INTRODUCTION — Lung cancer is the leading cause of cancer death in both men and women in the United States. The number of people dying from lung cancer each year has risen over the past 25 years. It is estimated that lung cancer will be responsible for approximately 160,000 deaths in the US during 2006. This is more than the estimated deaths from breast cancer, prostate cancer, and colorectal cancer combined. Several factors increase the risk of lung cancer, particularly cigarette smoking.
PREVENTING LUNG CANCER — Cigarette smoking is responsible for almost 90 percent of cases of lung cancer. Exposure to certain substances, such as asbestos, has also been linked to the development of lung cancer. Exposure to second-hand smoke and other environmental factors may play a role.
The best way to avoid getting lung cancer is not to smoke. Some smokers believe that once they have smoked for a long while, it does little good to quit. However, studies have shown that smokers who quit decrease their risk of lung cancer when compared to those who continue to smoke. Smokers who quit for more than 15 years have an 80 to 90 percent reduction in their risk of lung cancer compared to people who continue to smoke. (See "Patient information: Smoking cessation").
IS SCREENING WORTHWHILE? — Screening is a way to detect a disease in its earliest stages, before a person becomes ill or dies. To be recommended, it must be clear that screening is useful in identifying patients who have the disease in the early stages, and that this discovery can reduce the number of patients who become ill and/or die.
Some screening exams have proven to make a clear difference in patient outcomes. Examples are the Pap smear for detection of cervical cancer in women, and colonoscopy for detection of colon or rectal cancer in people over 50 years old. These exams are now part of routine health care in the United States.
SCREENING EXAMS FOR LUNG CANCER — Research studies have been done to determine if screening for lung cancer makes sense. In these studies, smokers (who are at highest risk to develop the disease) are divided into groups. Some groups have screening tests while others have no screening. The groups are then followed over many years. Data are gathered on how many patients in each group are diagnosed with lung cancer, how the cancer was treated, and how long patients with lung cancer survived after treatment.
So far, the data from these studies have not shown that screening for lung cancer makes a difference in deaths from the disease. For this reason, major medical advisory groups do not yet recommend lung cancer screening.
Still, the data from these studies are the subject of much debate in the medical community. Part of the debate surrounds the fact that outcomes other than overall mortality, such as the stage of the disease at diagnosis or five-year survival rate, seem to be favorably affected by screening. However, critics point out that data are difficult to interpret reliably. The debate is continuing, and more studies are underway to better understand the role of screening studies for lung cancer
Because of the lack of data on the efficacy of screening for lung cancer, most of these exams are not part of routine care and are only offered to smokers as part of ongoing clinical trials. One exception may be the annual chest x-ray.
Chest x-ray — Many doctors already recommend an annual chest x-ray for their patients who smoke. Some experts, in analyzing data from lung cancer screening trials, have concluded that an annual chest x-ray is a worthwhile screening exam for patients with lung cancer.
Two major studies have been done to find out whether more frequent chest x-rays are beneficial in lung cancer screening. So far, these studies have not shown a clear benefit in terms of deaths from lung cancer. In patients who had more frequent chest x-rays, more lung cancers at early stages were found, the cancers were more frequently removable by surgery, and the patients had longer five-year survival (from time of diagnosis) than patients with less frequent x-rays. However, overall mortality from lung cancer was not significantly affected.
Computed tomography (CT scan) — Studies of computed tomography (CT scan) of the lung have shown that the test can help detect early stage lung cancer, but it is not yet clear whether this will affect the number of patients who die from their cancer.
Sputum tests — Some studies have looked at the efficacy of analyzing a patient's sputum for evidence of cancer cells in order to detect lung cancer. So far, no clear benefit to this approach has been found. Additional studies that use new technologies to examine the sputum are underway.
PET scan — Researchers are looking at a number of other tools in an effort to help identify patients with lung cancer. Positron Emission Tomography (or PET scanning, which uses a small amount of radioactivity to provide a detailed picture of an organ's function) has been used in combination with CT scanning.
Other studies — Direct visualization of the lungs with bronchoscopy and breath analysis for cancer markers are two tests that may be used in future studies.
CLINICAL TRIALS — Because the data on lung cancer screening are inconclusive, large-scale clinical trials of various screening modalities are underway. Smokers or former smokers may be asked to participate in these trials.
Although it makes sense to think that early detection of lung cancer is a good idea, it is important to understand that routine screening for lung cancer cannot be recommended until the research clearly shows that it makes a difference. It is likely that recommendations on lung cancer screening will evolve over the next decades as these data become available.
SUMMARY Patients who smoke are at increased risk of developing lung cancer. The best way to avoid lung cancer is not to smoke. Even long-term smokers can benefit from quitting. Researchers are looking for ways to help smokers and non-smokers who develop lung cancer to live longer. Early detection and screening is a major focus of this effort It is not clear if lung cancer screening can reduce the number of people who die from their disease. Clinical trials are underway that will help provide answers to these questions.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.cancernet.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The American Cancer Society
(www.cancer.org)
Lung Cancer Alliance
(www.lungcanceralliance.org)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Jemal, A, Siegel, R, Ward, E, et al. Cancer statistics, 2006. CA Cancer J Clin 2007; 57:43.
2. Truong, MT, Munden, RF. Lung cancer screening. Curr Oncol Rep 2003; 5:309.
3. Nawa, T, Nakagawa, T, Kusano, S, et al. Lung cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies. Chest 2002; 122:15.
4. Bastarrika, G, Garcia-Velloso, MJ, Lozano, MD, et al. Early Lung Cancer Detection using Spiral Computed Tomography and Positron Emission Tomography. Am J Respir Crit Care Med 2005; 171:1378.
Friday, October 12, 2007
Lung cancer prevention and screening
INTRODUCTION — Lung cancer is the leading cause of cancer death in both men and women in the United States. The number of people dying from lung cancer each year has risen over the past 25 years. It is estimated that lung cancer will be responsible for approximately 160,000 deaths in the US during 2006. This is more than the estimated deaths from breast cancer, prostate cancer, and colorectal cancer combined. Several factors increase the risk of lung cancer, particularly cigarette smoking.
PREVENTING LUNG CANCER — Cigarette smoking is responsible for almost 90 percent of cases of lung cancer. Exposure to certain substances, such as asbestos, has also been linked to the development of lung cancer. Exposure to second-hand smoke and other environmental factors may play a role.
The best way to avoid getting lung cancer is not to smoke. Some smokers believe that once they have smoked for a long while, it does little good to quit. However, studies have shown that smokers who quit decrease their risk of lung cancer when compared to those who continue to smoke. Smokers who quit for more than 15 years have an 80 to 90 percent reduction in their risk of lung cancer compared to people who continue to smoke. (See "Patient information: Smoking cessation").
IS SCREENING WORTHWHILE? — Screening is a way to detect a disease in its earliest stages, before a person becomes ill or dies. To be recommended, it must be clear that screening is useful in identifying patients who have the disease in the early stages, and that this discovery can reduce the number of patients who become ill and/or die.
Some screening exams have proven to make a clear difference in patient outcomes. Examples are the Pap smear for detection of cervical cancer in women, and colonoscopy for detection of colon or rectal cancer in people over 50 years old. These exams are now part of routine health care in the United States.
SCREENING EXAMS FOR LUNG CANCER — Research studies have been done to determine if screening for lung cancer makes sense. In these studies, smokers (who are at highest risk to develop the disease) are divided into groups. Some groups have screening tests while others have no screening. The groups are then followed over many years. Data are gathered on how many patients in each group are diagnosed with lung cancer, how the cancer was treated, and how long patients with lung cancer survived after treatment.
So far, the data from these studies have not shown that screening for lung cancer makes a difference in deaths from the disease. For this reason, major medical advisory groups do not yet recommend lung cancer screening.
Still, the data from these studies are the subject of much debate in the medical community. Part of the debate surrounds the fact that outcomes other than overall mortality, such as the stage of the disease at diagnosis or five-year survival rate, seem to be favorably affected by screening. However, critics point out that data are difficult to interpret reliably. The debate is continuing, and more studies are underway to better understand the role of screening studies for lung cancer
Because of the lack of data on the efficacy of screening for lung cancer, most of these exams are not part of routine care and are only offered to smokers as part of ongoing clinical trials. One exception may be the annual chest x-ray.
Chest x-ray — Many doctors already recommend an annual chest x-ray for their patients who smoke. Some experts, in analyzing data from lung cancer screening trials, have concluded that an annual chest x-ray is a worthwhile screening exam for patients with lung cancer.
Two major studies have been done to find out whether more frequent chest x-rays are beneficial in lung cancer screening. So far, these studies have not shown a clear benefit in terms of deaths from lung cancer. In patients who had more frequent chest x-rays, more lung cancers at early stages were found, the cancers were more frequently removable by surgery, and the patients had longer five-year survival (from time of diagnosis) than patients with less frequent x-rays. However, overall mortality from lung cancer was not significantly affected.
Computed tomography (CT scan) — Studies of computed tomography (CT scan) of the lung have shown that the test can help detect early stage lung cancer, but it is not yet clear whether this will affect the number of patients who die from their cancer.
Sputum tests — Some studies have looked at the efficacy of analyzing a patient's sputum for evidence of cancer cells in order to detect lung cancer. So far, no clear benefit to this approach has been found. Additional studies that use new technologies to examine the sputum are underway.
PET scan — Researchers are looking at a number of other tools in an effort to help identify patients with lung cancer. Positron Emission Tomography (or PET scanning, which uses a small amount of radioactivity to provide a detailed picture of an organ's function) has been used in combination with CT scanning.
Other studies — Direct visualization of the lungs with bronchoscopy and breath analysis for cancer markers are two tests that may be used in future studies.
CLINICAL TRIALS — Because the data on lung cancer screening are inconclusive, large-scale clinical trials of various screening modalities are underway. Smokers or former smokers may be asked to participate in these trials.
Although it makes sense to think that early detection of lung cancer is a good idea, it is important to understand that routine screening for lung cancer cannot be recommended until the research clearly shows that it makes a difference. It is likely that recommendations on lung cancer screening will evolve over the next decades as these data become available.
SUMMARY Patients who smoke are at increased risk of developing lung cancer. The best way to avoid lung cancer is not to smoke. Even long-term smokers can benefit from quitting. Researchers are looking for ways to help smokers and non-smokers who develop lung cancer to live longer. Early detection and screening is a major focus of this effort It is not clear if lung cancer screening can reduce the number of people who die from their disease. Clinical trials are underway that will help provide answers to these questions.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.cancernet.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The American Cancer Society
(www.cancer.org)
Lung Cancer Alliance
(www.lungcanceralliance.org)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Jemal, A, Siegel, R, Ward, E, et al. Cancer statistics, 2006. CA Cancer J Clin 2007; 57:43.
2. Truong, MT, Munden, RF. Lung cancer screening. Curr Oncol Rep 2003; 5:309.
3. Nawa, T, Nakagawa, T, Kusano, S, et al. Lung cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies. Chest 2002; 122:15.
4. Bastarrika, G, Garcia-Velloso, MJ, Lozano, MD, et al. Early Lung Cancer Detection using Spiral Computed Tomography and Positron Emission Tomography. Am J Respir Crit Care Med 2005; 171:1378.
PREVENTING LUNG CANCER — Cigarette smoking is responsible for almost 90 percent of cases of lung cancer. Exposure to certain substances, such as asbestos, has also been linked to the development of lung cancer. Exposure to second-hand smoke and other environmental factors may play a role.
The best way to avoid getting lung cancer is not to smoke. Some smokers believe that once they have smoked for a long while, it does little good to quit. However, studies have shown that smokers who quit decrease their risk of lung cancer when compared to those who continue to smoke. Smokers who quit for more than 15 years have an 80 to 90 percent reduction in their risk of lung cancer compared to people who continue to smoke. (See "Patient information: Smoking cessation").
IS SCREENING WORTHWHILE? — Screening is a way to detect a disease in its earliest stages, before a person becomes ill or dies. To be recommended, it must be clear that screening is useful in identifying patients who have the disease in the early stages, and that this discovery can reduce the number of patients who become ill and/or die.
Some screening exams have proven to make a clear difference in patient outcomes. Examples are the Pap smear for detection of cervical cancer in women, and colonoscopy for detection of colon or rectal cancer in people over 50 years old. These exams are now part of routine health care in the United States.
SCREENING EXAMS FOR LUNG CANCER — Research studies have been done to determine if screening for lung cancer makes sense. In these studies, smokers (who are at highest risk to develop the disease) are divided into groups. Some groups have screening tests while others have no screening. The groups are then followed over many years. Data are gathered on how many patients in each group are diagnosed with lung cancer, how the cancer was treated, and how long patients with lung cancer survived after treatment.
So far, the data from these studies have not shown that screening for lung cancer makes a difference in deaths from the disease. For this reason, major medical advisory groups do not yet recommend lung cancer screening.
Still, the data from these studies are the subject of much debate in the medical community. Part of the debate surrounds the fact that outcomes other than overall mortality, such as the stage of the disease at diagnosis or five-year survival rate, seem to be favorably affected by screening. However, critics point out that data are difficult to interpret reliably. The debate is continuing, and more studies are underway to better understand the role of screening studies for lung cancer
Because of the lack of data on the efficacy of screening for lung cancer, most of these exams are not part of routine care and are only offered to smokers as part of ongoing clinical trials. One exception may be the annual chest x-ray.
Chest x-ray — Many doctors already recommend an annual chest x-ray for their patients who smoke. Some experts, in analyzing data from lung cancer screening trials, have concluded that an annual chest x-ray is a worthwhile screening exam for patients with lung cancer.
Two major studies have been done to find out whether more frequent chest x-rays are beneficial in lung cancer screening. So far, these studies have not shown a clear benefit in terms of deaths from lung cancer. In patients who had more frequent chest x-rays, more lung cancers at early stages were found, the cancers were more frequently removable by surgery, and the patients had longer five-year survival (from time of diagnosis) than patients with less frequent x-rays. However, overall mortality from lung cancer was not significantly affected.
Computed tomography (CT scan) — Studies of computed tomography (CT scan) of the lung have shown that the test can help detect early stage lung cancer, but it is not yet clear whether this will affect the number of patients who die from their cancer.
Sputum tests — Some studies have looked at the efficacy of analyzing a patient's sputum for evidence of cancer cells in order to detect lung cancer. So far, no clear benefit to this approach has been found. Additional studies that use new technologies to examine the sputum are underway.
PET scan — Researchers are looking at a number of other tools in an effort to help identify patients with lung cancer. Positron Emission Tomography (or PET scanning, which uses a small amount of radioactivity to provide a detailed picture of an organ's function) has been used in combination with CT scanning.
Other studies — Direct visualization of the lungs with bronchoscopy and breath analysis for cancer markers are two tests that may be used in future studies.
CLINICAL TRIALS — Because the data on lung cancer screening are inconclusive, large-scale clinical trials of various screening modalities are underway. Smokers or former smokers may be asked to participate in these trials.
