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Non-Small Cell Lung Cancer

WHAT IS LUNG CANCER?

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, bronchi divide successively 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, which are composed of a thin membrane through which oxygen and carbon dioxide pass to and from capillaries.
Capillaries, the smallest of our blood vessels, carry blood throughout the body.

Lung Cancer

Lung cancer develops when genetic mutations occur in a normal cell within the lung, causing it to become abnormal in shape and behavior and to reproduce ceaselessly. Such 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 metastasize to locations throughout the body.

The two major categories of lung cancer are non-small cell lung cancer and s mall cell lung cancer . Less common cancers of the lung are known as carcinoids, cylindromas, and certain sarcomas (cancer in soft tissues). Some experts believe that all primary lung cancers originate from a single common malignant so-called stem cell that, as it reproduces, develops into any one of these kinds of cancer in different individuals. In addition, cancers in the lung may have spread (metastasized) from other primary sites, such as the breast, thyroid, or colon.

Non-Small Cell Lung Cancers

Non-small cell lung cancers are categorized into three types: squamous cell carcinoma (also called epidermoid carcinoma ), adenocarcinoma, and large cell carcinoma . These separate types are grouped together because, in early stages before the cancers have spread, they all can be treated surgically.

Squamous Cell Carcinoma. Squamous cells are formed from reserve cells , which 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.

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

Squamous cell carcinoma is nearly always caused by smoking and used to be the most common cancer. It still makes up between 25% and 40% of all lung cancers.

Adenocarcinoma. Adenocarcinomas usually arise from the mucus-producing cells in the lung; about two-thirds of adenocarcinomas develop in the outer regions of the lung, while one-third develops centrally. In 1965, 12% of lung cancers were adenocarcinomas. They are now estimated to account for between 30% and 50% of all lung cancers and may even be the most common. It is the predominant lung cancer in women; in fact, a 2000 multicenter European study showed that nearly 34% of the women with lung cancer under investigation presented with adenocarcinoma, compared to 26.4% with squamous cell carcinoma and 22.3% with small cell lung cancer. (Adenocarcinoma is also increasing dramatically in men.)

Until recently, adenocarcinoma was only weakly linked to smoking. Experts now suggest, however, that the dramatic increase over the past decades in this lung cancer type may be due to low-tar, filtered cigarettes. People who smoke them draw tiny particles deeper into the lungs, thereby possibly increasing the risk for adenocarcinoma.

The course of this cancer varies widely. Most often, it develops slowly and causes no or few symptoms. In some cases, however, it can be extremely aggressive and rapidly fatal. In 50% of cases when it spreads, it metastasizes only to the brain. Other locations that it favors include the other lung, the liver, the adrenal glands, and bone.

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% to 20% of lung cancers, includes cancers that cannot be identified under the microscope as squamous cell cancers or adenocarcinomas.

Small Cell Lung Cancer

Small cell lung cancer may, like squamous cells, be derived from reserve cells or other cells in the epithelium. It causes between 15% and 25% 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.

WHAT CAUSES LUNG CANCER?

Triggers of the Lung Cancer Process

Cigarette Smoke. Smoking causes 87% of all cases of lung cancer, which is expected to kill nearly 157,400 people in 2001, accounting for 28% of all cancer deaths. Cigarettes, nicotine or both may contribute to lung cancer in one of 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 it, they bring tar into their lungs that itself includes 4,000 chemicals, some of which are carcinogenic. 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 of which are harmful gases.
Nicotine itself may be a hazard. A 2000 laboratory study suggested that the human body might be converting inhaled nicotine into a chemical called aminoketone, which has been linked to the formation of tobacco-related lung cancer. And another 2001 study reported that nicotine triggered new blood vessel growth, which could theoretically promote growth of any existing tumors. Whether or not these studies apply to long-term use of nicotine replacement products (such as patches), as well as from cigarette smoking, is still unclear. (They should certainly not discourage people from using nicotine replacement methods for quitting, but may indicate that these devices should not be used long-term.)

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 may be responsible for between 10% and 14% of lung cancer deaths, making it, after smoking, the second leading cause of this 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.

There is considerable debate over the lung cancer risk posed by depleted uranium used in military weapons (eg, in the Gulf and Balkan conflicts). A 2001 study estimated that it would cause an additional 8 deaths from lung cancer out of 10,000 people in soldiers who were highly exposed to this substance. The study was based on a mathematical model, however, and the issue is not settled.

Other lung carcinogens include asbestos, arsenic, certain petrochemicals, and other airborne byproducts of various mining and manufacturing processes.

Genetic Mutations

Genetic mutations that cause cancer generally occur in two types of genes: tumor-suppressor genes , which prevent unlimited cell reproduction, and proto-oncogenes , which stimulate cell reproduction. (When a proto-oncogene becomes mutated, it is then called an oncogene.) Damage to either type of gene can cause a mutation that results in the uncontrolled division of cells that form tumors. No one genetic abnormality is likely to emerge as a single cause of lung cancer. It probably takes a variety of mutations to promote the devastating cascade of cellular events leading to cancer. The following mutations are among those under investigation:

Tumor-suppressor genes, including p53, PPP2R1B, and p16, and oncogene K-ras . The chemical benzo[a]pyrene diol epoxide (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 replication. When they are impaired or blocked, rampant cell proliferation 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. Another important contributor to lung cancer is a genetically defective protein called retinoblastoma (Rb), which is associated with very aggressive tumors. Specifically, low levels of the normal Rb gene may sometimes predict aggressive clinical behavior, especially in patients with small cell lung cancer.
Mutations to the FHIT gene. Another potentially important mutation may be an abnormality in the so-called FHIT gene that causes the cells lining the lung to become more vulnerable to the effects of tobacco smoke and other carcinogens.

