• Proto-oncogenes, which encourage cells to keep making copies of themselves [when a proto-oncogene changes (becomes mutated), it is then called an oncogene]

Damage to either type of gene can cause a mutation that results in uncontrolled division of cells. This uncontrolled division forms tumors.

It is unlikely that a single specific abnormality causes all lung cancer. It probably takes a variety of mutations to start the devastating chain of events leading to cancer. The following mutations are among those under investigation:

• BPDE-caused mutations: The chemical BPDE, a byproduct of tobacco smoke, is involved with a number of genetic mutations, including those to an oncogene called K-ras and to three tumor-suppressor genes known as p53, PPP2R1B, and p16. When normal, the tumor-suppressor genes are involved in cell repair and healthy copying of the cell. When they are damaged or blocked, out-of-control cell production can occur, leading to cancer. About 10% of the population may carry a gene that protects against lung cancer by reducing levels of BPDE.
• Chemotherapy resistance genes: Tumors that contain the p53 mutation may also be more resistant to chemotherapy.
• Rb mutations: Another important contributor to lung cancer is a genetically defective protein called retinoblastoma (Rb), which is associated with very aggressive tumors. Low levels of the normal Rb gene may sometimes predict aggressive cancer, especially in patients with small cell lung cancer.
• Mutations to the FHIT gene: Another potentially important mutation may be an abnormality in the FHIT gene. This mutation causes the cells lining the lung to become more vulnerable to the effects of tobacco smoke and other cancer-causing substances.
• Alpha1-antitrypsin mutations: People who carry a common variation in the gene for alpha1-antitrypsin -- a substance that normally protects the walls of the alveoli in the lungs -- are 70% more likely to develop lung cancer than those without the mutation, regardless of whether they smoke.

Lung cancer is unlikely to produce symptoms until the disease is advanced. When symptoms develop, they may result from the lung tumor itself, from its effects on tissues outside the lung, or from the spread of cancerous cells to other organs.

Early Symptoms

Early symptoms may include the following:

• Frequent bouts of pneumonia, or pneumonia that does not clear up in a normal period of time
• Coughing (particularly coughing up blood)
• Weight loss
• Fever
• Shortness of breath
• Chest pain

Symptoms of Later Stages

Later-stage symptoms and complications include the following:

• Shortness of breath: This common symptom is the result of cancer that has spread in the lung and the pleura -- the membrane covering the lung.
• Superior vena cava syndrome: In some cases, tumor growth or spreading of the cancer presses against the superior vena cava, a large vein that returns blood from the upper part of the body to the heart. When this happens, a condition called superior vena cava syndrome may occur, leading to obvious swelling in the arms and face.
• Trouble swallowing: The esophagus is the pipe that takes food from the mouth to the stomach. The cancer may spread to or press against the esophagus, interfering with swallowing and nutrition.
• Hoarseness: Cancer can damage the nerves that control the voice box, causing hoarseness.
• Pancoast syndrome: Damage to the brachial plexus, a group of nerves branching from the neck, can cause pain, weakness, or numbness in the arm or hand (Pancoast syndrome).
• Bronchoalveolar lung cancer may produce very large amounts of mucus.
• Hypercalcemia: Some lung cancers produce substances that remove calcium from bone and release it into the bloodstream, causing a condition called hypercalcemia. Patients with this disorder can experience nausea, vomiting, constipation, weakness, and fatigue.

Other lung cancers (usually small cell cancer) cause the body to retain water, lowering the blood's sodium levels. This condition, called hyponatremia, can produce confusion, weakness, and even seizures.

Before cigarettes became popular in the beginning of the 20th century, lung cancer was rare. In 2008, lung cancer is expected to strike up to 215,020 Americans, and about 161,840 are expected to die from it. The disease usually occurs in people over 50 years old. Men have a significantly greater incidence of lung cancer compared to women. On the encouraging side, the rate of lung cancer in men has been declining significantly over the past decade. While lung cancer rates have been increasing dramatically in women (by 600% from 1950 to 2000), they now appear to be stabilizing. However, lung cancer deaths among female nonsmokers seem to be on the rise.

Smokers and Those Exposed to Cigarette Smoke

Smoking appears to be the primary risk factor in 85 - 90% of lung cancers. The risk of lung cancer in smokers is about 20 times that of nonsmokers. The risk depends on the duration of the addiction and the number of pack years. (One pack year equals the number of packs of cigarettes smoked per day, multiplied by the number of years that the person has smoked.) Genetic damage in the lung occurs in nearly all chronic smokers, even if cancer has not developed.

People who smoked can be at increased risk for lung cancer more than 20 years after quitting, although the risk drops significantly even in the first year after quitting. There are benefits to quitting smoking, even for people who are well into middle age.

Secondhand Smoke. The Environmental Protection Agency has classified secondhand smoke as a carcinogen (cancer-causing chemical). Exposure to secondhand tobacco smoke increases the risk of lung cancer in the nonsmoker by about 20 - 30%. A 2006 Surgeon General report found that about 3,000 nonsmokers die each year of lung cancer resulting from exposure to secondhand smoke.

Ethnic Differences

There may be some ethnic differences in lung cancer risk. For example, African-American men have about a 45% higher risk of developing lung cancer than Caucasian men. It is not clear what factors are responsible for this higher risk. Some African Americans appear to have a genetic vulnerability to the harmful chemicals in cigarette smoke.

In China, about one-third of all young male smokers will eventually die because of tobacco-related illnesses. Their risk for lung cancer, however, is much less than it is for chronic lung disease, the opposite of the Western trend. One study reported that the lower rate of lung cancer among Chinese people might be due to a slow rate of clearing nicotine, which results in smoking fewer cigarettes.

Socioeconomic Differences

Low income and a lack of education have been linked to an increased risk for lung cancer. Researchers say socioeconomic status is connected to other factors involved in lung cancer risk, such as smoking, diet, and exposure to cancer-causing chemicals in the workplace.

Environmental Factors

People with High Exposure to Radon. Studies have shown that radon raises the risk of lung cancer in underground miners by 40%. It is unclear whether the results of these studies would apply to people exposed to radon in their homes. A cumulative long-term exposure to radon and smoking also increases the danger. Most people move an average of 10 or 11 times over their lifetime, so the risk of developing lung cancer through radon exposure is very low in most individuals, even for those who lived for a while in areas with high radon levels. People with homes that have high radon levels and those who sleep or spend a long time in basements with detectable but moderate levels should consider taking protective measures.

Workers Highly Exposed to Carcinogens. An estimated 9,000 - 10,000 men and 900 - 1,900 women develop lung cancer each year because of occupational exposure to carcinogens. More than half of these cases are attributable to past exposure to asbestos, which has long been known to be a risk factor for mesothelioma (cancer of the pleura, the lining around the lung) and can increase the risk of lung cancer in smokers. With better protective measures, these rates are expected to fall in the future.

