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CT Scans Cut Lung Cancer Deaths by 20%
A large randomized national trial has provided the first evidence of a significant reduction in lung cancer deaths with a screening test.
The National Lung Screening Trial (NLST) reported a 20.3% reduction in lung cancer mortality among heavy smokers screened with low-dose helical computed tomography (CT), as compared with those given standard chest x-rays. The trial enrolled more than 53,000 older, high-risk individuals.
In addition, deaths from any cause, including lung cancer, were 7% lower among participants screened with low-dose helical CT, also known as spiral CT.
The initial results were released today by the study sponsor, the National Cancer Institute, after the study's independent data and safety monitoring board recommended halting the trial.
"The fact that low-dose helical CT provides a decided benefit is a result that will have implications for screening and management of lung cancer for many years to come," Dr. Christine Berg, project officer for the lung screening study at the NCI, said in a statement.
Beginning in 2002, the NLST recruited about 53,500 American men and women, aged 55-74 years, who were current or former smokers with a smoking history of at least 30 pack-years. It randomly assigned them to receive three annual screens with low-dose helical CT or chest x-ray. Helical CT uses x-rays to obtain a multiple-image scan of the entire chest during a 7- to 15-second breath-hold, whereas a standard chest x-ray produces only a single image of the chest from a sub-second breath-hold.
At the time of the Oct. 20, 2010 analysis, 354 deaths from lung cancer had occurred in the CT arm vs. 442 in the chest x-ray group. Approximately 25% of deaths in the NLST were due to lung cancer.
NCI director Dr. Harold E. Varmus said the well-designed study used rigorous scientific methods and that its findings could spare countless lives.
"Lung cancer is the leading cause of cancer mortality in the U.S. and throughout the world, so a validated approach that can reduce lung cancer mortality by even 20% has the potential to spare very significant numbers of people from the ravages of this disease," he said. "But these findings should in no way distract us from continued effort to curtail the use of tobacco, which will remain the major causative factor for lung cancer and several other diseases."
Like other screening strategies, the use of low-dose helical CT has disadvantages including the cumulative effects of radiation from multiple CT scans, complications among patients who need additional testing to make a definitive lung cancer diagnosis, and the anxiety and added cost associated with investigating incidental findings picked up on CT.
In 2009, investigators reported that low-dose CT screening was associated with twice the rate of false positives and more unneeded interventions, compared with chest x-ray, in a randomized feasibility trial that preceded the NLST. But low-dose CT also detected twice as many lung cancers as did chest x-ray screens in that study.
Although the NLST trial cohort was ethnically representative of the high-risk U.S. population, the researchers noted that participants were highly motivated and screened at major medical centers. Thus, the results may not accurately predict the effect of CT screening for other populations.
"What has happened here is that the technology shows you can cut down on lung cancer deaths, the leading cause of cancer mortality, and save nearly as many lives as the number of people who die from breast cancer per year. We as a medical community now need to figure out how to do this in a way that the cost is acceptable to the public," Dr. Bruce E. Johnson, an official with the American Society of Clinical Oncology and director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, said in a statement.
A more detailed analysis of the NLST results is expected to be published in the coming months, although a paper describing its design and protocol was published Nov. 3 by the journal Radiology.
The trial was conducted at 33 sites across the country by the American College of Radiology Imaging Network and the Lung Screening Study group.
The study was sponsored by the National Cancer Institute.
A large randomized national trial has provided the first evidence of a significant reduction in lung cancer deaths with a screening test.
The National Lung Screening Trial (NLST) reported a 20.3% reduction in lung cancer mortality among heavy smokers screened with low-dose helical computed tomography (CT), as compared with those given standard chest x-rays. The trial enrolled more than 53,000 older, high-risk individuals.
In addition, deaths from any cause, including lung cancer, were 7% lower among participants screened with low-dose helical CT, also known as spiral CT.
The initial results were released today by the study sponsor, the National Cancer Institute, after the study's independent data and safety monitoring board recommended halting the trial.
"The fact that low-dose helical CT provides a decided benefit is a result that will have implications for screening and management of lung cancer for many years to come," Dr. Christine Berg, project officer for the lung screening study at the NCI, said in a statement.
Beginning in 2002, the NLST recruited about 53,500 American men and women, aged 55-74 years, who were current or former smokers with a smoking history of at least 30 pack-years. It randomly assigned them to receive three annual screens with low-dose helical CT or chest x-ray. Helical CT uses x-rays to obtain a multiple-image scan of the entire chest during a 7- to 15-second breath-hold, whereas a standard chest x-ray produces only a single image of the chest from a sub-second breath-hold.
At the time of the Oct. 20, 2010 analysis, 354 deaths from lung cancer had occurred in the CT arm vs. 442 in the chest x-ray group. Approximately 25% of deaths in the NLST were due to lung cancer.
NCI director Dr. Harold E. Varmus said the well-designed study used rigorous scientific methods and that its findings could spare countless lives.
"Lung cancer is the leading cause of cancer mortality in the U.S. and throughout the world, so a validated approach that can reduce lung cancer mortality by even 20% has the potential to spare very significant numbers of people from the ravages of this disease," he said. "But these findings should in no way distract us from continued effort to curtail the use of tobacco, which will remain the major causative factor for lung cancer and several other diseases."
Like other screening strategies, the use of low-dose helical CT has disadvantages including the cumulative effects of radiation from multiple CT scans, complications among patients who need additional testing to make a definitive lung cancer diagnosis, and the anxiety and added cost associated with investigating incidental findings picked up on CT.
In 2009, investigators reported that low-dose CT screening was associated with twice the rate of false positives and more unneeded interventions, compared with chest x-ray, in a randomized feasibility trial that preceded the NLST. But low-dose CT also detected twice as many lung cancers as did chest x-ray screens in that study.
Although the NLST trial cohort was ethnically representative of the high-risk U.S. population, the researchers noted that participants were highly motivated and screened at major medical centers. Thus, the results may not accurately predict the effect of CT screening for other populations.
"What has happened here is that the technology shows you can cut down on lung cancer deaths, the leading cause of cancer mortality, and save nearly as many lives as the number of people who die from breast cancer per year. We as a medical community now need to figure out how to do this in a way that the cost is acceptable to the public," Dr. Bruce E. Johnson, an official with the American Society of Clinical Oncology and director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, said in a statement.
A more detailed analysis of the NLST results is expected to be published in the coming months, although a paper describing its design and protocol was published Nov. 3 by the journal Radiology.
The trial was conducted at 33 sites across the country by the American College of Radiology Imaging Network and the Lung Screening Study group.
The study was sponsored by the National Cancer Institute.
A large randomized national trial has provided the first evidence of a significant reduction in lung cancer deaths with a screening test.
The National Lung Screening Trial (NLST) reported a 20.3% reduction in lung cancer mortality among heavy smokers screened with low-dose helical computed tomography (CT), as compared with those given standard chest x-rays. The trial enrolled more than 53,000 older, high-risk individuals.
In addition, deaths from any cause, including lung cancer, were 7% lower among participants screened with low-dose helical CT, also known as spiral CT.
The initial results were released today by the study sponsor, the National Cancer Institute, after the study's independent data and safety monitoring board recommended halting the trial.
"The fact that low-dose helical CT provides a decided benefit is a result that will have implications for screening and management of lung cancer for many years to come," Dr. Christine Berg, project officer for the lung screening study at the NCI, said in a statement.
Beginning in 2002, the NLST recruited about 53,500 American men and women, aged 55-74 years, who were current or former smokers with a smoking history of at least 30 pack-years. It randomly assigned them to receive three annual screens with low-dose helical CT or chest x-ray. Helical CT uses x-rays to obtain a multiple-image scan of the entire chest during a 7- to 15-second breath-hold, whereas a standard chest x-ray produces only a single image of the chest from a sub-second breath-hold.