Research continues on the puzzle of how genetic and environmental factors work together in the development of lung cancer. For example, some investigators are finding that variant genetic forms (polymorphisms) may actually change a person's metabolism to raise or lower the degree of biologic exposure to carcinogens, and ultimately influence the risk of cancer development.

WHAT ARE THE SYMPTOMS OF NON-SMALL CELL LUNG CANCER?

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

Early Symptoms

Early symptoms may include the following:

Frequent bouts of pneumonia or an episode 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 include the following:

Shortness of breath from cancer that has spread to the pleura, the membrane covering the lung, is common.
In some cases, tumor growth or metastasis 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 upper extremities and face.
The cancer may spread to or press against the esophagus, interfering with swallowing and nutrition.
The nerves that control the larynx (voice box) can be damaged, causing hoarseness.
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's syndrome ).
Bronchoalveolar lung cancer may produce very large amounts of mucus.
Some lung cancers give out substances that remove calcium from bone and release it into the blood stream, 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.

WHO GETS LUNG CANCER?

Before cigarettes became popular in the beginning of the 20th century, lung cancer was considered a rare medical phenomenon. This year, lung cancer is expected to strike 169,500 people in the United States alone, and about 157,400 people are expected to die from it. The disease usually appears in people over 50 years old; its incidence is dropping in men, while lung cancer deaths in women have increased by 600% between 1950 and 2000. It now accounts for 25% of all cancer deaths in women.

Smokers and Those Exposed to Cigarette Smoke

Smoking appears to be the primary risk factor in 85% to 90% of lung cancers. About 15% of all people who smoke develop lung cancer, with the risk varying depending on the duration of the addiction and the number of pack years. (A pack year equals the number of packs of cigarettes smoked per day multiplied by the number of years that the person has smoked.) Chromosomal damage in the lung occurs in nearly all chronic smokers, even if cancer has not developed.

An elevated risk for lung cancer can persist for more than 20 years after quitting smoking, although the risk drops significantly even in the first year after quitting. And, there are benefits to quitting even for those who are well into middle age. [ See Table below.] In a British study of male smokers who quit at different ages, the risk for lung cancer by age 75 was the following:

Risk for Lung Cancer in Men at Age 75
Quitting Age	Percentage
30	2%
40	3%
50	6%
60	10%
Source: Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies, British Medical Journal. 321:323-329 ( 5 August 2000 )

Some studies indicate that women are more likely to develop lung cancer from smoking than men. In a 1999 study, the risk for older women was 2.3 times that of older men.

Second-Hand Smoke. One analysis of studies suggested that exposure to second-hand tobacco smoke may increase the risk of lung cancer in the nonsmoker by about 25%, but a 2000 study suggested that this figure may be an overestimate, since it was derived from many small and possibly biased studies. In one study, people who had been exposed to tobacco smoke as children, but not as adults, did not appear to have any higher risk.

Ethnic Differences

There appears to be some ethnic differences in lung cancer risk. For example, African Americans face a risk that is two to four times higher than that in Caucasians, regardless of smoking status; it is not clear what factors are responsible for this higher risk.

In China it is estimated that as many as a third of all young male smokers will eventually die because of a tobacco-related illnesses. Their risk for lung cancer, however, is much less than for chronic lung disease, a trend that is reversed in the West. A 2001 study reported that the lower rate of lung cancer among Chinese people may be due to a slow rate clearing nicotine, which results in fewer cigarettes smoked.

Environmental Factors

People with High Exposure to Radon. Studies have shown that radon raises the risk of lung cancer in underground miners to 40%. It has been unclear whether the results of these studies would apply to people exposed to radon in their homes. One study suggests that people with intense or prolonged exposure to radon in their homes do indeed face the same risk as miners exposed to similar levels of radon. 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 awhile in areas with high radon levels . People with homes that have high radon levels and those who sleep or spend many hours to days in basements with detectable but moderate levels should consider taking protective measures. [ See How Can Lung Cancer Be Prevented, below.]

Workers Highly Exposed to Carcinogens. An estimated 9,000 to 10,000 men and 900 to 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).

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, a 2000 study suggests that their exposure to endotoxin may be responsible. Endotoxin is a component of certain common bacteria found in soil and animals and may have effects on the immune system that protect against cancer.

Exposure to Smoke from Grills . Grilling and high-heat frying emit chemicals called heterocyclic amine, which are known to be carcinogenic. A 2000 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.) More research is warranted.

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 (or to second-hand smoke). Some studies have found an association between increased risk for lung cancer and the number of very small particulates, especially sulfates, present in polluted air. The risk, if any, is very small.

Alcohol. There is some association between alcohol consumption and lung cancer, but most researchers believe it is explained by a higher rate of smoking in people who drink. A 2001 study suggested, however, that alcohol, particularly beer, may increase the risk of lung cancer, independent of cigarette smoke. More research is needed to confirm or refute this association.

Family History

A family history of lung cancer may play a role in increasing susceptibility to this disease. In one study, people with parents or siblings with respiratory tract cancers had a 30% higher risk for lung cancer than people without a family history, and women with mothers or sisters with lung cancer had triple the risk. A higher risk occurred in both smokers and nonsmokers. There was no association between a history of other cancers and lung cancer. Both genetic factors and secondary smoke appeared 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.

