What are the types of lung cancer?
Lung cancers, also known as bronchogenic carcinomas, are broadly classified into two types: small cell lung cancers (SCLC) and non-small cell lung cancers (NSCLC). This classification is based upon the microscopic appearance of the tumor cells themselves, specifically the size of the cells. These two types of cancers grow and spread in different ways and may have different treatment options, so a distinction between these two types is important.
SCLC comprise about 20% of lung cancers and are the most aggressive and rapidly growing of all lung cancers. SCLC are strongly related to cigarette smoking, with only 1% of these tumors occurring in nonsmokers. SCLC metastasize rapidly to many sites within the body and are most often discovered after they have spread extensively. Referring to a specific cell appearance often seen when examining samples of SCLC under the microscope, these cancers are sometimes called oat cell carcinomas.
NSCLC are the most common lung cancers, accounting for about 80% of all lung cancers. NSCLC can be divided into three main types that are named based upon the type of cells found in the tumor:
Adenocarcinomas are the most commonly seen type of NSCLC in the U.S. and comprise up to 50% of NSCLC. While adenocarcinomas are associated with smoking, like other lung cancers, this type is observed as well in nonsmokers who develop lung cancer. Most adenocarcinomas arise in the outer, or peripheral, areas of the lungs.
Bronchioloalveolar carcinoma is a subtype of adenocarcinoma that frequently develops at multiple sites in the lungs and spreads along the preexisting alveolar walls.
Squamous cell carcinomas were formerly more common than adenocarcinomas; at present, they account for about 30% of NSCLC. Also known as epidermoid carcinomas, squamous cell cancers arise most frequently in the central chest area in the bronchi.
Large cell carcinomas, sometimes referred to as undifferentiated carcinomas, are the least common type of NSCLC.
Mixtures of different types of NSCLC also are seen.
Other types of cancers can arise in the lung; these types are much less common than NSCLC and SCLC and together comprise only 5%-10% of lung cancers:
Bronchial carcinoids account for up to 5% of lung cancers. These tumors are generally small (3 cm-4 cm or less) when diagnosed and occur most commonly in people under 40 years of age. Unrelated to cigarette smoking, carcinoid tumors can metastasize, and a small proportion of these tumors secrete hormone-like substances that may cause specific symptoms related to the hormone being produced. Carcinoids generally grow and spread more slowly than bronchogenic cancers, and many are detected early enough to be amenable to surgical resection.
Cancers of supporting lung tissue such as smooth muscle, blood vessels, or cells involved in the immune response can rarely occur in the lung.
As discussed previously, metastatic cancers from other primary tumors in the body are often found in the lung. Tumors from anywhere in the body may spread to the lungs either through the bloodstream, through the lymphatic system, or directly from nearby organs. Metastatic tumors are most often multiple, scattered throughout the lung, and concentrated in the peripheral rather than central areas of the lung
Saturday, April 30, 2016
Survival statistics for lung cancer
About the information on this page
On thiThis page has quite detailed information about the survival rates for different stages of lung cancer. People ask us for this information but not everyone diagnosed with cancer wants to read it. If you are not sure whether you want to know at the moment, you can always come back to it later.
The statistics here are intended as a general guide and can't tell you what is likely to happen in your individual case.
Back to top
Cancer statistics in general
We have a section with detailed explanations about cancer statistics and also about incidence, mortality and survival. Unless you are very familiar with medical statistics, it might help to read this before you read the statistics below.
Remember that statistics are averages based on large numbers of patients. They cannot predict exactly what will happen to you. No two people are exactly alike and the response to treatment also varies from one person to another.
You should feel free to ask your doctor about the likely outlook for your cancer (your prognosis). But not even your own doctor can tell you for sure exactly what will happen.
You may hear doctors talk about '1 year survival' and '5 year survival'. This relates to the number of people in research who lived for at least a year or at least 5 years after they were diagnosed. Doctors use these figures to compare the results of different treatments in research studies. It does not mean those people only lived for 1 year or 5 years.
Please note that there are no detailed UK statistics available for different stages of lung cancer or treatments that people may have had. Some of the statistics we present here are international statistics. They are pulled together from a variety of different sources. This includes the opinions and experience of the experts who check each section of Cancer Research UK's patient information.
Back to top
Overall outcome
Unfortunately, compared with some other types of cancer, the outlook for lung cancer is not very good. The statistics we have here are for all types of lung cancer in England and Wales. Overall, around 30 out of every 100 people (30%) will survive for 1 year or more after they are diagnosed. Around 10 out of every 100 people (10%) will survive for 5 years or more. And about 5 out of every 100 people (5%) will survive for 10 years or more after they are diagnosed.
As with many other types of cancer, the outcome depends on how advanced your cancer is when it is diagnosed. In other words, the stage of your cancer. Lung cancer is one of the most difficult cancers to treat. It is often diagnosed at a late stage. It tends to occur in older people who may also have other medical conditions.
With lung cancer the likely outcome will also depend very much on the type of lung cancer that you have. The statistics for non small cell lung cancer are different from the statistics for small cell lung cancer. So we have given them separately here.
Back to top
Outcome for non small cell lung cancer
There are 4 main stages for lung cancer. In 2007 a worldwide study (the Lung Cancer Staging Project) collected data about lung cancer on more than 81,000 patients from 19 countries. The study gave the following statistics about survival for non small cell lung cancer. There is a range of statistics for each stage because for some patients the stage was based on the results of scans and tests, and for other patients the stage was found during surgery.
Stage 1
This is the earliest stage and so has the best outcome. Depending on where the cancer is, it is often possible to remove stage 1 lung cancer with surgery. Unfortunately, it is not very common for lung cancer to be diagnosed this early. Stage 1 non small cell lung cancer is divided into 2 stages, stage 1A and 1B.
Of all the people with stage 1A non small cell lung cancer, between 58 and 73 people out of every 100 (58% to 73%) will survive for 5 years or more after diagnosis.
Of all the people with stage 1B non small cell lung cancer, between 43 and 58 people out of every 100 (43% to 58%) will survive for 5 years or more after they are diagnosed.
Stage 2
Non small cell lung cancer stage 2 is also divided into stage 2A and 2B.
For stage 2A lung cancer, between 36 and 46 out of every 100 people diagnosed (36% to 46%) will survive for 5 years or more with treatment.
For stage 2B non small cell lung cancer, between 25 and 36 out of every 100 people diagnosed (25% to 36%) will survive for 5 years or more after they are diagnosed.
Stage 3
As you might expect, the survival statistics fall with more advanced stages of lung cancer. Again, stage 3 is divided into stage 3A and stage 3B.
For stage 3A non small cell lung cancer, between 19 and 24 out of every 100 people diagnosed (19% to 24%) will survive for 5 years or more after they are diagnosed.
For stage 3B, between 7 and 9 out of every 100 people diagnosed (7% to 9%) will survive for 5 years or more after they are diagnosed.
Stage 4
The most advanced stage of lung cancer is stage 4. It means that the cancer has spread. Understandably, the survival statistics are very low for this stage. Unfortunately, lung cancer is often diagnosed late and for many people the cancer has already spread when they are diagnosed. Only between 2 and 13 out of every 100 people diagnosed with stage 4 non small cell lung cancer (2% to 13%) will survive for 5 years or more after diagnosis.
It can seem illogical for stage 3B cancer to have 5 year survival rates from 7% to 9% and stage 4 from 2% to 13%. This is because the staging system only looks at the extent of the cancer. It does not look at the specific types of cancer. So the stage 4 group may include more people who have slowly growing cancers or cancer that responds very well to particular treatments than the stage 3 group.
Back to top
Outcome for small cell lung cancer
Sometimes doctors divide small cell lung cancers into just 2 groups. These are limited disease (the cancer has not spread beyond the lung) and extensive disease (the cancer has spread beyond the lung).
Of all the people diagnosed with small cell lung cancer, around 30 out of 100 (30%) have limited disease at the time of diagnosis. With treatment about 25 out of every 100 people (25%) will survive for 2 years or more.
2 out of 3 people with small cell lung cancer already have extensive disease at the time of diagnosis. Unfortunately the survival rate is very low. With treatment, fewer than 5 out of every 100 people (5%) will survive for 5 years or more after diagnosis.
The Lung Cancer Staging Project used the TNM staging system to give the following statistics about survival based on the stage found by scans and tests. The project included more than 8,000 patients with small cell lung cancer.
Stage 1
The earliest stage of small cell lung cancer is stage 1. Doctors divide this group into 2 further stages, stage 1A and 1B.
Of all the people with stage 1A small cell lung cancer, almost 40 out of every 100 diagnosed (40%) will survive for 5 years or more after diagnosis.
Of all the people with stage 1B small cell lung cancer, around 20 out of every 100 diagnosed (20%) will survive for 5 years or more after they are diagnosed.
Stage 2
Small cell lung cancer that is stage 2 is also divided into stage 2a and 2B.
For stage 2A lung cancer, almost 40 out of every 100 people diagnosed (40%) will survive for 5 years or more after they are diagnosed.
For stage 2B small cell lung cancer, almost 20 out of every 100 people diagnosed (20%) will survive for 5 years or more after diagnosis.
The survival rates for stage 2A seemed to be higher than for stage 1B. Researchers think this is because the study had very few patients in the stage 2A group. They suggest that those statistics may not be so reliable as the others.
Stage 3
As you might expect, the survival statistics fall with more advanced stages of lung cancer. Again, stage 3 is divided into stage 3A and stage 3B.
For stage 3A small cell lung cancer, almost 15 out of every 100 people diagnosed (15%) will survive for 5 years or more after they are diagnosed.
For stage 3B, around 10 out of every 100 people diagnosed (10%) will survive for 5 years or more after diagnosis.
Stage 4
The most advanced stage of small cell lung cancer is stage 4. It means the cancer has spread to other parts of the body. Understandably, the survival statistics are lowest for this stage. Unfortunately, lung cancer is often diagnosed late and for many people the cancer has already spread when they are diagnosed.
Only about 1 out of every 100 people (1%) diagnosed with stage 4 small cell lung cancer will survive for 5 years or more.
Back to top
Overall health
Another factor that can affect your prognosis, apart from the stage of your cancer, is how well you are overall. Doctors call this your performance status. A score of 0 means you are completely able to look after yourself. A score of 1 means you can do most things for yourself but need some help. The scores continue to go up, depending on how much help you need.
For example, if you are weak from losing weight, pain and feel very tired, you will need more day to day help, so your performance score will be at least 1. Doctors or researchers sometimes write performance status as 'PS'.
Back to top
How reliable are cancer statistics?
No statistics can tell you what will happen to you. Your cancer is unique. The same type of cancer can grow at different rates in different people for example.
The statistics are not detailed enough to tell you about the different treatments people may have had. And they also don't tell us how that treatment may have affected their prognosis. Chemotherapy, surgery, biological therapy and radiotherapy may help people to live longer as well as relieve symptoms. Many individual factors will determine your treatment and prognosis.
Back to top
Clinical trials
The treatment for many types of cancer has improved through clinical trials. Trials are currently aiming to improve treatment and increase survival rates for lung cancer. We have a section explaining clinical trials.
You can search our clinical trials database for lung cancer trials.
lung cancer impact statement NHS
Back to top
More detailed statistics
If you would like to read more about survival rates and other statistics for lung cancer, go to our CancerStats page:
https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer
On thiThis page has quite detailed information about the survival rates for different stages of lung cancer. People ask us for this information but not everyone diagnosed with cancer wants to read it. If you are not sure whether you want to know at the moment, you can always come back to it later.
The statistics here are intended as a general guide and can't tell you what is likely to happen in your individual case.
Back to top
Cancer statistics in general
We have a section with detailed explanations about cancer statistics and also about incidence, mortality and survival. Unless you are very familiar with medical statistics, it might help to read this before you read the statistics below.
Remember that statistics are averages based on large numbers of patients. They cannot predict exactly what will happen to you. No two people are exactly alike and the response to treatment also varies from one person to another.
You should feel free to ask your doctor about the likely outlook for your cancer (your prognosis). But not even your own doctor can tell you for sure exactly what will happen.