At the time of the Oct. 20, 2010 analysis, 354 deaths from lung cancer had occurred in the CT arm vs. 442 in the chest x-ray group. Approximately 25% of deaths in the NLST were due to lung cancer.
NCI director Dr. Harold E. Varmus said the well-designed study used rigorous scientific methods and that its findings could spare countless lives.
"Lung cancer is the leading cause of cancer mortality in the U.S. and throughout the world, so a validated approach that can reduce lung cancer mortality by even 20% has the potential to spare very significant numbers of people from the ravages of this disease," he said. "But these findings should in no way distract us from continued effort to curtail the use of tobacco, which will remain the major causative factor for lung cancer and several other diseases."
Like other screening strategies, the use of low-dose helical CT has disadvantages including the cumulative effects of radiation from multiple CT scans, complications among patients who need additional testing to make a definitive lung cancer diagnosis, and the anxiety and added cost associated with investigating incidental findings picked up on CT.
In 2009, investigators reported that low-dose CT screening was associated with twice the rate of false positives and more unneeded interventions, compared with chest x-ray, in a randomized feasibility trial that preceded the NLST. But low-dose CT also detected twice as many lung cancers as did chest x-ray screens in that study.
Although the NLST trial cohort was ethnically representative of the high-risk U.S. population, the researchers noted that participants were highly motivated and screened at major medical centers. Thus, the results may not accurately predict the effect of CT screening for other populations.
"What has happened here is that the technology shows you can cut down on lung cancer deaths, the leading cause of cancer mortality, and save nearly as many lives as the number of people who die from breast cancer per year. We as a medical community now need to figure out how to do this in a way that the cost is acceptable to the public," Dr. Bruce E. Johnson, an official with the American Society of Clinical Oncology and director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, said in a statement.
A more detailed analysis of the NLST results is expected to be published in the coming months, although a paper describing its design and protocol was published Nov. 3 by the journal Radiology.
The trial was conducted at 33 sites across the country by the American College of Radiology Imaging Network and the Lung Screening Study group.
The study was sponsored by the National Cancer Institute.
The National Lung Screening Trial
Major Finding: Lung cancer deaths were reduced 20% among participants screened regularly with low-dose helical computed tomography vs. standard chest x-ray.
Data Source: The National Lung Cancer Screening Trial in about 53,500 current and former heavy smokers.
Disclosures: The study was sponsored by the National Cancer Institute.
CT Scans Cut Lung Cancer Deaths by 20% in Heavy Smokers
A large randomized national trial has provided the first evidence of a significant reduction in lung cancer deaths with a screening test.
The National Lung Screening Trial (NLST) reported a 20.3% reduction in lung cancer mortality among heavy smokers screened with low-dose helical computed tomography (CT), as compared with those given standard chest x-rays. The trial enrolled more than 53,000 older, high-risk individuals.
In addition, deaths from any cause, including lung cancer, were 7% lower among participants screened with low-dose helical CT, also known as spiral CT.
The initial results were released today by the study sponsor, the National Cancer Institute, after the study’s independent data and safety monitoring board recommended halting the trial.
"The fact that low-dose helical CT provides a decided benefit is a result that will have implications for screening and management of lung cancer for many years to come," Dr. Christine Berg, project officer for the lung screening study at the NCI, said in a statement.
Beginning in 2002, the NLST recruited about 53,500 American men and women, aged 55-74 years, who were current or former smokers with a smoking history of at least 30 pack-years. It randomly assigned them to receive three annual screens with low-dose helical CT or chest x-ray. Helical CT uses x-rays to obtain a multiple-image scan of the entire chest during a 7- to 15-second breath-hold, whereas a standard chest x-ray produces only a single image of the chest from a sub-second breath-hold.
At the time of the Oct. 20, 2010 analysis, 354 deaths from lung cancer had occurred in the CT arm vs. 442 in the chest x-ray group. Approximately 25% of deaths in the NLST were due to lung cancer.
NCI director Dr. Harold E. Varmus said the well-designed study used rigorous scientific methods and that its findings could spare countless lives.
"Lung cancer is the leading cause of cancer mortality in the U.S. and throughout the world, so a validated approach that can reduce lung cancer mortality by even 20% has the potential to spare very significant numbers of people from the ravages of this disease," he said. "But these findings should in no way distract us from continued effort to curtail the use of tobacco, which will remain the major causative factor for lung cancer and several other diseases."
Like other screening strategies, the use of low-dose helical CT has disadvantages including the cumulative effects of radiation from multiple CT scans, complications among patients who need additional testing to make a definitive lung cancer diagnosis, and the anxiety and added cost associated with investigating incidental findings picked up on CT.
In 2009, investigators reported that low-dose CT screening was associated with twice the rate of false positives and more unneeded interventions, compared with chest x-ray, in a randomized feasibility trial that preceded the NLST. But low-dose CT also detected twice as many lung cancers as did chest x-ray screens in that study.
Although the NLST trial cohort was ethnically representative of the high-risk U.S. population, the researchers noted that participants were highly motivated and screened at major medical centers. Thus, the results may not accurately predict the effect of CT screening for other populations.
"What has happened here is that the technology shows you can cut down on lung cancer deaths, the leading cause of cancer mortality, and save nearly as many lives as the number of people who die from breast cancer per year. We as a medical community now need to figure out how to do this in a way that the cost is acceptable to the public," Dr. Bruce E. Johnson, an official with the American Society of Clinical Oncology and director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, said in a statement.
A more detailed analysis of the NLST results is expected to be published in the coming months, although a paper describing its design and protocol was published Nov. 3 by the journal Radiology.
The trial was conducted at 33 sites across the country by the American College of Radiology Imaging Network and the Lung Screening Study group.
The study was sponsored by the National Cancer Institute.
A large randomized national trial has provided the first evidence of a significant reduction in lung cancer deaths with a screening test.
The National Lung Screening Trial (NLST) reported a 20.3% reduction in lung cancer mortality among heavy smokers screened with low-dose helical computed tomography (CT), as compared with those given standard chest x-rays. The trial enrolled more than 53,000 older, high-risk individuals.
In addition, deaths from any cause, including lung cancer, were 7% lower among participants screened with low-dose helical CT, also known as spiral CT.
The initial results were released today by the study sponsor, the National Cancer Institute, after the study’s independent data and safety monitoring board recommended halting the trial.
"The fact that low-dose helical CT provides a decided benefit is a result that will have implications for screening and management of lung cancer for many years to come," Dr. Christine Berg, project officer for the lung screening study at the NCI, said in a statement.
Beginning in 2002, the NLST recruited about 53,500 American men and women, aged 55-74 years, who were current or former smokers with a smoking history of at least 30 pack-years. It randomly assigned them to receive three annual screens with low-dose helical CT or chest x-ray. Helical CT uses x-rays to obtain a multiple-image scan of the entire chest during a 7- to 15-second breath-hold, whereas a standard chest x-ray produces only a single image of the chest from a sub-second breath-hold.
At the time of the Oct. 20, 2010 analysis, 354 deaths from lung cancer had occurred in the CT arm vs. 442 in the chest x-ray group. Approximately 25% of deaths in the NLST were due to lung cancer.
NCI director Dr. Harold E. Varmus said the well-designed study used rigorous scientific methods and that its findings could spare countless lives.
"Lung cancer is the leading cause of cancer mortality in the U.S. and throughout the world, so a validated approach that can reduce lung cancer mortality by even 20% has the potential to spare very significant numbers of people from the ravages of this disease," he said. "But these findings should in no way distract us from continued effort to curtail the use of tobacco, which will remain the major causative factor for lung cancer and several other diseases."