HOW CAN LUNG CANCER BE PREVENTED?

Quit Smoking

Quitting smoking is the first line of prevention. It should be noted, however, that it can take as long as 20 years, particularly in heavy smokers, for the lungs to be restored to a fully healthy condition in which the risk is as low as nonsmokers. Educational efforts, aggressive public health campaigns, anti-tobacco legislation, over-the-counter nicotine replacement therapies combined with specific antidepressants (eg, Zyban), and intense social pressures that "denormalize" smoking are helping smokers to quit. It is still a difficult process, however, with a high failure rate. Smokers should not be discouraged if they fail, but should continue their efforts to quit. [ For more information, see , Report #41, Smoking.] While they are in the quitting process, they should maintain as healthy a lifestyle as possible.

The risk for lung cancer drops significantly after even the first year of quitting; unfortunately, however, there is some evidence that a higher than normal risk persists for 20 years or more after quitting.

Dietary Factors

Phytochemicals. Some data suggests that diets rich in fresh fruits and vegetables may be protective against lung cancer in both smokers and non-smokers. (Oddly, a 2000 study found that fruits and vegetables provided protection for nonsmokers and female smokers, but not for male smokers, although the study had some important flaws.)

In any case, diets with plenty of fresh fruits and vegetables are rich not only in important vitamins but also in other beneficial nutrients called phytochemicals ( phyto simply means plant) that are necessary for all aspects of health. It is, however, 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. Important cancer-fighting phytochemicals include the following:

Isothiocyanates found in the cruciferous vegetables (eg, broccoli, cauliflower, and Brussels sprouts). These may help block the effects of carcinogens in smoke, suppress tumor growth, and inhibit 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, those who ate relatively more onions, apples, and white grapefruit had less than half the lung cancer risk as 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.
Soy protein. Soy has attracted particular interest; it contains genistein, a powerful flavonoid compound that appears to have anti-cancer properties, including actions against non-small lung cancer cells.
Lycopene is a food chemical known as a carotenoid. It is found in tomatoes, particularly cooked ones, which have been associated with a lower risk for lung cancer.

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 soybean and canola oil), and monounsaturated oils (found in olive and canola oils). Despite these intriguing pieces of information, the ability of these substances to protect against lung cancer remains controversial, and discontinuation of smoking remains the best advice.

Vitamins and Antioxidant Supplements. Vitamin supplements are unlikely to offer much protection and, in high doses, some may even be harmful. [ See Box Special Warning on High-Dose Antioxidant Supplements, below.]

Some B vitamins are being considered as cancer fighters. Folic acid and B12 convert the amino acid homocysteine to methionine, which in turn protects genes that help prevent malignancies in cells. One small study showed a reduction of lung cancer cells in smokers taking folic acid and vitamin B12, but the researchers stressed that the study was very small and of short duration, and that other factors might have biased the results.
Some studies, but not all, suggest that antioxidant vitamins, such as E and C, may be protective. For example, a 1999 study reported a reduced risk of around 20% in those with high blood levels of vitamin E. However, if there is any protection from vitamin E it is likely to exist only if smokers have a high intake of vitamin E in their early smoking years.
Vitamin A and nutrients called carotenes (some of which convert to vitamin A) have been researched for possible protection against lung cancer. (For example, a vitamin A derivative 13-cis retinoic acid may help slow or stop progression of precancerous changes in heavy smokers.) Studies have observed, however, higher rates of lung cancer in smokers who took beta carotene and a 1999 one found the lowest incidence of lung cancer in a group not treated with a vitamin A derivative. On the other hand, studies in 2000 and 2001 have suggested that diets rich in fruits and vegetables that contain carotenoids and vitamin A may lower the risk of developing lung cancer. (Such foods are typically dark-colored ones, yellow, red, green, or orange.)
Selenium appears to inhibit cell proliferation and may have other anti-carcinogenic properties. In one small study, people who took 200 micrograms of selenium for more than four years had half the rate of lung, colon, rectal, and prostate cancer than those who did not. A more recent study reported that people with low levels of selenium had a higher risk for lung cancer than did those with higher levels. Taking selenium, however, may only help people who are deficient to begin with; it may not offer benefits for those with adequate blood levels. As an example, natural selenium levels are highest in the United States and lowest in New Zealand, but the two countries have similar rates of cancer, suggesting that selenium levels alone may not have much impact. [ For more information, see Well-Connected, Report #39, Vitamins and Other Nutrients .]

Special Warning on High-Dose Antioxidants

Some studies are now suggesting that excessive use of antioxidant supplements may interfere with other nutrients or convert into pro-oxidants and become harmful. Of particular concern are studies that have found an increase in lung cancer and the overall mortality rate among smokers who took beta carotene supplements. A 2000 study further reported a higher risk for cancer in male smokers who took multivitamins plus A, C, or E. In determining reasons for this disturbing effect, one animal study suggested that beta carotene increased enzymes in the lungs that actually promote cancerous changes. And, even more worrisome, in people with existing cancer, high doses of antioxidant vitamins, such as vitamins A, C, E, or beta carotene, may actually protect cancer cells (just as they do healthy cells), including increasing their life span and resistance to anti-cancer treatments. In other words, antioxidants may actually be harmful in people who already harbor cancer cells.