You may hear doctors talk about '1 year survival' and '5 year survival'. This relates to the number of people in research who lived for at least a year or at least 5 years after they were diagnosed. Doctors use these figures to compare the results of different treatments in research studies. It does not mean those people only lived for 1 year or 5 years.
Please note that there are no detailed UK statistics available for different stages of lung cancer or treatments that people may have had. Some of the statistics we present here are international statistics. They are pulled together from a variety of different sources. This includes the opinions and experience of the experts who check each section of Cancer Research UK's patient information.
Back to top
Overall outcome
Unfortunately, compared with some other types of cancer, the outlook for lung cancer is not very good. The statistics we have here are for all types of lung cancer in England and Wales. Overall, around 30 out of every 100 people (30%) will survive for 1 year or more after they are diagnosed. Around 10 out of every 100 people (10%) will survive for 5 years or more. And about 5 out of every 100 people (5%) will survive for 10 years or more after they are diagnosed.
As with many other types of cancer, the outcome depends on how advanced your cancer is when it is diagnosed. In other words, the stage of your cancer. Lung cancer is one of the most difficult cancers to treat. It is often diagnosed at a late stage. It tends to occur in older people who may also have other medical conditions.
With lung cancer the likely outcome will also depend very much on the type of lung cancer that you have. The statistics for non small cell lung cancer are different from the statistics for small cell lung cancer. So we have given them separately here.
Back to top
Outcome for non small cell lung cancer
There are 4 main stages for lung cancer. In 2007 a worldwide study (the Lung Cancer Staging Project) collected data about lung cancer on more than 81,000 patients from 19 countries. The study gave the following statistics about survival for non small cell lung cancer. There is a range of statistics for each stage because for some patients the stage was based on the results of scans and tests, and for other patients the stage was found during surgery.
Stage 1
This is the earliest stage and so has the best outcome. Depending on where the cancer is, it is often possible to remove stage 1 lung cancer with surgery. Unfortunately, it is not very common for lung cancer to be diagnosed this early. Stage 1 non small cell lung cancer is divided into 2 stages, stage 1A and 1B.
Of all the people with stage 1A non small cell lung cancer, between 58 and 73 people out of every 100 (58% to 73%) will survive for 5 years or more after diagnosis.
Of all the people with stage 1B non small cell lung cancer, between 43 and 58 people out of every 100 (43% to 58%) will survive for 5 years or more after they are diagnosed.
Stage 2
Non small cell lung cancer stage 2 is also divided into stage 2A and 2B.
For stage 2A lung cancer, between 36 and 46 out of every 100 people diagnosed (36% to 46%) will survive for 5 years or more with treatment.
For stage 2B non small cell lung cancer, between 25 and 36 out of every 100 people diagnosed (25% to 36%) will survive for 5 years or more after they are diagnosed.
Stage 3
As you might expect, the survival statistics fall with more advanced stages of lung cancer. Again, stage 3 is divided into stage 3A and stage 3B.
For stage 3A non small cell lung cancer, between 19 and 24 out of every 100 people diagnosed (19% to 24%) will survive for 5 years or more after they are diagnosed.
For stage 3B, between 7 and 9 out of every 100 people diagnosed (7% to 9%) will survive for 5 years or more after they are diagnosed.
Stage 4
The most advanced stage of lung cancer is stage 4. It means that the cancer has spread. Understandably, the survival statistics are very low for this stage. Unfortunately, lung cancer is often diagnosed late and for many people the cancer has already spread when they are diagnosed. Only between 2 and 13 out of every 100 people diagnosed with stage 4 non small cell lung cancer (2% to 13%) will survive for 5 years or more after diagnosis.
It can seem illogical for stage 3B cancer to have 5 year survival rates from 7% to 9% and stage 4 from 2% to 13%. This is because the staging system only looks at the extent of the cancer. It does not look at the specific types of cancer. So the stage 4 group may include more people who have slowly growing cancers or cancer that responds very well to particular treatments than the stage 3 group.
Back to top
Outcome for small cell lung cancer
Sometimes doctors divide small cell lung cancers into just 2 groups. These are limited disease (the cancer has not spread beyond the lung) and extensive disease (the cancer has spread beyond the lung).
Of all the people diagnosed with small cell lung cancer, around 30 out of 100 (30%) have limited disease at the time of diagnosis. With treatment about 25 out of every 100 people (25%) will survive for 2 years or more.
2 out of 3 people with small cell lung cancer already have extensive disease at the time of diagnosis. Unfortunately the survival rate is very low. With treatment, fewer than 5 out of every 100 people (5%) will survive for 5 years or more after diagnosis.
The Lung Cancer Staging Project used the TNM staging system to give the following statistics about survival based on the stage found by scans and tests. The project included more than 8,000 patients with small cell lung cancer.
Stage 1
The earliest stage of small cell lung cancer is stage 1. Doctors divide this group into 2 further stages, stage 1A and 1B.
Of all the people with stage 1A small cell lung cancer, almost 40 out of every 100 diagnosed (40%) will survive for 5 years or more after diagnosis.
Of all the people with stage 1B small cell lung cancer, around 20 out of every 100 diagnosed (20%) will survive for 5 years or more after they are diagnosed.
Stage 2
Small cell lung cancer that is stage 2 is also divided into stage 2a and 2B.
For stage 2A lung cancer, almost 40 out of every 100 people diagnosed (40%) will survive for 5 years or more after they are diagnosed.
For stage 2B small cell lung cancer, almost 20 out of every 100 people diagnosed (20%) will survive for 5 years or more after diagnosis.
The survival rates for stage 2A seemed to be higher than for stage 1B. Researchers think this is because the study had very few patients in the stage 2A group. They suggest that those statistics may not be so reliable as the others.
Stage 3
As you might expect, the survival statistics fall with more advanced stages of lung cancer. Again, stage 3 is divided into stage 3A and stage 3B.
For stage 3A small cell lung cancer, almost 15 out of every 100 people diagnosed (15%) will survive for 5 years or more after they are diagnosed.
For stage 3B, around 10 out of every 100 people diagnosed (10%) will survive for 5 years or more after diagnosis.
Stage 4
The most advanced stage of small cell lung cancer is stage 4. It means the cancer has spread to other parts of the body. Understandably, the survival statistics are lowest for this stage. Unfortunately, lung cancer is often diagnosed late and for many people the cancer has already spread when they are diagnosed.
Only about 1 out of every 100 people (1%) diagnosed with stage 4 small cell lung cancer will survive for 5 years or more.
Back to top
Overall health
Another factor that can affect your prognosis, apart from the stage of your cancer, is how well you are overall. Doctors call this your performance status. A score of 0 means you are completely able to look after yourself. A score of 1 means you can do most things for yourself but need some help. The scores continue to go up, depending on how much help you need.
For example, if you are weak from losing weight, pain and feel very tired, you will need more day to day help, so your performance score will be at least 1. Doctors or researchers sometimes write performance status as 'PS'.
Back to top
How reliable are cancer statistics?
No statistics can tell you what will happen to you. Your cancer is unique. The same type of cancer can grow at different rates in different people for example.
The statistics are not detailed enough to tell you about the different treatments people may have had. And they also don't tell us how that treatment may have affected their prognosis. Chemotherapy, surgery, biological therapy and radiotherapy may help people to live longer as well as relieve symptoms. Many individual factors will determine your treatment and prognosis.
Back to top
Clinical trials
The treatment for many types of cancer has improved through clinical trials. Trials are currently aiming to improve treatment and increase survival rates for lung cancer. We have a section explaining clinical trials.
You can search our clinical trials database for lung cancer trials.
lung cancer impact statement NHS
Back to top
More detailed statistics
If you would like to read more about survival rates and other statistics for lung cancer, go to our CancerStats page:
https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer
lung cancer treatment stage 4
Lung cancer is a type of cancer that begins in the lungs. In Singapore, it is the second most common cancer diagnosed each year. Smokers have the highest risk of developing of lung cancer. The risk of lung cancer increases with the duration and number of cigarettes smoked. Once one quits smoking, the chance of developing lung cancer decreases, although it takes years to equal that of a non-smoker. Passive smokers, eg non-smoking spouses of smokers also have an increased risk of developing lung cancer.
Lung-pix4
Types of lung cancer
There are two major types of lung cancer based on the appearance of cancer cells under the microscope. Treatment decisions are based on which type of lung cancer is present. The 2 major types of lung cancer are:
Small cell lung cancer. Small cell lung cancer occurs almost exclusively in heavy smokers and is less common than non-small cell lung cancer. Prognosis is poor as patients usually present late with disease that has spread.
Non-small cell lung cancer. This is the most common type of cancer. Non-small cell lung cancer is an umbrella term for several types of lung cancers that behave in a similar way. Non-small cell lung cancers include squamous cell carcinoma, adenocarcinoma and large cell carcinoma.
Symptoms of suspected lung cancer
Signs and symptoms of lung cancer typically may not be noticeable in the early stages. One should seek medical attention when any of the following signs or symptoms begin to be of concern to you:
A cough that last more than 2 weeks
Change in a chronic cough or “smoker’s cough”
Coughing up blood (even if small amounts)
Breathlessness
Chest pain
Wheezing
Hoarseness
Unexplained weight loss
Bone/joint pain
Fatigue
Headache
Swelling of face or arms
Facial paralysis
Diagnosis
If you suspect you may have lung cancer, your doctor can order a number of tests to look for cancerous cells and to rule out other conditions. The first test is usually a chest X-ray. If the chest X-ray is abnormal, a chest CT Scan is usually ordered to clarify the abnormalities seen. Sometimes, CT picks up abnormalities that are not seen on a chest X-ray.
Subsequent tests may include:
Sputum cytology : If you have a cough and are producing sputum, looking at the sputum under the microscope can sometimes reveal the presence of lung cancer cells.
Lung biopsy : A sample of abnormal cells is removed in a procedure called a biopsy. Your doctor can perform a biopsy in a number of ways, including
Bronchoscopy : A lighted tube is inserted through the nose into the lungs. With it, your doctor is able to examine abnormal areas of your lungs and obtain lung tissue for analysis.
Mediastinoscopy : An incision is made at the neck and lymph node samples are taken.
Needle biopsy : Use of X-ray or chest CT to guide a needle through the chest wall and into the lung tissue to collect tissue samples.
A biopsy sample may also be taken from lymph nodes or other areas where cancer is thought to have spread, such as the liver.
Stages of Lung cancer
Once lung cancer is diagnosed, the doctor will order tests to determine the stage of your cancer. Staging determines the extent of the disease, specifically if the cancer has spread and where. To determine the stage of cancer, tests such as CT scans, magnetic resonance imaging (MRI), positron emission tomography (PET) and bone scans may be done to look for cancer spread beyond the lung.
Non small cell lung cancer is staged as 1 to 4. Stages 1 and 2 are early ie the cancer is limited to the chest. Stage 3 is also called locally advanced lung cancer and Stage 4 is late stage lung cancer, ie the cancer has spread to distant sites eg bones or brain.
Small cell lung cancer is usually staged as being limited or extensive. Limited stage indicates that cancer is limited to one lung. Extensive stage indicates that cancer has spread beyond the one lung.
Treatment
Early stage lung cancer (Stage 1 and 2) can be cured by surgery. This usually involves removing a lobe of the lung (ie lobectomy) or the whole lung (pneumonectomy). Obviously, one has to be fit for surgery before it is contemplated. Lung function testing is mandatory before lung cancer surgery is attempted. Routinely, the surgeon samples the lymph nodes at operation to ensure that microscopic spread has not occured.
Late stage lung cancer (Stage 4) is usually treated with chemotherapy. One or a combination of chemotherapy drugs may be given intravenously or orally. This is done over a period of weeks or months, with breaks in between to allow the body to recover.
Over the past few years, new oral chemotherapy agents that work only in lung cancer patients with genotypic variants have been used. These oral drugs are called targeted therapy and are less toxic and easier to administer. However, they only work in those whose cancer tissues demonstrate genetic abnormalities eg EGFR and ALK mutants.