Other chemicals that put workers at risk for lung cancer include:

• Arsenic (insecticide and herbicide sprayers, tanners, oil refinery workers)
• Chloromethyl methyl ether (workers exposed to certain polymers, water repellents, or products using chloride and formaldehyde)
• Chromium compounds (workers using certain alloys, paints, pigments, and preservatives)
• Depleted uranium (soldiers exposed to weapons during battlefield conditions)
• Crystalline silica

By contrast, agricultural workers seem to have a lower lung cancer rate, despite their possible occupational exposures to risky chemicals. While this rate has traditionally been attributed to good health habits, including low tobacco use, one study suggests that agricultural workers' exposure to endotoxin may be responsible. Endotoxin is a component of common bacteria found in soil and animals, and it may have cancer-preventing effects on the immune system.

Exposure to Smoke from Grills. Grilling and high-heat frying release chemicals called heterocyclic amines, which are known to cause cancer. One study of Chinese women found that smokers who stir-fried meat daily and inhaled cooking fumes had a higher risk of lung cancer than did those who stir-fried meat less frequently. No higher risk was found among nonsmokers.

Air Pollution. Although any risk from air pollution is very small, it nevertheless may be a contributor to those lung cancers not obviously related to smoking. Some studies have found an association between increased risk for lung cancer and long-term exposure to very small particulates, especially sulfates, in polluted air. The risk, if any, is very small.

Family History

A family history of lung cancer may play a role in increasing susceptibility to this disease. Women who had mothers or sisters with lung cancer have triple the risk. The risk is higher in both smokers and nonsmokers. There is no association between a history of other cancers and lung cancer. Both genetic factors and secondhand smoke appear to contribute to the danger in these individuals.

Other Diseases that Increase Risk

Smokers with emphysema or chronic inflammatory lung diseases, such as asthma, are at increased risk for lung cancer. Both smokers and nonsmokers whose lungs are scarred from recurrent lung diseases, such as pneumonia or tuberculosis, are also at increased risk, particularly for bronchoalveolar lung cancer.

Quitting Smoking

Quitting smoking improves lung function almost immediately. Some evidence suggests that the benefits for the lungs are even more significant for women who quit than for men. However, it can take 20 years or longer, particularly in heavy smokers, for the lungs to be restored to full health and the risk for lung cancer to be reduced as low as it is for nonsmokers. Quitting is extremely difficult. No one should be discouraged if they relapse. Everyone should keep trying to quit. With continued efforts, many people succeed.

At this time perhaps the most effective method for quitting is a combination of the following:

• Nicotine replacement products that reduce withdrawal symptoms and cravings.
• The antidepressants bupropion (Zyban) or nortriptyline (Pamelor, Aventyl), which reduce emotional effects and cravings associated with withdrawal, and improve abstinence rates.
• Professional counseling or support organizations that may, in addition to medication, help people stop smoking.

[For more information, see In-Depth Report #41: Smoking.]

While people are in the process of quitting (and afterwards), they should maintain as healthy a lifestyle as possible.

Dietary Factors

The research on diet and cancer suggests that antioxidants in certain foods may protect against the DNA damage that can lead cells to turn cancerous. It's important to note that, although studies have suggested an association between these factors and cancer risk, no cause-and-effect has been proven. Still, it is always a good idea to eat a generally healthy diet.

Phytochemicals. Some data suggest that diets rich in fresh fruits and vegetables may protect against lung cancer in both smokers and nonsmokers. Studies have reported protection from specific plant chemicals (phytochemicals), such as the following:

• Isothiocyanates. These chemicals are found in cruciferous vegetables (broccoli, cauliflower, and Brussels sprouts). They may help block the effects of carcinogens in smoke, suppress tumor growth, and inhibit cancer growth-promoting steroid hormones.
• Flavonoids. Major sources are apples, grapefruit, onions, red wine, and tea. In one study on flavonoids, apple eaters had the lowest cancer risk, 68% less than those who ate fruit infrequently. In another study, those who ate more onions, apples, and white grapefruit had less than half the lung cancer risk than people who ate relatively small amounts of these foods. Flavonoids are also found in soybeans, berries, broccoli, carrots, citrus fruits, eggplant, peppers, squash, and tomatoes. Specific flavonoids in dark chocolate may help protect against lung cancer (but not other cancers).
• Lycopene. Lycopene is found in tomatoes, which have been associated with a lower risk for lung cancer. Cooking the tomatoes appears to increase the potency of lycopene.
• Cryptoxanthin. Some studies suggest that eating foods rich in cryptoxanthin, a yellow-orange pigment, reduces the risk for lung cancer. Foods with high amounts of cryptoxanthin include pumpkins, corn, papayas, red bell peppers, tangerines, oranges, and peaches. More research is needed in this area, however.
• Isoflavones. Found in soybeans and flaxseed, isoflavones behave like estrogen in some ways and not in others. Some evidence suggests the genistein (a type of isoflavone) in soy may have properties that protect against lung cancer.

Click the icon to see an image of phytochemicals.

Note: Studies on these chemicals are not consistent. It is unlikely that individual phytochemicals offer protection, but rather that the benefits come from a collection of vitamins and plant chemicals contained in fruits and vegetables. Fruit, especially, appears to be protective.

Fats and Oils. Some studies have indicated that diets high in animal fats increase the risk for lung cancer. Others have suggested some protection from cod liver oil, which contains omega-3 fatty acids (found in fatty fish), omega-6 fatty acids (found in flax and in soybean and canola oils), and monounsaturated oils (found in olive and canola oils). However, the ability of these substances to protect against lung cancer remains controversial, and quitting smoking remains the best advice.

Click the icon to see an image of fats and oils.

Vitamin Supplements. Even in those who eat a healthful diet, smoking reduces the levels of a number of vitamins, importantly vitamin C. There is not enough evidence, however, to support any benefit from taking antioxidant supplements, including vitamins C, E, A, folate, or beta carotene.

In fact, evidence is now suggesting that high doses of vitamin C, vitamin E, and beta carotene supplements may have harmful effects. The strongest studies to date on the negative effects of antioxidant supplements have reported an increase in lung cancer and overall mortality rates among smokers who took beta carotene or vitamin E supplements. This is particularly important information for smokers, who may carry precancerous or cancerous cells for years before developing the disease. The best way to get healthy levels of important nutrients is by eating healthy foods.

Click the icon to see the benefits of vitamin A.

Click the icon to see dietary sources of vitamin A.

Trace Element Supplements. Trace elements may be important in cancer risk and prevention.