Like other screening strategies, the use of low-dose helical CT has disadvantages including the cumulative effects of radiation from multiple CT scans, complications among patients who need additional testing to make a definitive lung cancer diagnosis, and the anxiety and added cost associated with investigating incidental findings picked up on CT.
In 2009, investigators reported that low-dose CT screening was associated with twice the rate of false positives and more unneeded interventions, compared with chest x-ray, in a randomized feasibility trial that preceded the NLST. But low-dose CT also detected twice as many lung cancers as did chest x-ray screens in that study.
Although the NLST trial cohort was ethnically representative of the high-risk U.S. population, the researchers noted that participants were highly motivated and screened at major medical centers. Thus, the results may not accurately predict the effect of CT screening for other populations.
"What has happened here is that the technology shows you can cut down on lung cancer deaths, the leading cause of cancer mortality, and save nearly as many lives as the number of people who die from breast cancer per year. We as a medical community now need to figure out how to do this in a way that the cost is acceptable to the public," Dr. Bruce E. Johnson, an official with the American Society of Clinical Oncology and director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, said in a statement.
A more detailed analysis of the NLST results is expected to be published in the coming months, although a paper describing its design and protocol was published Nov. 3 by the journal Radiology.
The trial was conducted at 33 sites across the country by the American College of Radiology Imaging Network and the Lung Screening Study group.
The study was sponsored by the National Cancer Institute.
A large randomized national trial has provided the first evidence of a significant reduction in lung cancer deaths with a screening test.
The National Lung Screening Trial (NLST) reported a 20.3% reduction in lung cancer mortality among heavy smokers screened with low-dose helical computed tomography (CT), as compared with those given standard chest x-rays. The trial enrolled more than 53,000 older, high-risk individuals.
In addition, deaths from any cause, including lung cancer, were 7% lower among participants screened with low-dose helical CT, also known as spiral CT.
The initial results were released today by the study sponsor, the National Cancer Institute, after the study’s independent data and safety monitoring board recommended halting the trial.
"The fact that low-dose helical CT provides a decided benefit is a result that will have implications for screening and management of lung cancer for many years to come," Dr. Christine Berg, project officer for the lung screening study at the NCI, said in a statement.
Beginning in 2002, the NLST recruited about 53,500 American men and women, aged 55-74 years, who were current or former smokers with a smoking history of at least 30 pack-years. It randomly assigned them to receive three annual screens with low-dose helical CT or chest x-ray. Helical CT uses x-rays to obtain a multiple-image scan of the entire chest during a 7- to 15-second breath-hold, whereas a standard chest x-ray produces only a single image of the chest from a sub-second breath-hold.
At the time of the Oct. 20, 2010 analysis, 354 deaths from lung cancer had occurred in the CT arm vs. 442 in the chest x-ray group. Approximately 25% of deaths in the NLST were due to lung cancer.
NCI director Dr. Harold E. Varmus said the well-designed study used rigorous scientific methods and that its findings could spare countless lives.
"Lung cancer is the leading cause of cancer mortality in the U.S. and throughout the world, so a validated approach that can reduce lung cancer mortality by even 20% has the potential to spare very significant numbers of people from the ravages of this disease," he said. "But these findings should in no way distract us from continued effort to curtail the use of tobacco, which will remain the major causative factor for lung cancer and several other diseases."
Like other screening strategies, the use of low-dose helical CT has disadvantages including the cumulative effects of radiation from multiple CT scans, complications among patients who need additional testing to make a definitive lung cancer diagnosis, and the anxiety and added cost associated with investigating incidental findings picked up on CT.
In 2009, investigators reported that low-dose CT screening was associated with twice the rate of false positives and more unneeded interventions, compared with chest x-ray, in a randomized feasibility trial that preceded the NLST. But low-dose CT also detected twice as many lung cancers as did chest x-ray screens in that study.
Although the NLST trial cohort was ethnically representative of the high-risk U.S. population, the researchers noted that participants were highly motivated and screened at major medical centers. Thus, the results may not accurately predict the effect of CT screening for other populations.
"What has happened here is that the technology shows you can cut down on lung cancer deaths, the leading cause of cancer mortality, and save nearly as many lives as the number of people who die from breast cancer per year. We as a medical community now need to figure out how to do this in a way that the cost is acceptable to the public," Dr. Bruce E. Johnson, an official with the American Society of Clinical Oncology and director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, said in a statement.
A more detailed analysis of the NLST results is expected to be published in the coming months, although a paper describing its design and protocol was published Nov. 3 by the journal Radiology.
The trial was conducted at 33 sites across the country by the American College of Radiology Imaging Network and the Lung Screening Study group.
The study was sponsored by the National Cancer Institute.
Bar Code Scanning Can Reduce Pharmacy Errors
VANCOUVER, B.C. – A series of interventions aimed at reducing human error dramatically reduced mistakes made in the formulation of intravenous medications and solutions for children at Duke University Medical Center, based on the results of a retrospective analysis.
The primary interventions included initiation of bar code scanning of medication vials and IV bags, improvement of work flow processes in the IV room, and elimination of manual order entry when producing complex IV solutions, lead author Dr. Patrick Ethington said.
Before the interventions were fully implemented in December 2008, the hospital's electronic order entry system would generate an order by a physician that the pharmacist had to manually transcribe into the computer system used in the IV room. The pharmacy technicians would prepare the recipe and place the drug vials and syringes in a basket to be checked by the pharmacist. Although a pharmacist still manually checks the volume of medications created, the system electronically generates orders and labels without the need for manual transcription, and freezes if a scanning error is detected, said Dr. Ethington, a neonatology fellow at Duke University in Durham, N.C.
The impact of the interventions was evaluated by having pharmacy safety data for inpatient pediatric admissions recorded from March 3, 2007, to Sept. 24, 2009, and medication errors graded based on a severity index (SI) scored from 0 to 6. A score of 0 indicates the error never reached the patient and consequently caused no harm, 3 indicates the error reached the patient and caused transient adverse effects, and 6 indicates the error resulted in patient death.
There were no SI 3 or greater errors after the interventions, compared with a mean of 1.9 such errors per 100,000 doses created before the interventions (P value equals .04), Dr. Ethington said.
Scanning medication bar codes detected 2.7 errors per day; there was no way to score these errors for severity because they were not reported for SI scoring. It was noted that it was not possible to verify that scanned medications were added to the IV bag or that the correct volume of scanned medication was placed in the IV bag. A long-term goal is to have automated volume verification.
The hospital focused on the preparation of IV medications and solutions because 20% of SI events originated at this step. Between 2007 and 2009, Duke Children's Services at the medical center treated 30,638 children, generating 338,657 orders, 869,997 doses, and 2,041 errors.
Factors that contribute to these errors include high volume, and stressful work that is somewhat repetitive and goes against the strengths of humans to think conceptually, he said. Only a small minority of medications has a characteristic color, leaving the bedside nurse to trust that the product is accurately labeled.
The medication production process is also set up for human error to occur in that different drugs are produced with similar-looking labels and similar size, color, and shaped vials, said Dr. Ethington, a former process engineer.
Although the current interventions reduced serious errors, they are no place to stop, said Dr. Ethington, who noted that roughly 25% of errors at Duke occur at the bedside. A recent study showed that bar code scanning on units significantly reduced timing errors in medication administration, but not potential adverse drug events associated with those errors (N. Engl. J. Med. 2010;362:1698-707).
Scanning at the bedside is difficult, but is a long-term goal of the hospital, he said in an interview. The researchers also plan to look at subtle differences between the day and night shifts.
The traditional medication production process is set up for human error to occur.
Source DR. ETHINGTON
VANCOUVER, B.C. – A series of interventions aimed at reducing human error dramatically reduced mistakes made in the formulation of intravenous medications and solutions for children at Duke University Medical Center, based on the results of a retrospective analysis.