This is particularly important information for smokers, who may carry precancerous or cancerous cells for years prior to developing the disease. Until more research is conducted, people should not take high doses of any antioxidant supplements except under physician advisement. More research is needed in this important area.

Protecting the Home Against Radon

People concerned about radon in their home or area can purchase a test approved by the Environmental Protection Agency. Methods for removing radon include 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.

WHAT TESTS ARE USED TO DIAGNOSE, STAGE, AND TRACK NON-SMALL CELL LUNG CANCER?

Imaging Tests for Early Detection

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 in the center of the lung, cavities formed by squamous cell carcinoma, or thread-like infiltrates running through the lungs. By the time lung cancer is diagnosed by chest x-rays, however, it usually has already spread so far that it cannot be surgically cured. Even so, studies indicate that although chest x-rays do not reduce lung cancer mortality rates, they appear to prolong survival.

Computed Tomography. Imaging tests known as low-dose spiral (or helical) computed tomography (CT) scans are used for tracking the spread of cancer cells. Importantly, CT scans are also proving to be more effective than x-rays in identifying early tumors. In an early study, 82% of those identified with cancer from CT scans were still alive five years later. Some experts believe that the use of these scans could increase survival from lung cancer from 15% to 80%.

In a 2001 study from several New York medical institutions, older smokers at high risk for lung cancer were given two CT scans six to 18 months apart. Seven out of 841 patients had confirmed lung cancer About 2.5% of the 841 subjects required further testing and out of this group seven had cancer. The low cost of the screening procedure in this study ($2,500 per life year saved) relative to others ($40,000 per life year saved with either breast and cervical cancer screening tests) has encouraged some experts to recommend that smokers 60 years older or more have annual CT screenings. It is not clear, however, whether imaging tests for lung cancer actually improve survival rates from lung cancer. For example, evidence suggests that non-small cell lung cancer cells may be highly aggressive at the onset, when tumors are at microscopic levels. Therefore the cancer is highly likely to have already spread long before it is visible. Large trials are underway to determine the effectiveness of CT scanning in saving lives..

Imaging Tests for Staging and Tracking Cancer

Once cancer is diagnosed, chest x-rays and computed tomography (CT) scans are routinely performed to determine if the cancer has spread ( metastasized). Other imaging tests, however, may be more useful for staging and tracking lung cancers.

Positron Emission Tomography. Positron emission tomography (PET) is the most accurate noninvasive test 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), 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.

Scintigraphy. Scintigraphy is an imaging procedure in which patients are administered low-level radioactive agents that bind to cancer cells and which then can be tracked by special cameras to reveal the cancer cells' location and intensity. Agents selected are those that can best bind successfully with specific tumor types. For example, a 2001 study of the binding agent 111In-DOTA-LAN demonstrated excellent results in identifying non-small cell lung tumors. (This study further suggests the possibility of using such highly-targeted binding agents as lung cancer treatments.)

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 metastases that can be associated with lung cancer.

Biopsy and Thoracoscopy (Detecting Lung Cancer in the Outer Areas of the Lung)

Biopsy. To detect lung cancer that might be in the periphery (nearer the outside) of the lung, usually adenocarcinomas and large-cell cancers, the physician needs to perform a biopsy. Sometimes, a biopsy specimen is obtained by inserting a needle between the ribs, then guiding it with the use of computed tomography scans, ultrasound, or fluoroscopy (a device allowing an x-ray view). There is a 5% to 10% risk for bleeding or collapsed lung with this technique.

Thoracoscopy. The surgeon may also perform the biopsy using thoracoscopy, a surgical procedure that uses a fiber-optic tube to view the area:

The procedure requires a general anesthesia.
Small incisions are made in the chest, through which the surgeon passes surgical instruments and a fiber-optic tube with a camera to allow visualization of the lungs on a video screen.

This technique is usually very effective for diagnosing peripheral cancer or those involving the pleura (membrane surrounding the lungs).

Bronchoscopy (Detecting Lung Cancer in the Central Areas of the Lung)

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 as follows:

The patient is given a local anesthetic, supplementary 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 physician to view the wind-pipe and major airways. (In a procedure called fluorescence bronchoscopy, the patient is injected with a drug that makes cancer tissue appear red when exposed to laser light from the bronchoscope.)
The surgeon removes specimens for biopsy, ideally using a combination of techniques that include cutting tissue, using brushings, and using 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 very valuable additions.)

Bronchoscopy is usually very safe, but complications can occur; they include allergic reactions to the sedatives or anesthetics, asthma attacks in susceptible patients, and bleeding. Fever may follow the procedure.

Mediastinoscopy is performed if the physician suspects that cancer has spread to nearby lymph nodes. This procedure uses a tube inserted between the lungs to locate the appropriate areas for biopsy.

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, then 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.

Some biomarkers may prove to reveal the presence of cancer cells before they are evident on CT scans or other imaging tests. For example, in a 2000 report, researchers found molecular markers of lung cancer in sputum two years in advance of clinical detection. They are also showing promising for tracking the progress of the disease and effectiveness of treatments.