Although it makes sense to think that early detection of lung cancer is a good idea, it is important to understand that routine screening for lung cancer cannot be recommended until the research clearly shows that it makes a difference. It is likely that recommendations on lung cancer screening will evolve over the next decades as these data become available.
SUMMARY Patients who smoke are at increased risk of developing lung cancer. The best way to avoid lung cancer is not to smoke. Even long-term smokers can benefit from quitting. Researchers are looking for ways to help smokers and non-smokers who develop lung cancer to live longer. Early detection and screening is a major focus of this effort It is not clear if lung cancer screening can reduce the number of people who die from their disease. Clinical trials are underway that will help provide answers to these questions.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.cancernet.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The American Cancer Society
(www.cancer.org)
Lung Cancer Alliance
(www.lungcanceralliance.org)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Jemal, A, Siegel, R, Ward, E, et al. Cancer statistics, 2006. CA Cancer J Clin 2007; 57:43.
2. Truong, MT, Munden, RF. Lung cancer screening. Curr Oncol Rep 2003; 5:309.
3. Nawa, T, Nakagawa, T, Kusano, S, et al. Lung cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies. Chest 2002; 122:15.
4. Bastarrika, G, Garcia-Velloso, MJ, Lozano, MD, et al. Early Lung Cancer Detection using Spiral Computed Tomography and Positron Emission Tomography. Am J Respir Crit Care Med 2005; 171:1378.
Diagnosis and staging of lung cancer
INTRODUCTION — Lung cancer is a serious health problem. Although the death rate from lung cancer declined slightly (by 3.6 percent) in the 1990s after increasing steadily since the 1960s, the number of cases of lung cancer continues to increase, particularly in women, as the population ages and increases in size.
Cigarette smoking is the primary risk factor for lung cancer. A smoker's risk of developing lung cancer is 10 to 30 times greater than the risk for a non-smoker. Occupational or environmental exposure to other substances (eg, second-hand tobacco smoke, asbestos, radon, arsenic, radiation, polycyclic hydrocarbons, and nickel) also increase a person's risk of developing lung cancer, but the largest factor by far is smoking.
TYPES OF LUNG CANCER — The type of lung cancer is defined by the kind of cells that make up the cancerous tissue. The majority of lung cancers belong to one of four types: Squamous cell carcinoma (20 to 30 percent of lung cancers) Adenocarcinoma (30 to 40 percent) Large cell carcinoma (10 percent) Small cell or "oat cell" carcinoma (20 percent)
The first three types (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) are often collectively referred to as "non-small cell lung cancer" or NSCLC. In general, these tumors tend to behave in a comparable fashion, and they are treated similarly. In contrast, small cell lung cancer (SCLC) tends to grow and spread more quickly than NSCLC, and differs in the way treatment is approached.
SYMPTOMS — In a small number of patients (about 10 percent), lung cancer is first identified through an X-ray performed for some other reason, and no cancer-related symptoms are evident at the time of diagnosis. The majority of patients, however, are symptomatic at the time the lung cancer is diagnosed. Symptoms may be caused directly by the presence of the tumor itself in the lungs and chest, or by tumor that has spread or metastasized to other parts of the body, or they can be caused indirectly because a cancer is present somewhere in the body (eg, weight loss, fatigue, or paraneoplastic syndromes, which are explained below).
Lung and chest — The most common symptom of lung cancer is a cough, which may be present with or without sputum (phlegm) production. In patients who have a longstanding (chronic) cough, such as those with emphysema (also called chronic obstructive pulmonary disease or COPD), the development of a lung cancer may be signaled by a change in the character of their chronic cough. Other common symptoms include shortness of breath, coughing up bloody phlegm, chest pain, and wheezing.
Additional symptoms may appear as the cancer grows locally and spreads to other parts of the chest: Shortness of breath may develop if the cancer causes fluid to accumulate between the lung and chest wall (a condition called a pleural effusion). The ability of the heart to pump the blood throughout the body may be impaired if fluid accumulates around the heart (a condition called a pericardial effusion). Hoarseness may develop if the tumor presses on the laryngeal nerve (a nerve that travels through the chest and stimulates the larynx or "voice box" during speaking). Headache, shortness of breath, and swelling of the face, arms, or neck veins can occur if the tumor presses on the superior vena cava, a large blood vessel in the chest. A tumor that is located at the top of the lung can cause the "Pancoast syndrome", in which there is shoulder or arm pain, weakening of the hand muscles (both due to involvement of the brachial plexus, the nerve that stimulates the arm), a droopy eyelid, blurred vision, and a lack of sweating of the face on the side of the tumor.
Distant metastases — As lung cancer progresses, it can spread or metastasizes to other parts of the body. The most common sites of metastasis are the brain, bones, liver, and adrenal glands. Bone metastases can produce localized pain, while metastasis to the liver may cause weakness, jaundice (yellowing of the skin) and weight loss. Brain metastases can cause a range of symptoms including headache, nausea and vomiting, seizures, confusion, and personality changes.
Paraneoplastic syndromes — Paraneoplastic syndrome is a term used to describe a number of conditions that arise because of substances that are produced by the tumor, which then enter the bloodstream and act on the body to cause abnormalities. Thus, they are indirect effects of the tumor. About 10 to 20 percent of patients with lung cancer will experience symptoms due to a paraneoplastic syndrome; they are more common with SCLC than with NSCLC.
Symptoms may include an increase in the calcium level in the blood (hypercalcemia), broadening and thickening of the fingernails (digital clubbing), painful swollen joints, and neurologic symptoms.
Overproduction of hormones can also be caused by the tumor, and result in breast enlargement or discharge of a milky substance from the nipples. A hormone called ADH may also be secreted in unusually large quantities resulting in a low blood sodium level and concentrated urine. If untreated, oversecretion of ADH can lead to more serious symptoms including weakness, confusion, coma, and seizures.
INITIAL TESTING AND DIAGNOSIS — Once a patient presents with symptoms that suggest lung cancer, a chest X-ray is performed to check for the presence of a lung mass. If a mass is found, additional testing is performed to confirm the diagnosis, and determine the type of cancer. The additional tests also allow the physician to determine the "stage" of the cancer, or how widely it has spread. Accurate staging is important since it helps to define treatment and predict the long-term outcome of the cancer (the prognosis).
The physician first obtains a detailed history, performs a thorough physical examination, and obtains blood samples for testing. One or more radiologic tests are then performed to evaluate the local extent of tumor in the chest, and the possibility that it has spread outside of the chest. These tests may include a CT (computed tomography) scan of the chest, abdomen and/or head, PET scan, MRI (magnetic resonance imaging) scan, and bone scan.
Other procedures may be recommended to obtain tissue samples to examine the cancer cells and determine their type. A piece of the tissue can be obtained for study under the microscope in one of three ways: Bronchoscopy is a procedure where a lighted tube is inserted through the mouth into the windpipe (trachea, show figure 1) while the patient is sedated to directly visualize the airways. Any obvious areas of abnormality are then biopsied. (See "Patient information: Fiberoptic bronchoscopy"). CT-guided fine needle aspirate biopsy is a biopsy that is performed by a radiologist who inserts a thin needle through the skin of the chest into the lung. The needle's location is guided by computed tomography (CT scan). Mediastinoscopy is done under general anesthesia by a thoracic surgeon using a thin tube, inserted through the chest wall into the mediastinum, the central portion of the chest that represents the space between the right and left lung (show figure 1). A sample of tissue can then be removed through the tube.
STAGING OF NON-SMALL CELL LUNG CANCER — Staging is a way to define the extent of the tumor involvement, both in the chest and at distant sites, and is important in determining the most appropriate treatment.
In assigning a tumor stage in NSCLC, three factors are considered: Characteristics of the primary tumor (the T category, ranging from T1 to T4) The degree of lymph node involvement (the N category) Spread or metastasis to distant locations in the body (the M category)
Each factor (T, N, and M) is evaluated separately and assigned a value depending upon the extent of involvement (show table 1). Combinations of T, N, and M levels are grouped together to form stage groupings, which range from stage I (the least advanced degree of tumor involvement) through stage IV, the most advanced (show table 1). Stages I, II, and III disease are further subdivided into A and B subcategories.
Staging of NSCLC can be accomplished clinically (nonoperatively through x-ray studies and by physical examination); however, the final surgical or pathologic stage requires an operation and examination of the surgical specimen. This is especially important for patients who appear to have early stage (stage I to II) tumors, since involvement of lymph nodes in the mediastinum significantly alters the treatment approach. Often, a mediastinoscopy will be recommended to evaluate these lymph nodes under the microscope. Radical surgery may be offered to patients with stage I or II disease, while stage III disease is often treated with radiation and chemotherapy, and less often with surgery.
The following is a general description of the different tumor stages:
Stage I — At stage I, tumor is present in the lungs but the cancer has not spread to the lymph nodes or metastasized to other locations. Stage I lung cancer is considered a limited, local disease, and is not associated with any regional lymph node involvement.
Stage I disease is subdivided into stages IA and IB, primarily based upon the size of the primary tumor. Stage IA is associated with a primary tumor that is less than 3 cm in diameter. In contrast, stage IB is associated with a larger tumor, or with partial collapse of the lung. (See "Patient information: Treatment of early stage (stage I and II) non-small cell lung cancer").
Stage II — Stage II cancers have either begun to involve the adjacent lymph nodes, or have invaded surrounding tissues in the chest more extensively. However, no distant metastases are apparent, and the cancer is still considered a local disease. Stage II NSCLC is subdivided into stages IIA and IIB, based upon the size of the primary tumor. Stage IIA — The tumor is 3 cm or smaller and has invaded nearby tissue minimally if at all. One or more lymph nodes on the same side of the chest are involved, and there is no evidence of disease in the mediastinum nor distant metastases (T1 N1 M0). Stage IIB — Stage IIB disease comprises at least two situations: there is a T2 tumor (larger than 3 cm with some invasion of nearby tissue) and the cancer involves one or more lymph nodes on the same side of the chest (T2 N1 M0). Stage IIB is also assigned to cancers that have no lymph node involvement, but have either invaded chest structures outside the lung or are located within 2 cm of the carina (T3 N0 M0). (The carina is the point at which the trachea, or the tube that carries air to the lungs, splits in two to reach the right and left lung).
Stage III — Stage III NSCLC represents more advanced disease. The tumor has invaded chest tissues more extensively than in stage II and/or the cancer has spread to more distant lymph nodes located in the mediastinum. However, distant metastases are still not present. Stage III NSCLC is subdivided into stages IIIA and IIIB. (See "Patient information: Treatment of locally advanced (stage III) non-small cell lung cancer"). Stage IIIA — Stage IIIA is assigned if the cancer involves an invasive T3 tumor and lymph nodes on the same side of the chest (T3 N1 M0). The disease is also staged IIIA if the tumor involves more distant lymph nodes such as those in the mediastinum, or below the carina, regardless of the primary T designation (T1-3 N2 M0). Stage IIIB — Stage IIIB includes cancers that have invaded local structures extensively (T4 tumor), and cancers that have spread to more distant lymph nodes including those on the opposite side of the mediastinum (N3). (Possible TNM categories include T1-4 N3 M0 or T4 N1-N4 M0).
Stage IV — In stage IV lung cancer, the cancer has metastasized to distant locations (M1). (See "Patient information: Treatment of advanced unresectable; metastatic; and recurrent non-small cell lung cancer").
STAGING SMALL CELL LUNG CANCER — The system used to stage NSCLC is of limited value in staging small cell lung cancer (SCLC). This is because surgery is rarely used in this disease. For treatment purposes, SCLC is categorized more simply as either "limited" or "extensive" disease. Limited disease refers to small cell lung cancers that are confined to one side of the chest. Extensive disease refers to small cell lung cancers that have spread to the other side of the chest or that have metastasized to more distant locations.
As is the case for NSCLC, treatment and prognosis for SCLC varies depending upon the classification. (See "Patient information: Treatment of small cell lung cancer").
CLINICAL TRIALS — Progress in treating lung cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.cancernet.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The American Cancer Society
(www.cancer.org)
Lung Cancer Alliance
(www.lungcanceralliance.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Kim, K, Rice, TW, Murthy, SC, et al. Combined bronchoscopy, mediastinoscopy, and thoracotomy for lung cancer: who benefits?. J Thorac Cardiovasc Surg 2004; 127:850.
2. Mountain, CF. Revisions in the international system for staging lung cancer. Chest 1997; 111:1710.
3. Pretreatment evaluation of non-small-cell lung cancer. The American Thoracic Society and The European Respiratory Society. Am J Respir Crit Care Med 1997; 156:320.
4. Argiris, A, Murren, JR. Staging and clinical prognostic factors for small-cell lung cancer. Cancer J 2001; 7:437.
5. Micke, P, Faldum, A, Metz, T, et al. Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer-what limits limited disease?. Lung Cancer 2002; 37:271.
Cigarette smoking is the primary risk factor for lung cancer. A smoker's risk of developing lung cancer is 10 to 30 times greater than the risk for a non-smoker. Occupational or environmental exposure to other substances (eg, second-hand tobacco smoke, asbestos, radon, arsenic, radiation, polycyclic hydrocarbons, and nickel) also increase a person's risk of developing lung cancer, but the largest factor by far is smoking.
TYPES OF LUNG CANCER — The type of lung cancer is defined by the kind of cells that make up the cancerous tissue. The majority of lung cancers belong to one of four types: Squamous cell carcinoma (20 to 30 percent of lung cancers) Adenocarcinoma (30 to 40 percent) Large cell carcinoma (10 percent) Small cell or "oat cell" carcinoma (20 percent)
The first three types (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) are often collectively referred to as "non-small cell lung cancer" or NSCLC. In general, these tumors tend to behave in a comparable fashion, and they are treated similarly. In contrast, small cell lung cancer (SCLC) tends to grow and spread more quickly than NSCLC, and differs in the way treatment is approached.
SYMPTOMS — In a small number of patients (about 10 percent), lung cancer is first identified through an X-ray performed for some other reason, and no cancer-related symptoms are evident at the time of diagnosis. The majority of patients, however, are symptomatic at the time the lung cancer is diagnosed. Symptoms may be caused directly by the presence of the tumor itself in the lungs and chest, or by tumor that has spread or metastasized to other parts of the body, or they can be caused indirectly because a cancer is present somewhere in the body (eg, weight loss, fatigue, or paraneoplastic syndromes, which are explained below).
Lung and chest — The most common symptom of lung cancer is a cough, which may be present with or without sputum (phlegm) production. In patients who have a longstanding (chronic) cough, such as those with emphysema (also called chronic obstructive pulmonary disease or COPD), the development of a lung cancer may be signaled by a change in the character of their chronic cough. Other common symptoms include shortness of breath, coughing up bloody phlegm, chest pain, and wheezing.