Selenium appears to inhibit cell production and may have other anti-cancer properties. A few studies have reported some protection with selenium. However, one major analysis found that taking selenium only helps people who are deficient in the nutrient to begin with.

Click the icon to see the benefits of selenium.

Zinc may prove to be more important than selenium. Some research suggests that zinc may help protect smokers by blocking cadmium. Smokers have higher levels of cadmium in their body, and there may be a link between cadmium and a higher risk for lung cancer. Some laboratory studies have indicated that zinc might help protect against tumor progression. There is no evidence that taking zinc supplements will reduce the risk for lung cancer, however.

Protecting the Home against Radon

People concerned about radon in their home or area can purchase a test approved by the Environmental Protection Agency. One way to remove radon is by installing a soil suction system. It should be noted, however, that home prevention measures rarely reduce radon levels to zero. Simply sleeping by an open window reduces the risk.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and COX-2 Inhibitors (Coxibs)

Nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors (coxibs) both block cyclooxygenase (COX) enzymes. NSAIDs block COX-1 and 2, and coxibs selectively block COX-2. Evidence now strongly suggests that the COX-2 enzyme plays a role in blood vessel growth (angiogenesis) that can feed lung cancers.

NSAIDs. NSAIDs include aspirin, ibuprofen (Advil), and naproxen (such as Aleve, Naprosyn, Naprelan, amd Anaprox). These drugs inhibit COX-2, but they also target another COX enzyme. Studies are now reporting an association between regular use of aspirin or other NSAIDs and a reduced risk for non-small cell lung cancer.

COX-2 Inhibitors. The COX-2 inhibitors are more recent forms of NSAIDs. Only celecoxib (Celebrex) is still on the market. Because these medications target the COX-2 enzyme specifically, researchers are focusing on these drugs for a possible role in treating lung cancer and preventing its recurrence.

These medications are not currently recommended specifically for the purpose of reducing cancer risk.

Chest X-Rays. In a small percentage of cases, a routine chest x-ray reveals the first signs of lung cancer. Usually, however, symptoms of existing lung cancer, such as coughing, chest pain, and blood in the sputum, will lead to a chest x-ray. If non-small cell lung cancer is present, chest x-rays may show lesions (damaged or abnormal tissue) in the center of the lung, cavities formed by squamous cell carcinoma, or a lace-like pattern of cells spreading through the lungs. By the time lung cancer is diagnosed by chest x-rays, however, it has often spread so far that it cannot be surgically cured. Four major studies found no survival benefits in early detection from chest x-rays and sputum screening. Regular screening for lung cancer using x-rays is therefore not recommended.

Computed Tomography. Computed tomography (CT), particularly the specific technique called low-dose spiral (or helical) CT, is more effective than x-rays for detecting cancer in patients with suspected lung cancer. It is the standard imaging procedure for determining if and where the cancer has spread (metastasized). Surgeons also use CT scans to evaluate patients before lung surgery.

The use of helical CT for early screening is still controversial. Studies of CT scans in smokers suggest that early screening will detect about 2% of lung cancers, most of these in the early stages. In the studies, 62 - 82% of the patients with stage 1A cancer (when the tumor has not yet spread) were still alive at 5 years. Neither study, however, was controlled (compared with other groups, such as nonsmokers). The survival figures were likely to be higher than in actual practice.

Click the icon to see an image of a CT scan of the chest.

Evidence to date has not proven a survival benefit of using CT scans to screen people without symptoms. Many experts are highly opposed to widespread screening for lung cancer. Some evidence, for example, suggests that lung cancer cells in non-small cell lung cancer are often very aggressive at microscopic levels (before a tumor is formed). If this were true, the cancer would be highly likely to have spread long before it was visible with CT scans. Moreover, some studies have found no association between tumor size at the time of diagnosis and survival times.

It should also be noted that about 98% of suspicious areas seen on CT scans turn out to be benign. Even after rescreening, many scans will show suspicious areas that turn out to be harmless but will require invasive and expensive biopsies. In these cases, patients might be more likely to die from aggressive treatments than from the disease itself. Additional experience with CT scans, however, may allow experts to better determine which abnormalities are likely to be benign.

High-risk individuals who are still interested in early screening with CT scans should ask their doctor about available clinical trials.

Other Imaging Tests for Staging and Tracking Cancer

Computed tomography is the standard imaging procedure for determining if and where the cancer has spread (metastasized). Other imaging tests, however, may also be useful for staging and tracking lung cancers (staging means finding out how advanced the cancer is).

Positron Emission Tomography. Positron emission tomography (PET), specifically a technique known as FDG/PET, is the most accurate noninvasive test for detecting early lung cancer. It can diagnose lung tumors as small as 1 centimeter with very high accuracy, and reduce the need for unnecessary surgical procedures. Researchers say PET works best when used with CT scans. PET is also the best imaging technique for staging lung cancers -- not only those located in the lungs, but also those that have spread, particularly into the space between the two lungs (the mediastinum). With this imaging test, the patient is first injected with a specially formulated liquid sugar (called FDG), and then viewed with a machine that records energy given off by tumor cells.

PET is expensive and not widely available. However, its supporters suggest that it may prevent many unnecessary surgeries by identifying patients whose cancer has advanced past the stage at which surgery is helpful.

Magnetic Resonance Imaging. Magnetic resonance imaging (MRI), an imaging procedure that uses radio wave energy, is frequently used instead of CT scanning to locate brain and bone cancers that have spread from the lung.

Biopsy Procedures

Biopsies of lung tissue are needed to confirm lung cancer. This requires invasive procedures that may vary from simple needle aspiration to chest surgery.

Needle Aspiration. Sometimes, a biopsy specimen is obtained by inserting a needle between the ribs, and then guiding it with the use of CT scans, ultrasound, or fluoroscopy (a device allowing an x-ray view). Specific techniques include transbronchial or transthoracic needle aspiration (TBNA or TTNA) or endoscopic ultrasound-guided needle aspiration (EUS-NA). Their use depends on how much of the area can be observed with less invasive imaging methods. There is a 5 -10% risk for bleeding or collapsed lung with needle aspiration.

Thoracoscopy. Thoracoscopy is usually very effective for diagnosing cancer in the outer areas of the lungs, or those involving the pleura (membrane surrounding the lungs). This is a surgical procedure that uses a fiber optic tube to view the area. The procedure requires general anesthesia. The surgeon passes surgical instruments and a fiber optic tube through a small incision in the chest. The tube has a camera in it, which allows the surgeon to look at the lungs on a video screen.