The primary interventions included initiation of bar code scanning of medication vials and IV bags, improvement of work flow processes in the IV room, and elimination of manual order entry when producing complex IV solutions, lead author Dr. Patrick Ethington said.
Before the interventions were fully implemented in December 2008, the hospital's electronic order entry system would generate an order by a physician that the pharmacist had to manually transcribe into the computer system used in the IV room. The pharmacy technicians would prepare the recipe and place the drug vials and syringes in a basket to be checked by the pharmacist. Although a pharmacist still manually checks the volume of medications created, the system electronically generates orders and labels without the need for manual transcription, and freezes if a scanning error is detected, said Dr. Ethington, a neonatology fellow at Duke University in Durham, N.C.
The impact of the interventions was evaluated by having pharmacy safety data for inpatient pediatric admissions recorded from March 3, 2007, to Sept. 24, 2009, and medication errors graded based on a severity index (SI) scored from 0 to 6. A score of 0 indicates the error never reached the patient and consequently caused no harm, 3 indicates the error reached the patient and caused transient adverse effects, and 6 indicates the error resulted in patient death.
There were no SI 3 or greater errors after the interventions, compared with a mean of 1.9 such errors per 100,000 doses created before the interventions (P value equals .04), Dr. Ethington said.
Scanning medication bar codes detected 2.7 errors per day; there was no way to score these errors for severity because they were not reported for SI scoring. It was noted that it was not possible to verify that scanned medications were added to the IV bag or that the correct volume of scanned medication was placed in the IV bag. A long-term goal is to have automated volume verification.
The hospital focused on the preparation of IV medications and solutions because 20% of SI events originated at this step. Between 2007 and 2009, Duke Children's Services at the medical center treated 30,638 children, generating 338,657 orders, 869,997 doses, and 2,041 errors.
Factors that contribute to these errors include high volume, and stressful work that is somewhat repetitive and goes against the strengths of humans to think conceptually, he said. Only a small minority of medications has a characteristic color, leaving the bedside nurse to trust that the product is accurately labeled.
The medication production process is also set up for human error to occur in that different drugs are produced with similar-looking labels and similar size, color, and shaped vials, said Dr. Ethington, a former process engineer.
Although the current interventions reduced serious errors, they are no place to stop, said Dr. Ethington, who noted that roughly 25% of errors at Duke occur at the bedside. A recent study showed that bar code scanning on units significantly reduced timing errors in medication administration, but not potential adverse drug events associated with those errors (N. Engl. J. Med. 2010;362:1698-707).
Scanning at the bedside is difficult, but is a long-term goal of the hospital, he said in an interview. The researchers also plan to look at subtle differences between the day and night shifts.
The traditional medication production process is set up for human error to occur.
Source DR. ETHINGTON
VANCOUVER, B.C. – A series of interventions aimed at reducing human error dramatically reduced mistakes made in the formulation of intravenous medications and solutions for children at Duke University Medical Center, based on the results of a retrospective analysis.
The primary interventions included initiation of bar code scanning of medication vials and IV bags, improvement of work flow processes in the IV room, and elimination of manual order entry when producing complex IV solutions, lead author Dr. Patrick Ethington said.
Before the interventions were fully implemented in December 2008, the hospital's electronic order entry system would generate an order by a physician that the pharmacist had to manually transcribe into the computer system used in the IV room. The pharmacy technicians would prepare the recipe and place the drug vials and syringes in a basket to be checked by the pharmacist. Although a pharmacist still manually checks the volume of medications created, the system electronically generates orders and labels without the need for manual transcription, and freezes if a scanning error is detected, said Dr. Ethington, a neonatology fellow at Duke University in Durham, N.C.
The impact of the interventions was evaluated by having pharmacy safety data for inpatient pediatric admissions recorded from March 3, 2007, to Sept. 24, 2009, and medication errors graded based on a severity index (SI) scored from 0 to 6. A score of 0 indicates the error never reached the patient and consequently caused no harm, 3 indicates the error reached the patient and caused transient adverse effects, and 6 indicates the error resulted in patient death.
There were no SI 3 or greater errors after the interventions, compared with a mean of 1.9 such errors per 100,000 doses created before the interventions (P value equals .04), Dr. Ethington said.
Scanning medication bar codes detected 2.7 errors per day; there was no way to score these errors for severity because they were not reported for SI scoring. It was noted that it was not possible to verify that scanned medications were added to the IV bag or that the correct volume of scanned medication was placed in the IV bag. A long-term goal is to have automated volume verification.
The hospital focused on the preparation of IV medications and solutions because 20% of SI events originated at this step. Between 2007 and 2009, Duke Children's Services at the medical center treated 30,638 children, generating 338,657 orders, 869,997 doses, and 2,041 errors.
Factors that contribute to these errors include high volume, and stressful work that is somewhat repetitive and goes against the strengths of humans to think conceptually, he said. Only a small minority of medications has a characteristic color, leaving the bedside nurse to trust that the product is accurately labeled.
The medication production process is also set up for human error to occur in that different drugs are produced with similar-looking labels and similar size, color, and shaped vials, said Dr. Ethington, a former process engineer.
Although the current interventions reduced serious errors, they are no place to stop, said Dr. Ethington, who noted that roughly 25% of errors at Duke occur at the bedside. A recent study showed that bar code scanning on units significantly reduced timing errors in medication administration, but not potential adverse drug events associated with those errors (N. Engl. J. Med. 2010;362:1698-707).
Scanning at the bedside is difficult, but is a long-term goal of the hospital, he said in an interview. The researchers also plan to look at subtle differences between the day and night shifts.
The traditional medication production process is set up for human error to occur.
Source DR. ETHINGTON
Depression in Epilepsy Linked to Unexplained Pain, Brain Trauma
CHICAGO – Clinicians should be on the lookout for medically unexplained pain, a history of traumatic brain injury, and interictal migraine headaches in patients with epilepsy.
"These may be clinical clues to the possibility of an underlying depression in our patients with epilepsy," said Dr. Steven Schachter, past president of the American Epilepsy Society and professor of neurology at Harvard Medical School in Boston.
Depression affects 20%-55% of patients with refractory epilepsy, but it often goes undiagnosed and untreated. Screening is uncommon and depressive disorders frequently have an atypical clinical expression in patients with epilepsy. Patients may also fail to report depressive symptoms because of the common misconception that depression is a normal reaction to living with seizures, or is a part of the epilepsy itself and does not require special treatment.
There is growing evidence that depression and pain – much like epilepsy and depression – share a variety of interrelated biological pathways and neurotransmitters, said Dr. Schachter, who is also the chief academic officer at the Center for Integration of Medicine and Innovative Technology in Boston. This interaction has been called the depression-pain dyad because the two conditions frequently coexist and exacerbate each other, and may respond to similar treatments.
Dr. Schachter highlighted a review of the literature on comorbid depression and pain that cited studies in which the prevalence of pain in patients with depression ranged from 15% to 100% (mean, 65%). Conversely, the mean prevalence of concurrent depression in patients with pain complaints ranged from 13% in gynecologic clinics assessing pelvic pain to 85% among patients with facial pain in dental clinics (Arch. Intern. Med. 2003;163:2433-45).
"Given that epilepsy patients often hit their heads [and] bite their tongues, where do they fit in?" Dr. Schachter asked the audience at the Epilepsy and Depressive Disorders Conference, which was sponsored by Elsevier and its journal, Epilepsy and Behavior. (Elsevier also publishes this Web site.)
The increased likelihood of head injury during seizures and the frequent report of interictal headaches in epilepsy patients also may indicate a link between depression and epilepsy because of the high prevalence of depression in patients with migraine or traumatic brain injury, even among patients with apparently minor brain injury.
"Maybe we should think of it as an epilepsy-depression-pain triad?" Dr. Schachter posited.