Additional symptoms may appear as the cancer grows locally and spreads to other parts of the chest: Shortness of breath may develop if the cancer causes fluid to accumulate between the lung and chest wall (a condition called a pleural effusion). The ability of the heart to pump the blood throughout the body may be impaired if fluid accumulates around the heart (a condition called a pericardial effusion). Hoarseness may develop if the tumor presses on the laryngeal nerve (a nerve that travels through the chest and stimulates the larynx or "voice box" during speaking). Headache, shortness of breath, and swelling of the face, arms, or neck veins can occur if the tumor presses on the superior vena cava, a large blood vessel in the chest. A tumor that is located at the top of the lung can cause the "Pancoast syndrome", in which there is shoulder or arm pain, weakening of the hand muscles (both due to involvement of the brachial plexus, the nerve that stimulates the arm), a droopy eyelid, blurred vision, and a lack of sweating of the face on the side of the tumor.
Distant metastases — As lung cancer progresses, it can spread or metastasizes to other parts of the body. The most common sites of metastasis are the brain, bones, liver, and adrenal glands. Bone metastases can produce localized pain, while metastasis to the liver may cause weakness, jaundice (yellowing of the skin) and weight loss. Brain metastases can cause a range of symptoms including headache, nausea and vomiting, seizures, confusion, and personality changes.
Paraneoplastic syndromes — Paraneoplastic syndrome is a term used to describe a number of conditions that arise because of substances that are produced by the tumor, which then enter the bloodstream and act on the body to cause abnormalities. Thus, they are indirect effects of the tumor. About 10 to 20 percent of patients with lung cancer will experience symptoms due to a paraneoplastic syndrome; they are more common with SCLC than with NSCLC.
Symptoms may include an increase in the calcium level in the blood (hypercalcemia), broadening and thickening of the fingernails (digital clubbing), painful swollen joints, and neurologic symptoms.
Overproduction of hormones can also be caused by the tumor, and result in breast enlargement or discharge of a milky substance from the nipples. A hormone called ADH may also be secreted in unusually large quantities resulting in a low blood sodium level and concentrated urine. If untreated, oversecretion of ADH can lead to more serious symptoms including weakness, confusion, coma, and seizures.
INITIAL TESTING AND DIAGNOSIS — Once a patient presents with symptoms that suggest lung cancer, a chest X-ray is performed to check for the presence of a lung mass. If a mass is found, additional testing is performed to confirm the diagnosis, and determine the type of cancer. The additional tests also allow the physician to determine the "stage" of the cancer, or how widely it has spread. Accurate staging is important since it helps to define treatment and predict the long-term outcome of the cancer (the prognosis).
The physician first obtains a detailed history, performs a thorough physical examination, and obtains blood samples for testing. One or more radiologic tests are then performed to evaluate the local extent of tumor in the chest, and the possibility that it has spread outside of the chest. These tests may include a CT (computed tomography) scan of the chest, abdomen and/or head, PET scan, MRI (magnetic resonance imaging) scan, and bone scan.
Other procedures may be recommended to obtain tissue samples to examine the cancer cells and determine their type. A piece of the tissue can be obtained for study under the microscope in one of three ways: Bronchoscopy is a procedure where a lighted tube is inserted through the mouth into the windpipe (trachea, show figure 1) while the patient is sedated to directly visualize the airways. Any obvious areas of abnormality are then biopsied. (See "Patient information: Fiberoptic bronchoscopy"). CT-guided fine needle aspirate biopsy is a biopsy that is performed by a radiologist who inserts a thin needle through the skin of the chest into the lung. The needle's location is guided by computed tomography (CT scan). Mediastinoscopy is done under general anesthesia by a thoracic surgeon using a thin tube, inserted through the chest wall into the mediastinum, the central portion of the chest that represents the space between the right and left lung (show figure 1). A sample of tissue can then be removed through the tube.
STAGING OF NON-SMALL CELL LUNG CANCER — Staging is a way to define the extent of the tumor involvement, both in the chest and at distant sites, and is important in determining the most appropriate treatment.
In assigning a tumor stage in NSCLC, three factors are considered: Characteristics of the primary tumor (the T category, ranging from T1 to T4) The degree of lymph node involvement (the N category) Spread or metastasis to distant locations in the body (the M category)
Each factor (T, N, and M) is evaluated separately and assigned a value depending upon the extent of involvement (show table 1). Combinations of T, N, and M levels are grouped together to form stage groupings, which range from stage I (the least advanced degree of tumor involvement) through stage IV, the most advanced (show table 1). Stages I, II, and III disease are further subdivided into A and B subcategories.
Staging of NSCLC can be accomplished clinically (nonoperatively through x-ray studies and by physical examination); however, the final surgical or pathologic stage requires an operation and examination of the surgical specimen. This is especially important for patients who appear to have early stage (stage I to II) tumors, since involvement of lymph nodes in the mediastinum significantly alters the treatment approach. Often, a mediastinoscopy will be recommended to evaluate these lymph nodes under the microscope. Radical surgery may be offered to patients with stage I or II disease, while stage III disease is often treated with radiation and chemotherapy, and less often with surgery.
The following is a general description of the different tumor stages:
Stage I — At stage I, tumor is present in the lungs but the cancer has not spread to the lymph nodes or metastasized to other locations. Stage I lung cancer is considered a limited, local disease, and is not associated with any regional lymph node involvement.
Stage I disease is subdivided into stages IA and IB, primarily based upon the size of the primary tumor. Stage IA is associated with a primary tumor that is less than 3 cm in diameter. In contrast, stage IB is associated with a larger tumor, or with partial collapse of the lung. (See "Patient information: Treatment of early stage (stage I and II) non-small cell lung cancer").
Stage II — Stage II cancers have either begun to involve the adjacent lymph nodes, or have invaded surrounding tissues in the chest more extensively. However, no distant metastases are apparent, and the cancer is still considered a local disease. Stage II NSCLC is subdivided into stages IIA and IIB, based upon the size of the primary tumor. Stage IIA — The tumor is 3 cm or smaller and has invaded nearby tissue minimally if at all. One or more lymph nodes on the same side of the chest are involved, and there is no evidence of disease in the mediastinum nor distant metastases (T1 N1 M0). Stage IIB — Stage IIB disease comprises at least two situations: there is a T2 tumor (larger than 3 cm with some invasion of nearby tissue) and the cancer involves one or more lymph nodes on the same side of the chest (T2 N1 M0). Stage IIB is also assigned to cancers that have no lymph node involvement, but have either invaded chest structures outside the lung or are located within 2 cm of the carina (T3 N0 M0). (The carina is the point at which the trachea, or the tube that carries air to the lungs, splits in two to reach the right and left lung).
Stage III — Stage III NSCLC represents more advanced disease. The tumor has invaded chest tissues more extensively than in stage II and/or the cancer has spread to more distant lymph nodes located in the mediastinum. However, distant metastases are still not present. Stage III NSCLC is subdivided into stages IIIA and IIIB. (See "Patient information: Treatment of locally advanced (stage III) non-small cell lung cancer"). Stage IIIA — Stage IIIA is assigned if the cancer involves an invasive T3 tumor and lymph nodes on the same side of the chest (T3 N1 M0). The disease is also staged IIIA if the tumor involves more distant lymph nodes such as those in the mediastinum, or below the carina, regardless of the primary T designation (T1-3 N2 M0). Stage IIIB — Stage IIIB includes cancers that have invaded local structures extensively (T4 tumor), and cancers that have spread to more distant lymph nodes including those on the opposite side of the mediastinum (N3). (Possible TNM categories include T1-4 N3 M0 or T4 N1-N4 M0).
Stage IV — In stage IV lung cancer, the cancer has metastasized to distant locations (M1). (See "Patient information: Treatment of advanced unresectable; metastatic; and recurrent non-small cell lung cancer").
STAGING SMALL CELL LUNG CANCER — The system used to stage NSCLC is of limited value in staging small cell lung cancer (SCLC). This is because surgery is rarely used in this disease. For treatment purposes, SCLC is categorized more simply as either "limited" or "extensive" disease. Limited disease refers to small cell lung cancers that are confined to one side of the chest. Extensive disease refers to small cell lung cancers that have spread to the other side of the chest or that have metastasized to more distant locations.
As is the case for NSCLC, treatment and prognosis for SCLC varies depending upon the classification. (See "Patient information: Treatment of small cell lung cancer").
CLINICAL TRIALS — Progress in treating lung cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.cancernet.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The American Cancer Society
(www.cancer.org)
Lung Cancer Alliance
(www.lungcanceralliance.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Kim, K, Rice, TW, Murthy, SC, et al. Combined bronchoscopy, mediastinoscopy, and thoracotomy for lung cancer: who benefits?. J Thorac Cardiovasc Surg 2004; 127:850.
2. Mountain, CF. Revisions in the international system for staging lung cancer. Chest 1997; 111:1710.
3. Pretreatment evaluation of non-small-cell lung cancer. The American Thoracic Society and The European Respiratory Society. Am J Respir Crit Care Med 1997; 156:320.
4. Argiris, A, Murren, JR. Staging and clinical prognostic factors for small-cell lung cancer. Cancer J 2001; 7:437.
5. Micke, P, Faldum, A, Metz, T, et al. Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer-what limits limited disease?. Lung Cancer 2002; 37:271.
Diagnosis and staging of lung cancer
INTRODUCTION — Lung cancer is a serious health problem. Although the death rate from lung cancer declined slightly (by 3.6 percent) in the 1990s after increasing steadily since the 1960s, the number of cases of lung cancer continues to increase, particularly in women, as the population ages and increases in size.
Cigarette smoking is the primary risk factor for lung cancer. A smoker's risk of developing lung cancer is 10 to 30 times greater than the risk for a non-smoker. Occupational or environmental exposure to other substances (eg, second-hand tobacco smoke, asbestos, radon, arsenic, radiation, polycyclic hydrocarbons, and nickel) also increase a person's risk of developing lung cancer, but the largest factor by far is smoking.
TYPES OF LUNG CANCER — The type of lung cancer is defined by the kind of cells that make up the cancerous tissue. The majority of lung cancers belong to one of four types: Squamous cell carcinoma (20 to 30 percent of lung cancers) Adenocarcinoma (30 to 40 percent) Large cell carcinoma (10 percent) Small cell or "oat cell" carcinoma (20 percent)
The first three types (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) are often collectively referred to as "non-small cell lung cancer" or NSCLC. In general, these tumors tend to behave in a comparable fashion, and they are treated similarly. In contrast, small cell lung cancer (SCLC) tends to grow and spread more quickly than NSCLC, and differs in the way treatment is approached.
SYMPTOMS — In a small number of patients (about 10 percent), lung cancer is first identified through an X-ray performed for some other reason, and no cancer-related symptoms are evident at the time of diagnosis. The majority of patients, however, are symptomatic at the time the lung cancer is diagnosed. Symptoms may be caused directly by the presence of the tumor itself in the lungs and chest, or by tumor that has spread or metastasized to other parts of the body, or they can be caused indirectly because a cancer is present somewhere in the body (eg, weight loss, fatigue, or paraneoplastic syndromes, which are explained below).
Lung and chest — The most common symptom of lung cancer is a cough, which may be present with or without sputum (phlegm) production. In patients who have a longstanding (chronic) cough, such as those with emphysema (also called chronic obstructive pulmonary disease or COPD), the development of a lung cancer may be signaled by a change in the character of their chronic cough. Other common symptoms include shortness of breath, coughing up bloody phlegm, chest pain, and wheezing.
Additional symptoms may appear as the cancer grows locally and spreads to other parts of the chest: Shortness of breath may develop if the cancer causes fluid to accumulate between the lung and chest wall (a condition called a pleural effusion). The ability of the heart to pump the blood throughout the body may be impaired if fluid accumulates around the heart (a condition called a pericardial effusion). Hoarseness may develop if the tumor presses on the laryngeal nerve (a nerve that travels through the chest and stimulates the larynx or "voice box" during speaking). Headache, shortness of breath, and swelling of the face, arms, or neck veins can occur if the tumor presses on the superior vena cava, a large blood vessel in the chest. A tumor that is located at the top of the lung can cause the "Pancoast syndrome", in which there is shoulder or arm pain, weakening of the hand muscles (both due to involvement of the brachial plexus, the nerve that stimulates the arm), a droopy eyelid, blurred vision, and a lack of sweating of the face on the side of the tumor.
Distant metastases — As lung cancer progresses, it can spread or metastasizes to other parts of the body. The most common sites of metastasis are the brain, bones, liver, and adrenal glands. Bone metastases can produce localized pain, while metastasis to the liver may cause weakness, jaundice (yellowing of the skin) and weight loss. Brain metastases can cause a range of symptoms including headache, nausea and vomiting, seizures, confusion, and personality changes.
Paraneoplastic syndromes — Paraneoplastic syndrome is a term used to describe a number of conditions that arise because of substances that are produced by the tumor, which then enter the bloodstream and act on the body to cause abnormalities. Thus, they are indirect effects of the tumor. About 10 to 20 percent of patients with lung cancer will experience symptoms due to a paraneoplastic syndrome; they are more common with SCLC than with NSCLC.
Symptoms may include an increase in the calcium level in the blood (hypercalcemia), broadening and thickening of the fingernails (digital clubbing), painful swollen joints, and neurologic symptoms.
Overproduction of hormones can also be caused by the tumor, and result in breast enlargement or discharge of a milky substance from the nipples. A hormone called ADH may also be secreted in unusually large quantities resulting in a low blood sodium level and concentrated urine. If untreated, oversecretion of ADH can lead to more serious symptoms including weakness, confusion, coma, and seizures.
INITIAL TESTING AND DIAGNOSIS — Once a patient presents with symptoms that suggest lung cancer, a chest X-ray is performed to check for the presence of a lung mass. If a mass is found, additional testing is performed to confirm the diagnosis, and determine the type of cancer. The additional tests also allow the physician to determine the "stage" of the cancer, or how widely it has spread. Accurate staging is important since it helps to define treatment and predict the long-term outcome of the cancer (the prognosis).
The physician first obtains a detailed history, performs a thorough physical examination, and obtains blood samples for testing. One or more radiologic tests are then performed to evaluate the local extent of tumor in the chest, and the possibility that it has spread outside of the chest. These tests may include a CT (computed tomography) scan of the chest, abdomen and/or head, PET scan, MRI (magnetic resonance imaging) scan, and bone scan.
Other procedures may be recommended to obtain tissue samples to examine the cancer cells and determine their type. A piece of the tissue can be obtained for study under the microscope in one of three ways: Bronchoscopy is a procedure where a lighted tube is inserted through the mouth into the windpipe (trachea, show figure 1) while the patient is sedated to directly visualize the airways. Any obvious areas of abnormality are then biopsied. (See "Patient information: Fiberoptic bronchoscopy"). CT-guided fine needle aspirate biopsy is a biopsy that is performed by a radiologist who inserts a thin needle through the skin of the chest into the lung. The needle's location is guided by computed tomography (CT scan). Mediastinoscopy is done under general anesthesia by a thoracic surgeon using a thin tube, inserted through the chest wall into the mediastinum, the central portion of the chest that represents the space between the right and left lung (show figure 1). A sample of tissue can then be removed through the tube.
STAGING OF NON-SMALL CELL LUNG CANCER — Staging is a way to define the extent of the tumor involvement, both in the chest and at distant sites, and is important in determining the most appropriate treatment.