Biomarkers can be enzymes, hormones, amino-acid compounds, antigens (identified by antibodies that specifically target them), growth factors, and other chemicals. Some under investigation include the following:

Carcinoembryonic antigen (CEA) is a sensitive marker, and elevated levels are found in 50% of patients with non-small cell lung cancer.
Telomerase is a naturally occurring enzyme that controls cell lifespan. Changes in telomerase can make a cell "immortal" (as cancer cells are). Studies have reported high telomerase activity was detected in as many as 75% of non-small-cell lung cancer patients, many of whom in a 2000 study had early-stage tumors. One approach proposed by scientists involves the use of spiral CT scans on smokers whose blood shows the presence of the telomerase.
Among other markers being investigated for non-small cell lung cancer are substances known as circulating extracellular matrix complex (CEMC), cytokeratin 19, squamous cell carcinoma (SCC) antigen, CD4+ lymphocytes, and hnRNPA2/B1.
Defective genes detected in DNA analyses may also provide markers for the presence, risk, or prognosis of lung cancer and suggest treatment options. For example, in patients already diagnosed with lung cancer, evidence of p53 mutations suggests that certain treatments such as docetaxel in combination with gene therapy, may be more effective than others. Another important genetic marker for aggressive lung cancer may prove to be pRb2/p130, a member of a gene family known as retinoblastomas.

Other Tests

As part of the doctor's initial examination, patients may undergo pulmonary function testing to evaluate lung strength and capacity. Also, since the cardiac and respiratory systems are often involved in complications following lung cancer surgery, the doctor may be particularly interested in taking a complete history of those systems in prospective surgical patients.

HOW SERIOUS IS NON-SMALL CELL LUNG CANCER?

Lung cancer accounts for almost a third of all cancer deaths and is expected to kill 157,400 people this year. Advances in treatment are improving survival time, and some experts now believe that surgery in patients with Stage I lung cancer offers a reasonable chance for a cure. Only about 20% of lung cancer cases, however, are operable and, among these patients, the survival rate after five years is only 40%. If the cancer cannot be removed, then survival is less than 10%. A 1999 survey of cancer diagnosis and treatment statistics confirmed these grim numbers and reported other findings:

Stage I surgical patients had a five-year survival rate of greater than 50%, but the 10-year relative survival rate for all treated patients was only 8%.
The study reported that women and younger patients tended to do slightly better than men and older individuals, but the difference is slight.
Small-cell cancers had the poorest outlook and adenocarcinomas had the best long-term survival (although it was still only 10%).

Selected patient groups may do better than these results suggest. In addition, treatment advances may be improving these results.

The effects of the cancer on nearby organs and its metastases to other parts of the body, including the liver, bones, and brain, are particularly fearsome aspects of the disease. The control and improvement of symptoms caused by the disease locally and in other parts of the body are the primary goals of treatment for most patients.

WHAT IS THE GENERAL APPROACH FOR TREATING NON-SMALL CELL LUNG CANCER?

Initial Approach to the Patient with Lung Cancer

Tests to Determine Cancer Stage. Once a diagnosis of non-small cell lung cancer has been made, the physician 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, including the following:

The cancer cells are examined microscopically for size, shape, and other configurations.
Computer tomography (CT), magnetic resonance imaging (MRI), or both are used to scan the lung and perhaps other locations, such as the liver, upper abdomen, and brain, are used to determine the extent of the disease.

Physical Examination. A detailed physical examination of the whole body is very important to identify or rule out metastases to other areas and to determine the general condition of the patient. For example, questions about vertigo or headaches can help the doctor determine if the cancer has spread to the brain, while bone or joint pain might suggest the presence of bone metastases. The doctor will also look for head and neck symptoms that might reveal the presence of other tumors. Also, according to a 2000 review, the patient's weight loss and ability to function are the two most important factors for predicting survival following treatment: patients who are mobile and have lost less than 10% of their pre-treatment weight seem to have a better survival rate.

Staging Systems

In lung cancer, disease stage at diagnosis is a major factor in determining how to treat the cancer and how long the patient can be expected 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 regions of the body. Staging is based on the results of physical and surgical examinations, laboratory and imaging tests, and 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 [ See Box The TNM System].
The TNM categories then determine the stage (numbered 0 to IV), which indicates how advanced the cancer is. [See What Are the Treatment by Staging Categories?]

The TNM System

The TNM system is defined as T (for tumor), N (for regional lymph nodes), and M (for metastasis).

T refers to the size and extension of the tumor itself.

In TX and T0, the tumor is indicated by cancer cells in sputum or lung samples but cannot be visualized.

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 dimension, is still contained in the lung or the membrane covering the lung (the visceral pleura ), and has not reached the main airway ( bronchus).

In T2, the tumor has one or more of the following features: greater than 3 cm; involves the main bronchus; 2 cm or more away from the ridge (the carina) at the lowest part of the windpipe ( trachea); has invaded the visceral pleura; is associated with collapsed lung tissue ( atelectasis) or obstructive inflammation of lung tissue but does not involve the entire lung.

In T3, a tumor of any size has directly invaded any of the following: chest wall, diaphragm, the membrane covering organs and structures in the chest, the outer wall of the membrane around the heart ( pericardium); the tumor is in the main airway and less than 2 cm away from the carina but has not involved the trachea; the tumor is associated with atelectasis or obstructive inflammation of the entire lung.

In T4, the tumor has invaded any of the following: the area between the lungs ( mediastinum), the heart, the great vessels, carina, trachea, esophagus, main portion of the spine; separate tumor nodules are present in the same lobe; the tumor is accompanied by a malignant pleural effusion (increased amount of fluid between the membrane and the lung).

N followed by 0 to 3 refers to whether the cancer has reached regional lymph nodes.