There are a number of mechanisms that have been hypothesized to contribute to this triad. Perhaps the most compelling hypothesis, he suggested, is involvement of the serotonergic and noradrenergic networks that extend throughout the brain, brainstem, and spinal cord.
"Determining the underlying neurobiological alterations in pain pathways as they intersect with the neuroanatomy of depression holds a lot of promise in epilepsy," Dr. Schachter said.
The key for clinicians is to improve early identification and timely treatment of depression in patients with epilepsy. In a recent study of 8- to 18-year-old children with new-onset epilepsy, 23% had a depressive disorder and 36% had an anxiety disorder, with a striking 45% of children exhibiting Axis I disorders before their first recognized seizure (Dev. Med. Child Neurol. 2007;49:493-7). Depression may also be a factor in drug-resistant epilepsy, with patients failing to comply with their epilepsy medications because of comorbid depression, Dr. Schachter said.
Dr. Schachter reported no conflicts of interest.
CHICAGO – Clinicians should be on the lookout for medically unexplained pain, a history of traumatic brain injury, and interictal migraine headaches in patients with epilepsy.
"These may be clinical clues to the possibility of an underlying depression in our patients with epilepsy," said Dr. Steven Schachter, past president of the American Epilepsy Society and professor of neurology at Harvard Medical School in Boston.
Depression affects 20%-55% of patients with refractory epilepsy, but it often goes undiagnosed and untreated. Screening is uncommon and depressive disorders frequently have an atypical clinical expression in patients with epilepsy. Patients may also fail to report depressive symptoms because of the common misconception that depression is a normal reaction to living with seizures, or is a part of the epilepsy itself and does not require special treatment.
There is growing evidence that depression and pain – much like epilepsy and depression – share a variety of interrelated biological pathways and neurotransmitters, said Dr. Schachter, who is also the chief academic officer at the Center for Integration of Medicine and Innovative Technology in Boston. This interaction has been called the depression-pain dyad because the two conditions frequently coexist and exacerbate each other, and may respond to similar treatments.
Dr. Schachter highlighted a review of the literature on comorbid depression and pain that cited studies in which the prevalence of pain in patients with depression ranged from 15% to 100% (mean, 65%). Conversely, the mean prevalence of concurrent depression in patients with pain complaints ranged from 13% in gynecologic clinics assessing pelvic pain to 85% among patients with facial pain in dental clinics (Arch. Intern. Med. 2003;163:2433-45).
"Given that epilepsy patients often hit their heads [and] bite their tongues, where do they fit in?" Dr. Schachter asked the audience at the Epilepsy and Depressive Disorders Conference, which was sponsored by Elsevier and its journal, Epilepsy and Behavior. (Elsevier also publishes this Web site.)
The increased likelihood of head injury during seizures and the frequent report of interictal headaches in epilepsy patients also may indicate a link between depression and epilepsy because of the high prevalence of depression in patients with migraine or traumatic brain injury, even among patients with apparently minor brain injury.
"Maybe we should think of it as an epilepsy-depression-pain triad?" Dr. Schachter posited.
There are a number of mechanisms that have been hypothesized to contribute to this triad. Perhaps the most compelling hypothesis, he suggested, is involvement of the serotonergic and noradrenergic networks that extend throughout the brain, brainstem, and spinal cord.
"Determining the underlying neurobiological alterations in pain pathways as they intersect with the neuroanatomy of depression holds a lot of promise in epilepsy," Dr. Schachter said.
The key for clinicians is to improve early identification and timely treatment of depression in patients with epilepsy. In a recent study of 8- to 18-year-old children with new-onset epilepsy, 23% had a depressive disorder and 36% had an anxiety disorder, with a striking 45% of children exhibiting Axis I disorders before their first recognized seizure (Dev. Med. Child Neurol. 2007;49:493-7). Depression may also be a factor in drug-resistant epilepsy, with patients failing to comply with their epilepsy medications because of comorbid depression, Dr. Schachter said.
Dr. Schachter reported no conflicts of interest.
CHICAGO – Clinicians should be on the lookout for medically unexplained pain, a history of traumatic brain injury, and interictal migraine headaches in patients with epilepsy.
"These may be clinical clues to the possibility of an underlying depression in our patients with epilepsy," said Dr. Steven Schachter, past president of the American Epilepsy Society and professor of neurology at Harvard Medical School in Boston.
Depression affects 20%-55% of patients with refractory epilepsy, but it often goes undiagnosed and untreated. Screening is uncommon and depressive disorders frequently have an atypical clinical expression in patients with epilepsy. Patients may also fail to report depressive symptoms because of the common misconception that depression is a normal reaction to living with seizures, or is a part of the epilepsy itself and does not require special treatment.
There is growing evidence that depression and pain – much like epilepsy and depression – share a variety of interrelated biological pathways and neurotransmitters, said Dr. Schachter, who is also the chief academic officer at the Center for Integration of Medicine and Innovative Technology in Boston. This interaction has been called the depression-pain dyad because the two conditions frequently coexist and exacerbate each other, and may respond to similar treatments.
Dr. Schachter highlighted a review of the literature on comorbid depression and pain that cited studies in which the prevalence of pain in patients with depression ranged from 15% to 100% (mean, 65%). Conversely, the mean prevalence of concurrent depression in patients with pain complaints ranged from 13% in gynecologic clinics assessing pelvic pain to 85% among patients with facial pain in dental clinics (Arch. Intern. Med. 2003;163:2433-45).
"Given that epilepsy patients often hit their heads [and] bite their tongues, where do they fit in?" Dr. Schachter asked the audience at the Epilepsy and Depressive Disorders Conference, which was sponsored by Elsevier and its journal, Epilepsy and Behavior. (Elsevier also publishes this Web site.)
The increased likelihood of head injury during seizures and the frequent report of interictal headaches in epilepsy patients also may indicate a link between depression and epilepsy because of the high prevalence of depression in patients with migraine or traumatic brain injury, even among patients with apparently minor brain injury.
"Maybe we should think of it as an epilepsy-depression-pain triad?" Dr. Schachter posited.
There are a number of mechanisms that have been hypothesized to contribute to this triad. Perhaps the most compelling hypothesis, he suggested, is involvement of the serotonergic and noradrenergic networks that extend throughout the brain, brainstem, and spinal cord.
"Determining the underlying neurobiological alterations in pain pathways as they intersect with the neuroanatomy of depression holds a lot of promise in epilepsy," Dr. Schachter said.
The key for clinicians is to improve early identification and timely treatment of depression in patients with epilepsy. In a recent study of 8- to 18-year-old children with new-onset epilepsy, 23% had a depressive disorder and 36% had an anxiety disorder, with a striking 45% of children exhibiting Axis I disorders before their first recognized seizure (Dev. Med. Child Neurol. 2007;49:493-7). Depression may also be a factor in drug-resistant epilepsy, with patients failing to comply with their epilepsy medications because of comorbid depression, Dr. Schachter said.
Dr. Schachter reported no conflicts of interest.
Longer Is Better for First-Line Chemo in Metastatic Breast Cancer
MILAN – A systematic review of 11 trials involving 2,269 women supports the common American practice of prolonging first-line chemotherapy in metastatic breast cancer until disease progression.
Longer chemotherapy duration was associated with a 36% reduction in the risk of progression (hazard ratio, 0.64; P less than .001,) and a 9% reduction in the risk of death (HR, 0.91; P = .04), lead author Dr. Alessandra Gennari reported at the annual congress of the European Society for Medical Oncology.
In subgroup analyses, the effect of longer chemotherapy was independent of time of randomization (either before or after induction chemotherapy), trial design (same vs. different maintenance), duration of chemotherapy in the control arm (fewer than six cycles vs. six or more cycles), and concomitant endocrine therapy (yes or no).