In assigning a tumor stage in NSCLC, three factors are considered: Characteristics of the primary tumor (the T category, ranging from T1 to T4) The degree of lymph node involvement (the N category) Spread or metastasis to distant locations in the body (the M category)
Each factor (T, N, and M) is evaluated separately and assigned a value depending upon the extent of involvement (show table 1). Combinations of T, N, and M levels are grouped together to form stage groupings, which range from stage I (the least advanced degree of tumor involvement) through stage IV, the most advanced (show table 1). Stages I, II, and III disease are further subdivided into A and B subcategories.
Staging of NSCLC can be accomplished clinically (nonoperatively through x-ray studies and by physical examination); however, the final surgical or pathologic stage requires an operation and examination of the surgical specimen. This is especially important for patients who appear to have early stage (stage I to II) tumors, since involvement of lymph nodes in the mediastinum significantly alters the treatment approach. Often, a mediastinoscopy will be recommended to evaluate these lymph nodes under the microscope. Radical surgery may be offered to patients with stage I or II disease, while stage III disease is often treated with radiation and chemotherapy, and less often with surgery.
The following is a general description of the different tumor stages:
Stage I — At stage I, tumor is present in the lungs but the cancer has not spread to the lymph nodes or metastasized to other locations. Stage I lung cancer is considered a limited, local disease, and is not associated with any regional lymph node involvement.
Stage I disease is subdivided into stages IA and IB, primarily based upon the size of the primary tumor. Stage IA is associated with a primary tumor that is less than 3 cm in diameter. In contrast, stage IB is associated with a larger tumor, or with partial collapse of the lung. (See "Patient information: Treatment of early stage (stage I and II) non-small cell lung cancer").
Stage II — Stage II cancers have either begun to involve the adjacent lymph nodes, or have invaded surrounding tissues in the chest more extensively. However, no distant metastases are apparent, and the cancer is still considered a local disease. Stage II NSCLC is subdivided into stages IIA and IIB, based upon the size of the primary tumor. Stage IIA — The tumor is 3 cm or smaller and has invaded nearby tissue minimally if at all. One or more lymph nodes on the same side of the chest are involved, and there is no evidence of disease in the mediastinum nor distant metastases (T1 N1 M0). Stage IIB — Stage IIB disease comprises at least two situations: there is a T2 tumor (larger than 3 cm with some invasion of nearby tissue) and the cancer involves one or more lymph nodes on the same side of the chest (T2 N1 M0). Stage IIB is also assigned to cancers that have no lymph node involvement, but have either invaded chest structures outside the lung or are located within 2 cm of the carina (T3 N0 M0). (The carina is the point at which the trachea, or the tube that carries air to the lungs, splits in two to reach the right and left lung).
Stage III — Stage III NSCLC represents more advanced disease. The tumor has invaded chest tissues more extensively than in stage II and/or the cancer has spread to more distant lymph nodes located in the mediastinum. However, distant metastases are still not present. Stage III NSCLC is subdivided into stages IIIA and IIIB. (See "Patient information: Treatment of locally advanced (stage III) non-small cell lung cancer"). Stage IIIA — Stage IIIA is assigned if the cancer involves an invasive T3 tumor and lymph nodes on the same side of the chest (T3 N1 M0). The disease is also staged IIIA if the tumor involves more distant lymph nodes such as those in the mediastinum, or below the carina, regardless of the primary T designation (T1-3 N2 M0). Stage IIIB — Stage IIIB includes cancers that have invaded local structures extensively (T4 tumor), and cancers that have spread to more distant lymph nodes including those on the opposite side of the mediastinum (N3). (Possible TNM categories include T1-4 N3 M0 or T4 N1-N4 M0).
Stage IV — In stage IV lung cancer, the cancer has metastasized to distant locations (M1). (See "Patient information: Treatment of advanced unresectable; metastatic; and recurrent non-small cell lung cancer").
STAGING SMALL CELL LUNG CANCER — The system used to stage NSCLC is of limited value in staging small cell lung cancer (SCLC). This is because surgery is rarely used in this disease. For treatment purposes, SCLC is categorized more simply as either "limited" or "extensive" disease. Limited disease refers to small cell lung cancers that are confined to one side of the chest. Extensive disease refers to small cell lung cancers that have spread to the other side of the chest or that have metastasized to more distant locations.
As is the case for NSCLC, treatment and prognosis for SCLC varies depending upon the classification. (See "Patient information: Treatment of small cell lung cancer").
CLINICAL TRIALS — Progress in treating lung cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.cancernet.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The American Cancer Society
(www.cancer.org)
Lung Cancer Alliance
(www.lungcanceralliance.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Kim, K, Rice, TW, Murthy, SC, et al. Combined bronchoscopy, mediastinoscopy, and thoracotomy for lung cancer: who benefits?. J Thorac Cardiovasc Surg 2004; 127:850.
2. Mountain, CF. Revisions in the international system for staging lung cancer. Chest 1997; 111:1710.
3. Pretreatment evaluation of non-small-cell lung cancer. The American Thoracic Society and The European Respiratory Society. Am J Respir Crit Care Med 1997; 156:320.
4. Argiris, A, Murren, JR. Staging and clinical prognostic factors for small-cell lung cancer. Cancer J 2001; 7:437.
5. Micke, P, Faldum, A, Metz, T, et al. Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer-what limits limited disease?. Lung Cancer 2002; 37:271.
Cigarette smoking is the primary risk factor for lung cancer. A smoker's risk of developing lung cancer is 10 to 30 times greater than the risk for a non-smoker. Occupational or environmental exposure to other substances (eg, second-hand tobacco smoke, asbestos, radon, arsenic, radiation, polycyclic hydrocarbons, and nickel) also increase a person's risk of developing lung cancer, but the largest factor by far is smoking.
TYPES OF LUNG CANCER — The type of lung cancer is defined by the kind of cells that make up the cancerous tissue. The majority of lung cancers belong to one of four types: Squamous cell carcinoma (20 to 30 percent of lung cancers) Adenocarcinoma (30 to 40 percent) Large cell carcinoma (10 percent) Small cell or "oat cell" carcinoma (20 percent)
The first three types (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) are often collectively referred to as "non-small cell lung cancer" or NSCLC. In general, these tumors tend to behave in a comparable fashion, and they are treated similarly. In contrast, small cell lung cancer (SCLC) tends to grow and spread more quickly than NSCLC, and differs in the way treatment is approached.
SYMPTOMS — In a small number of patients (about 10 percent), lung cancer is first identified through an X-ray performed for some other reason, and no cancer-related symptoms are evident at the time of diagnosis. The majority of patients, however, are symptomatic at the time the lung cancer is diagnosed. Symptoms may be caused directly by the presence of the tumor itself in the lungs and chest, or by tumor that has spread or metastasized to other parts of the body, or they can be caused indirectly because a cancer is present somewhere in the body (eg, weight loss, fatigue, or paraneoplastic syndromes, which are explained below).
Lung and chest — The most common symptom of lung cancer is a cough, which may be present with or without sputum (phlegm) production. In patients who have a longstanding (chronic) cough, such as those with emphysema (also called chronic obstructive pulmonary disease or COPD), the development of a lung cancer may be signaled by a change in the character of their chronic cough. Other common symptoms include shortness of breath, coughing up bloody phlegm, chest pain, and wheezing.
Additional symptoms may appear as the cancer grows locally and spreads to other parts of the chest: Shortness of breath may develop if the cancer causes fluid to accumulate between the lung and chest wall (a condition called a pleural effusion). The ability of the heart to pump the blood throughout the body may be impaired if fluid accumulates around the heart (a condition called a pericardial effusion). Hoarseness may develop if the tumor presses on the laryngeal nerve (a nerve that travels through the chest and stimulates the larynx or "voice box" during speaking). Headache, shortness of breath, and swelling of the face, arms, or neck veins can occur if the tumor presses on the superior vena cava, a large blood vessel in the chest. A tumor that is located at the top of the lung can cause the "Pancoast syndrome", in which there is shoulder or arm pain, weakening of the hand muscles (both due to involvement of the brachial plexus, the nerve that stimulates the arm), a droopy eyelid, blurred vision, and a lack of sweating of the face on the side of the tumor.
Distant metastases — As lung cancer progresses, it can spread or metastasizes to other parts of the body. The most common sites of metastasis are the brain, bones, liver, and adrenal glands. Bone metastases can produce localized pain, while metastasis to the liver may cause weakness, jaundice (yellowing of the skin) and weight loss. Brain metastases can cause a range of symptoms including headache, nausea and vomiting, seizures, confusion, and personality changes.
Paraneoplastic syndromes — Paraneoplastic syndrome is a term used to describe a number of conditions that arise because of substances that are produced by the tumor, which then enter the bloodstream and act on the body to cause abnormalities. Thus, they are indirect effects of the tumor. About 10 to 20 percent of patients with lung cancer will experience symptoms due to a paraneoplastic syndrome; they are more common with SCLC than with NSCLC.
Symptoms may include an increase in the calcium level in the blood (hypercalcemia), broadening and thickening of the fingernails (digital clubbing), painful swollen joints, and neurologic symptoms.
Overproduction of hormones can also be caused by the tumor, and result in breast enlargement or discharge of a milky substance from the nipples. A hormone called ADH may also be secreted in unusually large quantities resulting in a low blood sodium level and concentrated urine. If untreated, oversecretion of ADH can lead to more serious symptoms including weakness, confusion, coma, and seizures.
INITIAL TESTING AND DIAGNOSIS — Once a patient presents with symptoms that suggest lung cancer, a chest X-ray is performed to check for the presence of a lung mass. If a mass is found, additional testing is performed to confirm the diagnosis, and determine the type of cancer. The additional tests also allow the physician to determine the "stage" of the cancer, or how widely it has spread. Accurate staging is important since it helps to define treatment and predict the long-term outcome of the cancer (the prognosis).
The physician first obtains a detailed history, performs a thorough physical examination, and obtains blood samples for testing. One or more radiologic tests are then performed to evaluate the local extent of tumor in the chest, and the possibility that it has spread outside of the chest. These tests may include a CT (computed tomography) scan of the chest, abdomen and/or head, PET scan, MRI (magnetic resonance imaging) scan, and bone scan.
Other procedures may be recommended to obtain tissue samples to examine the cancer cells and determine their type. A piece of the tissue can be obtained for study under the microscope in one of three ways: Bronchoscopy is a procedure where a lighted tube is inserted through the mouth into the windpipe (trachea, show figure 1) while the patient is sedated to directly visualize the airways. Any obvious areas of abnormality are then biopsied. (See "Patient information: Fiberoptic bronchoscopy"). CT-guided fine needle aspirate biopsy is a biopsy that is performed by a radiologist who inserts a thin needle through the skin of the chest into the lung. The needle's location is guided by computed tomography (CT scan). Mediastinoscopy is done under general anesthesia by a thoracic surgeon using a thin tube, inserted through the chest wall into the mediastinum, the central portion of the chest that represents the space between the right and left lung (show figure 1). A sample of tissue can then be removed through the tube.
STAGING OF NON-SMALL CELL LUNG CANCER — Staging is a way to define the extent of the tumor involvement, both in the chest and at distant sites, and is important in determining the most appropriate treatment.
In assigning a tumor stage in NSCLC, three factors are considered: Characteristics of the primary tumor (the T category, ranging from T1 to T4) The degree of lymph node involvement (the N category) Spread or metastasis to distant locations in the body (the M category)
Each factor (T, N, and M) is evaluated separately and assigned a value depending upon the extent of involvement (show table 1). Combinations of T, N, and M levels are grouped together to form stage groupings, which range from stage I (the least advanced degree of tumor involvement) through stage IV, the most advanced (show table 1). Stages I, II, and III disease are further subdivided into A and B subcategories.
Staging of NSCLC can be accomplished clinically (nonoperatively through x-ray studies and by physical examination); however, the final surgical or pathologic stage requires an operation and examination of the surgical specimen. This is especially important for patients who appear to have early stage (stage I to II) tumors, since involvement of lymph nodes in the mediastinum significantly alters the treatment approach. Often, a mediastinoscopy will be recommended to evaluate these lymph nodes under the microscope. Radical surgery may be offered to patients with stage I or II disease, while stage III disease is often treated with radiation and chemotherapy, and less often with surgery.
The following is a general description of the different tumor stages:
Stage I — At stage I, tumor is present in the lungs but the cancer has not spread to the lymph nodes or metastasized to other locations. Stage I lung cancer is considered a limited, local disease, and is not associated with any regional lymph node involvement.
Stage I disease is subdivided into stages IA and IB, primarily based upon the size of the primary tumor. Stage IA is associated with a primary tumor that is less than 3 cm in diameter. In contrast, stage IB is associated with a larger tumor, or with partial collapse of the lung. (See "Patient information: Treatment of early stage (stage I and II) non-small cell lung cancer").
Stage II — Stage II cancers have either begun to involve the adjacent lymph nodes, or have invaded surrounding tissues in the chest more extensively. However, no distant metastases are apparent, and the cancer is still considered a local disease. Stage II NSCLC is subdivided into stages IIA and IIB, based upon the size of the primary tumor. Stage IIA — The tumor is 3 cm or smaller and has invaded nearby tissue minimally if at all. One or more lymph nodes on the same side of the chest are involved, and there is no evidence of disease in the mediastinum nor distant metastases (T1 N1 M0). Stage IIB — Stage IIB disease comprises at least two situations: there is a T2 tumor (larger than 3 cm with some invasion of nearby tissue) and the cancer involves one or more lymph nodes on the same side of the chest (T2 N1 M0). Stage IIB is also assigned to cancers that have no lymph node involvement, but have either invaded chest structures outside the lung or are located within 2 cm of the carina (T3 N0 M0). (The carina is the point at which the trachea, or the tube that carries air to the lungs, splits in two to reach the right and left lung).
Stage III — Stage III NSCLC represents more advanced disease. The tumor has invaded chest tissues more extensively than in stage II and/or the cancer has spread to more distant lymph nodes located in the mediastinum. However, distant metastases are still not present. Stage III NSCLC is subdivided into stages IIIA and IIIB. (See "Patient information: Treatment of locally advanced (stage III) non-small cell lung cancer"). Stage IIIA — Stage IIIA is assigned if the cancer involves an invasive T3 tumor and lymph nodes on the same side of the chest (T3 N1 M0). The disease is also staged IIIA if the tumor involves more distant lymph nodes such as those in the mediastinum, or below the carina, regardless of the primary T designation (T1-3 N2 M0). Stage IIIB — Stage IIIB includes cancers that have invaded local structures extensively (T4 tumor), and cancers that have spread to more distant lymph nodes including those on the opposite side of the mediastinum (N3). (Possible TNM categories include T1-4 N3 M0 or T4 N1-N4 M0).
Stage IV — In stage IV lung cancer, the cancer has metastasized to distant locations (M1). (See "Patient information: Treatment of advanced unresectable; metastatic; and recurrent non-small cell lung cancer").