In stage N0, the regional lymph nodes are still cancer-free.

In N1, the cancer has spread to nearest lymph nodes around the airways, in the hilum (a depression in the lung where blood and lymph vessels enter), or in both. The tumor has extended directly into lymph nodes within the lung.

In N2, the cancer has spread to lymph nodes in areas in the middle of the chest that are still adjacent to the affected lung, to the nodes below the carina, or both regions.

In N3 the cancer has spread to lymph nodes in areas in the middle of the chest that are adjacent 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 clavicle (collar bone).

Stages M refer to metastasis.

In M0, metastasis has not occurred.

In M1 distant metastasis has occurred. This includes the presence of a separate tumor in a different lobe.

Other Factors Determining Treatment Choices and Outcome

In addition, staging factors are also used to help determine treatment and outlook. The following suggest a more aggressive disease:

The presence of respiratory symptoms.
A tumor larger than 3 centimeters.
High numbers of blood vessels in the tumor.
are always looking for more accurate ways to determine a treatment and prognosis for lung cancer. For example, some research involves specific biomarkers and related microscopic blood vessel development ( angiogenesis) within tumors that might eventually help determine how aggressive a cancer is likely to be and the optimal treatment approach.

General Treatment Approach after Staging

If the cancer is still localized, cure is possible. (Unfortunately, very few patients are diagnosed at such early stages.) In these cases, the primary treatments are surgery and radiation. Because of the generally poor outlook for lung cancer, however, nearly all newly diagnosed lung cancer patients are potential candidates for clinical trials of experimental procedures.

Even if an initial tumor has been surgically removed or irradiated, cancer recurrence rates are very high. (The risk for recurrence is lower in smokers who quit after treatment.)

In advanced cases, chemotherapy may be used to prolong survival and both radiation and chemotherapy are administered to alleviate pain and symptoms.

It should be noted that even with improved response rates, the mortality rate for lung cancer is still extremely high, and reports of improved response or survival rates using drugs or combinations therapies do not mean cures. Ultimately, the patient must weigh a diminished quality of life using some aggressive treatments against a chance for a modestly prolonged life.

Treatment of the Elderly

The approach to treating the elderly is under debate. A 2001 study, suggested that elderly patients with operable cancer and who often suffer from other health condition might do much better with therapies that relieve symptoms rather than intensive treatments. In fact, the study suggested that survival rates in this population were the same with either approach.

Some physicians also prefer not to aggressively treat older people with advanced lung cancer. Studies from 1999 and 2000 reported, however, that older people who were in otherwise good physical health had a significantly higher survival rate when treated with aggressive chemotherapy than did those who were only given supportive care. In one 1999 study, physically fit older adults did as well as fit younger adults, and younger people in poor health did just as badly as older people who were ill. Older people, however, do have a higher prevalence of certain side effects and they must weight this against any modest duration in survival time.

WHAT ARE THE TREATMENTS FOR NON-SMALL LUNG CANCER BY STAGING CATEGORIES?

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. [To determine definitions of T, N, and M, See Box TNM System .]

Treatment Options. S urgical 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 (wedgectomy or segmentectomy). Photodynamic therapy.

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. Primary treatment is surgery to remove sections of the lung. Depending on the circumstances, lobectomy (removal of a whole lobe) or partial lobectomy is standard treatment. It should be noted that to date there is no convincing evidence that early-stage lung cancer patients who supplement their surgical treatment with radiation or chemotherapy have higher survival rates. Overall five-year survival rates for early stage-cancer are in the range of 30% to 50%. Clinical trials should be considered for prevention of recurring cancer after primary treatment.

Stage IA (T1, N0, M0). The five-year survival rates for stage IA patients after successful treatment can be as high as 80%. 1. Wedge or segment resection may be beneficial, particularly for Stage IA patients with poor lung function, who would have a higher risk for life-threatening complications with lobectomy. Survival rates may be equal to those of lobectomy, but cancer recurrence after wedge or segment resection is higher (50%) than after lobectomy (10% for second lung cancers and 20% for any second cancer). The risk for recurrence is highest in patients who continue to smoke. 2. Radiation, even with intent to cure, in selected patients whose condition is inoperable (eg, older patients with T1 tumors). Five-year survival rates can be equal to those from surgery, between 32% and 60%.
Stage 1B (T2, N0, M0). Stage IB survival rates after treatment can be over 60%. 1. Lobectomy. 2. Clinical trials of chemotherapy before surgery ( induction therapy ). (Studies are promising.) 3. Clinical trials for radiation, even with intent to cure, in selected patients whose condition is inoperable. 4. Clinical trials of chemotherapy before, after, or during radiation treatments. 5. Clinical trials with adjuvant chemotherapy following surgery. (Study results mixed; many have been disappointing.) 6. Trials using isotretinoin (vitamin A derivative) following surgery. 7. Clinical trials with adjuvant radiation following surgery. (Studies to date have not reported survival benefits.)