Radiation therapy uses high-powered energy beams, such as X-rays, to kill the cancer cells. Radiation therapy can be directed at the lung cancer from outside your body (external beam radiation) or it can be placed inside needles, seeds or catheters and inserted inside the body near the cancer (brachytherapy). Radiation therapy can be used alone or with other lung cancer treatments. Sometimes it’s administered at the same time as chemotherapy.
For very small tumours, stereotactic body radiotherapy may be used. This form of radiation aims many beams of radiation from different angles at the lung cancer. Stereotactic body radiotherapy treatment is typically completed in one or a few treatments. Radiotherapy is particularly used if the cancer has spread to the brain or bones.
The prognosis of lung cancer remains dismal , with 5-10% 5 year survival.
Useful Links: http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient
Lung-pix4
Types of lung cancer
There are two major types of lung cancer based on the appearance of cancer cells under the microscope. Treatment decisions are based on which type of lung cancer is present. The 2 major types of lung cancer are:
Small cell lung cancer. Small cell lung cancer occurs almost exclusively in heavy smokers and is less common than non-small cell lung cancer. Prognosis is poor as patients usually present late with disease that has spread.
Non-small cell lung cancer. This is the most common type of cancer. Non-small cell lung cancer is an umbrella term for several types of lung cancers that behave in a similar way. Non-small cell lung cancers include squamous cell carcinoma, adenocarcinoma and large cell carcinoma.
Symptoms of suspected lung cancer
Signs and symptoms of lung cancer typically may not be noticeable in the early stages. One should seek medical attention when any of the following signs or symptoms begin to be of concern to you:
A cough that last more than 2 weeks
Change in a chronic cough or “smoker’s cough”
Coughing up blood (even if small amounts)
Breathlessness
Chest pain
Wheezing
Hoarseness
Unexplained weight loss
Bone/joint pain
Fatigue
Headache
Swelling of face or arms
Facial paralysis
Diagnosis
If you suspect you may have lung cancer, your doctor can order a number of tests to look for cancerous cells and to rule out other conditions. The first test is usually a chest X-ray. If the chest X-ray is abnormal, a chest CT Scan is usually ordered to clarify the abnormalities seen. Sometimes, CT picks up abnormalities that are not seen on a chest X-ray.
Subsequent tests may include:
Sputum cytology : If you have a cough and are producing sputum, looking at the sputum under the microscope can sometimes reveal the presence of lung cancer cells.
Lung biopsy : A sample of abnormal cells is removed in a procedure called a biopsy. Your doctor can perform a biopsy in a number of ways, including
Bronchoscopy : A lighted tube is inserted through the nose into the lungs. With it, your doctor is able to examine abnormal areas of your lungs and obtain lung tissue for analysis.
Mediastinoscopy : An incision is made at the neck and lymph node samples are taken.
Needle biopsy : Use of X-ray or chest CT to guide a needle through the chest wall and into the lung tissue to collect tissue samples.
A biopsy sample may also be taken from lymph nodes or other areas where cancer is thought to have spread, such as the liver.
Stages of Lung cancer
Once lung cancer is diagnosed, the doctor will order tests to determine the stage of your cancer. Staging determines the extent of the disease, specifically if the cancer has spread and where. To determine the stage of cancer, tests such as CT scans, magnetic resonance imaging (MRI), positron emission tomography (PET) and bone scans may be done to look for cancer spread beyond the lung.
Non small cell lung cancer is staged as 1 to 4. Stages 1 and 2 are early ie the cancer is limited to the chest. Stage 3 is also called locally advanced lung cancer and Stage 4 is late stage lung cancer, ie the cancer has spread to distant sites eg bones or brain.
Small cell lung cancer is usually staged as being limited or extensive. Limited stage indicates that cancer is limited to one lung. Extensive stage indicates that cancer has spread beyond the one lung.
Treatment
Early stage lung cancer (Stage 1 and 2) can be cured by surgery. This usually involves removing a lobe of the lung (ie lobectomy) or the whole lung (pneumonectomy). Obviously, one has to be fit for surgery before it is contemplated. Lung function testing is mandatory before lung cancer surgery is attempted. Routinely, the surgeon samples the lymph nodes at operation to ensure that microscopic spread has not occured.
Late stage lung cancer (Stage 4) is usually treated with chemotherapy. One or a combination of chemotherapy drugs may be given intravenously or orally. This is done over a period of weeks or months, with breaks in between to allow the body to recover.
Over the past few years, new oral chemotherapy agents that work only in lung cancer patients with genotypic variants have been used. These oral drugs are called targeted therapy and are less toxic and easier to administer. However, they only work in those whose cancer tissues demonstrate genetic abnormalities eg EGFR and ALK mutants.
Radiation therapy uses high-powered energy beams, such as X-rays, to kill the cancer cells. Radiation therapy can be directed at the lung cancer from outside your body (external beam radiation) or it can be placed inside needles, seeds or catheters and inserted inside the body near the cancer (brachytherapy). Radiation therapy can be used alone or with other lung cancer treatments. Sometimes it’s administered at the same time as chemotherapy.
For very small tumours, stereotactic body radiotherapy may be used. This form of radiation aims many beams of radiation from different angles at the lung cancer. Stereotactic body radiotherapy treatment is typically completed in one or a few treatments. Radiotherapy is particularly used if the cancer has spread to the brain or bones.
The prognosis of lung cancer remains dismal , with 5-10% 5 year survival.
Useful Links: http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient
Erlotinib in Previously Treated Non–Small-Cell Lung Cancer
Lung cancer is the leading cause of
cancer death among men and women in
North America.
1
In advanced non–small-cell
lung cancer, chemotherapy offers symptomatic re-
lief and modest improvement in survival
2
; respons-
es are brief, with a median time to progression of
three to five
months. Second-line chemotherapy
with docetaxel can prolong survival after platinum-
based therapy for non–small-cell lung cancer.
3,4
However, there is at present no defined role for
third-line
chemotherapy. The futility of offering
third-line chemotherapy was demonstrated by Mas-
sarelli et al.,
5
who reported a response rate of only
2 percent and a median survival of four months.
Sheph
erd et al.
6
showed that among patients treat-
ed with docetaxel after the
failure of two
or more
chemotherapy regimens, survival
was identical to
that among patients treated with supportive care.
The epidermal growth factor receptor (EGFR)
family is part of a complex signal-transduction net-
work that is central to several critical cellular pro-
cesses. Since EGFR is often found in non–small-
cell lung cancer cells,
7,8
it has been the focus of
efforts
to develop new agents that target the EGFR
pathway. Erlotinib (Tarceva, OSI Pharmaceuticals)
and
gefitinib (Iressa, AstraZeneca) inhibit the ty-
rosine kinase activity of EGFR and have been stud-
ied
extensively.
9-12
In randomized phase 2 trials of
gefitinib (Iressa Dose Evaluation in Advanced Lung
Cancer [IDEAL] 1 and 2),
10,11
the tumors of 10 to
20 percent of patients who were previously treat-
ed with platinum-based regimens responded, and
in a phase 2 trial of erlotinib among previously
treated patie
nts with non–small-cell lung cancer in
which 10
percent or more of the cells expressed
EGFR, the response rate was 12.3 percent.
12
These
promising rates are perhaps higher than those pos-
sible with other forms of chemotherapy,
3-6
but it
is unknown whether treatment with an EGFR inhib-
itor
prolongs survival. For this reason, the National
Cancer Institute of Canada Clinical Trials Group
(NCIC CTG) conducted a trial (BR.21) to compare
erlotinib with placebo after the failure of standard
chemotherapy for non–small-cell lung cancer. The
inclusion of a control group receiving placebo was
considered ethical in view of the lack of benefit from
further chemotherapy after the failure of standard
treatment.
5,6
study design
This international, phase 3, randomized, double-
blind, placebo-controlled trial of erlotinib after the
failure of first-line or second-line chemotherapy
for non–small-cell lung cancer was designed by the
NCIC CTG. Patients were randomly assigned in a
2:1 ratio to receive oral erlotinib at a dose of 150 mg
daily or placebo. Randomization was performed
centrally by Applied Logic Associates (Houston),
with the use of the minimization method.
13
Pa-
tients were stratified according to center, Eastern
Cooperative Oncology Group performance status
(0 or 1 vs. 2 or 3, with higher scores indicating
greater impairment), best response to prior thera-
py (complete or partial response vs. stable disease
vs. progressive disease), number of prior regimens
received (one vs. two), and exposure to prior plati-
num therapy (yes vs. no).
The primary end point was overall survival.
Secondary end points included progression-free
survival, overall response rate (complete and par-
tial), duration of response, toxic effects, and qual-
ity of life. Responses were assessed with the use of
the Response Evaluation Criteria in Solid T
umors
(RECIST),
14
and toxic effects were assessed accord-
ing to
the Common Toxicity Criteria of the
Nation-
al Cancer Institute (version 2.0). The European Or-
ganization for Research and Treatment of Cancer
(EORTC) quality-of-life questionnaire (QLQ-C30)
and the quality-of-life questionnaire for patients
with lung cancer (QLQ-LC13) were used to evalu-
ate p
atients’ quality of life.
The protocol was approved by the ethics review
boards
at all participating institutions, and all pa-
tients provided written informed consent. Support
was provided by the NCIC and OSI Pharmaceuti-
cals. Data
were collected, managed, and analyzed
by the
NCIC CTG, and the manuscript was written
by membe
rs of the NCIC CTG. OSI Pharmaceuti-
cals reviewed the final manuscript and provided
comments on it. Confidentiality was maintained by
both the NCIC CTG and OSI Pharmaceuticals. The
study chair, Dr. Shepherd, and the physician coordi-
nator, Dr.
Seymour, reviewed all the data and con-
firmed their co
mpleteness and accuracy.
l
methods
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at UNIVERSITY OF WISCONSIN on August 1, 2007 .
n engl j med
353;2
www.nejm.org
july
14, 2005
erlotinib in previously treated non–small-cell lung cancer
125
eligibility criteria
Patients 18 years of age or older with an Eastern
Cooperative Oncology Group (ECOG) performance
status between 0 and 3 were eligible in the presence
of documented pathological evidence of non–small-
cell lung cancer. The patients had to have received
one or two regimens of combination chemother-
apy and not be eligible for further chemotherapy.
Patients 70
years of age or older may have received
therapy with one or two single agents. Patients had
to have recovered from any toxic effects of therapy
and were randomly assigned to the study treatment
at least 21 days after chemotherapy (14 days after
treatment with vinca alkaloids or gemcitabine) and
7 days after radiation. Adequate hematologic and
bioc
hemical values were required.
Patients with prior breast cancer, melanoma, or
hypernephroma were ineligible, as were those with
other malignant diseases (except basal-cell skin
cancers) within the preceding five years. Other ex-
clusion
criteria were symptomatic
brain metasta-
ses, clinically significant cardiac
disease
within one
year, ventricular arrhythmias
requiring med
ication,
and clinically significant ophthalmologic or gastro-
intestinal
abnormalities.
study procedures
Within seven days before randomization, a history
and physical examination were obtained and hema-
tologic and biochemical testing, chest radiography,
and assessments of toxic effects and quality of life
were obtained. Computed tomographic scans of
the chest and abdomen were obtained within 28
days before randomization. For a patient to be eval-
uated for a response, at least one measurable lesion
was required, but measurable disease was not man-
datory for eligibility. Only patients with measur-
able disea
se were included in the analyses of com-
plete or partial response.
Administration of the study medication was to
start within two days after randomization. For
grade 2 diarrhea, loperamide was recommended
without reduction of the dose of erlotinib. For
grade 3 diarrhea, the study treatment was with-
held until the
diarrhea was grade 1 or less, and then
erlotinib at a dose of 100 mg daily was started. For
grade 1
or 2 rash, treatment modification was not
recommended. For grade 3 rash, treatment was
withheld, the rash was treated symptomatically, and
erlotinib at a dose of 100 mg daily was restarted
when t
he rash was grade 1 or less.