“In a pragmatic way, these results support the clinical approach of prolonging first-line chemotherapy in the absence of significant toxicity and disease progression,” said Dr. Gennari of the Galliera Hospital in Genoa, Italy.
Despite many years of research, the optimal length of first-line chemotherapy is still a matter of debate among clinical oncologists. Although many American clinicians administer first-line chemotherapy in metastatic breast disease until progression, chemotherapy in Europe is often given for a predetermined number of cycles, with duration dictated by treatment response, tolerability, and physician preference, Dr. Gennari explained during a press briefing at the meeting.
The National Comprehensive Cancer Network guidelines for metastatic breast cancer also state that “due to the lack of overall survival differences, the use of prolonged versus shorter chemotherapy needs to be weighted against the detrimental effects of continuous chemotherapy on overall quality of life.”
“The first question that all patients with metastatic disease ask is not ‘How [long] will I live?’ but ‘How many cycles of chemotherapy will I receive?’?” she told reporters. “It should be clear that today the best answer is ‘As long as you can, because this means you will remain free of disease and possibly live longer.’?”
The meta-analysis included 11 trials conducted between 1987 and 2010, of which 10 were published in peer-reviewed journals.
Invited discussant Dr. Miguel Martin said the meta-analysis features trials with very different designs and strategies, and he questioned whether the standard arms would be considered standard today since, for example, six used different anthracycline combinations and three used only three to four cycles of chemotherapy. He also suggested there could be a potential literature bias since many negative trials are rejected or never submitted for publication, and that trial registration at Web sites such as clinicaltrials.gov started only in 1997.
“Even considering all the mentioned caveats, this Italian study provides support for the administration of chemotherapy until disease progression,” said Dr. Martin of the Hospital General Universitario Gregorio Marañón in Madrid.
Assuming that the median overall survival of metastatic breast cancer after first-line chemotherapy is 24 months, he said that longer chemotherapy is associated with an absolute improvement in median progression-free survival of around 3 months and an absolute increase in overall survival of around 2 months.
“Do more prolonged side effects justify a gain of 3 months of progression-free survival and 2 months for overall survival? I guess that most patients would accept that in exchange for more toxicity,” Dr. Martin said.
Dr. Gennari said that several open questions remain, including what the optimal maintenance chemotherapy is and whether oncologists should maintain patients on the same drugs or give planned sequences using different single agents. Also unclear is the role for prolonged low-dose maintenance therapy and what the optimal association of chemotherapy is with targeted agents such as anti-HER2 and antiangiogenesis therapies.
The Italian Association for Cancer Research supported the trial. Dr. Gennari and her colleagues disclosed no conflicts of interest. Dr. Martin disclosed no conflicts.
MILAN – A systematic review of 11 trials involving 2,269 women supports the common American practice of prolonging first-line chemotherapy in metastatic breast cancer until disease progression.
Longer chemotherapy duration was associated with a 36% reduction in the risk of progression (hazard ratio, 0.64; P less than .001,) and a 9% reduction in the risk of death (HR, 0.91; P = .04), lead author Dr. Alessandra Gennari reported at the annual congress of the European Society for Medical Oncology.
In subgroup analyses, the effect of longer chemotherapy was independent of time of randomization (either before or after induction chemotherapy), trial design (same vs. different maintenance), duration of chemotherapy in the control arm (fewer than six cycles vs. six or more cycles), and concomitant endocrine therapy (yes or no).
“In a pragmatic way, these results support the clinical approach of prolonging first-line chemotherapy in the absence of significant toxicity and disease progression,” said Dr. Gennari of the Galliera Hospital in Genoa, Italy.
Despite many years of research, the optimal length of first-line chemotherapy is still a matter of debate among clinical oncologists. Although many American clinicians administer first-line chemotherapy in metastatic breast disease until progression, chemotherapy in Europe is often given for a predetermined number of cycles, with duration dictated by treatment response, tolerability, and physician preference, Dr. Gennari explained during a press briefing at the meeting.
The National Comprehensive Cancer Network guidelines for metastatic breast cancer also state that “due to the lack of overall survival differences, the use of prolonged versus shorter chemotherapy needs to be weighted against the detrimental effects of continuous chemotherapy on overall quality of life.”
“The first question that all patients with metastatic disease ask is not ‘How [long] will I live?’ but ‘How many cycles of chemotherapy will I receive?’?” she told reporters. “It should be clear that today the best answer is ‘As long as you can, because this means you will remain free of disease and possibly live longer.’?”
The meta-analysis included 11 trials conducted between 1987 and 2010, of which 10 were published in peer-reviewed journals.
Invited discussant Dr. Miguel Martin said the meta-analysis features trials with very different designs and strategies, and he questioned whether the standard arms would be considered standard today since, for example, six used different anthracycline combinations and three used only three to four cycles of chemotherapy. He also suggested there could be a potential literature bias since many negative trials are rejected or never submitted for publication, and that trial registration at Web sites such as clinicaltrials.gov started only in 1997.
“Even considering all the mentioned caveats, this Italian study provides support for the administration of chemotherapy until disease progression,” said Dr. Martin of the Hospital General Universitario Gregorio Marañón in Madrid.
Assuming that the median overall survival of metastatic breast cancer after first-line chemotherapy is 24 months, he said that longer chemotherapy is associated with an absolute improvement in median progression-free survival of around 3 months and an absolute increase in overall survival of around 2 months.
“Do more prolonged side effects justify a gain of 3 months of progression-free survival and 2 months for overall survival? I guess that most patients would accept that in exchange for more toxicity,” Dr. Martin said.
Dr. Gennari said that several open questions remain, including what the optimal maintenance chemotherapy is and whether oncologists should maintain patients on the same drugs or give planned sequences using different single agents. Also unclear is the role for prolonged low-dose maintenance therapy and what the optimal association of chemotherapy is with targeted agents such as anti-HER2 and antiangiogenesis therapies.
The Italian Association for Cancer Research supported the trial. Dr. Gennari and her colleagues disclosed no conflicts of interest. Dr. Martin disclosed no conflicts.
MILAN – A systematic review of 11 trials involving 2,269 women supports the common American practice of prolonging first-line chemotherapy in metastatic breast cancer until disease progression.
Longer chemotherapy duration was associated with a 36% reduction in the risk of progression (hazard ratio, 0.64; P less than .001,) and a 9% reduction in the risk of death (HR, 0.91; P = .04), lead author Dr. Alessandra Gennari reported at the annual congress of the European Society for Medical Oncology.
In subgroup analyses, the effect of longer chemotherapy was independent of time of randomization (either before or after induction chemotherapy), trial design (same vs. different maintenance), duration of chemotherapy in the control arm (fewer than six cycles vs. six or more cycles), and concomitant endocrine therapy (yes or no).
“In a pragmatic way, these results support the clinical approach of prolonging first-line chemotherapy in the absence of significant toxicity and disease progression,” said Dr. Gennari of the Galliera Hospital in Genoa, Italy.
Despite many years of research, the optimal length of first-line chemotherapy is still a matter of debate among clinical oncologists. Although many American clinicians administer first-line chemotherapy in metastatic breast disease until progression, chemotherapy in Europe is often given for a predetermined number of cycles, with duration dictated by treatment response, tolerability, and physician preference, Dr. Gennari explained during a press briefing at the meeting.
The National Comprehensive Cancer Network guidelines for metastatic breast cancer also state that “due to the lack of overall survival differences, the use of prolonged versus shorter chemotherapy needs to be weighted against the detrimental effects of continuous chemotherapy on overall quality of life.”
“The first question that all patients with metastatic disease ask is not ‘How [long] will I live?’ but ‘How many cycles of chemotherapy will I receive?’?” she told reporters. “It should be clear that today the best answer is ‘As long as you can, because this means you will remain free of disease and possibly live longer.’?”