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 literature review places the numbers as high as 40% to 50%, but notes that they can drop to 25% and below if it has spread beyond the immediate lymph nodes. Patients whose cancer is inoperable may consider radiation treatments. In appropriate candidates who can complete treatment, five-year survival rates average 20% to 30%, with higher rates for IIA. Clinical trials should be considered 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%. 1. Surgery. 2. Radiation with intent to cure in selected patients. 3. Clinical trials with postoperative (adjuvant) chemotherapy. 4. Clinical trials with adjuvant radiation following surgery. (To date no survival advantage.) 5. Clinical trials of chemotherapy before, after, or during radiation treatments. 6. Clinical trials of chemotherapy (induction therapy) to reduce tumor size before surgery.
Stage IIB (T2, N1, M0) or (T3, N0, M0). Survival rates can be over 40%. 1. Surgery 2. Radiation treatment in selected patients. 3. Clinical trials with postoperative (adjuvant) chemotherapy. (To date, no strong evidence of survival advantage.) 4. Clinical trials with adjuvant radiation following surgery. (To date no survival advantage.) 5. Clinical trials of chemotherapy before, after, or concurrent with radiation treatments. 6. Clinical trials of chemotherapy before surgery (induction therapy).

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, Stage III tumors are treated with radiation and sometimes with surgery, chemotherapy, or combinations of each. Combination approaches may be significantly more effective than single treatments. For example, of particular interest is a treatment approach that uses initial concurrent chemotherapy and radiation followed by surgery. In one study five-year survival in Stage III patients was nearly 50%.

Stage IIIA (T1, N2, M0) or (T2, N2, M0) or (T3, N1, M0) or (T3, N2, M0). 1. Surgery is often possible if used in combination with chemotherapy and radiation. Survival rates in some studies are as high as 30%, but are often lower. 2. Radiation treatment. Best candidates are those in otherwise good health and whose cancer is inoperable. 3. Chemotherapy. 4. Clinical trials with concurrent cisplatin-based chemotherapy combinations plus radiation followed by surgery and/or preventive radiation therapy to the brain. (Some, but not all, studies have reported improved survival rates from concurrent over sequential chemotherapy and radiation.) 5. Clinical trials using induction chemotherapy to reduce tumors, which are then treated with surgery or radiation. 6. Clinical trials with adjuvant cisplatin-based chemotherapy after surgery. (Some trials showing promise in prolonging survival.) 7. Clinical trials using adjuvant radiation following surgery. (To date no survival advantage.) 8. Other clinical trials using hyperfractionated radiation, laser therapy, paclitaxel or gemcitabine as a single agent for second-line treatment, and others.
Stage IIIB (Any T, N3, M0) or (T4, Any N, M0). Cancer cannot be treated surgically, unless there is no lymph node involvement. (T4, N0 may respond to surgery.) . 1. Radiation alone. (Usually for symptom control. In certain patients, such as those with node involvement above the clavicle, radiation may improve survival.) 2. Chemotherapy alone. A major 2000 study reported that including chemotherapy in the treatment for advanced lung cancer improved the one-year survival rate for patients with Stage IIIB or IV from 20%-25% to 35%-40%. 3. Clinical trials with concurrent cisplatin-based chemotherapy combinations plus radiation sometimes followed by surgery and/or preventive radiation therapy to the brain. 4. Clinical trials using induction chemotherapy alone to reduce tumors, which may then be treated with surgery or radiation. 5. Paclitaxel or gemcitabine as a single agent for second-line treatment. 6. Other clinical trials (hyperfractionated radiation, drugs that enhance radiation, immunotherapy, and others).

Stage IV

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

Treatment Options. 1. Combination of two- or three-drug chemotherapies that include platinum-based and other drugs. Best patient candidates are those in otherwise good health who have a limited number of distant metastasized sites. No standard regimen established to date. 2. External-beam radiation for symptoms. 3. Chemotherapy. A major 2000 study reported that including chemotherapy in treatment for advanced lung cancer improved the chance of patients with Stage IIIB or IV surviving one year after diagnosis. 4. Paclitaxel or gemcitabine as a single agent. 5. Other clinical trials. 6. If metastasized cancer involves only one or two areas in the brain, it may respond to surgical resection followed by radiation to the brain.

Recurring or Additional New Tumors

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

Treatment Options. 1. Radiation for symptom control. 2. Chemotherapy. 3. If metastasized cancer strikes only one site and in the brain, it may be treated surgically and with postoperative whole-brain radiation. Prolonged disease-free survival is possible. If not operable, the brain tumor is treated with radiation. Even if cancer returns in the brain (in 50% of cases), retreatment is possible in many patients if the disease has not metastasized elsewhere. 4. Laser therapy or interstitial radiation for tumors within the airways. 5. Stereotactic radiosurgery (in a few selected patients).

WHAT ARE THE SURGICAL PROCEDURES FOR NON-SMALL CELL LUNG CANCER?

Indications for Surgery

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 (although a cure at this stage is virtually nonexistent).
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% to 5%, with older patients having the highest risk.

Pneumonectomy. Pneumonectomy removes the entire lung. The procedure itself carries a mortality rate of 5% to 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 surgical interventions that relieve cancer symptoms for late stages.

Thoracoscopy. Thoracoscopy 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. Such procedures can have significant drawbacks, though. For instance, one such operation, the thoracoscopic wedge resection , does not allow the surgeon to fully determine the extent of lymph node involvement or the presence of metastatic disease outside of the lung's lobes. When thoracoscopy is used for a lobectomy, it may offer little advantage in reducing postsurgical pain. Thoroscopies are also difficult to perform and are still considered experimental.

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

Photodynamic Therapy. Photodynamic therapy uses bronchoscopy and special laser light beams combined with a photosensitive 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.

Electric Cauterization. Electric cauterization also is under investigation as a treatment for early-stage disease.

WHAT ARE THE RADIATION THERAPIES FOR NON-SMALL CELL LUNG CANCER?