History taking, physical examination, and he-
matologic and biochemical testing were performed
every four weeks, and radiologic investigations ev-
ery eight weeks. Patients’ quality of life was evaluat-
ed every four weeks in countries with validated ver-
sions of the questionnaires.
egfr expression
Separate written consent for optional tissue bank-
ing and correlative studies was obtained. EGFR ex-
pression was determined with the use of immuno-
histochemistry in a central laboratory that used
Dako
kits (DakoCytomation). Positivity was defined
as more than 10 percent of cells staining at any in-
tensity for EGFR.
statistical analysis
The trial was designed to detect, with 90 percent
power
and a two-sided type I error of 5 percent, a
33 percent improvement in median survival from
four months as estimated in the placebo group. For
the final analysis, 582 deaths were required and
were
projected to occur with a sample size of 700
patients enrolled over a period of 14 months with
6 months of follow-up. The required number of
deaths
had occurred by January 2004, and the data-
base was locked as of April 23, 2004. There was no
interim analysis. Tumor responses were validated
centrally for the first 333 patients in the trial.
The stratified log-rank test, accounting for strat-
ification factors
at randomization (except center)
and EGFR protein expression (positive vs. negative
vs. unknown), was used to compare progression-
free
survival and overall survival between treatment
groups. Exploratory forward stepwise regression
analys
es with the use of the Cox model were per-
formed to adjust for treatment effect and to iden-
tify prog
nostic factors for progression-free survival
and overall survival. Candidate covariates includ-
ed EGFR expression, stratification factors (except
center), sex, age (60 years or less vs. more than 60
years), race or ethnic group (Asian vs. others), prior
radiotherapy (yes vs. no), histologic subtype of can-
cer (adenocarcinoma vs. others), and smoking sta-
tus (smoker vs. nonsmoker vs. unknown). Race was
self-reported or
determined by study personnel and
was not based on country of domicile. Fisher’s exact
test was used to
compare response rates between
levels of potential p
redictors and rates of toxic ef-
fects between t
reatments. Times to deterioration
(a 10-point increase from the baseline score) for
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at UNIVERSITY OF WISCONSIN on August 1, 2007 .
cancer death among men and women in
North America.
1
In advanced non–small-cell
lung cancer, chemotherapy offers symptomatic re-
lief and modest improvement in survival
2
; respons-
es are brief, with a median time to progression of
three to five
months. Second-line chemotherapy
with docetaxel can prolong survival after platinum-
based therapy for non–small-cell lung cancer.
3,4
However, there is at present no defined role for
third-line
chemotherapy. The futility of offering
third-line chemotherapy was demonstrated by Mas-
sarelli et al.,
5
who reported a response rate of only
2 percent and a median survival of four months.
Sheph
erd et al.
6
showed that among patients treat-
ed with docetaxel after the
failure of two
or more
chemotherapy regimens, survival
was identical to
that among patients treated with supportive care.
The epidermal growth factor receptor (EGFR)
family is part of a complex signal-transduction net-
work that is central to several critical cellular pro-
cesses. Since EGFR is often found in non–small-
cell lung cancer cells,
7,8
it has been the focus of
efforts
to develop new agents that target the EGFR
pathway. Erlotinib (Tarceva, OSI Pharmaceuticals)
and
gefitinib (Iressa, AstraZeneca) inhibit the ty-
rosine kinase activity of EGFR and have been stud-
ied
extensively.
9-12
In randomized phase 2 trials of
gefitinib (Iressa Dose Evaluation in Advanced Lung
Cancer [IDEAL] 1 and 2),
10,11
the tumors of 10 to
20 percent of patients who were previously treat-
ed with platinum-based regimens responded, and
in a phase 2 trial of erlotinib among previously
treated patie
nts with non–small-cell lung cancer in
which 10
percent or more of the cells expressed
EGFR, the response rate was 12.3 percent.
12
These
promising rates are perhaps higher than those pos-
sible with other forms of chemotherapy,
3-6
but it
is unknown whether treatment with an EGFR inhib-
itor
prolongs survival. For this reason, the National
Cancer Institute of Canada Clinical Trials Group
(NCIC CTG) conducted a trial (BR.21) to compare
erlotinib with placebo after the failure of standard
chemotherapy for non–small-cell lung cancer. The
inclusion of a control group receiving placebo was
considered ethical in view of the lack of benefit from
further chemotherapy after the failure of standard
treatment.
5,6
study design
This international, phase 3, randomized, double-
blind, placebo-controlled trial of erlotinib after the
failure of first-line or second-line chemotherapy
for non–small-cell lung cancer was designed by the
NCIC CTG. Patients were randomly assigned in a
2:1 ratio to receive oral erlotinib at a dose of 150 mg
daily or placebo. Randomization was performed
centrally by Applied Logic Associates (Houston),
with the use of the minimization method.
13
Pa-
tients were stratified according to center, Eastern
Cooperative Oncology Group performance status
(0 or 1 vs. 2 or 3, with higher scores indicating
greater impairment), best response to prior thera-
py (complete or partial response vs. stable disease
vs. progressive disease), number of prior regimens
received (one vs. two), and exposure to prior plati-
num therapy (yes vs. no).
The primary end point was overall survival.
Secondary end points included progression-free
survival, overall response rate (complete and par-
tial), duration of response, toxic effects, and qual-
ity of life. Responses were assessed with the use of
the Response Evaluation Criteria in Solid T
umors
(RECIST),
14
and toxic effects were assessed accord-
ing to
the Common Toxicity Criteria of the
Nation-
al Cancer Institute (version 2.0). The European Or-
ganization for Research and Treatment of Cancer
(EORTC) quality-of-life questionnaire (QLQ-C30)
and the quality-of-life questionnaire for patients
with lung cancer (QLQ-LC13) were used to evalu-
ate p
atients’ quality of life.
The protocol was approved by the ethics review
boards
at all participating institutions, and all pa-
tients provided written informed consent. Support
was provided by the NCIC and OSI Pharmaceuti-
cals. Data
were collected, managed, and analyzed
by the
NCIC CTG, and the manuscript was written
by membe
rs of the NCIC CTG. OSI Pharmaceuti-
cals reviewed the final manuscript and provided
comments on it. Confidentiality was maintained by
both the NCIC CTG and OSI Pharmaceuticals. The
study chair, Dr. Shepherd, and the physician coordi-
nator, Dr.
Seymour, reviewed all the data and con-
firmed their co
mpleteness and accuracy.
l
methods
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at UNIVERSITY OF WISCONSIN on August 1, 2007 .
n engl j med
353;2
www.nejm.org
july
14, 2005
erlotinib in previously treated non–small-cell lung cancer
125
eligibility criteria
Patients 18 years of age or older with an Eastern
Cooperative Oncology Group (ECOG) performance
status between 0 and 3 were eligible in the presence
of documented pathological evidence of non–small-
cell lung cancer. The patients had to have received
one or two regimens of combination chemother-
apy and not be eligible for further chemotherapy.
Patients 70
years of age or older may have received
therapy with one or two single agents. Patients had
to have recovered from any toxic effects of therapy
and were randomly assigned to the study treatment
at least 21 days after chemotherapy (14 days after
treatment with vinca alkaloids or gemcitabine) and
7 days after radiation. Adequate hematologic and
bioc
hemical values were required.
Patients with prior breast cancer, melanoma, or
hypernephroma were ineligible, as were those with
other malignant diseases (except basal-cell skin
cancers) within the preceding five years. Other ex-
clusion
criteria were symptomatic
brain metasta-
ses, clinically significant cardiac
disease
within one
year, ventricular arrhythmias
requiring med
ication,
and clinically significant ophthalmologic or gastro-
intestinal
abnormalities.
study procedures
Within seven days before randomization, a history
and physical examination were obtained and hema-
tologic and biochemical testing, chest radiography,
and assessments of toxic effects and quality of life
were obtained. Computed tomographic scans of
the chest and abdomen were obtained within 28
days before randomization. For a patient to be eval-
uated for a response, at least one measurable lesion
was required, but measurable disease was not man-
datory for eligibility. Only patients with measur-
able disea
se were included in the analyses of com-
plete or partial response.
Administration of the study medication was to
start within two days after randomization. For
grade 2 diarrhea, loperamide was recommended
without reduction of the dose of erlotinib. For
grade 3 diarrhea, the study treatment was with-
held until the
diarrhea was grade 1 or less, and then
erlotinib at a dose of 100 mg daily was started. For
grade 1
or 2 rash, treatment modification was not
recommended. For grade 3 rash, treatment was
withheld, the rash was treated symptomatically, and
erlotinib at a dose of 100 mg daily was restarted
when t
he rash was grade 1 or less.
History taking, physical examination, and he-
matologic and biochemical testing were performed
every four weeks, and radiologic investigations ev-
ery eight weeks. Patients’ quality of life was evaluat-
ed every four weeks in countries with validated ver-
sions of the questionnaires.
egfr expression
Separate written consent for optional tissue bank-
ing and correlative studies was obtained. EGFR ex-
pression was determined with the use of immuno-
histochemistry in a central laboratory that used
Dako
kits (DakoCytomation). Positivity was defined
as more than 10 percent of cells staining at any in-
tensity for EGFR.
statistical analysis
The trial was designed to detect, with 90 percent
power
and a two-sided type I error of 5 percent, a
33 percent improvement in median survival from
four months as estimated in the placebo group. For
the final analysis, 582 deaths were required and
were
projected to occur with a sample size of 700
patients enrolled over a period of 14 months with
6 months of follow-up. The required number of
deaths
had occurred by January 2004, and the data-
base was locked as of April 23, 2004. There was no
interim analysis. Tumor responses were validated
centrally for the first 333 patients in the trial.
The stratified log-rank test, accounting for strat-
ification factors
at randomization (except center)
and EGFR protein expression (positive vs. negative
vs. unknown), was used to compare progression-
free
survival and overall survival between treatment
groups. Exploratory forward stepwise regression
analys
es with the use of the Cox model were per-
formed to adjust for treatment effect and to iden-
tify prog
nostic factors for progression-free survival
and overall survival. Candidate covariates includ-
ed EGFR expression, stratification factors (except
center), sex, age (60 years or less vs. more than 60
years), race or ethnic group (Asian vs. others), prior
radiotherapy (yes vs. no), histologic subtype of can-
cer (adenocarcinoma vs. others), and smoking sta-
tus (smoker vs. nonsmoker vs. unknown). Race was
self-reported or
determined by study personnel and
was not based on country of domicile. Fisher’s exact
test was used to
compare response rates between
levels of potential p
redictors and rates of toxic ef-
fects between t
reatments. Times to deterioration
(a 10-point increase from the baseline score) for
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at UNIVERSITY OF WISCONSIN on August 1, 2007 .
t cell lung cancer treatment
Lung cancer is the leading cause of cancer death among men and women in North America.1 In advanced non–small-cell lung cancer, chemotherapy offers symptomatic relief and modest improvement in survival2; responses are brief, with a median time to progression of three to five months. Second-line chemotherapy with docetaxel can prolong survival after platinum-based therapy for non–small-cell lung cancer.3,4 However, there is at present no defined role for third-line chemotherapy. The futility of offering third-line chemotherapy was demonstrated by Massarelli et al.,5 who reported a response rate of only 2 percent and a median survival of four months. Shepherd et al.6 showed that among patients treated with docetaxel after the failure of two or more chemotherapy regimens, survival was identical to that among patients treated with supportive care.