STAGING SMALL CELL LUNG CANCER — The system used to stage NSCLC is of limited value in staging small cell lung cancer (SCLC). This is because surgery is rarely used in this disease. For treatment purposes, SCLC is categorized more simply as either "limited" or "extensive" disease. Limited disease refers to small cell lung cancers that are confined to one side of the chest. Extensive disease refers to small cell lung cancers that have spread to the other side of the chest or that have metastasized to more distant locations.
As is the case for NSCLC, treatment and prognosis for SCLC varies depending upon the classification. (See "Patient information: Treatment of small cell lung cancer").
CLINICAL TRIALS — Progress in treating lung cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.cancernet.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The American Cancer Society
(www.cancer.org)
Lung Cancer Alliance
(www.lungcanceralliance.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Kim, K, Rice, TW, Murthy, SC, et al. Combined bronchoscopy, mediastinoscopy, and thoracotomy for lung cancer: who benefits?. J Thorac Cardiovasc Surg 2004; 127:850.
2. Mountain, CF. Revisions in the international system for staging lung cancer. Chest 1997; 111:1710.
3. Pretreatment evaluation of non-small-cell lung cancer. The American Thoracic Society and The European Respiratory Society. Am J Respir Crit Care Med 1997; 156:320.
4. Argiris, A, Murren, JR. Staging and clinical prognostic factors for small-cell lung cancer. Cancer J 2001; 7:437.
5. Micke, P, Faldum, A, Metz, T, et al. Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer-what limits limited disease?. Lung Cancer 2002; 37:271.
Diagnosis and staging of lung cancer
INTRODUCTION — Lung cancer is a serious health problem. Although the death rate from lung cancer declined slightly (by 3.6 percent) in the 1990s after increasing steadily since the 1960s, the number of cases of lung cancer continues to increase, particularly in women, as the population ages and increases in size.
Cigarette smoking is the primary risk factor for lung cancer. A smoker's risk of developing lung cancer is 10 to 30 times greater than the risk for a non-smoker. Occupational or environmental exposure to other substances (eg, second-hand tobacco smoke, asbestos, radon, arsenic, radiation, polycyclic hydrocarbons, and nickel) also increase a person's risk of developing lung cancer, but the largest factor by far is smoking.
TYPES OF LUNG CANCER — The type of lung cancer is defined by the kind of cells that make up the cancerous tissue. The majority of lung cancers belong to one of four types: Squamous cell carcinoma (20 to 30 percent of lung cancers) Adenocarcinoma (30 to 40 percent) Large cell carcinoma (10 percent) Small cell or "oat cell" carcinoma (20 percent)
The first three types (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) are often collectively referred to as "non-small cell lung cancer" or NSCLC. In general, these tumors tend to behave in a comparable fashion, and they are treated similarly. In contrast, small cell lung cancer (SCLC) tends to grow and spread more quickly than NSCLC, and differs in the way treatment is approached.
SYMPTOMS — In a small number of patients (about 10 percent), lung cancer is first identified through an X-ray performed for some other reason, and no cancer-related symptoms are evident at the time of diagnosis. The majority of patients, however, are symptomatic at the time the lung cancer is diagnosed. Symptoms may be caused directly by the presence of the tumor itself in the lungs and chest, or by tumor that has spread or metastasized to other parts of the body, or they can be caused indirectly because a cancer is present somewhere in the body (eg, weight loss, fatigue, or paraneoplastic syndromes, which are explained below).
Lung and chest — The most common symptom of lung cancer is a cough, which may be present with or without sputum (phlegm) production. In patients who have a longstanding (chronic) cough, such as those with emphysema (also called chronic obstructive pulmonary disease or COPD), the development of a lung cancer may be signaled by a change in the character of their chronic cough. Other common symptoms include shortness of breath, coughing up bloody phlegm, chest pain, and wheezing.
Additional symptoms may appear as the cancer grows locally and spreads to other parts of the chest: Shortness of breath may develop if the cancer causes fluid to accumulate between the lung and chest wall (a condition called a pleural effusion). The ability of the heart to pump the blood throughout the body may be impaired if fluid accumulates around the heart (a condition called a pericardial effusion). Hoarseness may develop if the tumor presses on the laryngeal nerve (a nerve that travels through the chest and stimulates the larynx or "voice box" during speaking). Headache, shortness of breath, and swelling of the face, arms, or neck veins can occur if the tumor presses on the superior vena cava, a large blood vessel in the chest. A tumor that is located at the top of the lung can cause the "Pancoast syndrome", in which there is shoulder or arm pain, weakening of the hand muscles (both due to involvement of the brachial plexus, the nerve that stimulates the arm), a droopy eyelid, blurred vision, and a lack of sweating of the face on the side of the tumor.
Distant metastases — As lung cancer progresses, it can spread or metastasizes to other parts of the body. The most common sites of metastasis are the brain, bones, liver, and adrenal glands. Bone metastases can produce localized pain, while metastasis to the liver may cause weakness, jaundice (yellowing of the skin) and weight loss. Brain metastases can cause a range of symptoms including headache, nausea and vomiting, seizures, confusion, and personality changes.
Paraneoplastic syndromes — Paraneoplastic syndrome is a term used to describe a number of conditions that arise because of substances that are produced by the tumor, which then enter the bloodstream and act on the body to cause abnormalities. Thus, they are indirect effects of the tumor. About 10 to 20 percent of patients with lung cancer will experience symptoms due to a paraneoplastic syndrome; they are more common with SCLC than with NSCLC.
Symptoms may include an increase in the calcium level in the blood (hypercalcemia), broadening and thickening of the fingernails (digital clubbing), painful swollen joints, and neurologic symptoms.
Overproduction of hormones can also be caused by the tumor, and result in breast enlargement or discharge of a milky substance from the nipples. A hormone called ADH may also be secreted in unusually large quantities resulting in a low blood sodium level and concentrated urine. If untreated, oversecretion of ADH can lead to more serious symptoms including weakness, confusion, coma, and seizures.
INITIAL TESTING AND DIAGNOSIS — Once a patient presents with symptoms that suggest lung cancer, a chest X-ray is performed to check for the presence of a lung mass. If a mass is found, additional testing is performed to confirm the diagnosis, and determine the type of cancer. The additional tests also allow the physician to determine the "stage" of the cancer, or how widely it has spread. Accurate staging is important since it helps to define treatment and predict the long-term outcome of the cancer (the prognosis).
The physician first obtains a detailed history, performs a thorough physical examination, and obtains blood samples for testing. One or more radiologic tests are then performed to evaluate the local extent of tumor in the chest, and the possibility that it has spread outside of the chest. These tests may include a CT (computed tomography) scan of the chest, abdomen and/or head, PET scan, MRI (magnetic resonance imaging) scan, and bone scan.
Other procedures may be recommended to obtain tissue samples to examine the cancer cells and determine their type. A piece of the tissue can be obtained for study under the microscope in one of three ways: Bronchoscopy is a procedure where a lighted tube is inserted through the mouth into the windpipe (trachea, show figure 1) while the patient is sedated to directly visualize the airways. Any obvious areas of abnormality are then biopsied. (See "Patient information: Fiberoptic bronchoscopy"). CT-guided fine needle aspirate biopsy is a biopsy that is performed by a radiologist who inserts a thin needle through the skin of the chest into the lung. The needle's location is guided by computed tomography (CT scan). Mediastinoscopy is done under general anesthesia by a thoracic surgeon using a thin tube, inserted through the chest wall into the mediastinum, the central portion of the chest that represents the space between the right and left lung (show figure 1). A sample of tissue can then be removed through the tube.
STAGING OF NON-SMALL CELL LUNG CANCER — Staging is a way to define the extent of the tumor involvement, both in the chest and at distant sites, and is important in determining the most appropriate treatment.
In assigning a tumor stage in NSCLC, three factors are considered: Characteristics of the primary tumor (the T category, ranging from T1 to T4) The degree of lymph node involvement (the N category) Spread or metastasis to distant locations in the body (the M category)
Each factor (T, N, and M) is evaluated separately and assigned a value depending upon the extent of involvement (show table 1). Combinations of T, N, and M levels are grouped together to form stage groupings, which range from stage I (the least advanced degree of tumor involvement) through stage IV, the most advanced (show table 1). Stages I, II, and III disease are further subdivided into A and B subcategories.
Staging of NSCLC can be accomplished clinically (nonoperatively through x-ray studies and by physical examination); however, the final surgical or pathologic stage requires an operation and examination of the surgical specimen. This is especially important for patients who appear to have early stage (stage I to II) tumors, since involvement of lymph nodes in the mediastinum significantly alters the treatment approach. Often, a mediastinoscopy will be recommended to evaluate these lymph nodes under the microscope. Radical surgery may be offered to patients with stage I or II disease, while stage III disease is often treated with radiation and chemotherapy, and less often with surgery.
The following is a general description of the different tumor stages:
Stage I — At stage I, tumor is present in the lungs but the cancer has not spread to the lymph nodes or metastasized to other locations. Stage I lung cancer is considered a limited, local disease, and is not associated with any regional lymph node involvement.
Stage I disease is subdivided into stages IA and IB, primarily based upon the size of the primary tumor. Stage IA is associated with a primary tumor that is less than 3 cm in diameter. In contrast, stage IB is associated with a larger tumor, or with partial collapse of the lung. (See "Patient information: Treatment of early stage (stage I and II) non-small cell lung cancer").
Stage II — Stage II cancers have either begun to involve the adjacent lymph nodes, or have invaded surrounding tissues in the chest more extensively. However, no distant metastases are apparent, and the cancer is still considered a local disease. Stage II NSCLC is subdivided into stages IIA and IIB, based upon the size of the primary tumor. Stage IIA — The tumor is 3 cm or smaller and has invaded nearby tissue minimally if at all. One or more lymph nodes on the same side of the chest are involved, and there is no evidence of disease in the mediastinum nor distant metastases (T1 N1 M0). Stage IIB — Stage IIB disease comprises at least two situations: there is a T2 tumor (larger than 3 cm with some invasion of nearby tissue) and the cancer involves one or more lymph nodes on the same side of the chest (T2 N1 M0). Stage IIB is also assigned to cancers that have no lymph node involvement, but have either invaded chest structures outside the lung or are located within 2 cm of the carina (T3 N0 M0). (The carina is the point at which the trachea, or the tube that carries air to the lungs, splits in two to reach the right and left lung).
Stage III — Stage III NSCLC represents more advanced disease. The tumor has invaded chest tissues more extensively than in stage II and/or the cancer has spread to more distant lymph nodes located in the mediastinum. However, distant metastases are still not present. Stage III NSCLC is subdivided into stages IIIA and IIIB. (See "Patient information: Treatment of locally advanced (stage III) non-small cell lung cancer"). Stage IIIA — Stage IIIA is assigned if the cancer involves an invasive T3 tumor and lymph nodes on the same side of the chest (T3 N1 M0). The disease is also staged IIIA if the tumor involves more distant lymph nodes such as those in the mediastinum, or below the carina, regardless of the primary T designation (T1-3 N2 M0). Stage IIIB — Stage IIIB includes cancers that have invaded local structures extensively (T4 tumor), and cancers that have spread to more distant lymph nodes including those on the opposite side of the mediastinum (N3). (Possible TNM categories include T1-4 N3 M0 or T4 N1-N4 M0).
Stage IV — In stage IV lung cancer, the cancer has metastasized to distant locations (M1). (See "Patient information: Treatment of advanced unresectable; metastatic; and recurrent non-small cell lung cancer").
STAGING SMALL CELL LUNG CANCER — The system used to stage NSCLC is of limited value in staging small cell lung cancer (SCLC). This is because surgery is rarely used in this disease. For treatment purposes, SCLC is categorized more simply as either "limited" or "extensive" disease. Limited disease refers to small cell lung cancers that are confined to one side of the chest. Extensive disease refers to small cell lung cancers that have spread to the other side of the chest or that have metastasized to more distant locations.
As is the case for NSCLC, treatment and prognosis for SCLC varies depending upon the classification. (See "Patient information: Treatment of small cell lung cancer").
CLINICAL TRIALS — Progress in treating lung cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.cancernet.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The American Cancer Society
(www.cancer.org)
Lung Cancer Alliance
(www.lungcanceralliance.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Kim, K, Rice, TW, Murthy, SC, et al. Combined bronchoscopy, mediastinoscopy, and thoracotomy for lung cancer: who benefits?. J Thorac Cardiovasc Surg 2004; 127:850.
2. Mountain, CF. Revisions in the international system for staging lung cancer. Chest 1997; 111:1710.
3. Pretreatment evaluation of non-small-cell lung cancer. The American Thoracic Society and The European Respiratory Society. Am J Respir Crit Care Med 1997; 156:320.
4. Argiris, A, Murren, JR. Staging and clinical prognostic factors for small-cell lung cancer. Cancer J 2001; 7:437.
5. Micke, P, Faldum, A, Metz, T, et al. Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer-what limits limited disease?. Lung Cancer 2002; 37:271.
Cigarette smoking is the primary risk factor for lung cancer. A smoker's risk of developing lung cancer is 10 to 30 times greater than the risk for a non-smoker. Occupational or environmental exposure to other substances (eg, second-hand tobacco smoke, asbestos, radon, arsenic, radiation, polycyclic hydrocarbons, and nickel) also increase a person's risk of developing lung cancer, but the largest factor by far is smoking.
TYPES OF LUNG CANCER — The type of lung cancer is defined by the kind of cells that make up the cancerous tissue. The majority of lung cancers belong to one of four types: Squamous cell carcinoma (20 to 30 percent of lung cancers) Adenocarcinoma (30 to 40 percent) Large cell carcinoma (10 percent) Small cell or "oat cell" carcinoma (20 percent)
The first three types (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) are often collectively referred to as "non-small cell lung cancer" or NSCLC. In general, these tumors tend to behave in a comparable fashion, and they are treated similarly. In contrast, small cell lung cancer (SCLC) tends to grow and spread more quickly than NSCLC, and differs in the way treatment is approached.
SYMPTOMS — In a small number of patients (about 10 percent), lung cancer is first identified through an X-ray performed for some other reason, and no cancer-related symptoms are evident at the time of diagnosis. The majority of patients, however, are symptomatic at the time the lung cancer is diagnosed. Symptoms may be caused directly by the presence of the tumor itself in the lungs and chest, or by tumor that has spread or metastasized to other parts of the body, or they can be caused indirectly because a cancer is present somewhere in the body (eg, weight loss, fatigue, or paraneoplastic syndromes, which are explained below).
Lung and chest — The most common symptom of lung cancer is a cough, which may be present with or without sputum (phlegm) production. In patients who have a longstanding (chronic) cough, such as those with emphysema (also called chronic obstructive pulmonary disease or COPD), the development of a lung cancer may be signaled by a change in the character of their chronic cough. Other common symptoms include shortness of breath, coughing up bloody phlegm, chest pain, and wheezing.