Bronchoscopy. To locate cancer that develops in the central areas and major airways of the lung (usually squamous or small-cell cancer), bronchoscopy is typically performed. The procedure is done as follows:

• The patient is given a local anesthetic, oxygen, and sedatives.
• The doctor inserts a bronchoscope -- a hollow flexible tube, often containing a fiber optic light source, into the lower respiratory tract through the nose or mouth.
• The tube acts like a telescope into the body, allowing the doctor to see the windpipe and major airways. In a procedure called fluorescence bronchoscopy, the doctor injects the patient with a drug that makes cancer tissue appear red when exposed to laser light from the bronchoscope.
• The surgeon removes specimens for biopsy, ideally combining techniques to include cutting tissue, brushings, and a washing process called bronchoalveolar lavage (BAL). BAL involves injecting saline through the bronchoscope into the lung and then immediately suctioning the fluid back through the hollow tube of the bronchoscope. The fluid is then analyzed in the laboratory. Both brushing and washing procedures may be very valuable additions to this procedure.

Advances in bronchoscopy, such as laser-induced fluorescence endoscopic bronchoscopy, may improve early detection of cancer.

Bronchoscopy is usually very safe, but complications can occur. They include:

• Allergic reactions to the sedatives or anesthetics
• Asthma attacks in susceptible patients
• Bleeding

Patients may develop a fever after the procedure.

Click the icon to see an image of a bronchoscopy procedure.

Click the icon to see an image of a bronchoscope.

Mediastinoscopy. Mediastinoscopy uses a tube inserted between the lungs to locate the appropriate areas for biopsy. It is performed if the physician suspects that cancer has spread to nearby lymph nodes but has not yet spread to other parts of the body.

Laboratory Tests

Sputum Analysis for Presence of Cancer Cells. Some experts are now recommending an analysis of coughed-up sputum as a useful and cost-effective measure for identifying cancer cells, particularly those located in central areas of the lung. However, although sputum analysis appears to be as accurate as any other screening test currently conducted, it may miss cancers such as adenocarcinoma, which form in mucus-producing cells typically in the outer portion of the lungs. If a sputum analysis does not show cancer cells, but other signs of lung cancer are present, including blood in the sputum and suspicious areas on x-rays, other tests are performed.

Biomarkers. Biologic markers, called biomarkers, are high levels of substances that are released by tumors and indicate the presence of specific cancers. Biomarkers can be found in sputum, blood, and tissue samples. They can include:

• Enzymes
• Hormones
• Amino-acid compounds
• Antigens (identified by antibodies that specifically target them)
• Growth factors
• Other chemicals

A blood test based on four proteins in the blood (carcinoembryonic antigen, retinol binding protein, alpha1-antitrypsin, and squamous cell carcinoma antigen) appears to be very sensitive for diagnosing lung cancer. Researchers say the test, which is still experimental, may help determine whether patients with suspicious lung lesions seen on x-rays need biopsies.

Some biomarkers may reveal the presence of cancer cells before these cells are evident on CT scans or other imaging tests. For example, genetic mutations, notably K-ras and p53, can now be detected in cells found in sputum, or cells taken during bronchoscopy. Such mutations occur only with cancerous changes and may allow the disease to be detected early. Other markers that may prove to be important for predicting aggressive cancers are high levels of matrix metalloproteinase (MMP9) and vascular endothelial growth factor (VEGF), which are compounds involved with the growth of blood vessels that feed tumors (angiogenesis).

Other Tests

As part of the doctor's initial examination, patients may have a pulmonary function test to evaluate lung health and capacity. The doctor may also take a complete history of the heart and lungs, because they are often involved in complications following lung cancer surgery.

Tests to Determine Cancer Stage. After diagnosing non-small cell lung cancer, the doctor makes treatment choices by determining the cancer's stage (how large the tumor is and how far the cancer has spread). To stage the cancer and determine other aspects of the disease, a number of tests are conducted:

• The cancer cells are examined microscopically for size, shape, and other configurations that may indicate whether the cancer is likely to spread, even if the tumor is small.
• Computer tomography (CT) and positron emission tomography (PET) are used to scan the lung and perhaps other locations, such as the liver, upper abdomen, and brain, to determine if and how far the disease has spread. Magnetic resonance imaging (MRI) is also sometimes used. Research is finding that PET scans are more accurate than CT scans for staging lung cancer. Regardless of which imaging test is used, experts say the results should be confirmed with a biopsy.

Physical Examination. A detailed physical examination of the whole body is very important to identify or rule out the spread of cancer to other areas, and to determine the patient's general condition. For example, questions about dizziness or headaches can help the doctor determine if the cancer has spread to the brain. Bone or joint pain might suggest that the cancer has spread to the bone. The doctor will also look for head and neck symptoms that might indicate other tumors. Also, the patient's weight loss and ability to function are two very important factors for predicting survival following treatment. Patients who are mobile and have lost less than 10% of their pre-treatment weight tend to have better survival rates.

Staging Systems

In lung cancer, the stage of the disease at the time of diagnosis is a major factor in determining how to treat the cancer, and how long the patient can expect to live. In general, survival is longest for patients with very early-stage disease and shortest for patients with very advanced disease that has spread to several areas of the body. Staging is based on the results of physical and surgical examinations, and laboratory and imaging tests, including biopsies.

To determine the stage, medical professionals first categorize each tumor by size and by how far it has extended. This identification method is called the TNM system.

The TNM categories then determine the stage (numbered 0 to IV) of the cancer.

The TNM System

TNM stands for Tumor, regional lymph Nodes, and Metastasis (cancer spread beyond the original tumor).

T refers to the size and spread of the tumor. In TX and T0, the tumor is indicated by cancer cells in sputum or lung samples but it cannot be seen.

Tis: Carcinoma in situ. The cells are cancerous, but the tumor does not show evidence of spreading.

In T1, the tumor is 3 cm or less in size, is still contained in the lung or the membrane covering the lung, and has not reached the main airway.

In T2, the tumor has one or more of the following features:

• It is greater than 3 cm
• It involves the main airway
• It is 2 cm or more away from the ridge (the carina) at the lowest part of the windpipe
• It has invaded the pleura
• It is associated with collapsed lung tissue (atelectasis) or swelling that blocks part (but not all) of the lung

In T3, a tumor of any size has directly invaded any of the following:

• Chest wall
• Diaphragm
• Membrane covering organs and structures in the chest
• Outer wall of the membrane around the heart (pericardium)

In addition, one or more of the following conditions are present:

• The tumor is in the main airway, less than 2 cm away from the carina, but is not in the trachea (windpipe).
• The tumor is associated with a collapsed lung or swelling that blocks the entire lung.

In T4, the tumor has invaded any of the following:

• Area between the lungs (mediastinum)
• Heart
• Great vessels (the blood vessels that carry blood from the heart)
• Carina, trachea, or esophagus
• Main portion of the spine

In addition, one or both of the following occurs:

• Separate tumors are present in the same lobe
• The tumor is accompanied by an increased amount of fluid between the pleural membrane and the lung.