The meta-analysis included 11 trials conducted between 1987 and 2010, of which 10 were published in peer-reviewed journals.
Invited discussant Dr. Miguel Martin said the meta-analysis features trials with very different designs and strategies, and he questioned whether the standard arms would be considered standard today since, for example, six used different anthracycline combinations and three used only three to four cycles of chemotherapy. He also suggested there could be a potential literature bias since many negative trials are rejected or never submitted for publication, and that trial registration at Web sites such as clinicaltrials.gov started only in 1997.
“Even considering all the mentioned caveats, this Italian study provides support for the administration of chemotherapy until disease progression,” said Dr. Martin of the Hospital General Universitario Gregorio Marañón in Madrid.
Assuming that the median overall survival of metastatic breast cancer after first-line chemotherapy is 24 months, he said that longer chemotherapy is associated with an absolute improvement in median progression-free survival of around 3 months and an absolute increase in overall survival of around 2 months.
“Do more prolonged side effects justify a gain of 3 months of progression-free survival and 2 months for overall survival? I guess that most patients would accept that in exchange for more toxicity,” Dr. Martin said.
Dr. Gennari said that several open questions remain, including what the optimal maintenance chemotherapy is and whether oncologists should maintain patients on the same drugs or give planned sequences using different single agents. Also unclear is the role for prolonged low-dose maintenance therapy and what the optimal association of chemotherapy is with targeted agents such as anti-HER2 and antiangiogenesis therapies.
The Italian Association for Cancer Research supported the trial. Dr. Gennari and her colleagues disclosed no conflicts of interest. Dr. Martin disclosed no conflicts.
Major Finding: Longer chemotherapy duration was associated with a 36% reduction in the risk of progression (HR, 0.64; P less than .001) and a 9% reduction in the risk of death (HR, 0.91; P = .04).
Data Source: Systematic review of 11 trials involving 2,269 women with metastatic breast cancer.
Disclosures: The Italian Association for Cancer Research supported the study. Dr. Gennari and her colleagues disclosed no conflicts of interest. Dr. Martin disclosed no conflicts.
Panitumumab Plus Platinum Chemo Misses Mark in Advanced Head and Neck Cancer
MILAN – Panitumumab plus chemotherapy with cisplatin and 5-fluorouracil proved clinically active, but failed to boost overall survival significantly in first-line recurrent or metastatic head and neck cancer in the global, phase III SPECTRUM trial.
The primary end point of median overall survival showed a statistically insignificant increase from 9.0 months with chemotherapy alone to 11.1 months with the addition of panitumumab (Vectibix) (hazard ratio, 0.87; log-rank P = .14).
Subgroup analysis revealed, however, that the effect of panitumumab, an anti–epidermal growth factor receptor (EGFR) monoclonal antibody, was not the same for all patients in the international study, lead author Dr. Jan Vermorken said at the annual congress of the European Society for Medical Oncology.
Regional differences were observed, suggesting a greater benefit in patients from North/South America (HR, 0.69) and Western Europe (HR, 0.73) than in those in Eastern Europe (HR, 1.11). Asian Pacific patients fell somewhere in the middle (HR, 0.99).
About 45% of patients in each arm used some form of subsequent antitumor activity once off the study protocol, but differences cropped up here as well. The use of cytotoxic chemotherapy was imbalanced at 30% in the panitumumab arm vs. 25% in the chemotherapy arm, while twice as many patients in the chemotherapy arm (12% vs. 6%) received subsequent targeted systemic therapy driven largely by the use of anti-EGFR monoclonal antibodies, observed Dr. Vermorken of the Antwerp University Hospital in Edegem, Belgium.
“It’s clear this is the first analysis shown to you, and it’s also very clear that further analyses need to be done to identify subgroups that may have greater benefit than others with the combination of panitumumab with platinum-based chemotherapy,” he said.
SPECTRUM was conducted at 120 sites in 26 countries, and randomized 657 patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck to six 21-day cycles of cisplatin 100 mg/m2 on day 1 plus 5-FU 1,000 mg/m2 on days 1-4 with or without panitumumab 9 mg/kg on day 1.
Carboplatin was substituted for cisplatin because of severe neurotoxicity or a decrease in creatinine clearance in 21% of the 327 panitumumab patients and 26% of the 330 chemotherapy patients. Also, 33% of patients in the experimental arm opted to remain on panitumumab 9 mg/kg every 3 weeks, for a median of 11 weeks.
The median time to disease progression was significantly longer in patients receiving panitumumab at 5.8 months vs. 4.6 months with chemotherapy alone (log-rank P = .004, descriptive only; HR, 0.78), Dr. Vermorken said.
The objective response rate was 36% in the experimental arm vs. 25% in the control arm (P = .007, descriptive only). A complete response was achieved by 2% of patients in the experimental and control arms; partial responses in 35% and 24%, respectively; and stable disease in 46% and 47%.
The disease control rate also favored panitumumab at 82%, vs. 72% for chemotherapy alone (P = .004, descriptive only).
The safety profile of the experimental arm was in line with other trials of panitumumab and comparable with the use of other monoclonal antibodies in combination with chemotherapy, Dr. Vermorken said. Grade 3 and 4 events occurred in 31% and 15% of the panitumumab group, and in 18% and 8% of the chemotherapy group. Infusion reactions of any grade occurred in 3% of the panitumumab group and 2% of the chemotherapy group.
“The utility of this [triplet] appears significant,” said Dr. Marshall Posner, who was invited to discuss the late-breaking abstract. “The toxicity appears to be manageable, there are no infusion reactions, and the every three-week dosing makes this a somewhat easier agent to give than cetuximab.”
He suggested that the lack of survival advantage with panitumumab may be due to limited accessibility in some populations, notably the Eastern Europeans, to anti-EGFR antibodies, particularly cetuximab (Erbitux). In addition, cultural and regional differences in their cancer and the management of their care may have confounded survival.
What is not known is whether the oropharyngeal site, which has proved to do better in several other trials, did better in SPECTRUM and how well the triplet will work in second-line monotherapy, said Dr. Posner, medical director of the head and neck medical oncology program and cancer clinical trials office at Mount Sinai Medical Center in New York.
Amgen Inc. supported the trial. Dr. Vermorken reported participating in advisory boards for and receiving honoraria from Amgen, Merck-Serono, Lilly, Boehringer-Ingelheim, and Sanofi-Aventis. Two coinvestigators reported employee/stockholder relationships with Amgen. Dr. Posner disclosed consulting for several pharmaceutical companies.
MILAN – Panitumumab plus chemotherapy with cisplatin and 5-fluorouracil proved clinically active, but failed to boost overall survival significantly in first-line recurrent or metastatic head and neck cancer in the global, phase III SPECTRUM trial.
The primary end point of median overall survival showed a statistically insignificant increase from 9.0 months with chemotherapy alone to 11.1 months with the addition of panitumumab (Vectibix) (hazard ratio, 0.87; log-rank P = .14).
Subgroup analysis revealed, however, that the effect of panitumumab, an anti–epidermal growth factor receptor (EGFR) monoclonal antibody, was not the same for all patients in the international study, lead author Dr. Jan Vermorken said at the annual congress of the European Society for Medical Oncology.
Regional differences were observed, suggesting a greater benefit in patients from North/South America (HR, 0.69) and Western Europe (HR, 0.73) than in those in Eastern Europe (HR, 1.11). Asian Pacific patients fell somewhere in the middle (HR, 0.99).
About 45% of patients in each arm used some form of subsequent antitumor activity once off the study protocol, but differences cropped up here as well. The use of cytotoxic chemotherapy was imbalanced at 30% in the panitumumab arm vs. 25% in the chemotherapy arm, while twice as many patients in the chemotherapy arm (12% vs. 6%) received subsequent targeted systemic therapy driven largely by the use of anti-EGFR monoclonal antibodies, observed Dr. Vermorken of the Antwerp University Hospital in Edegem, Belgium.