Additional symptoms may appear as the cancer grows locally and spreads to other parts of the chest: Shortness of breath may develop if the cancer causes fluid to accumulate between the lung and chest wall (a condition called a pleural effusion). The ability of the heart to pump the blood throughout the body may be impaired if fluid accumulates around the heart (a condition called a pericardial effusion). Hoarseness may develop if the tumor presses on the laryngeal nerve (a nerve that travels through the chest and stimulates the larynx or "voice box" during speaking). Headache, shortness of breath, and swelling of the face, arms, or neck veins can occur if the tumor presses on the superior vena cava, a large blood vessel in the chest. A tumor that is located at the top of the lung can cause the "Pancoast syndrome", in which there is shoulder or arm pain, weakening of the hand muscles (both due to involvement of the brachial plexus, the nerve that stimulates the arm), a droopy eyelid, blurred vision, and a lack of sweating of the face on the side of the tumor.
Distant metastases — As lung cancer progresses, it can spread or metastasizes to other parts of the body. The most common sites of metastasis are the brain, bones, liver, and adrenal glands. Bone metastases can produce localized pain, while metastasis to the liver may cause weakness, jaundice (yellowing of the skin) and weight loss. Brain metastases can cause a range of symptoms including headache, nausea and vomiting, seizures, confusion, and personality changes.
Paraneoplastic syndromes — Paraneoplastic syndrome is a term used to describe a number of conditions that arise because of substances that are produced by the tumor, which then enter the bloodstream and act on the body to cause abnormalities. Thus, they are indirect effects of the tumor. About 10 to 20 percent of patients with lung cancer will experience symptoms due to a paraneoplastic syndrome; they are more common with SCLC than with NSCLC.
Symptoms may include an increase in the calcium level in the blood (hypercalcemia), broadening and thickening of the fingernails (digital clubbing), painful swollen joints, and neurologic symptoms.
Overproduction of hormones can also be caused by the tumor, and result in breast enlargement or discharge of a milky substance from the nipples. A hormone called ADH may also be secreted in unusually large quantities resulting in a low blood sodium level and concentrated urine. If untreated, oversecretion of ADH can lead to more serious symptoms including weakness, confusion, coma, and seizures.
INITIAL TESTING AND DIAGNOSIS — Once a patient presents with symptoms that suggest lung cancer, a chest X-ray is performed to check for the presence of a lung mass. If a mass is found, additional testing is performed to confirm the diagnosis, and determine the type of cancer. The additional tests also allow the physician to determine the "stage" of the cancer, or how widely it has spread. Accurate staging is important since it helps to define treatment and predict the long-term outcome of the cancer (the prognosis).
The physician first obtains a detailed history, performs a thorough physical examination, and obtains blood samples for testing. One or more radiologic tests are then performed to evaluate the local extent of tumor in the chest, and the possibility that it has spread outside of the chest. These tests may include a CT (computed tomography) scan of the chest, abdomen and/or head, PET scan, MRI (magnetic resonance imaging) scan, and bone scan.
Other procedures may be recommended to obtain tissue samples to examine the cancer cells and determine their type. A piece of the tissue can be obtained for study under the microscope in one of three ways: Bronchoscopy is a procedure where a lighted tube is inserted through the mouth into the windpipe (trachea, show figure 1) while the patient is sedated to directly visualize the airways. Any obvious areas of abnormality are then biopsied. (See "Patient information: Fiberoptic bronchoscopy"). CT-guided fine needle aspirate biopsy is a biopsy that is performed by a radiologist who inserts a thin needle through the skin of the chest into the lung. The needle's location is guided by computed tomography (CT scan). Mediastinoscopy is done under general anesthesia by a thoracic surgeon using a thin tube, inserted through the chest wall into the mediastinum, the central portion of the chest that represents the space between the right and left lung (show figure 1). A sample of tissue can then be removed through the tube.
STAGING OF NON-SMALL CELL LUNG CANCER — Staging is a way to define the extent of the tumor involvement, both in the chest and at distant sites, and is important in determining the most appropriate treatment.
In assigning a tumor stage in NSCLC, three factors are considered: Characteristics of the primary tumor (the T category, ranging from T1 to T4) The degree of lymph node involvement (the N category) Spread or metastasis to distant locations in the body (the M category)
Each factor (T, N, and M) is evaluated separately and assigned a value depending upon the extent of involvement (show table 1). Combinations of T, N, and M levels are grouped together to form stage groupings, which range from stage I (the least advanced degree of tumor involvement) through stage IV, the most advanced (show table 1). Stages I, II, and III disease are further subdivided into A and B subcategories.
Staging of NSCLC can be accomplished clinically (nonoperatively through x-ray studies and by physical examination); however, the final surgical or pathologic stage requires an operation and examination of the surgical specimen. This is especially important for patients who appear to have early stage (stage I to II) tumors, since involvement of lymph nodes in the mediastinum significantly alters the treatment approach. Often, a mediastinoscopy will be recommended to evaluate these lymph nodes under the microscope. Radical surgery may be offered to patients with stage I or II disease, while stage III disease is often treated with radiation and chemotherapy, and less often with surgery.
The following is a general description of the different tumor stages:
Stage I — At stage I, tumor is present in the lungs but the cancer has not spread to the lymph nodes or metastasized to other locations. Stage I lung cancer is considered a limited, local disease, and is not associated with any regional lymph node involvement.
Stage I disease is subdivided into stages IA and IB, primarily based upon the size of the primary tumor. Stage IA is associated with a primary tumor that is less than 3 cm in diameter. In contrast, stage IB is associated with a larger tumor, or with partial collapse of the lung. (See "Patient information: Treatment of early stage (stage I and II) non-small cell lung cancer").
Stage II — Stage II cancers have either begun to involve the adjacent lymph nodes, or have invaded surrounding tissues in the chest more extensively. However, no distant metastases are apparent, and the cancer is still considered a local disease. Stage II NSCLC is subdivided into stages IIA and IIB, based upon the size of the primary tumor. Stage IIA — The tumor is 3 cm or smaller and has invaded nearby tissue minimally if at all. One or more lymph nodes on the same side of the chest are involved, and there is no evidence of disease in the mediastinum nor distant metastases (T1 N1 M0). Stage IIB — Stage IIB disease comprises at least two situations: there is a T2 tumor (larger than 3 cm with some invasion of nearby tissue) and the cancer involves one or more lymph nodes on the same side of the chest (T2 N1 M0). Stage IIB is also assigned to cancers that have no lymph node involvement, but have either invaded chest structures outside the lung or are located within 2 cm of the carina (T3 N0 M0). (The carina is the point at which the trachea, or the tube that carries air to the lungs, splits in two to reach the right and left lung).
Stage III — Stage III NSCLC represents more advanced disease. The tumor has invaded chest tissues more extensively than in stage II and/or the cancer has spread to more distant lymph nodes located in the mediastinum. However, distant metastases are still not present. Stage III NSCLC is subdivided into stages IIIA and IIIB. (See "Patient information: Treatment of locally advanced (stage III) non-small cell lung cancer"). Stage IIIA — Stage IIIA is assigned if the cancer involves an invasive T3 tumor and lymph nodes on the same side of the chest (T3 N1 M0). The disease is also staged IIIA if the tumor involves more distant lymph nodes such as those in the mediastinum, or below the carina, regardless of the primary T designation (T1-3 N2 M0). Stage IIIB — Stage IIIB includes cancers that have invaded local structures extensively (T4 tumor), and cancers that have spread to more distant lymph nodes including those on the opposite side of the mediastinum (N3). (Possible TNM categories include T1-4 N3 M0 or T4 N1-N4 M0).
Stage IV — In stage IV lung cancer, the cancer has metastasized to distant locations (M1). (See "Patient information: Treatment of advanced unresectable; metastatic; and recurrent non-small cell lung cancer").
STAGING SMALL CELL LUNG CANCER — The system used to stage NSCLC is of limited value in staging small cell lung cancer (SCLC). This is because surgery is rarely used in this disease. For treatment purposes, SCLC is categorized more simply as either "limited" or "extensive" disease. Limited disease refers to small cell lung cancers that are confined to one side of the chest. Extensive disease refers to small cell lung cancers that have spread to the other side of the chest or that have metastasized to more distant locations.
As is the case for NSCLC, treatment and prognosis for SCLC varies depending upon the classification. (See "Patient information: Treatment of small cell lung cancer").
CLINICAL TRIALS — Progress in treating lung cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.cancernet.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The American Cancer Society
(www.cancer.org)
Lung Cancer Alliance
(www.lungcanceralliance.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Kim, K, Rice, TW, Murthy, SC, et al. Combined bronchoscopy, mediastinoscopy, and thoracotomy for lung cancer: who benefits?. J Thorac Cardiovasc Surg 2004; 127:850.
2. Mountain, CF. Revisions in the international system for staging lung cancer. Chest 1997; 111:1710.
3. Pretreatment evaluation of non-small-cell lung cancer. The American Thoracic Society and The European Respiratory Society. Am J Respir Crit Care Med 1997; 156:320.
4. Argiris, A, Murren, JR. Staging and clinical prognostic factors for small-cell lung cancer. Cancer J 2001; 7:437.
5. Micke, P, Faldum, A, Metz, T, et al. Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer-what limits limited disease?. Lung Cancer 2002; 37:271.
Treatment of acute myeloid leukemia (AML) in adults
INTRODUCTION — Acute myeloid leukemia (AML) is a type of cancer of the blood. It affects a group of white blood cells called myeloid cells. Normally, myeloid and other blood cells are produced by the bone marrow (the spongy area in the middle of bones) in a controlled fashion. In someone with AML, this production process is abnormal and large numbers of immature cells are produced and released into the blood stream.
The overproduction of myeloid cells prevents the bone marrow from producing other important blood cells, including red blood cells, other types of white blood cells, and platelets. This results in a variety of systemic symptoms, anemia, bleeding, and an increased risk of infection.
GENERAL INFORMATION ABOUT TREATMENT — A number of chemotherapy medications are effective against AML. Studies are in progress to find the best medicines, doses, and treatment schedules for patients with AML. Researchers have discovered that the genetic makeup of the leukemia cells can vary, which affects how a particular patient responds to treatment. Alterations in treatment can be made depending upon careful analysis of this genetic material. Leukemia research centers are constantly investigating new treatment regimens to improve outcomes.
Treatment of AML also depends upon the age of the patient. Regimens that tend to work well in young patients may not work as well or have dangerous side effects in patients over age 60 (see "Treatment in older patients" below).
Side effects of treatment depend on the dose, schedule, and type of medication used. Many of the chemotherapy medicines used to treat AML cause loss of hair (which is temporary), nausea and vomiting, mouth sores, and an increased risk of infections and bleeding. Treatment to minimize these side effects is available and is generally quite effective.
The usual treatment of AML is divided into two phases: induction of remission and postremission therapy.
INDUCTION OF REMISSION — The most common remission induction regimen includes cytarabine (cytosine arabinoside, Ara-C, or Cytosar), given continuously for seven days through an intravenous (IV) line. Daunorubicin (Daunomycin, Cerubidine, or Rubidomycin) is given in a single IV dose for the first three days of treatment. This is sometimes known as the "7+3" regimen. In some medical centers a variation of this regimen is used, in which daunorubicin is replaced by idarubicin, or cytarabine is given alone in much higher doses. In some cases, other medicines such as etoposide or 6-thioguanine may be added to the "7+3" regimen.
This phase of treatment takes about four weeks and is almost always performed while the patient remains in the hospital. The induction phase usually consists of one or two cycles. A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover.
Chemotherapy drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment, including anemia (lowered red blood cell count), susceptibility to infection (lowered white blood cell count) and bleeding (lowered platelet count).
Induction of remission frequently results in a complete remission of the AML, meaning that there are no detectable leukemic cells in the blood or bone marrow and that the bone marrow is functioning normally. However, such remissions are usually short-lived unless additional, postremission chemotherapy is given.
POSTREMISSION THERAPY — There are three basic treatment choices for postremission therapy: additional chemotherapy, stem cell transplantation from a donor (allogeneic stem cell transplantation), or stem cell transplantation using the patient's own stem cells (autologous stem cell transplantation).
Additional chemotherapy — The same chemotherapy regimen used for remission induction can be repeated for one or more cycles, referred to as consolidation chemotherapy. Genetic analysis of the leukemia (done before the initial induction of remission treatment) is useful in deciding which chemotherapy regimen is best. In some cases, other chemotherapy agents may be used. High dose cytarabine is sometimes given to younger patients. Some regimens call for periodic chemotherapy cycles given for up to three years, which is known as remission "maintenance" therapy. Side effects and potential toxicities vary depending on the medications used.
Stem cell transplantation — Stem cell transplantation, also called bone marrow transplantation or hematopoietic cell transplantation, is a treatment in which the patient is given very high doses of chemotherapy or radiation. This is intended to kill cancer cells, but it also destroys all normal cells developing in the bone marrow. This means that the body's normal source of critical blood components (ie, the bone marrow) is no longer functional. After the treatment, the patient must have a healthy supply of very young blood cells (called stem cells) reintroduced, or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. (See "Patient information: Overview of bone marrow transplantation").
Stem cell transplantation is not recommended for all patients with AML. Complications are higher than those seen with chemotherapy. In certain groups of patients, there is no clear benefit of stem cell transplantation over chemotherapy. However, transplantation may be appropriate in some patients, such as those with more aggressive forms of AML, those who have a relapse following remission, or those patients who fail to achieve a remission following initial induction therapy.
There are two main types of stem cell transplantation: allogeneic and autologous. Allogeneic transplantation uses stem cells from a donor other than the patient, ideally a sibling with a similar genetic makeup (called a matched related donor). If the patient does not have a sibling with similar genetic characteristics, an unrelated person with a similar genetic makeup may be used (called a matched unrelated donor). One other possibility is to use a sibling with partially similar genetic characteristics, although this is not as well studied.
Allogeneic transplantation treats ALL in two ways. First, high doses of chemotherapy or radiation are given immediately before the transplant, which aggressively attacks and kills the leukemia cells present in the blood and bone marrow. Second, when cells from another person are injected, the donor stem cells undergo an immune response that helps destroy any remaining leukemia cells. This is called the "graft versus leukemia" or "graft versus tumor" effect. Unfortunately, this response is closely associated with a complication called "graft versus host disease", in which the immune response includes an attack on some of the patient's own organs. Symptoms can include severe skin rash, diarrhea, liver damage, and other problems. Still, allogeneic transplant is preferred over autologous transplantation in patients with ALL. In an autologous transplant, the patient's own normal stem cells are removed while he/she is in remission, before the high dose chemotherapy or radiation is given. In some cases, the cells are treated in order to remove any lingering leukemia cells that may be present, then they are frozen for later use. After the patient's chemotherapy or radiation is complete, the harvested cells are thawed and returned to the patient by transfusion.
Because the transplanted stem cells do not come from another person, there is no "graft versus host" disease. This helps reduce some of the side effects of treatment, but in general it also makes autologous transplantation somewhat less effective than allogeneic transplantation in fighting the leukemia, because of the lack of a "graft versus leukemia" effect.