N followed by a number from 0 to 3 refers to whether the cancer has reached regional (in the area of tumor) lymph nodes.

• In stage N0, the regional lymph nodes are still cancer-free.
• In N1, the cancer has spread to the nearest lymph nodes around the airways, to the hilum (a central zone in the lung where blood and lymph vessels enter), or both. The tumor has extended directly into lymph nodes within the lung.
• In N2, the cancer has spread to lymph nodes in the middle of the chest next to the affected lung, to the nodes below the carina, or to both regions.
• In N3 the cancer has spread to lymph nodes in the middle of the chest that are next to the opposite lung, to the hilum in the opposite lung, to lymph nodes in nearby or opposite muscle tissue, or to lymph nodes above the collar bone.

M Stages refer to cancer spread (metastasis).

• In M0, spread has not occurred.
• In M1 distant spread has occurred. This includes the presence of a separate tumor in a different lobe of the lung.

Other Factors Determining Treatment Choices and Outcome

Staging factors are used to help determine treatment and outlook. The following suggest a more aggressive disease:

• The presence of respiratory symptoms
• A tumor larger than 3 cm
• High numbers of blood vessels in the tumor

Researchers are always looking for more accurate ways to determine lung cancer treatment and outlook. For example, some research involves specific biomarkers and related blood vessel development within tumors. These markers might eventually help predict the cancer's aggressiveness and determine the best treatment approach.

Occult Stage

In the occult stage (TX, N0, M0), cancer cells are found in a sample of a patient's coughed-up sputum, but no cancer cells have yet been detected in the lung.

Treatment Options. Surgically removing the tumor (if one can be located) can allow doctors to identify the stage, and often results in a cure.

Stage 0 or Carcinoma in Situ

Stage 0 or carcinoma in situ (Tis, N0, M0) are noninvasive cancers. Only a few layers of cancer cells are detected within one local area. The cancer has not grown through to the top lining in the lung and can be surgically removed. There is a high risk for development of a second tumor, however.

Treatment Options:

• Surgery, often a limited procedure, where only part of a lobe is removed from the lung.
• In patients who cannot be treated surgically, consider photodynamic therapy, cryotherapy, or brachytherapy.

Stage I

In stage I, the cancer has reached the higher layers of the lung but has not spread into the lymph nodes or beyond the lung.

General Treatment Options. The primary treatment is surgery, such as lobectomy (removal of a whole lobe), if possible. Patients with poor lung function should have partial lobectomy, if possible. Radiation treatments may be appropriate and beneficial for patients who cannot have surgery. It is not clear if early-stage lung cancer patients who have radiation or chemotherapy in addition to surgery have higher survival rates. The overall 5-year survival rates for early stage-cancer are in the range of 30 - 50%. Patients should consider clinical trials to prevent cancer from returning after the initial treatment. The risk for recurrence is highest in patients who continue to smoke.

• Stage IA (T1, N0, M0). Treatment options are:
  • Lobectomy or sometimes pneumonectomy (removal of one lung)
  • Wedge or segment removal, particularly in patients with poor lung function who cannot handle lobectomy
  • Radiation in selected patients whose condition is inoperable (for example, frail patients) or whose cancer cannot be fully removed
  • In general, chemotherapy is not done following surgery unless the tumor is not completely removed
• Stage 1B (T2, N0, M0). Treatment options are:
  • Lobectomy or sometimes pneumonectomy; wedge or segment removal, particularly in patients with poor lung function
  • Radiation in selected patients whose condition is inoperable (for example, frail patients) or cannot be fully resected
  • In general, chemotherapy is not done following surgery unless the tumor is not completely removed

Stage II

In stage II the cancer cells have spread to nearby lymph nodes.

General Treatment Options. Surgery, usually removal of a lobe (lobectomy) or one lung (pneumonectomy), is the treatment of choice. Five-year survival rates associated with stage II surgery can vary.

If the tumor is completely removed, radiation therapy is usually not performed after surgery. Patients whose cancer is inoperable may consider radiation and chemotherapy treatments.

Patients who do well after surgical resection often receive a platinum-based chemotherapy regimen.

In patients who can complete treatment, 5-year survival rates average 20 - 30%, with higher rates for stage IIA.

Stage III

In stage III, the cancer cells have spread beyond the lung to the chest wall, diaphragm, or further lymph nodes, such as those in the neck.

General Treatment Options. Generally, the treatment of choice for stage III tumors is radiation and sometimes surgery, chemotherapy, or combinations of all three.

Combination approaches may be significantly more effective than single treatments. One treatment approach starts with chemotherapy and radiation, given at the same time, followed by surgery. In one study, 5-year survival in stage III patients treated this way was nearly 50%.

• Stage IIIA (T1, N2, M0) or (T2, N2, M0) or (T3, N1, M0) or (T3, N2, M0).
  • Surgery, if the tumor and affected lymph nodes can be completely removed. Consider platinum-based chemotherapy or radiation therapy after surgery.
  • Radiation treatment plus platinum-based chemotherapy, given at the same time, is an option for those in otherwise good health. This regimen should be followed by surgery, if possible. This is generally not recommended outside of a clinical trial, however.
  • Consider clinical trials using advanced radiation techniques, including continuous hyperfractionated accelerated radiation, or 3-D conformal radiation.
  • Consider other clinical trials, including those of various combination treatments, preventive radiation therapy to the brain, and new second-line drugs.
• Stage IIIB (Any T, N3, M0) or (T4, Any N, M0). Some patients may consider surgery if the lymph nodes are not involved (T4, N0), and the tumor can be removed. Surgery is not an option for other patients with stage IIIB cancer.

Treatment Options.

• Radiation alone, usually for symptom control; it may improve survival in certain patients, such as those with lymph node involvement above the collar bone
• Chemotherapy alone
• Cisplatin-based chemotherapy given at the same time (concurrent) as radiation, sometimes followed by surgery, if possible
• Clinical trials using induction chemotherapy alone to shrink tumors, which may then be treated with surgery or radiation
• Clinical trials using advanced radiation techniques, including continuous hyperfractionated accelerated radiation, or 3-D conformal radiation
• Other clinical trials, including those of various combination treatments, preventive radiation therapy to the brain, and new second-line drugs

Stage IV

In stage IV (any T, any N, M1), the cancer has spread (metastasized) to other parts of the body.

Treatment Options.