The epidermal growth factor receptor (EGFR) family is part of a complex signal-transduction network that is central to several critical cellular processes. Since EGFR is often found in non–small-cell lung cancer cells,7,8 it has been the focus of efforts to develop new agents that target the EGFR pathway. Erlotinib (Tarceva, OSI Pharmaceuticals) and gefitinib (Iressa, AstraZeneca) inhibit the tyrosine kinase activity of EGFR and have been studied extensively.9-12 In randomized phase 2 trials of gefitinib (Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL] 1 and 2),10,11 the tumors of 10 to 20 percent of patients who were previously treated with platinum-based regimens responded, and in a phase 2 trial of erlotinib among previously treated patients with non–small-cell lung cancer in which 10 percent or more of the cells expressed EGFR, the response rate was 12.3 percent.12 These promising rates are perhaps higher than those possible with other forms of chemotherapy,3-6 but it is unknown whether treatment with an EGFR inhibitor prolongs survival. For this reason, the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) conducted a trial (BR.21) to compare erlotinib with placebo after the failure of standard chemotherapy for non–small-cell lung cancer. The inclusion of a control group receiving placebo was considered ethical in view of the lack of benefit from further chemotherapy after the failure of standard treatment.5,6
Methods
Study Design
This international, phase 3, randomized, double-blind, placebo-controlled trial of erlotinib after the failure of first-line or second-line chemotherapy for non–small-cell lung cancer was designed by the NCIC CTG. Patients were randomly assigned in a 2:1 ratio to receive oral erlotinib at a dose of 150 mg daily or placebo. Randomization was performed centrally by Applied Logic Associates (Houston), with the use of the minimization method.13 Patients were stratified according to center, Eastern Cooperative Oncology Group performance status (0 or 1 vs. 2 or 3, with higher scores indicating greater impairment), best response to prior therapy (complete or partial response vs. stable disease vs. progressive disease), number of prior regimens received (one vs. two), and exposure to prior platinum therapy (yes vs. no).
The primary end point was overall survival. Secondary end points included progression-free survival, overall response rate (complete and partial), duration of response, toxic effects, and quality of life. Responses were assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST),14 and toxic effects were assessed according to the Common Toxicity Criteria of the National Cancer Institute (version 2.0). The European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ-C30) and the quality-of-life questionnaire for patients with lung cancer (QLQ-LC13) were used to evaluate patients' quality of life.
The protocol was approved by the ethics review boards at all participating institutions, and all patients provided written informed consent. Support was provided by the NCIC and OSI Pharmaceuticals. Data were collected, managed, and analyzed by the NCIC CTG, and the manuscript was written by members of the NCIC CTG. OSI Pharmaceuticals reviewed the final manuscript and provided comments on it. Confidentiality was maintained by both the NCIC CTG and OSI Pharmaceuticals. The study chair, Dr. Shepherd, and the physician coordinator, Dr. Seymour, reviewed all the data and confirmed their completeness and accuracy.
Eligibility Criteria
Patients 18 years of age or older with an Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 3 were eligible in the presence of documented pathological evidence of non–small-cell lung cancer. The patients had to have received one or two regimens of combination chemotherapy and not be eligible for further chemotherapy. Patients 70 years of age or older may have received therapy with one or two single agents. Patients had to have recovered from any toxic effects of therapy and were randomly assigned to the study treatment at least 21 days after chemotherapy (14 days after treatment with vinca alkaloids or gemcitabine) and 7 days after radiation. Adequate hematologic and biochemical values were required.
Patients with prior breast cancer, melanoma, or hypernephroma were ineligible, as were those with other malignant diseases (except basal-cell skin cancers) within the preceding five years. Other exclusion criteria were symptomatic brain metastases, clinically significant cardiac disease within one year, ventricular arrhythmias requiring medication, and clinically significant ophthalmologic or gastrointestinal abnormalities.
Study Procedures
Within seven days before randomization, a history and physical examination were obtained and hematologic and biochemical testing, chest radiography, and assessments of toxic effects and quality of life were obtained. Computed tomographic scans of the chest and abdomen were obtained within 28 days before randomization. For a patient to be evaluated for a response, at least one measurable lesion was required, but measurable disease was not mandatory for eligibility. Only patients with measurable disease were included in the analyses of complete or partial response.
Administration of the study medication was to start within two days after randomization. For grade 2 diarrhea, loperamide was recommended without reduction of the dose of erlotinib. For grade 3 diarrhea, the study treatment was withheld until the diarrhea was grade 1 or less, and then erlotinib at a dose of 100 mg daily was started. For grade 1 or 2 rash, treatment modification was not recommended. For grade 3 rash, treatment was withheld, the rash was treated symptomatically, and erlotinib at a dose of 100 mg daily was restarted when the rash was grade 1 or less.
History taking, physical examination, and hematologic and biochemical testing were performed every four weeks, and radiologic investigations every eight weeks. Patients' quality of life was evaluated every four weeks in countries with validated versions of the questionnaires.
EGFR Expression
Separate written consent for optional tissue banking and correlative studies was obtained. EGFR expression was determined with the use of immunohistochemistry in a central laboratory that used Dako kits (DakoCytomation). Positivity was defined as more than 10 percent of cells staining at any intensity for EGFR.
Statistical Analysis
The trial was designed to detect, with 90 percent power and a two-sided type I error of 5 percent, a 33 percent improvement in median survival from four months as estimated in the placebo group. For the final analysis, 582 deaths were required and were projected to occur with a sample size of 700 patients enrolled over a period of 14 months with 6 months of follow-up. The required number of deaths had occurred by January 2004, and the database was locked as of April 23, 2004. There was no interim analysis. Tumor responses were validated centrally for the first 333 patients in the trial.
The stratified log-rank test, accounting for stratification factors at randomization (except center) and EGFR protein expression (positive vs. negative vs. unknown), was used to compare progression-free survival and overall survival between treatment groups. Exploratory forward stepwise regression analyses with the use of the Cox model were performed to adjust for treatment effect and to identify prognostic factors for progression-free survival and overall survival. Candidate covariates included EGFR expression, stratification factors (except center), sex, age (60 years or less vs. more than 60 years), race or ethnic group (Asian vs. others), prior radiotherapy (yes vs. no), histologic subtype of cancer (adenocarcinoma vs. others), and smoking status (smoker vs. nonsmoker vs. unknown). Race was self-reported or determined by study personnel and was not based on country of domicile. Fisher's exact test was used to compare response rates between levels of potential predictors and rates of toxic effects between treatments. Times to deterioration (a 10-point increase from the baseline score) for cough, dyspnea, and pain were identified prospectively as the primary end points for the analysis of quality of life15 and were analyzed with the use of the log-rank test, with adjustment according to the Hochberg method16 for the comparison of multiple end points. All P values were two-sided.
Results
Patient Characteristics
Between August 2001 and January 2003, 731 patients were randomly assigned to erlotinib (488) or placebo (243). Twenty-two patients (12 assigned to erlotinib and 10 assigned to placebo) were ineligible for the following reasons: three prior chemotherapy regimens (9); single-agent chemotherapy for patients less than 70 years of age (2); inadequate time since the last treatment (5); abnormal biochemistry results (4); and symptomatic brain metastases (2). All 731 patients were included in the efficacy analyses, and 727 treated patients (485 assigned to erlotinib and 242 assigned to placebo) were included in the safety analyses. Eight patients assigned to erlotinib (1.6 percent) and 18 assigned to placebo (7.4 percent) received other EGFR inhibitors after study medication was discontinued. The groups were balanced with respect to baseline characteristics and important prognostic variables (Table 1Table 1Baseline Characteristics of the Patients.).
Response and Survival
In patients with at least one target lesion, the lesions were evaluated according to RECIST (427 patients assigned to erlotinib and 211 assigned to placebo). In the erlotinib group, the rates of complete response and partial response were 0.7 percent and 8.2 percent, respectively (median duration, 7.9 months); in the placebo group, the rate of partial response was less than 1 percent (P<0.001), but these responses were not externally validated. In an intention-to-treat analysis of all patients randomly assigned to treatment, the disease-control rate (i.e., the rate of complete or partial responses and stable disease) in the erlotinib group was 45 percent; 38 percent of the patients had progressive disease, and among the remaining 17 percent progression was not confirmed. The likelihood of a response to erlotinib (Table 2Table 2Analysis of Responses to the Study Treatment.) among patients with non–small-cell lung cancer was not significantly altered by performance status, prior treatments, prior response, or age, but it was higher among women (P=0.006), nonsmokers (P<0.001), Asians (P=0.02), patients with adenocarcinoma (P<0.001), and patients in whom 10 percent or more of the tumor cells expressed EGFR (P=0.10). In multiple logistic-regression analyses, never having smoked (P<0.001), the presence of adenocarcinoma (P=0.01), and EGFR expression (P=0.03) were associated with responsiveness to erlotinib.
At the time of analysis, 587 deaths had occurred (378 in the erlotinib group and 209 in the placebo group). Figure 1Figure 1Kaplan–Meier Curves for Overall Survival (Panel A) and Progression-free Survival (Panel B) among All Patients Randomly Assigned to Erlotinib or Placebo. shows Kaplan–Meier curves for overall survival and progression-free survival. Median overall survival in the erlotinib group was 6.7 months, and in the placebo group it was 4.7 months (adjusted hazard ratio, 0.70; 95 percent confidence interval, 0.58 to 0.85; P<0.001). In the Cox regression analysis, erlotinib remained associated with longer survival (P=0.002), as did Asian origin (P=0.01), adenocarcinoma on histologic examination (P=0.004), and never having smoked (P=0.048 vs. current or past smoking). Table 3Table 3Analysis of Survival. shows the exploratory subgroup analyses. Although the sample sizes may be inadequate to detect small or moderate differences, a benefit from erlotinib was apparent in most of the subgroups. The interaction between treatment and the covariate defining the subgroup was statistically significant only for smoking status. At the time of analysis, 682 patients had had progression of disease (450 in the erlotinib group and 232 in the placebo group). Median progression-free survival was 2.2 months in the erlotinib group and 1.8 months in the placebo group (adjusted hazard ratio, 0.61; 95 percent confidence interval, 0.51 to 0.74; P<0.001). In the Cox model, treatment with erlotinib (P<0.001) and never having smoked (P<0.01 for the comparison with current or past smoking) were associated with longer progression-free survival.
Toxic Effects
Four patients who underwent randomization did not receive treatment. Table 4Table 4Toxic Effects and Dose Modifications among 727 Patients Receiving the Study Drugs. shows that 19 percent of the erlotinib group required dose reductions because of drug-related toxic effects, as compared with 2 percent of the placebo group, most frequently because of rash (12 percent) and diarrhea (5 percent); 26 patients (5 percent) discontinued erlotinib because of drug-related toxic effects, as compared with 4 patients (2 percent) receiving placebo. There was a higher incidence of infection among the erlotinib patients, which may reflect longer follow-up (P<0.001). There were similar rates of pneumonitis and pulmonary fibrosis in the two groups. Two patients died of pneumonitis (one in each group).
Quality of Life
Compliance was similar in the two groups. Patients who had responded to the quality-of-life questionnaire at baseline and had one follow-up assessment were included in the analysis. The median time to deterioration with regard to cough (4.9 months among patients receiving erlotinib and 3.7 months among those receiving placebo, P=0.04 with Hochberg adjustment), dyspnea (4.7 months and 2.9 months, respectively; adjusted P=0.03), and pain (2.8 months and 1.9 months, respectively; adjusted P=0.04) in favor of erlotinib. These results are consistent with response-based analyses of the quality of life, which found that more patients receiving erlotinib had improvement in cough, pain, and dyspnea and in the domain of overall physical function (further information is in the Supplementary Appendix, available with the complete text of this article at www.nejm.org).
Discussion
Docetaxel is the only agent known to prolong survival among patients with disease progression after cisplatin-based chemotherapy for non–small-cell lung cancer.3,4,17 Few options are available for the treatment of patients with disease progression after docetaxel or those who are not eligible for second-line chemotherapy.5,6 Clearly, new treatments are needed for such patients.