TREATMENT IN OLDER PATIENTS — In general, patients over 60 years old do not respond as well to treatment for AML. This is related to the following factors: Adverse characteristics of the leukemia cells may be more common in older people An increased prevalence of previous blood disorders (such as polycythemia vera or myelodysplasia) makes AML more difficult to treat The presence of other disorders, such as diabetes, kidney, lung, or heart disease, increase the risk of treatment related complications
Treatment decisions for older patients with AML are best made on a case by case basis. Sometimes, induction of remission is a reasonable goal. In an otherwise healthy older patient who does not have high-risk genetic findings, administration of standard chemotherapy induction regimens may be advised. In other patients, the expected benefit in terms of long-term outcome may not be worth the anticipated discomfort, hospitalization, and toxicity of chemotherapy or other treatments.
In some patients, supportive care can provide benefits that are equivalent to chemotherapy with a lower risk of complications or toxicity. There are cases in which the AML does not progress quickly, and these patients may do better with an approach that treats AML related problems, such as infection or anemia, as they occur rather than trying to cure the disease. Transfusions and antibiotics can be given as needed in place of more aggressive forms of therapy.
Patients and families should get information from their healthcare provider about the type of AML, expected benefits of various treatments, possible side effects and toxicities, and long term outlook. These discussions are critical in determining the best course of action for the individual patient.
TREATMENT OF RELAPSED OR RESISTANT DISEASE — A limited number of agents are effective in the treatment of AML. Thus, when patients fail to respond or relapse after initial chemotherapy, management is more difficult: Approximately 50 percent of patients with long first remissions (greater than one year) have a second induction of remission with daunorubicin and cytarabine or high-dose cytarabine (HDAC), but the duration of the second remission is usually shorter than the first. Because of this, hematopoietic cell transplantation should be considered for any patient who relapses after their initial treatment. Patients who relapse within 12 months of initial diagnosis usually have significant drug resistance and a lower rates of a second complete remission. Medicines specifically approved for use in patients with relapsed AML (eg, Mylotarg) or experimental agents may be useful in this setting, with hematopoietic cell transplantation considered for responding patients.
LONG TERM MONITORING — Patients in complete remission need long term monitoring so that any reemergence (relapse) of the disease can be detected and treated. Typically, patients undergo examination of the bone marrow every three to six months for at least two years following remission. Patients with AML who maintain complete, continuous remission for three to five years are considered cured and no longer need routine bone marrow examination.
THE ROLE OF CLINICAL TRIALS — Many patients with leukemia will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your doctor for more information, or read about clinical trials at: www.cancer.gov/clinical_trials/ http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-6]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Schiffer, CA, Dodge, R, Larson, RA. Long-term followup of Cancer and Leukemia Group B studies in acute myeloid leukemia. Cancer 1997; 80:2210.
2. Estey, EH. Therapeutic options for acute myelogenous leukemia. Cancer 2001; 92:1059.
3. Benjamin, S, Kroll, ME, Cartwright, RA, et al. Haematologists' approaches to the management of adolescents and young adults with acute leukaemia. Br J Haematol 2000; 111:1045.
4. Cassileth, PA, Harrington, DP, Appelbaum, FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998; 339:1649.
5. Estey, EH. How I treat older patients with AML. Blood 2000; 96:1670.
6. Wahlin, A, Markevarn, B, Golovleva, I, Nilsson, M. Prognostic significance of risk group stratification in elderly patients with acute myeloid leukaemia. Br J Haematol 2001; 115:25.
The overproduction of myeloid cells prevents the bone marrow from producing other important blood cells, including red blood cells, other types of white blood cells, and platelets. This results in a variety of systemic symptoms, anemia, bleeding, and an increased risk of infection.
GENERAL INFORMATION ABOUT TREATMENT — A number of chemotherapy medications are effective against AML. Studies are in progress to find the best medicines, doses, and treatment schedules for patients with AML. Researchers have discovered that the genetic makeup of the leukemia cells can vary, which affects how a particular patient responds to treatment. Alterations in treatment can be made depending upon careful analysis of this genetic material. Leukemia research centers are constantly investigating new treatment regimens to improve outcomes.
Treatment of AML also depends upon the age of the patient. Regimens that tend to work well in young patients may not work as well or have dangerous side effects in patients over age 60 (see "Treatment in older patients" below).
Side effects of treatment depend on the dose, schedule, and type of medication used. Many of the chemotherapy medicines used to treat AML cause loss of hair (which is temporary), nausea and vomiting, mouth sores, and an increased risk of infections and bleeding. Treatment to minimize these side effects is available and is generally quite effective.
The usual treatment of AML is divided into two phases: induction of remission and postremission therapy.
INDUCTION OF REMISSION — The most common remission induction regimen includes cytarabine (cytosine arabinoside, Ara-C, or Cytosar), given continuously for seven days through an intravenous (IV) line. Daunorubicin (Daunomycin, Cerubidine, or Rubidomycin) is given in a single IV dose for the first three days of treatment. This is sometimes known as the "7+3" regimen. In some medical centers a variation of this regimen is used, in which daunorubicin is replaced by idarubicin, or cytarabine is given alone in much higher doses. In some cases, other medicines such as etoposide or 6-thioguanine may be added to the "7+3" regimen.
This phase of treatment takes about four weeks and is almost always performed while the patient remains in the hospital. The induction phase usually consists of one or two cycles. A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover.
Chemotherapy drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment, including anemia (lowered red blood cell count), susceptibility to infection (lowered white blood cell count) and bleeding (lowered platelet count).
Induction of remission frequently results in a complete remission of the AML, meaning that there are no detectable leukemic cells in the blood or bone marrow and that the bone marrow is functioning normally. However, such remissions are usually short-lived unless additional, postremission chemotherapy is given.
POSTREMISSION THERAPY — There are three basic treatment choices for postremission therapy: additional chemotherapy, stem cell transplantation from a donor (allogeneic stem cell transplantation), or stem cell transplantation using the patient's own stem cells (autologous stem cell transplantation).
Additional chemotherapy — The same chemotherapy regimen used for remission induction can be repeated for one or more cycles, referred to as consolidation chemotherapy. Genetic analysis of the leukemia (done before the initial induction of remission treatment) is useful in deciding which chemotherapy regimen is best. In some cases, other chemotherapy agents may be used. High dose cytarabine is sometimes given to younger patients. Some regimens call for periodic chemotherapy cycles given for up to three years, which is known as remission "maintenance" therapy. Side effects and potential toxicities vary depending on the medications used.
Stem cell transplantation — Stem cell transplantation, also called bone marrow transplantation or hematopoietic cell transplantation, is a treatment in which the patient is given very high doses of chemotherapy or radiation. This is intended to kill cancer cells, but it also destroys all normal cells developing in the bone marrow. This means that the body's normal source of critical blood components (ie, the bone marrow) is no longer functional. After the treatment, the patient must have a healthy supply of very young blood cells (called stem cells) reintroduced, or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. (See "Patient information: Overview of bone marrow transplantation").
Stem cell transplantation is not recommended for all patients with AML. Complications are higher than those seen with chemotherapy. In certain groups of patients, there is no clear benefit of stem cell transplantation over chemotherapy. However, transplantation may be appropriate in some patients, such as those with more aggressive forms of AML, those who have a relapse following remission, or those patients who fail to achieve a remission following initial induction therapy.
There are two main types of stem cell transplantation: allogeneic and autologous. Allogeneic transplantation uses stem cells from a donor other than the patient, ideally a sibling with a similar genetic makeup (called a matched related donor). If the patient does not have a sibling with similar genetic characteristics, an unrelated person with a similar genetic makeup may be used (called a matched unrelated donor). One other possibility is to use a sibling with partially similar genetic characteristics, although this is not as well studied.
Allogeneic transplantation treats ALL in two ways. First, high doses of chemotherapy or radiation are given immediately before the transplant, which aggressively attacks and kills the leukemia cells present in the blood and bone marrow. Second, when cells from another person are injected, the donor stem cells undergo an immune response that helps destroy any remaining leukemia cells. This is called the "graft versus leukemia" or "graft versus tumor" effect. Unfortunately, this response is closely associated with a complication called "graft versus host disease", in which the immune response includes an attack on some of the patient's own organs. Symptoms can include severe skin rash, diarrhea, liver damage, and other problems. Still, allogeneic transplant is preferred over autologous transplantation in patients with ALL. In an autologous transplant, the patient's own normal stem cells are removed while he/she is in remission, before the high dose chemotherapy or radiation is given. In some cases, the cells are treated in order to remove any lingering leukemia cells that may be present, then they are frozen for later use. After the patient's chemotherapy or radiation is complete, the harvested cells are thawed and returned to the patient by transfusion.
Because the transplanted stem cells do not come from another person, there is no "graft versus host" disease. This helps reduce some of the side effects of treatment, but in general it also makes autologous transplantation somewhat less effective than allogeneic transplantation in fighting the leukemia, because of the lack of a "graft versus leukemia" effect.
TREATMENT IN OLDER PATIENTS — In general, patients over 60 years old do not respond as well to treatment for AML. This is related to the following factors: Adverse characteristics of the leukemia cells may be more common in older people An increased prevalence of previous blood disorders (such as polycythemia vera or myelodysplasia) makes AML more difficult to treat The presence of other disorders, such as diabetes, kidney, lung, or heart disease, increase the risk of treatment related complications
Treatment decisions for older patients with AML are best made on a case by case basis. Sometimes, induction of remission is a reasonable goal. In an otherwise healthy older patient who does not have high-risk genetic findings, administration of standard chemotherapy induction regimens may be advised. In other patients, the expected benefit in terms of long-term outcome may not be worth the anticipated discomfort, hospitalization, and toxicity of chemotherapy or other treatments.
In some patients, supportive care can provide benefits that are equivalent to chemotherapy with a lower risk of complications or toxicity. There are cases in which the AML does not progress quickly, and these patients may do better with an approach that treats AML related problems, such as infection or anemia, as they occur rather than trying to cure the disease. Transfusions and antibiotics can be given as needed in place of more aggressive forms of therapy.
Patients and families should get information from their healthcare provider about the type of AML, expected benefits of various treatments, possible side effects and toxicities, and long term outlook. These discussions are critical in determining the best course of action for the individual patient.
TREATMENT OF RELAPSED OR RESISTANT DISEASE — A limited number of agents are effective in the treatment of AML. Thus, when patients fail to respond or relapse after initial chemotherapy, management is more difficult: Approximately 50 percent of patients with long first remissions (greater than one year) have a second induction of remission with daunorubicin and cytarabine or high-dose cytarabine (HDAC), but the duration of the second remission is usually shorter than the first. Because of this, hematopoietic cell transplantation should be considered for any patient who relapses after their initial treatment. Patients who relapse within 12 months of initial diagnosis usually have significant drug resistance and a lower rates of a second complete remission. Medicines specifically approved for use in patients with relapsed AML (eg, Mylotarg) or experimental agents may be useful in this setting, with hematopoietic cell transplantation considered for responding patients.
LONG TERM MONITORING — Patients in complete remission need long term monitoring so that any reemergence (relapse) of the disease can be detected and treated. Typically, patients undergo examination of the bone marrow every three to six months for at least two years following remission. Patients with AML who maintain complete, continuous remission for three to five years are considered cured and no longer need routine bone marrow examination.
THE ROLE OF CLINICAL TRIALS — Many patients with leukemia will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your doctor for more information, or read about clinical trials at: www.cancer.gov/clinical_trials/ http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-6]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Schiffer, CA, Dodge, R, Larson, RA. Long-term followup of Cancer and Leukemia Group B studies in acute myeloid leukemia. Cancer 1997; 80:2210.
2. Estey, EH. Therapeutic options for acute myelogenous leukemia. Cancer 2001; 92:1059.
3. Benjamin, S, Kroll, ME, Cartwright, RA, et al. Haematologists' approaches to the management of adolescents and young adults with acute leukaemia. Br J Haematol 2000; 111:1045.
4. Cassileth, PA, Harrington, DP, Appelbaum, FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998; 339:1649.
5. Estey, EH. How I treat older patients with AML. Blood 2000; 96:1670.
6. Wahlin, A, Markevarn, B, Golovleva, I, Nilsson, M. Prognostic significance of risk group stratification in elderly patients with acute myeloid leukaemia. Br J Haematol 2001; 115:25.
Treatment of acute myeloid leukemia (AML) in adults
INTRODUCTION — Acute myeloid leukemia (AML) is a type of cancer of the blood. It affects a group of white blood cells called myeloid cells. Normally, myeloid and other blood cells are produced by the bone marrow (the spongy area in the middle of bones) in a controlled fashion. In someone with AML, this production process is abnormal and large numbers of immature cells are produced and released into the blood stream.
The overproduction of myeloid cells prevents the bone marrow from producing other important blood cells, including red blood cells, other types of white blood cells, and platelets. This results in a variety of systemic symptoms, anemia, bleeding, and an increased risk of infection.
GENERAL INFORMATION ABOUT TREATMENT — A number of chemotherapy medications are effective against AML. Studies are in progress to find the best medicines, doses, and treatment schedules for patients with AML. Researchers have discovered that the genetic makeup of the leukemia cells can vary, which affects how a particular patient responds to treatment. Alterations in treatment can be made depending upon careful analysis of this genetic material. Leukemia research centers are constantly investigating new treatment regimens to improve outcomes.
Treatment of AML also depends upon the age of the patient. Regimens that tend to work well in young patients may not work as well or have dangerous side effects in patients over age 60 (see "Treatment in older patients" below).
Side effects of treatment depend on the dose, schedule, and type of medication used. Many of the chemotherapy medicines used to treat AML cause loss of hair (which is temporary), nausea and vomiting, mouth sores, and an increased risk of infections and bleeding. Treatment to minimize these side effects is available and is generally quite effective.
The usual treatment of AML is divided into two phases: induction of remission and postremission therapy.
INDUCTION OF REMISSION — The most common remission induction regimen includes cytarabine (cytosine arabinoside, Ara-C, or Cytosar), given continuously for seven days through an intravenous (IV) line. Daunorubicin (Daunomycin, Cerubidine, or Rubidomycin) is given in a single IV dose for the first three days of treatment. This is sometimes known as the "7+3" regimen. In some medical centers a variation of this regimen is used, in which daunorubicin is replaced by idarubicin, or cytarabine is given alone in much higher doses. In some cases, other medicines such as etoposide or 6-thioguanine may be added to the "7+3" regimen.
This phase of treatment takes about four weeks and is almost always performed while the patient remains in the hospital. The induction phase usually consists of one or two cycles. A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover.
Chemotherapy drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment, including anemia (lowered red blood cell count), susceptibility to infection (lowered white blood cell count) and bleeding (lowered platelet count).
Induction of remission frequently results in a complete remission of the AML, meaning that there are no detectable leukemic cells in the blood or bone marrow and that the bone marrow is functioning normally. However, such remissions are usually short-lived unless additional, postremission chemotherapy is given.
POSTREMISSION THERAPY — There are three basic treatment choices for postremission therapy: additional chemotherapy, stem cell transplantation from a donor (allogeneic stem cell transplantation), or stem cell transplantation using the patient's own stem cells (autologous stem cell transplantation).