• Combination of two- or three-drug chemotherapies that include platinum-based drugs and newer drugs; the best candidates are patients in otherwise good health, who have a limited number of distant tumors. Chemotherapy is not recommended for patients who are too ill.
• Bevacizumab (Avastin) may be used for patients with non-squamous lung cancer, no spread to the brain, and who are not coughing up blood.
• External-beam radiation for symptom relief
• Paclitaxel, gemcitabine, or docetaxol are all additional drug options
• Other clinical trials
• If metastasized cancer involves only one or two areas in the brain, it may respond to surgery followed by radiation to the brain.

Recurring or Additional New Tumors

Recurring or new tumors occur (usually in the lung again) in half of treated patients. Research shows that a single tumor in the lung is more often a new tumor that, in many cases, may be operable.

Treatment Options.

• Radiation for symptom control
• Chemotherapy with or without bevacizumab (Avastin)
• If the cancer has spread to only one site in the brain, it may respond to surgery, followed by whole-brain radiation. Extended disease-free survival is possible. If the brain tumor is not operable, it is treated with radiation. Even if cancer returns in the brain (in 50% of cases), treating it again is possible in many patients, if the disease has not spread elsewhere in the body.
• Laser therapy or interstitial radiation for tumors inside the airways
• Stereotactic radiosurgery (in a few selected patients)

Surgery is performed in the following circumstances:

• The surgical removal of an entire lobe or parts of a lung is the primary treatment for eligible patients in early stages of cancer. Recurrence is high after surgery, although the new tumor is often operable.
• Some patients with stage IIIA cancer may also benefit from surgery. The intent at this stage is to extend survival time, rather than cure the disease.
• Surgery is not out of the question in rare cases of metastasis when the cancer appears in a single operable location, such as the brain.

Unfortunately, lung surgery may be too risky for patients with other lung diseases or serious medical conditions, and because lung cancers tend to occur in smokers over 50, such health problems are likely to be present. Long-term survival rates appear to be better in patients treated at hospitals that perform large numbers of lung cancer surgeries, and when surgeries are performed by thoracic surgeons, who specialize in chest procedures.

Standard Surgical Procedures

The type of surgery depends on the amount of lung or other tissue that needs to be removed.

Wedge Resection or Segmentectomy. Wedge resection and segmentectomy remove only a small part of the lung; consequently, they preserve almost normal breathing function after the operation.

Lobectomy. Removal of one of the lobes of the lung is called lobectomy. The patient's lung function must be adequate before undergoing this procedure. The operation carries an overall mortality rate of 3 - 5%, with older patients having the highest risk.

Click the icon to see an illustrated series detailing surgery to remove diseased lobes of the lung.

Pneumonectomy. Pneumonectomy removes the entire lung. The procedure itself carries a mortality rate of 5 - 8%, with the oldest patients having the greatest risk. In such patients, recurrence almost always occurs.

Other Procedures

Surgical advances are allowing a wider range of options, including minimal surgeries for early cancers and surgeries that relieve cancer symptoms in late stages of the disease.

Thoracoscopy. Thoracoscopy, also known as video-assisted thoracic surgery (VATS), is a less-invasive technique that employs a thin tube containing a miniature camera and surgical instruments. It requires much smaller incisions than open surgery and speeds recovery to the point that patients are up within hours. Though the procedure is not appropriate in all cases, it offers significant advantages, especially in older or frail patients. The death and complication rates following VATS are lower than those following conventional surgeries. Pain is reduced, and patients are released from the hospital quicker. Several studies found that the 5-year survival and recurrence rates in patients with stage I NSCLC treated with VATS were comparable to those in patients treated with traditional open chest surgeries.

Laser Surgery. Laser surgeries allow removal of minimal amounts of lung tissue and are proving useful for improving symptoms in stage II and IIIA patients. They may also be beneficial in treating cancers that have spread to the throat, obstructing it.

Photodynamic Therapy. Photodynamic therapy uses bronchoscopy and special laser light beams combined with a light-sensitive drug, called porfimer sodium (Photofrin), to kill cancer cells. The most common side effect is sun sensitivity. Serious side effects include bleeding in the lungs. Photodynamic therapy may be considered for patients in early-stage disease who are not candidates for other surgical procedures. It may also be used to reduce symptoms in late-stage disease.

Cryosurgery. Cryosurgery uses a probe chilled to below freezing to destroy the tumor cells on contact and is being investigated in combination with radiation therapy. It may also be an alternative in early stage cancer for patients who cannot have surgery.

Electric Cauterization. Electric cauterization, the use of electricity to produce heat that destroys tissue, is also under investigation as a treatment for early-stage disease.

Back Surgery. Spinal cord compression is a common cause of pain in patients with advanced lung cancer. Because such patients can live for a year or longer, some research indicates that back surgery followed by radiation therapy can significantly improve the quality of life for many of these patients.

In addition to surgery, radiation is the other primary treatment for early-stage lung cancer. Doctors are also studying the benefits of radiation treatment in advanced lung cancer.

Radical Radiation in Early-Stage Cancer. Radical radiation is used as the sole procedure in stage I and some stage II patients who have adequate lung function but, for medical or other reasons, cannot be treated with surgery. In these cases, the 5-year survival rate is about 20%, and the cancer is likely to recur. Survival rates may be higher or lower, depending on the tumor size. In general, treatment with radiation therapy alone shows less benefit with larger tumors. A 2002 analysis suggested that the use of radiotherapy after surgery in patients whose tumors had been completely removed might be associated with reduced survival rates. Nevertheless, a recent study confirmed earlier results that show that radiation therapy by itself is as effective as surgery in patients who are unable or unwilling to have surgery for early stage non-small cell lung cancer.

Combined Treatments for Improving Survival in Advanced Cancer. Radiation is also being investigated in various combinations with chemotherapy, surgery, or both. At this time, concurrent radiation treatment plus platinum-based chemotherapy may extend survival times in advanced lung cancer. Other combinations are showing promise.

Palliative Radiation. Doctors use palliative radiation to shrink tumors and reduce pain and symptoms. Palliative radiation is appropriate for patients with advanced disease and poor lung functions, or in those with metastasized cancer. In up to 85% of patients with advanced disease, palliative radiation therapy helps relieve pain, shortness of breath, the superior vena cava syndrome, coughing up blood, and symptoms caused by brain metastases. Radiation, in these cases, is not generally used with the intention of reducing mortality rates, although it may increase survival in some patients, such as those with excellent lung function whose tumors are small.

Delaying radiation therapy until symptoms develop does not appear to reduce survival times or impair quality of life compared to starting it right away, in patients with minimal or no symptoms.

Radiation Therapy in Metastasis to the Brain. Radiation is the primary treatment when cancer has spread to the brain unless the cancer is small enough to be treated surgically. When radiation is used, a technique called stereotactic radiosurgery may be used to deliver powerful, highly targeted radiation to specific areas in the brain. Some trials are investigating using radiation to the head to prevent metastasis to the brain.