Expression of EGFR is common in non–small-cell lung cancer.18-20 Several agents that target EGFR are in various phases of clinical evaluation.9,21 The orally active EGFR tyrosine kinase inhibitors gefitinib and erlotinib have been evaluated in several trials. In the IDEAL 1 trial,10 patients with non–small-cell lung cancer with disease progression after platinum-based chemotherapy were randomly assigned to receive gefitinib, at a dose of 250 mg or 500 mg daily. There were no differences between the two doses with respect to response rate, time to progression, or median survival. The response rates were also similar whether gefitinib was used as second-line treatment (17.9 percent of patients) or third-line treatment (19.8 percent of patients). In the IDEAL 2 trial,11 which enrolled symptomatic patients in whom two or more chemotherapy regimens containing platinum and docetaxel had failed, the response rates were 12 percent and 9 percent, respectively, for the two dose levels. More adverse events were seen with the dose of 500 mg in both trials, but discontinuation of treatment because of toxic effects was uncommon at either dose. In a phase 2 trial of erlotinib, the response rate was 12 percent, and response did not correlate with level of EGFR in the tumor.12
In our trial, the response rate of 8.9 percent was similar to rates reported for erlotinib and gefitinib.10-12 Some investigators have reported that responsiveness to EGFR inhibitors correlates with sex, histologic type, race or ethnic origin, and smoking status.10,11,21 We also found that response was higher among Asians, women, patients with adenocarcinoma, and lifetime nonsmokers. Contrary to previous reports,12 the response rate in our trial was higher when 10 percent or more of tumor cells expressed EGFR.
Activating mutations in the EGFR gene have been found to predict a response to gefitinib.22-27 The results of our assays for the number of copies and mutation status of the EGFR gene are published in this issue of the Journal.28 Higher response rates were found among patients with high numbers of gene copies and mutations, but the difference was significant only for gene copies.
Because none of the early trials10-12 had a placebo control group, it is not possible to determine whether EGFR-inhibitor therapy was superior to palliative treatment. In our placebo-controlled trial, erlotinib did provide clinically meaningful prolongation of survival. According to the Kaplan–Meier estimates, the median survival was prolonged by two months, and 31 percent of patients treated with erlotinib were alive at one year, as compared with 22 percent in the placebo group. The two-month prolongation of survival is similar to that achieved with docetaxel in the setting of second-line chemotherapy,3,4 even though half the patients in our trial were treated after both first-line and second-line chemotherapy. In this trial and another trial,3 a significant prolongation of survival was achieved despite response rates of less than 10 percent, perhaps because a high proportion of the patients had durable stable disease while receiving treatment. Survival in this trial appears to be longer than what was achieved in a similar trial of gefitinib, although the response rates were similar in both studies. The characteristics of the patients in these two trials, however, may have differed somewhat.29
Exploratory multivariate analyses showed that only Asian origin, adenocarcinoma on histologic examination, and a history of not smoking were significant independent predictors of survival after adjustment for treatment and other potential predictors. Erlotinib had a beneficial effect on survival in almost all subgroups tested, but only the interaction between smoking status and treatment was significantly predictive of a differential effect on survival. Notably, the presence of EGFR gene mutations was not predictive of a survival benefit from erlotinib in our study.28
In the IDEAL 2 trial,11 gefitinib rapidly reduced symptoms in 35 percent to 43 percent of patients. In our trial, significantly more patients in the erlotinib group than in the placebo group had reductions in dyspnea, pain, and cough. Furthermore, the time to exacerbation of these symptoms was significantly longer in the erlotinib group. The analysis of the quality of life showed that symptom improvement was also associated with significantly improved physical function.
Rash30 and diarrhea are the main toxic effects of EGFR inhibitors.9 They led to dose reduction in 12 percent and 5 percent of patients, respectively, in our trial. Pneumonitis has been reported mainly in Japan following treatment with gefitinib.31 However, four trials of gefitinib or erlotinib combined with chemotherapy for non–small-cell lung cancer reported similar rates of pneumonitis in active-treatment and placebo groups.32-35 We rarely encountered pneumonitis or pulmonary fibrosis.
In summary, this trial shows that erlotinib, an oral tyrosine kinase inhibitor of EGFR, prolongs survival and decreases symptoms, as compared with placebo, in previously treated patients with non–small-cell lung cancer.
Supported in part by a grant from OSI Pharmaceuticals to the National Cancer Institute of Canada Clinical Trials Group.
We are indebted to Dr. Joseph Pater and Dr. Keyue Ding for their contribution to the trial; to T. Masterson, W. Gollogly, S. Melinyshyn, A. Sadura, M. Whitehead, L. Lafond, K. Hann, J. Ottaway, D. Voskoglou-Nomikos, D. Jones-Moar, T. Boyd, M. Savoie, A. Urton, T. Hanna, T. Feener, and S. Virk of the National Cancer Institute of Canada Clinical Trials Group; and to M. Ptaszynski and B. Geiger of OSI Pharmaceuticals.
Source Information
From the Departments of Medical Oncology and Hematology (F.A.S.) and Radiation Oncology (A.B.), the University Health Network, Princess Margaret Hospital Site, and the University of Toronto (F.A.S., A.B.) — both in Toronto; the Instituto de Cancer Arnaldo Vieira de Carvalho, São Paulo (J.R.P.); the Oncological Institute Ion Chiricuta, Cluj-Napoca, Romania (T.C.); the Department of Medical Oncology, National Cancer Centre, Singapore (E.H.T.); the Department of Oncology, McGill University, Montreal (V.H.); the Faculty of Medicine, Chiangmai University, Chiangmai, Thailand (S.T.); the Confidence Medical Center, San Isidro, Argentina (D.C.); Pramongkutklao Hospital, Bangkok, Thailand (S.M.); Cross Cancer Institute, Edmonton, Alta., Canada (M.S.); the Instituto Nacional de Cancer, Praça da Cruz Vermelha, Rio de Janeiro, Brazil (R.M.); the Instituto Medico Alexander Fleming, Buenos Aires (M.K.); the Oncology Institute, Bucharest, Romania (M.D.); Hôtel Dieu Health Sciences Hospital, St. Catharines, Ont., Canada (B.F.); the National Cancer Institute of Canada Clinical Trials Group, Kingston, Ont., Canada (D.T., D.J., L.S.); and OSI Pharmaceuticals, Boulder, Colo. (G.C., P.S.).
The investigators and centers participating in this National Cancer Institute of Canada Clinical Trials Group study are listed in the Appendix.
Appendix
The following investigators and centers participated in this National Cancer Institute of Canada Clinical Trials Group study: A.M. Alvarez, J.L. Martinez, M. Varela, M. Van Kooten, S. Jovtis, Buenos Aires; M. Freue, Lanus, Argentina; M. Rosenthal, Parkville, Australia; D. Yip, Garran, Australia; R. De Boer, Footscray, Australia; S. Ackland, Waratah, Australia; P. Clingan, Wollongong, Australia; D. Campos, San Isidro, Argentina; A. del Giglio, Santo Andre, Brazil; C. Mathias, Bahia, Brazil; I.L Santoro, J.R. Pereira, São Paulo; A.M. Murad, Belo Horizonte, Brazil; R.D.A. Ribeiro, Ceara, Brazil; S. Lago, Porto Alegre, Brazil; J. Vinholes, Porto Alegre, Brazil; R. Martins, Rio de Janeiro; S. Rorke, St. John's, Canada; W. Morzycki, Halifax, Canada; F. Laberge, R. Whittom, Ste.-Foy, Canada; V. Hirsh, J. Ayoub, Montreal; R.W. Gregg, Kingston, Canada; S. Laurie, Ottawa; F. Wierzbicki, Oshawa, Canada; B. Findlay, St. Catharines, Canada; A. Arnold, Hamilton, Canada; L.A. Zibdawi, Newmarket, Canada; J. Meharchand, F. Shepherd, R.L. Burkes, Y.C. Ung, Toronto; J.J. Wilson, Weston, Canada; B. Pressnail, Barrie, Canada; R. Myers, Mississauga, Canada; J. Noble, Sudbury, Canada; D. Walde, Sault Ste. Marie, Canada; S. Navaratnam, Winnipeg, Canada; H.I. Chalchal, Regina, Canada; D.G. Morris, Calgary, Canada; M. Smylie, Edmonton, Canada; D. Fenton, Kelowna, Canada; H. Martins, Victoria, Canada; J. Gutierrez, Las Condes, Chile; U. Gatzemeier, Grobhansdorf, Germany; J. von Pawel, Gauting, Germany; R. Loddenkemper, Berlin; A. Gerogianni, Athens; R. Chan, Pokfulam, Hong Kong; D. Flex, Petach Tikva, Israel; D. Loven, Afula, Israel; M.C. Wollner, Haifa, Israel; H. Biran, Rehovot, Israel; M. Levitt, Tel Hashomer, Israel; A. Cyjon, Zerifin, Israel; J. Lopez, Dviango, Mexico; J. Robles, Mexico City; G. Calderillo, Tlalpan, Mexico; T. Christmas, Auckland, New Zealand; A.B. Simpson, Wellington, New Zealand; M. Dediu, Bucharest, Romania; T.-E. Ciuleanu, Cluj-Napaca, Romania; M. Patran, Sibiu, Romania; L. Miron, Lasi, Romania; L. Ek, Lund, Sweden; B. Bergman, Gothenburg, Sweden; R. Soo, E.H. Tan, Singapore; S. Maoleekoonpairoj, A. Cheirsilpa, Bangkok, Thailand; S. Thongprasert, Chiangmai, Thailand; C.M. Rudin, Chicago; P. Ruff, Johannesburg, South Africa; D.J. Hacking, Westridge, South Africa; S.J. Fourie, Pretoria, South Africa; C. Jacobs, Port Elizabeth, South Africa; C.F. Slabber, Brooklyn Square, South Africa; D.A. Vorobiof, Parklands, South Africa; K. Chi-Hei, Pokfulam, Hong Kong; W. Arpornwirat, Bangkok, Thailand; M. Zukin, Rio de Janeiro.
source: http://www.nejm.org
The epidermal growth factor receptor (EGFR) family is part of a complex signal-transduction network that is central to several critical cellular processes. Since EGFR is often found in non–small-cell lung cancer cells,7,8 it has been the focus of efforts to develop new agents that target the EGFR pathway. Erlotinib (Tarceva, OSI Pharmaceuticals) and gefitinib (Iressa, AstraZeneca) inhibit the tyrosine kinase activity of EGFR and have been studied extensively.9-12 In randomized phase 2 trials of gefitinib (Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL] 1 and 2),10,11 the tumors of 10 to 20 percent of patients who were previously treated with platinum-based regimens responded, and in a phase 2 trial of erlotinib among previously treated patients with non–small-cell lung cancer in which 10 percent or more of the cells expressed EGFR, the response rate was 12.3 percent.12 These promising rates are perhaps higher than those possible with other forms of chemotherapy,3-6 but it is unknown whether treatment with an EGFR inhibitor prolongs survival. For this reason, the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) conducted a trial (BR.21) to compare erlotinib with placebo after the failure of standard chemotherapy for non–small-cell lung cancer. The inclusion of a control group receiving placebo was considered ethical in view of the lack of benefit from further chemotherapy after the failure of standard treatment.5,6
Methods
Study Design
This international, phase 3, randomized, double-blind, placebo-controlled trial of erlotinib after the failure of first-line or second-line chemotherapy for non–small-cell lung cancer was designed by the NCIC CTG. Patients were randomly assigned in a 2:1 ratio to receive oral erlotinib at a dose of 150 mg daily or placebo. Randomization was performed centrally by Applied Logic Associates (Houston), with the use of the minimization method.13 Patients were stratified according to center, Eastern Cooperative Oncology Group performance status (0 or 1 vs. 2 or 3, with higher scores indicating greater impairment), best response to prior therapy (complete or partial response vs. stable disease vs. progressive disease), number of prior regimens received (one vs. two), and exposure to prior platinum therapy (yes vs. no).
The primary end point was overall survival. Secondary end points included progression-free survival, overall response rate (complete and partial), duration of response, toxic effects, and quality of life. Responses were assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST),14 and toxic effects were assessed according to the Common Toxicity Criteria of the National Cancer Institute (version 2.0). The European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ-C30) and the quality-of-life questionnaire for patients with lung cancer (QLQ-LC13) were used to evaluate patients' quality of life.
The protocol was approved by the ethics review boards at all participating institutions, and all patients provided written informed consent. Support was provided by the NCIC and OSI Pharmaceuticals. Data were collected, managed, and analyzed by the NCIC CTG, and the manuscript was written by members of the NCIC CTG. OSI Pharmaceuticals reviewed the final manuscript and provided comments on it. Confidentiality was maintained by both the NCIC CTG and OSI Pharmaceuticals. The study chair, Dr. Shepherd, and the physician coordinator, Dr. Seymour, reviewed all the data and confirmed their completeness and accuracy.