Indications for Radiation

Radiation is the other primary treatment for early-stage lung cancer. It is may be used in the following wash:

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 surgically. In these cases, the five-year survival rate is about 20%, and the cancer is likely to recur, although survival rates may be higher or lower depending on the tumor size. In general, with radiation therapy alone, the larger the tumor, the lower a patient's chance of survival.
For Stage III patients with poor lung function and those with metastasized cancer. Radiation, in these cases, is not generally used with the intention of improving survival rates, but to shrink cancers and reduce pain and other symptoms, such as coughing and shortness of breath. It may even improve survival in those with excellent lung function and whose tumors are small enough that thoracoscopy is needed to detect them. In up to 85% of patients with advanced disease, radiation therapy helps relieve pain, shortness of breath, the superior vena cava syndrome, coughed-up blood, and symptoms caused by brain metastases.

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 at the same time destroying surrounding healthy tissues. Different procedures may be tried. The exact radiation procedure depends on the site of the cancer or its extent:

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

Other Radiation Procedures

New radiotherapy techniques and sequences are being developed to allow higher doses with fewer side effects and sometimes better results:

Hyperfractionated Radiotherapy. Hyperfractionated radiotherapy administers smaller than standard doses a number of times a day (usually two or three). This allows a higher cumulative dose over the whole course of treatment. It is not useful as sole therapy, however; it needs to 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 levels. This allows the total dose of radiation to be administered over a shorter time period than the standard six weeks. CHART is proving to extend two-year survival of patients with localized cancer over that of standard radiotherapy or non-accelerated hyperfractionated radiation. Though it causes more severe swallowing problems than does standard radiotherapy, a modification in which treatment is suspended for two days out of seven may help reduce this effect.

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. In such cases, a technique called stereotactic radiosurgery may be employed that delivers powerful, highly targeted radiation to specific areas in the brain.

Three-Dimensional Conformal Radiotherapy. Three-dimensional (3-D) conformal radiotherapy involves external-beam radiation that is designed to conform closely to the specific targeted organs or tissues, therefore allowing higher doses. Stereotactic body radiotherapy is a recent advance on conformal radiation that uses a body frame and an abdominal press to immobilize the patient's body and limit breath movement. This allows a more precise delivery of high-energy photons, which are delivered to the tumor using a linear accelerator. The technique is not widely available, however, and is still investigational.

WHAT ARE THE CHEMOTHERAPY TREATMENTS USED IN NON-SMALL CELL LUNG CANCER?

Indications for Chemotherapy

Chemotherapy employs drugs given orally or by injection to destroy cancer cells that may have gone beyond the tumor.

It is being investigated in early stages as an additional treatment with surgery or radiation.
It is typically used in late stages to reduce symptoms and, in some cases, improve survival.

Administration

Chemotherapy treatments are usually performed in an outpatient setting and in regular cycles for several months. How many chemotherapy cycles to administer in late stage cancers is still a matter of debate. For instance, research released in 2001 suggested that a three-course cycle may have the same survival times and better quality of life than the standard of six or more (rarely more than eight). More research is needed, including trials using newer chemotherapy schedules.

Chemotherapy Drugs and Regimens

Powerful platinum compounds, either cisplatin (Platinol) or carboplatin (Paraplatin), are the basis for most chemotherapy regimens. For late stage cancers, they may be used alone or more often in two-drug combinations.

Two-drug combinations may include the following:

Cisplatin with vinblastine or similar derivatives (vindesine and vinorelbine). (Carboplatin has also been investigated in this combination but survival times are shorter.)
Carboplatin or cisplatin with paclitaxel (Taxol). Of note, in a 2000 study, patients with Stage IIIB or IV cancers responded more quickly to the carboplatin/paclitaxel combination administered every 21 days than to high-dose cisplatin alone. The average survival rates and quality of life, however, were nearly the same with either approach.
is also commonly used with gemcitabine or docetaxel. A 2002 study suggested that most of these combinations are equally effective.
drugs are under investigation and some combinations showing promise include the following:
Cisplatin with irinotecan (Camptosar). Studies have been conflicting on the effect of this combination on survival rates. Some Japanese studies have reported one-year survival rates of 33% and 58% in late stage cancers. Other studies have reported no survival advantages, but changes in administration schedules may improve their results. Other combinations with irinotecan are under investigation.
Paclitaxel and gemcitabine (Gemzar). In one early 2001 study of this combination there was a one-year survival probability of 48%, an indication that further research is warranted.
Paclitaxel and etoposide (an oral agent). In an early 2001 study, one-year survival was 36% with a specific schedule. Severe side effects were at acceptable levels.

Examples of other agents under investigation alone or in combination include, docetaxel (Taxotere), topotecan (Hycamtin), mitomycin, and trastuzumab (Herceptin).

To date, studies of drug combinations have produced contradictory results when measuring significant improvements in survival. In fact, it is not clear that combinations offer any benefits over single agents. For example, in one study gemcitabine (Gemzar) used alone produced equal survival rates and had stronger and longer-lasting medical benefits than a combination of cisplatin and vindesine.

research suggests that three-drug combinations using newer drugs may prove to be both tolerable and more effective than two-drug combinations. Some examples include the following:
A platinum-based agent plus gemcitabine followed by paclitaxel may prove to have particular benefits.
An oral combination of uracil and tegafur (UFT) and cisplatin has low toxicity and may be especially useful for olde