Standard Radiation Procedures

The goal of radiation treatment is to administer doses as high as possible to kill as many cancer cells as possible, without destroying surrounding healthy tissues or causing a dangerous reaction. Doctors may try different procedures for the same patient. The exact radiation procedure depends on the site of the cancer or how far it has spread:

• External-Beam Radiation. External-beam radiation therapy focuses a beam of radiation directly on the tumor. It is generally used for metastasized cancer.
• Brachytherapy. Brachytherapy involved the implantation of radioactive seeds through thin tubes directly into the cancer sites. Brachytherapy may be used for lung cancers that have spread to the throat and caused obstruction. High-dose-rate brachytherapy may also have some value for patients with inoperable tumors in the central region of the lung.

Hyperfractionated Radiotherapy

Hyperfractionated radiotherapy gives smaller than standard doses a number of times a day (usually two or three). This allows doctors to use a higher cumulative dose over the whole course of treatment. It is not as useful as therapy by itself, but should be combined with chemotherapy to have any survival benefits.

Hyperfractionated Accelerated Radiotherapy. Continuous hyperfractionated accelerated radiotherapy (CHART) administers multiple doses per day but uses standard doses. This allows the total dose of radiation to be administered over a shorter time period than the standard 6 weeks. CHART is proving to extend survival rates of patients with localized cancer over that of standard radiotherapy or non-accelerated hyperfractionated radiation. It can cause severe swallowing problems. A modification in which treatment is suspended for 2 days out of 7 may help reduce this effect.

Three-Dimensional Conformal Radiotherapy

Three-dimensional (3-D) conformal radiotherapy delivers external-beam radiation designed to closely match the specific targeted organs or tissues. This allows significantly higher doses to attack the cancer while reducing the risk to healthy cells. In a 2003 report, 3-year survival rates in stage IIIA patients were nearly 60%, and nearly half the patients experienced no side effects.

Stereotactic body radiotherapy, an advance on conformal radiation, uses a body frame and an abdominal press to immobilize the patient's body and limit breath movement. This allows a more accurate delivery of high-energy radiation. The technique is still investigational.

Side Effects of Radiation Therapy

Radiation can have significant side effects when used as part of intensive treatments, such as hyperfractionated radiotherapy or radiotherapy in combination with chemotherapy. Among the most serious problems is severe inflammation in the esophagus (esophagitis) or the lungs (pneumonitis). Infection is also a danger.

The use of targeted approaches, such as conformal radiotherapy, may help reduce these complications. Investigators are also studying drugs, notably amifostine, which appear to help reduce throat and lung inflammation caused by radiation, without reducing its cancer-fighting effects.

Occult Stage

In the occult stage (TX, N0, M0), cancer cells are found in a sample of a patient's coughed-up sputum, but no cancer cells have yet been detected in the lung.

Treatment Options. Surgical removal of the tumor, if one can be located, allows identification of its stage and often results in cure.

Stage 0 or Carcinoma in Situ

Stage 0 or carcinoma in situ (Tis, N0, M0) are noninvasive cancers and only a few layers of cancer cells are detected within one local area. The cancer has not grown through to the top lining in the lung and can be surgically removed. There is a high risk for development of a second tumor, however.

Treatment Options:

• Surgery, often a limited procedure, where only part of a lobe is removed from the lung.
• In patients who cannot be treated surgically, consider photodynamic therapy, cryotherapy, or brachytherapy.

Stage I

In stage I, the cancer has reached higher layers of the lung but has not spread into the lymph nodes or beyond the lung.

General Treatment Options. The primary treatment is surgery, such as lobectomy (removal of a whole lobe), if possible. Patients with poor lung function should undergo partial lobectomy, if possible. Radiation treatments may be appropriate and beneficial for patients who cannot have surgery. It is not clear if early-stage lung cancer patients, who have radiation or chemotherapy in addition to surgery, have higher survival rates. A 2002 analysis suggested that the use of radiotherapy after surgery in patients whose tumors had been completely removed might be associated with reduced survival rates. An analysis of studies using chemotherapy in addition to surgery or radiotherapy, however, indicated benefits in survival. The overall 5-year survival rates for early stage-cancer are in the range of 30 - 50%. Patients should consider clinical trials for prevention of recurring (returning) cancer after the initial treatment. The risk for recurrence is highest in patients who continue to smoke.

• Stage IA (T1, N0, M0). The 5-year survival rates for stage IA patients after successful treatment can be as high as 80%. Treatment options are:
  • Lobectomy or sometimes pneumonectomy (removal of one lung)
  • Wedge or segment removal, particularly in patients with poor lung function who cannot withstand lobectomy
  • Radiation in selected patients whose condition is inoperable (for example, frail patients with T1 tumors); 5-year survival rates can be equal to those with surgery, between 32 - 60%
  • Clinical trials of adjuvant chemotherapy following surgery

• Stage 1B (T2, N0, M0). Stage IB survival rates after treatment can be better than 60%. Treatment options are:
  • Lobectomy or sometimes pneumonectomy; wedge or segment removal, particularly patients with poor lung function
  • Clinical trials of chemotherapy following surgery
  • Clinical trials of chemotherapy before surgery (induction therapy; studies are promising)
  • Clinical trials for radiation treatments in selected patients whose condition is inoperable
  • Clinical trials of chemotherapy before, after, or during radiation treatments

Stage II

In stage II the cancer cells have spread to nearby lymph nodes.

General Treatment Options. Surgery, usually removal of a lobe (lobectomy) or one lung (pneumonectomy), is the treatment of choice. Five-year survival rates associated with stage II surgery can vary. A 2000 review of existing research places the numbers as high as 40 - 50%, but notes that they can drop to 25% and below if the cancer has spread beyond the immediate lymph nodes.

Patients whose cancer is inoperable may consider radiation treatments. In patients who can complete treatment, 5-year survival rates average 20 - 30%, with higher rates for stage IIA. Patients should consider clinical trials for prevention of recurring cancer after primary treatment. To date, however, supplementing surgical treatment with radiation or chemotherapy does not appear to prolong survival rates.

• Stage IIA (T1, N1, M0). Survival rates can be as high as 60%. Treatment options are:
  • Surgery
  • Radiation
  • Clinical trials of chemotherapy following surgery
  • Clinical trials of chemotherapy before, after, or during radiation treatments
  • Clinical trials of chemotherapy to reduce tumor size before surgery (induction therapy)
• Stage IIB (T2, N1, M0) or (T3, N0, M0). Survival rates can be over 40%. Treatment options are:
  • Surgery
  • Radiation
  • Clinical trials of chemotherapy following surgery
  • Clinical trials of chemotherapy before surgery (induction therapy)
  • Clinical trials of chemotherapy before, after, or given at the same time as radiation treatments

Stage III

In stage III, the cancer cells have spread beyond the lung to the chest wall, diaphragm, or further lymph nodes, such as those in the neck.