Additional chemotherapy — The same chemotherapy regimen used for remission induction can be repeated for one or more cycles, referred to as consolidation chemotherapy. Genetic analysis of the leukemia (done before the initial induction of remission treatment) is useful in deciding which chemotherapy regimen is best. In some cases, other chemotherapy agents may be used. High dose cytarabine is sometimes given to younger patients. Some regimens call for periodic chemotherapy cycles given for up to three years, which is known as remission "maintenance" therapy. Side effects and potential toxicities vary depending on the medications used.
Stem cell transplantation — Stem cell transplantation, also called bone marrow transplantation or hematopoietic cell transplantation, is a treatment in which the patient is given very high doses of chemotherapy or radiation. This is intended to kill cancer cells, but it also destroys all normal cells developing in the bone marrow. This means that the body's normal source of critical blood components (ie, the bone marrow) is no longer functional. After the treatment, the patient must have a healthy supply of very young blood cells (called stem cells) reintroduced, or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. (See "Patient information: Overview of bone marrow transplantation").
Stem cell transplantation is not recommended for all patients with AML. Complications are higher than those seen with chemotherapy. In certain groups of patients, there is no clear benefit of stem cell transplantation over chemotherapy. However, transplantation may be appropriate in some patients, such as those with more aggressive forms of AML, those who have a relapse following remission, or those patients who fail to achieve a remission following initial induction therapy.
There are two main types of stem cell transplantation: allogeneic and autologous. Allogeneic transplantation uses stem cells from a donor other than the patient, ideally a sibling with a similar genetic makeup (called a matched related donor). If the patient does not have a sibling with similar genetic characteristics, an unrelated person with a similar genetic makeup may be used (called a matched unrelated donor). One other possibility is to use a sibling with partially similar genetic characteristics, although this is not as well studied.
Allogeneic transplantation treats ALL in two ways. First, high doses of chemotherapy or radiation are given immediately before the transplant, which aggressively attacks and kills the leukemia cells present in the blood and bone marrow. Second, when cells from another person are injected, the donor stem cells undergo an immune response that helps destroy any remaining leukemia cells. This is called the "graft versus leukemia" or "graft versus tumor" effect. Unfortunately, this response is closely associated with a complication called "graft versus host disease", in which the immune response includes an attack on some of the patient's own organs. Symptoms can include severe skin rash, diarrhea, liver damage, and other problems. Still, allogeneic transplant is preferred over autologous transplantation in patients with ALL. In an autologous transplant, the patient's own normal stem cells are removed while he/she is in remission, before the high dose chemotherapy or radiation is given. In some cases, the cells are treated in order to remove any lingering leukemia cells that may be present, then they are frozen for later use. After the patient's chemotherapy or radiation is complete, the harvested cells are thawed and returned to the patient by transfusion.
Because the transplanted stem cells do not come from another person, there is no "graft versus host" disease. This helps reduce some of the side effects of treatment, but in general it also makes autologous transplantation somewhat less effective than allogeneic transplantation in fighting the leukemia, because of the lack of a "graft versus leukemia" effect.
TREATMENT IN OLDER PATIENTS — In general, patients over 60 years old do not respond as well to treatment for AML. This is related to the following factors: Adverse characteristics of the leukemia cells may be more common in older people An increased prevalence of previous blood disorders (such as polycythemia vera or myelodysplasia) makes AML more difficult to treat The presence of other disorders, such as diabetes, kidney, lung, or heart disease, increase the risk of treatment related complications
Treatment decisions for older patients with AML are best made on a case by case basis. Sometimes, induction of remission is a reasonable goal. In an otherwise healthy older patient who does not have high-risk genetic findings, administration of standard chemotherapy induction regimens may be advised. In other patients, the expected benefit in terms of long-term outcome may not be worth the anticipated discomfort, hospitalization, and toxicity of chemotherapy or other treatments.
In some patients, supportive care can provide benefits that are equivalent to chemotherapy with a lower risk of complications or toxicity. There are cases in which the AML does not progress quickly, and these patients may do better with an approach that treats AML related problems, such as infection or anemia, as they occur rather than trying to cure the disease. Transfusions and antibiotics can be given as needed in place of more aggressive forms of therapy.
Patients and families should get information from their healthcare provider about the type of AML, expected benefits of various treatments, possible side effects and toxicities, and long term outlook. These discussions are critical in determining the best course of action for the individual patient.
TREATMENT OF RELAPSED OR RESISTANT DISEASE — A limited number of agents are effective in the treatment of AML. Thus, when patients fail to respond or relapse after initial chemotherapy, management is more difficult: Approximately 50 percent of patients with long first remissions (greater than one year) have a second induction of remission with daunorubicin and cytarabine or high-dose cytarabine (HDAC), but the duration of the second remission is usually shorter than the first. Because of this, hematopoietic cell transplantation should be considered for any patient who relapses after their initial treatment. Patients who relapse within 12 months of initial diagnosis usually have significant drug resistance and a lower rates of a second complete remission. Medicines specifically approved for use in patients with relapsed AML (eg, Mylotarg) or experimental agents may be useful in this setting, with hematopoietic cell transplantation considered for responding patients.
LONG TERM MONITORING — Patients in complete remission need long term monitoring so that any reemergence (relapse) of the disease can be detected and treated. Typically, patients undergo examination of the bone marrow every three to six months for at least two years following remission. Patients with AML who maintain complete, continuous remission for three to five years are considered cured and no longer need routine bone marrow examination.
THE ROLE OF CLINICAL TRIALS — Many patients with leukemia will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your doctor for more information, or read about clinical trials at: www.cancer.gov/clinical_trials/ http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-6]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Schiffer, CA, Dodge, R, Larson, RA. Long-term followup of Cancer and Leukemia Group B studies in acute myeloid leukemia. Cancer 1997; 80:2210.
2. Estey, EH. Therapeutic options for acute myelogenous leukemia. Cancer 2001; 92:1059.
3. Benjamin, S, Kroll, ME, Cartwright, RA, et al. Haematologists' approaches to the management of adolescents and young adults with acute leukaemia. Br J Haematol 2000; 111:1045.
4. Cassileth, PA, Harrington, DP, Appelbaum, FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998; 339:1649.
5. Estey, EH. How I treat older patients with AML. Blood 2000; 96:1670.
6. Wahlin, A, Markevarn, B, Golovleva, I, Nilsson, M. Prognostic significance of risk group stratification in elderly patients with acute myeloid leukaemia. Br J Haematol 2001; 115:25.
The overproduction of myeloid cells prevents the bone marrow from producing other important blood cells, including red blood cells, other types of white blood cells, and platelets. This results in a variety of systemic symptoms, anemia, bleeding, and an increased risk of infection.
GENERAL INFORMATION ABOUT TREATMENT — A number of chemotherapy medications are effective against AML. Studies are in progress to find the best medicines, doses, and treatment schedules for patients with AML. Researchers have discovered that the genetic makeup of the leukemia cells can vary, which affects how a particular patient responds to treatment. Alterations in treatment can be made depending upon careful analysis of this genetic material. Leukemia research centers are constantly investigating new treatment regimens to improve outcomes.
Treatment of AML also depends upon the age of the patient. Regimens that tend to work well in young patients may not work as well or have dangerous side effects in patients over age 60 (see "Treatment in older patients" below).
Side effects of treatment depend on the dose, schedule, and type of medication used. Many of the chemotherapy medicines used to treat AML cause loss of hair (which is temporary), nausea and vomiting, mouth sores, and an increased risk of infections and bleeding. Treatment to minimize these side effects is available and is generally quite effective.
The usual treatment of AML is divided into two phases: induction of remission and postremission therapy.
INDUCTION OF REMISSION — The most common remission induction regimen includes cytarabine (cytosine arabinoside, Ara-C, or Cytosar), given continuously for seven days through an intravenous (IV) line. Daunorubicin (Daunomycin, Cerubidine, or Rubidomycin) is given in a single IV dose for the first three days of treatment. This is sometimes known as the "7+3" regimen. In some medical centers a variation of this regimen is used, in which daunorubicin is replaced by idarubicin, or cytarabine is given alone in much higher doses. In some cases, other medicines such as etoposide or 6-thioguanine may be added to the "7+3" regimen.
This phase of treatment takes about four weeks and is almost always performed while the patient remains in the hospital. The induction phase usually consists of one or two cycles. A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover.
Chemotherapy drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment, including anemia (lowered red blood cell count), susceptibility to infection (lowered white blood cell count) and bleeding (lowered platelet count).
Induction of remission frequently results in a complete remission of the AML, meaning that there are no detectable leukemic cells in the blood or bone marrow and that the bone marrow is functioning normally. However, such remissions are usually short-lived unless additional, postremission chemotherapy is given.
POSTREMISSION THERAPY — There are three basic treatment choices for postremission therapy: additional chemotherapy, stem cell transplantation from a donor (allogeneic stem cell transplantation), or stem cell transplantation using the patient's own stem cells (autologous stem cell transplantation).
Additional chemotherapy — The same chemotherapy regimen used for remission induction can be repeated for one or more cycles, referred to as consolidation chemotherapy. Genetic analysis of the leukemia (done before the initial induction of remission treatment) is useful in deciding which chemotherapy regimen is best. In some cases, other chemotherapy agents may be used. High dose cytarabine is sometimes given to younger patients. Some regimens call for periodic chemotherapy cycles given for up to three years, which is known as remission "maintenance" therapy. Side effects and potential toxicities vary depending on the medications used.
Stem cell transplantation — Stem cell transplantation, also called bone marrow transplantation or hematopoietic cell transplantation, is a treatment in which the patient is given very high doses of chemotherapy or radiation. This is intended to kill cancer cells, but it also destroys all normal cells developing in the bone marrow. This means that the body's normal source of critical blood components (ie, the bone marrow) is no longer functional. After the treatment, the patient must have a healthy supply of very young blood cells (called stem cells) reintroduced, or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. (See "Patient information: Overview of bone marrow transplantation").
Stem cell transplantation is not recommended for all patients with AML. Complications are higher than those seen with chemotherapy. In certain groups of patients, there is no clear benefit of stem cell transplantation over chemotherapy. However, transplantation may be appropriate in some patients, such as those with more aggressive forms of AML, those who have a relapse following remission, or those patients who fail to achieve a remission following initial induction therapy.
There are two main types of stem cell transplantation: allogeneic and autologous. Allogeneic transplantation uses stem cells from a donor other than the patient, ideally a sibling with a similar genetic makeup (called a matched related donor). If the patient does not have a sibling with similar genetic characteristics, an unrelated person with a similar genetic makeup may be used (called a matched unrelated donor). One other possibility is to use a sibling with partially similar genetic characteristics, although this is not as well studied.
Allogeneic transplantation treats ALL in two ways. First, high doses of chemotherapy or radiation are given immediately before the transplant, which aggressively attacks and kills the leukemia cells present in the blood and bone marrow. Second, when cells from another person are injected, the donor stem cells undergo an immune response that helps destroy any remaining leukemia cells. This is called the "graft versus leukemia" or "graft versus tumor" effect. Unfortunately, this response is closely associated with a complication called "graft versus host disease", in which the immune response includes an attack on some of the patient's own organs. Symptoms can include severe skin rash, diarrhea, liver damage, and other problems. Still, allogeneic transplant is preferred over autologous transplantation in patients with ALL. In an autologous transplant, the patient's own normal stem cells are removed while he/she is in remission, before the high dose chemotherapy or radiation is given. In some cases, the cells are treated in order to remove any lingering leukemia cells that may be present, then they are frozen for later use. After the patient's chemotherapy or radiation is complete, the harvested cells are thawed and returned to the patient by transfusion.
Because the transplanted stem cells do not come from another person, there is no "graft versus host" disease. This helps reduce some of the side effects of treatment, but in general it also makes autologous transplantation somewhat less effective than allogeneic transplantation in fighting the leukemia, because of the lack of a "graft versus leukemia" effect.
TREATMENT IN OLDER PATIENTS — In general, patients over 60 years old do not respond as well to treatment for AML. This is related to the following factors: Adverse characteristics of the leukemia cells may be more common in older people An increased prevalence of previous blood disorders (such as polycythemia vera or myelodysplasia) makes AML more difficult to treat The presence of other disorders, such as diabetes, kidney, lung, or heart disease, increase the risk of treatment related complications
Treatment decisions for older patients with AML are best made on a case by case basis. Sometimes, induction of remission is a reasonable goal. In an otherwise healthy older patient who does not have high-risk genetic findings, administration of standard chemotherapy induction regimens may be advised. In other patients, the expected benefit in terms of long-term outcome may not be worth the anticipated discomfort, hospitalization, and toxicity of chemotherapy or other treatments.
In some patients, supportive care can provide benefits that are equivalent to chemotherapy with a lower risk of complications or toxicity. There are cases in which the AML does not progress quickly, and these patients may do better with an approach that treats AML related problems, such as infection or anemia, as they occur rather than trying to cure the disease. Transfusions and antibiotics can be given as needed in place of more aggressive forms of therapy.
Patients and families should get information from their healthcare provider about the type of AML, expected benefits of various treatments, possible side effects and toxicities, and long term outlook. These discussions are critical in determining the best course of action for the individual patient.
TREATMENT OF RELAPSED OR RESISTANT DISEASE — A limited number of agents are effective in the treatment of AML. Thus, when patients fail to respond or relapse after initial chemotherapy, management is more difficult: Approximately 50 percent of patients with long first remissions (greater than one year) have a second induction of remission with daunorubicin and cytarabine or high-dose cytarabine (HDAC), but the duration of the second remission is usually shorter than the first. Because of this, hematopoietic cell transplantation should be considered for any patient who relapses after their initial treatment. Patients who relapse within 12 months of initial diagnosis usually have significant drug resistance and a lower rates of a second complete remission. Medicines specifically approved for use in patients with relapsed AML (eg, Mylotarg) or experimental agents may be useful in this setting, with hematopoietic cell transplantation considered for responding patients.
LONG TERM MONITORING — Patients in complete remission need long term monitoring so that any reemergence (relapse) of the disease can be detected and treated. Typically, patients undergo examination of the bone marrow every three to six months for at least two years following remission. Patients with AML who maintain complete, continuous remission for three to five years are considered cured and no longer need routine bone marrow examination.
THE ROLE OF CLINICAL TRIALS — Many patients with leukemia will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your doctor for more information, or read about clinical trials at: www.cancer.gov/clinical_trials/ http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-6]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Schiffer, CA, Dodge, R, Larson, RA. Long-term followup of Cancer and Leukemia Group B studies in acute myeloid leukemia. Cancer 1997; 80:2210.
2. Estey, EH. Therapeutic options for acute myelogenous leukemia. Cancer 2001; 92:1059.
3. Benjamin, S, Kroll, ME, Cartwright, RA, et al. Haematologists' approaches to the management of adolescents and young adults with acute leukaemia. Br J Haematol 2000; 111:1045.
4. Cassileth, PA, Harrington, DP, Appelbaum, FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998; 339:1649.
5. Estey, EH. How I treat older patients with AML. Blood 2000; 96:1670.
6. Wahlin, A, Markevarn, B, Golovleva, I, Nilsson, M. Prognostic significance of risk group stratification in elderly patients with acute myeloid leukaemia. Br J Haematol 2001; 115:25.
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