Eligibility Criteria
Patients 18 years of age or older with an Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 3 were eligible in the presence of documented pathological evidence of non–small-cell lung cancer. The patients had to have received one or two regimens of combination chemotherapy and not be eligible for further chemotherapy. Patients 70 years of age or older may have received therapy with one or two single agents. Patients had to have recovered from any toxic effects of therapy and were randomly assigned to the study treatment at least 21 days after chemotherapy (14 days after treatment with vinca alkaloids or gemcitabine) and 7 days after radiation. Adequate hematologic and biochemical values were required.
Patients with prior breast cancer, melanoma, or hypernephroma were ineligible, as were those with other malignant diseases (except basal-cell skin cancers) within the preceding five years. Other exclusion criteria were symptomatic brain metastases, clinically significant cardiac disease within one year, ventricular arrhythmias requiring medication, and clinically significant ophthalmologic or gastrointestinal abnormalities.
Study Procedures
Within seven days before randomization, a history and physical examination were obtained and hematologic and biochemical testing, chest radiography, and assessments of toxic effects and quality of life were obtained. Computed tomographic scans of the chest and abdomen were obtained within 28 days before randomization. For a patient to be evaluated for a response, at least one measurable lesion was required, but measurable disease was not mandatory for eligibility. Only patients with measurable disease were included in the analyses of complete or partial response.
Administration of the study medication was to start within two days after randomization. For grade 2 diarrhea, loperamide was recommended without reduction of the dose of erlotinib. For grade 3 diarrhea, the study treatment was withheld until the diarrhea was grade 1 or less, and then erlotinib at a dose of 100 mg daily was started. For grade 1 or 2 rash, treatment modification was not recommended. For grade 3 rash, treatment was withheld, the rash was treated symptomatically, and erlotinib at a dose of 100 mg daily was restarted when the rash was grade 1 or less.
History taking, physical examination, and hematologic and biochemical testing were performed every four weeks, and radiologic investigations every eight weeks. Patients' quality of life was evaluated every four weeks in countries with validated versions of the questionnaires.
EGFR Expression
Separate written consent for optional tissue banking and correlative studies was obtained. EGFR expression was determined with the use of immunohistochemistry in a central laboratory that used Dako kits (DakoCytomation). Positivity was defined as more than 10 percent of cells staining at any intensity for EGFR.
Statistical Analysis
The trial was designed to detect, with 90 percent power and a two-sided type I error of 5 percent, a 33 percent improvement in median survival from four months as estimated in the placebo group. For the final analysis, 582 deaths were required and were projected to occur with a sample size of 700 patients enrolled over a period of 14 months with 6 months of follow-up. The required number of deaths had occurred by January 2004, and the database was locked as of April 23, 2004. There was no interim analysis. Tumor responses were validated centrally for the first 333 patients in the trial.
The stratified log-rank test, accounting for stratification factors at randomization (except center) and EGFR protein expression (positive vs. negative vs. unknown), was used to compare progression-free survival and overall survival between treatment groups. Exploratory forward stepwise regression analyses with the use of the Cox model were performed to adjust for treatment effect and to identify prognostic factors for progression-free survival and overall survival. Candidate covariates included EGFR expression, stratification factors (except center), sex, age (60 years or less vs. more than 60 years), race or ethnic group (Asian vs. others), prior radiotherapy (yes vs. no), histologic subtype of cancer (adenocarcinoma vs. others), and smoking status (smoker vs. nonsmoker vs. unknown). Race was self-reported or determined by study personnel and was not based on country of domicile. Fisher's exact test was used to compare response rates between levels of potential predictors and rates of toxic effects between treatments. Times to deterioration (a 10-point increase from the baseline score) for cough, dyspnea, and pain were identified prospectively as the primary end points for the analysis of quality of life15 and were analyzed with the use of the log-rank test, with adjustment according to the Hochberg method16 for the comparison of multiple end points. All P values were two-sided.
Results
Patient Characteristics
Between August 2001 and January 2003, 731 patients were randomly assigned to erlotinib (488) or placebo (243). Twenty-two patients (12 assigned to erlotinib and 10 assigned to placebo) were ineligible for the following reasons: three prior chemotherapy regimens (9); single-agent chemotherapy for patients less than 70 years of age (2); inadequate time since the last treatment (5); abnormal biochemistry results (4); and symptomatic brain metastases (2). All 731 patients were included in the efficacy analyses, and 727 treated patients (485 assigned to erlotinib and 242 assigned to placebo) were included in the safety analyses. Eight patients assigned to erlotinib (1.6 percent) and 18 assigned to placebo (7.4 percent) received other EGFR inhibitors after study medication was discontinued. The groups were balanced with respect to baseline characteristics and important prognostic variables (Table 1Table 1Baseline Characteristics of the Patients.).
Response and Survival
In patients with at least one target lesion, the lesions were evaluated according to RECIST (427 patients assigned to erlotinib and 211 assigned to placebo). In the erlotinib group, the rates of complete response and partial response were 0.7 percent and 8.2 percent, respectively (median duration, 7.9 months); in the placebo group, the rate of partial response was less than 1 percent (P<0.001), but these responses were not externally validated. In an intention-to-treat analysis of all patients randomly assigned to treatment, the disease-control rate (i.e., the rate of complete or partial responses and stable disease) in the erlotinib group was 45 percent; 38 percent of the patients had progressive disease, and among the remaining 17 percent progression was not confirmed. The likelihood of a response to erlotinib (Table 2Table 2Analysis of Responses to the Study Treatment.) among patients with non–small-cell lung cancer was not significantly altered by performance status, prior treatments, prior response, or age, but it was higher among women (P=0.006), nonsmokers (P<0.001), Asians (P=0.02), patients with adenocarcinoma (P<0.001), and patients in whom 10 percent or more of the tumor cells expressed EGFR (P=0.10). In multiple logistic-regression analyses, never having smoked (P<0.001), the presence of adenocarcinoma (P=0.01), and EGFR expression (P=0.03) were associated with responsiveness to erlotinib.
At the time of analysis, 587 deaths had occurred (378 in the erlotinib group and 209 in the placebo group). Figure 1Figure 1Kaplan–Meier Curves for Overall Survival (Panel A) and Progression-free Survival (Panel B) among All Patients Randomly Assigned to Erlotinib or Placebo. shows Kaplan–Meier curves for overall survival and progression-free survival. Median overall survival in the erlotinib group was 6.7 months, and in the placebo group it was 4.7 months (adjusted hazard ratio, 0.70; 95 percent confidence interval, 0.58 to 0.85; P<0.001). In the Cox regression analysis, erlotinib remained associated with longer survival (P=0.002), as did Asian origin (P=0.01), adenocarcinoma on histologic examination (P=0.004), and never having smoked (P=0.048 vs. current or past smoking). Table 3Table 3Analysis of Survival. shows the exploratory subgroup analyses. Although the sample sizes may be inadequate to detect small or moderate differences, a benefit from erlotinib was apparent in most of the subgroups. The interaction between treatment and the covariate defining the subgroup was statistically significant only for smoking status. At the time of analysis, 682 patients had had progression of disease (450 in the erlotinib group and 232 in the placebo group). Median progression-free survival was 2.2 months in the erlotinib group and 1.8 months in the placebo group (adjusted hazard ratio, 0.61; 95 percent confidence interval, 0.51 to 0.74; P<0.001). In the Cox model, treatment with erlotinib (P<0.001) and never having smoked (P<0.01 for the comparison with current or past smoking) were associated with longer progression-free survival.
Toxic Effects
Four patients who underwent randomization did not receive treatment. Table 4Table 4Toxic Effects and Dose Modifications among 727 Patients Receiving the Study Drugs. shows that 19 percent of the erlotinib group required dose reductions because of drug-related toxic effects, as compared with 2 percent of the placebo group, most frequently because of rash (12 percent) and diarrhea (5 percent); 26 patients (5 percent) discontinued erlotinib because of drug-related toxic effects, as compared with 4 patients (2 percent) receiving placebo. There was a higher incidence of infection among the erlotinib patients, which may reflect longer follow-up (P<0.001). There were similar rates of pneumonitis and pulmonary fibrosis in the two groups. Two patients died of pneumonitis (one in each group).
Quality of Life
Compliance was similar in the two groups. Patients who had responded to the quality-of-life questionnaire at baseline and had one follow-up assessment were included in the analysis. The median time to deterioration with regard to cough (4.9 months among patients receiving erlotinib and 3.7 months among those receiving placebo, P=0.04 with Hochberg adjustment), dyspnea (4.7 months and 2.9 months, respectively; adjusted P=0.03), and pain (2.8 months and 1.9 months, respectively; adjusted P=0.04) in favor of erlotinib. These results are consistent with response-based analyses of the quality of life, which found that more patients receiving erlotinib had improvement in cough, pain, and dyspnea and in the domain of overall physical function (further information is in the Supplementary Appendix, available with the complete text of this article at www.nejm.org).
Discussion
Docetaxel is the only agent known to prolong survival among patients with disease progression after cisplatin-based chemotherapy for non–small-cell lung cancer.3,4,17 Few options are available for the treatment of patients with disease progression after docetaxel or those who are not eligible for second-line chemotherapy.5,6 Clearly, new treatments are needed for such patients.
Expression of EGFR is common in non–small-cell lung cancer.18-20 Several agents that target EGFR are in various phases of clinical evaluation.9,21 The orally active EGFR tyrosine kinase inhibitors gefitinib and erlotinib have been evaluated in several trials. In the IDEAL 1 trial,10 patients with non–small-cell lung cancer with disease progression after platinum-based chemotherapy were randomly assigned to receive gefitinib, at a dose of 250 mg or 500 mg daily. There were no differences between the two doses with respect to response rate, time to progression, or median survival. The response rates were also similar whether gefitinib was used as second-line treatment (17.9 percent of patients) or third-line treatment (19.8 percent of patients). In the IDEAL 2 trial,11 which enrolled symptomatic patients in whom two or more chemotherapy regimens containing platinum and docetaxel had failed, the response rates were 12 percent and 9 percent, respectively, for the two dose levels. More adverse events were seen with the dose of 500 mg in both trials, but discontinuation of treatment because of toxic effects was uncommon at either dose. In a phase 2 trial of erlotinib, the response rate was 12 percent, and response did not correlate with level of EGFR in the tumor.12
In our trial, the response rate of 8.9 percent was similar to rates reported for erlotinib and gefitinib.10-12 Some investigators have reported that responsiveness to EGFR inhibitors correlates with sex, histologic type, race or ethnic origin, and smoking status.10,11,21 We also found that response was higher among Asians, women, patients with adenocarcinoma, and lifetime nonsmokers. Contrary to previous reports,12 the response rate in our trial was higher when 10 percent or more of tumor cells expressed EGFR.
Activating mutations in the EGFR gene have been found to predict a response to gefitinib.22-27 The results of our assays for the number of copies and mutation status of the EGFR gene are published in this issue of the Journal.28 Higher response rates were found among patients with high numbers of gene copies and mutations, but the difference was significant only for gene copies.