General Treatment Options. Generally, the treatment of choice for stage III tumors is radiation and sometimes surgery, chemotherapy, or combinations of all three.

Combination approaches may be significantly more effective than single treatments. For example, of particular interest is a treatment approach that starts with chemotherapy and radiation, given at the same time, followed by surgery. In one study, 5-year survival in stage III patients treated this way was nearly 50%.

• Stage IIIA (T1, N2, M0) or (T2, N2, M0) or (T3, N1, M0) or (T3, N2, M0).
  • Surgery, if the tumor and affected lymph nodes can be completely removed. Consider platinum-based chemotherapy or radiation therapy after surgery.
  • Radiation treatment plus platinum-based chemotherapy, given at the same time, is an option for those in otherwise good health. This regimen should be followed by surgery, if possible.
  • Consider clinical trials using advanced radiation techniques, including continuous hyperfractionated accelerated radiation, or 3-D conformal radiation.
  • Consider other clinical trials, including those of various combination treatments, preventive radiation therapy to the brain, and new second-line drugs.
• Stage IIIB (Any T, N3, M0) or (T4, Any N, M0). Some patients may consider surgery if there is no lymph node involvement (T4, N0), and tumor can be removed. Surgery is not an option for other patients with stage IIIB cancer. Treatment options are:
  • Radiation alone, usually for symptom control; it may improve survival in certain patients, such as those with lymph node involvement above the collar bone
  • Chemotherapy alone
  • Concurrent (given at the same time) cisplatin-based chemotherapy plus radiation, sometimes followed by surgery if possible
  • Clinical trials using induction chemotherapy alone to shrink tumors, which may then be treated with surgery or radiation
  • Clinical trials using advanced radiation techniques, including continuous hyperfractionated accelerated radiation, or 3-D conformal radiation
  • Other clinical trials, including those of various combination treatments, preventive radiation therapy to the brain, and new second-line drugs

Stage IV

In stage IV (any T, any N, M1), the cancer has spread (metastasized) to other parts of the body.

Treatment Options are:

• Combination of two- or three-drug chemotherapies that include platinum-based drugs and newer agents; the best patient candidates are those in otherwise good health, who have a limited number of distant metastasized sites. Chemotherapy is not recommended for patients who are too ill
• External-beam radiation for symptom relief
• Paclitaxel or gemcitabine as a single medication
• Other clinical trials
• If metastasized cancer involves only one or two areas in the brain, it may respond to surgery followed by radiation to the brain

Recurring or Additional New Tumors

Recurring or additional new tumors occur, usually in the lung again, in half of treated patients. Research shows that a single tumor in the lung is more often a new tumor that, in many cases, may be operable.

Treatment Options are:

• Radiation for symptom control
• Chemotherapy with or without bevacisumab (Avastin)
• If the cancer spread to only one site in the brain, it may respond to surgery, followed by whole-brain radiation. Extended disease-free survival is possible. If the brain tumor is not operable, it is treated with radiation. Even if cancer returns in the brain (in 50% of cases), treating it again is possible in many patients, if the disease has not spread elsewhere
• Laser therapy or interstitial radiation for tumors inside the airways
• Stereotactic radiosurgery (in a few selected patients)

According to a 2001 article, of the nearly 500 cancer drugs currently in development, 58 of them (about 13%) are aimed at fighting lung cancer. Only breast cancer had a higher percentage of new drugs in development. Unfortunately, no drugs to date have shown any real benefit in terms of patient survival. However, some drugs are showing promise, and at this time, these agents are the best hope for improving lung cancer survival rates.

Monoclonal Antibodies (MAbs)

Monoclonal antibodies (MAbs) are genetically designed immune factors. MAbs mark foreign compounds called antigens for attack by the immune system. Bevacizumab (Avastin) was approved in October 2006 as a first-line treatment (in combination with carboplatin and paclitaxel) for inoperable, locally advanced, metastatic, or recurrent non-squamous, non-small cell lung cancer. Trastuzumab (Herceptin) and cetuximab (Erbitux) are MAbs under investigation for lung cancer.

All of these MAbs block epidermal growth factor. These drugs are of particular interest for patients who have cancers that produce too much of the protein called HER2. They show great promise in combination with chemotherapies and newer drugs, such as the tyrosine kinase inhibitors. For example, adding bevacizumab to platinum-based chemotherapy extends the disease-free survival time in patients with advanced non-small cell lung cancer.

Antisense Oligonucleotide

Antisense oligonucleotides are drugs that block the molecules that result in the uncontrolled cell growth of cancer. LY900003 (Affinitak), for example, targets an enzyme called PKC-alpha, which promotes tumor growth. Early studies with Affinitak showed some promising results. However, a 2003 study found no difference in survival when patients received Affinitak in combination with platinum-based chemotherapy, compared to patients receiving chemotherapy alone.

Genasense (G3139, oblimersen) blocks Bcl-2. Bcl-2 is a protein that is expressed in abnormally high amounts in some cancers. This antisense drug is also under investigation.

Gene Therapy

The gene therapy advexin is showing promise. In one early study, 60% of patients who received this drug in combination with radiation experienced partial or total tumor shrinkage. A 2006 study in Japan found that 10 out of 13 patients with advanced non-small cell lung cancer who received Advexin stabilized. Three of the stabilized patients remained stable for over 9 months. One patient had a partial response to Advexin. The only side effect of the multiple doses was a fever that disappeared within 24 hours. Advexin is in Phase II clinical trials for non-small cell lung cancer.

Vaccines

Vaccines use inactivated genetic materials from cancer cells to cause a highly targeted immune response to attack the cancer.

Retinoids

Retinoids are vitamin A-like antioxidant chemicals that help repair cell damage and appear to support the growth of lung cells. A number of retinoid-like agents (retinal palmitate, TAC-101, 23-cis-retinoic acid, N-acetyl-cysteine) are being studied for the treatment or prevention of lung cancer.

• www.cancer.gov -- National Cancer Institute
• www.cancer.org -- American Cancer Society
• www.cancercare.org -- Cancer Care
• www.lungusa.org -- The American Lung Association
• www.asco.org -- American Society of Clinical Oncology
• www.alcase.org -- Alliance for Lung Cancer
• www.lungcancer.org -- Joint project of Cancer Care and the Oncology Nursing Society
• www.nccn.org -- National Comprehensive Cancer Network
• www.lungcanceronline.org -- Lung cancer information
• www.epa.gov/iaq/radon -- National radon information
• www.clinicaltrials.gov -- Find clinical trials
• www.cancer.gov/clinicaltrials -- Find clinical trials

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