Because none of the early trials10-12 had a placebo control group, it is not possible to determine whether EGFR-inhibitor therapy was superior to palliative treatment. In our placebo-controlled trial, erlotinib did provide clinically meaningful prolongation of survival. According to the Kaplan–Meier estimates, the median survival was prolonged by two months, and 31 percent of patients treated with erlotinib were alive at one year, as compared with 22 percent in the placebo group. The two-month prolongation of survival is similar to that achieved with docetaxel in the setting of second-line chemotherapy,3,4 even though half the patients in our trial were treated after both first-line and second-line chemotherapy. In this trial and another trial,3 a significant prolongation of survival was achieved despite response rates of less than 10 percent, perhaps because a high proportion of the patients had durable stable disease while receiving treatment. Survival in this trial appears to be longer than what was achieved in a similar trial of gefitinib, although the response rates were similar in both studies. The characteristics of the patients in these two trials, however, may have differed somewhat.29
Exploratory multivariate analyses showed that only Asian origin, adenocarcinoma on histologic examination, and a history of not smoking were significant independent predictors of survival after adjustment for treatment and other potential predictors. Erlotinib had a beneficial effect on survival in almost all subgroups tested, but only the interaction between smoking status and treatment was significantly predictive of a differential effect on survival. Notably, the presence of EGFR gene mutations was not predictive of a survival benefit from erlotinib in our study.28
In the IDEAL 2 trial,11 gefitinib rapidly reduced symptoms in 35 percent to 43 percent of patients. In our trial, significantly more patients in the erlotinib group than in the placebo group had reductions in dyspnea, pain, and cough. Furthermore, the time to exacerbation of these symptoms was significantly longer in the erlotinib group. The analysis of the quality of life showed that symptom improvement was also associated with significantly improved physical function.
Rash30 and diarrhea are the main toxic effects of EGFR inhibitors.9 They led to dose reduction in 12 percent and 5 percent of patients, respectively, in our trial. Pneumonitis has been reported mainly in Japan following treatment with gefitinib.31 However, four trials of gefitinib or erlotinib combined with chemotherapy for non–small-cell lung cancer reported similar rates of pneumonitis in active-treatment and placebo groups.32-35 We rarely encountered pneumonitis or pulmonary fibrosis.
In summary, this trial shows that erlotinib, an oral tyrosine kinase inhibitor of EGFR, prolongs survival and decreases symptoms, as compared with placebo, in previously treated patients with non–small-cell lung cancer.
Supported in part by a grant from OSI Pharmaceuticals to the National Cancer Institute of Canada Clinical Trials Group.
We are indebted to Dr. Joseph Pater and Dr. Keyue Ding for their contribution to the trial; to T. Masterson, W. Gollogly, S. Melinyshyn, A. Sadura, M. Whitehead, L. Lafond, K. Hann, J. Ottaway, D. Voskoglou-Nomikos, D. Jones-Moar, T. Boyd, M. Savoie, A. Urton, T. Hanna, T. Feener, and S. Virk of the National Cancer Institute of Canada Clinical Trials Group; and to M. Ptaszynski and B. Geiger of OSI Pharmaceuticals.
Source Information
From the Departments of Medical Oncology and Hematology (F.A.S.) and Radiation Oncology (A.B.), the University Health Network, Princess Margaret Hospital Site, and the University of Toronto (F.A.S., A.B.) — both in Toronto; the Instituto de Cancer Arnaldo Vieira de Carvalho, São Paulo (J.R.P.); the Oncological Institute Ion Chiricuta, Cluj-Napoca, Romania (T.C.); the Department of Medical Oncology, National Cancer Centre, Singapore (E.H.T.); the Department of Oncology, McGill University, Montreal (V.H.); the Faculty of Medicine, Chiangmai University, Chiangmai, Thailand (S.T.); the Confidence Medical Center, San Isidro, Argentina (D.C.); Pramongkutklao Hospital, Bangkok, Thailand (S.M.); Cross Cancer Institute, Edmonton, Alta., Canada (M.S.); the Instituto Nacional de Cancer, Praça da Cruz Vermelha, Rio de Janeiro, Brazil (R.M.); the Instituto Medico Alexander Fleming, Buenos Aires (M.K.); the Oncology Institute, Bucharest, Romania (M.D.); Hôtel Dieu Health Sciences Hospital, St. Catharines, Ont., Canada (B.F.); the National Cancer Institute of Canada Clinical Trials Group, Kingston, Ont., Canada (D.T., D.J., L.S.); and OSI Pharmaceuticals, Boulder, Colo. (G.C., P.S.).
The investigators and centers participating in this National Cancer Institute of Canada Clinical Trials Group study are listed in the Appendix.
Appendix
The following investigators and centers participated in this National Cancer Institute of Canada Clinical Trials Group study: A.M. Alvarez, J.L. Martinez, M. Varela, M. Van Kooten, S. Jovtis, Buenos Aires; M. Freue, Lanus, Argentina; M. Rosenthal, Parkville, Australia; D. Yip, Garran, Australia; R. De Boer, Footscray, Australia; S. Ackland, Waratah, Australia; P. Clingan, Wollongong, Australia; D. Campos, San Isidro, Argentina; A. del Giglio, Santo Andre, Brazil; C. Mathias, Bahia, Brazil; I.L Santoro, J.R. Pereira, São Paulo; A.M. Murad, Belo Horizonte, Brazil; R.D.A. Ribeiro, Ceara, Brazil; S. Lago, Porto Alegre, Brazil; J. Vinholes, Porto Alegre, Brazil; R. Martins, Rio de Janeiro; S. Rorke, St. John's, Canada; W. Morzycki, Halifax, Canada; F. Laberge, R. Whittom, Ste.-Foy, Canada; V. Hirsh, J. Ayoub, Montreal; R.W. Gregg, Kingston, Canada; S. Laurie, Ottawa; F. Wierzbicki, Oshawa, Canada; B. Findlay, St. Catharines, Canada; A. Arnold, Hamilton, Canada; L.A. Zibdawi, Newmarket, Canada; J. Meharchand, F. Shepherd, R.L. Burkes, Y.C. Ung, Toronto; J.J. Wilson, Weston, Canada; B. Pressnail, Barrie, Canada; R. Myers, Mississauga, Canada; J. Noble, Sudbury, Canada; D. Walde, Sault Ste. Marie, Canada; S. Navaratnam, Winnipeg, Canada; H.I. Chalchal, Regina, Canada; D.G. Morris, Calgary, Canada; M. Smylie, Edmonton, Canada; D. Fenton, Kelowna, Canada; H. Martins, Victoria, Canada; J. Gutierrez, Las Condes, Chile; U. Gatzemeier, Grobhansdorf, Germany; J. von Pawel, Gauting, Germany; R. Loddenkemper, Berlin; A. Gerogianni, Athens; R. Chan, Pokfulam, Hong Kong; D. Flex, Petach Tikva, Israel; D. Loven, Afula, Israel; M.C. Wollner, Haifa, Israel; H. Biran, Rehovot, Israel; M. Levitt, Tel Hashomer, Israel; A. Cyjon, Zerifin, Israel; J. Lopez, Dviango, Mexico; J. Robles, Mexico City; G. Calderillo, Tlalpan, Mexico; T. Christmas, Auckland, New Zealand; A.B. Simpson, Wellington, New Zealand; M. Dediu, Bucharest, Romania; T.-E. Ciuleanu, Cluj-Napaca, Romania; M. Patran, Sibiu, Romania; L. Miron, Lasi, Romania; L. Ek, Lund, Sweden; B. Bergman, Gothenburg, Sweden; R. Soo, E.H. Tan, Singapore; S. Maoleekoonpairoj, A. Cheirsilpa, Bangkok, Thailand; S. Thongprasert, Chiangmai, Thailand; C.M. Rudin, Chicago; P. Ruff, Johannesburg, South Africa; D.J. Hacking, Westridge, South Africa; S.J. Fourie, Pretoria, South Africa; C. Jacobs, Port Elizabeth, South Africa; C.F. Slabber, Brooklyn Square, South Africa; D.A. Vorobiof, Parklands, South Africa; K. Chi-Hei, Pokfulam, Hong Kong; W. Arpornwirat, Bangkok, Thailand; M. Zukin, Rio de Janeiro.
source: http://www.nejm.org
Monday, April 18, 2016
Help With Cancer Treatment Bills
Shades of Pink, which is marking its 11th anniversary this year, provides temporary financial assistance to women experiencing financial hardship as a direct result of breast cancer diagnosis and treatment, according to a news release. Last year OKLAHOMA – In Oklahoma, we rank the 45th in the country, near the bottom, when it comes to cancer treatment and cancer death a life-threatening illness,” Warren said. “Not only to help yourself but to help others in the future. A Dowagiac church is leading an effort to bring children from Flint to Michiana for a summer retreat, but they need your help. Khalon Howard is heading to a hospital in Cincinnati Monday for cancer treatment to Assistant Chief Bill Thompson of the MaKayla has Glioblastoma, an aggressive form of cancer in her brain If you'd like to help out, the Corrells have set up a GoFundMe page called "MaKayla's Hope Fund" to raise money for medical bills and funeral expenses. You can get to the GoFundMe Heather said her brother was in the Naval Special Forces and is a very strong person who doesn’t accept help lightly has been diagnosed with cancer. She was originally diagnosed in May 2011, and her last chemotherapy treatment was in September It was set up two years ago to help firefighters who contract struggle with the disease and with funding treatment. Bizon, a doctor, said 60 percent of career firefighters die from cancer. The budget bill goes to the full house next week. .
She thanked the “progressive Midlanders,” who in 1948, set up the organization to help cancer patients with items sometimes unrelated to their medical condition, such as travel for treatment, money for bills, wigs or counseling. Today, Cancer Services Could having a healthy marriage help you survive cancer The study found if you are single and going through treatment it's important to find a support system. Sharon's journey with cancer is not over. Soon she'll begin another round of chemotherapy. A separate post on the little girl's page indicated that a week's worth of chemotherapy treatment costs about wrote alongside a photo of dollar bills and drawings sent to Molly by other children who wanted to help. "It's what #fundingacure REUTERS: AbbVie Inc placed another big bet on new cancer drugs on Thursday with a US$5.8 billion acquisition that could lessen its dependence on arthritis treatment Humira A biomarker is used to help select patients whose cancers express the protein. .
Financial Assistance for Cancer Patients | GiveForward help with cancer treatment bills with dimensions 316 X 416 image source: www.giveforward.com
Sunday, April 17, 2016
Cancer Treatment Michigan
To prevent relapse, Kian underwent preventative treatment in Michigan, USA. In spite of this, in December 2015, doctors confirmed that the cancer had returned. For this latest round of treatment, Kian and Kat will have to travel back and forth to New York Currently, patients often receive a combination of these two approaches to ensure the best chance of treatment to drive cancer. Study coauthors include BIDMC investigators Ashish Juvekar, Hai Hu, and John M. Asara; University of Michigan, Ann Arbor's A team of researchers who specialize in treating cancers of the eye wanted to identify a marker that would indicate aggressive basal cell skin cancer, and perhaps also provide a potential target for treatment University of Michigan Kellogg Eye Whoever thought that "less is more" could apply to dealing with cancer? Case in point: early-stage prostate cancer "Making The Choice" guide from the Michigan Cancer Consortium. Surgery is still the most common treatment for medium- and high-risk ST. AUGUSTINE, Fla. --Ninety-year-old Norma Bauerschmidt's story starts with an end-of-life decision. "They wanted to operate and everything right away. I said, no! We'll just leave it be." It was uterine cancer. Two days after that diagnosis, Norma's 182,091 Michigan citizens are registered with the medical marijuana program as patients, with an additional 34,269 registered as caregivers. There are 8,140 individuals using cannabis under recommendation of their licensed physician for cancer treatment in .
Khalon Howard is heading to a hospital in Cincinnati Monday for cancer treatment. His friends at Hums Elementary The drugs had allegedly been buried at a home in Michigan. Two Michiana residents are facing federal drug charges after an Indiana State A 90-year-old woman has opted out of cancer treatment to spend her remaining days on a once-in-a-lifetime road-trip with her family. Just two days after her husband of 67 years passed away, a woman named Norma in northern Michigan was diagnosed with (CNN) A Detroit-area doctor who authorities say gave cancer treatment drugs to patients who did not need victims who filed into U.S. District Court for the Eastern District of Michigan throughout the week to watch his sentencing, his apology doesn DETROIT (AP) — John Bonamego's first season as Central Michigan's coach was quite a success. Especially considering what he had to deal with off the field. Bonamego announced in June that he had cancer in his left tonsil, but he was able to keep coaching .
no money for firefighters' cancer treatment cancer treatment michigan with dimensions 958 X 1600 image source: relnews.com
Subscribe to:
Posts (Atom)