“It’s clear this is the first analysis shown to you, and it’s also very clear that further analyses need to be done to identify subgroups that may have greater benefit than others with the combination of panitumumab with platinum-based chemotherapy,” he said.
SPECTRUM was conducted at 120 sites in 26 countries, and randomized 657 patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck to six 21-day cycles of cisplatin 100 mg/m2 on day 1 plus 5-FU 1,000 mg/m2 on days 1-4 with or without panitumumab 9 mg/kg on day 1.
Carboplatin was substituted for cisplatin because of severe neurotoxicity or a decrease in creatinine clearance in 21% of the 327 panitumumab patients and 26% of the 330 chemotherapy patients. Also, 33% of patients in the experimental arm opted to remain on panitumumab 9 mg/kg every 3 weeks, for a median of 11 weeks.
The median time to disease progression was significantly longer in patients receiving panitumumab at 5.8 months vs. 4.6 months with chemotherapy alone (log-rank P = .004, descriptive only; HR, 0.78), Dr. Vermorken said.
The objective response rate was 36% in the experimental arm vs. 25% in the control arm (P = .007, descriptive only). A complete response was achieved by 2% of patients in the experimental and control arms; partial responses in 35% and 24%, respectively; and stable disease in 46% and 47%.
The disease control rate also favored panitumumab at 82%, vs. 72% for chemotherapy alone (P = .004, descriptive only).
The safety profile of the experimental arm was in line with other trials of panitumumab and comparable with the use of other monoclonal antibodies in combination with chemotherapy, Dr. Vermorken said. Grade 3 and 4 events occurred in 31% and 15% of the panitumumab group, and in 18% and 8% of the chemotherapy group. Infusion reactions of any grade occurred in 3% of the panitumumab group and 2% of the chemotherapy group.
“The utility of this [triplet] appears significant,” said Dr. Marshall Posner, who was invited to discuss the late-breaking abstract. “The toxicity appears to be manageable, there are no infusion reactions, and the every three-week dosing makes this a somewhat easier agent to give than cetuximab.”
He suggested that the lack of survival advantage with panitumumab may be due to limited accessibility in some populations, notably the Eastern Europeans, to anti-EGFR antibodies, particularly cetuximab (Erbitux). In addition, cultural and regional differences in their cancer and the management of their care may have confounded survival.
What is not known is whether the oropharyngeal site, which has proved to do better in several other trials, did better in SPECTRUM and how well the triplet will work in second-line monotherapy, said Dr. Posner, medical director of the head and neck medical oncology program and cancer clinical trials office at Mount Sinai Medical Center in New York.
Amgen Inc. supported the trial. Dr. Vermorken reported participating in advisory boards for and receiving honoraria from Amgen, Merck-Serono, Lilly, Boehringer-Ingelheim, and Sanofi-Aventis. Two coinvestigators reported employee/stockholder relationships with Amgen. Dr. Posner disclosed consulting for several pharmaceutical companies.
MILAN – Panitumumab plus chemotherapy with cisplatin and 5-fluorouracil proved clinically active, but failed to boost overall survival significantly in first-line recurrent or metastatic head and neck cancer in the global, phase III SPECTRUM trial.
The primary end point of median overall survival showed a statistically insignificant increase from 9.0 months with chemotherapy alone to 11.1 months with the addition of panitumumab (Vectibix) (hazard ratio, 0.87; log-rank P = .14).
Subgroup analysis revealed, however, that the effect of panitumumab, an anti–epidermal growth factor receptor (EGFR) monoclonal antibody, was not the same for all patients in the international study, lead author Dr. Jan Vermorken said at the annual congress of the European Society for Medical Oncology.
Regional differences were observed, suggesting a greater benefit in patients from North/South America (HR, 0.69) and Western Europe (HR, 0.73) than in those in Eastern Europe (HR, 1.11). Asian Pacific patients fell somewhere in the middle (HR, 0.99).
About 45% of patients in each arm used some form of subsequent antitumor activity once off the study protocol, but differences cropped up here as well. The use of cytotoxic chemotherapy was imbalanced at 30% in the panitumumab arm vs. 25% in the chemotherapy arm, while twice as many patients in the chemotherapy arm (12% vs. 6%) received subsequent targeted systemic therapy driven largely by the use of anti-EGFR monoclonal antibodies, observed Dr. Vermorken of the Antwerp University Hospital in Edegem, Belgium.
“It’s clear this is the first analysis shown to you, and it’s also very clear that further analyses need to be done to identify subgroups that may have greater benefit than others with the combination of panitumumab with platinum-based chemotherapy,” he said.
SPECTRUM was conducted at 120 sites in 26 countries, and randomized 657 patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck to six 21-day cycles of cisplatin 100 mg/m2 on day 1 plus 5-FU 1,000 mg/m2 on days 1-4 with or without panitumumab 9 mg/kg on day 1.
Carboplatin was substituted for cisplatin because of severe neurotoxicity or a decrease in creatinine clearance in 21% of the 327 panitumumab patients and 26% of the 330 chemotherapy patients. Also, 33% of patients in the experimental arm opted to remain on panitumumab 9 mg/kg every 3 weeks, for a median of 11 weeks.
The median time to disease progression was significantly longer in patients receiving panitumumab at 5.8 months vs. 4.6 months with chemotherapy alone (log-rank P = .004, descriptive only; HR, 0.78), Dr. Vermorken said.
The objective response rate was 36% in the experimental arm vs. 25% in the control arm (P = .007, descriptive only). A complete response was achieved by 2% of patients in the experimental and control arms; partial responses in 35% and 24%, respectively; and stable disease in 46% and 47%.
The disease control rate also favored panitumumab at 82%, vs. 72% for chemotherapy alone (P = .004, descriptive only).
The safety profile of the experimental arm was in line with other trials of panitumumab and comparable with the use of other monoclonal antibodies in combination with chemotherapy, Dr. Vermorken said. Grade 3 and 4 events occurred in 31% and 15% of the panitumumab group, and in 18% and 8% of the chemotherapy group. Infusion reactions of any grade occurred in 3% of the panitumumab group and 2% of the chemotherapy group.
“The utility of this [triplet] appears significant,” said Dr. Marshall Posner, who was invited to discuss the late-breaking abstract. “The toxicity appears to be manageable, there are no infusion reactions, and the every three-week dosing makes this a somewhat easier agent to give than cetuximab.”
He suggested that the lack of survival advantage with panitumumab may be due to limited accessibility in some populations, notably the Eastern Europeans, to anti-EGFR antibodies, particularly cetuximab (Erbitux). In addition, cultural and regional differences in their cancer and the management of their care may have confounded survival.
What is not known is whether the oropharyngeal site, which has proved to do better in several other trials, did better in SPECTRUM and how well the triplet will work in second-line monotherapy, said Dr. Posner, medical director of the head and neck medical oncology program and cancer clinical trials office at Mount Sinai Medical Center in New York.
Amgen Inc. supported the trial. Dr. Vermorken reported participating in advisory boards for and receiving honoraria from Amgen, Merck-Serono, Lilly, Boehringer-Ingelheim, and Sanofi-Aventis. Two coinvestigators reported employee/stockholder relationships with Amgen. Dr. Posner disclosed consulting for several pharmaceutical companies.
FROM THE ANNUAL CONGRESS OF THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY
Major Finding: Median overall survival was 9.0 months with chemotherapy alone vs. 11.1 months with the addition of panitumumab (hazard ratio, 0.87, log-rank P = .14).
Data Source: International, randomized phase III SPECTRUM trial in 657 patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.
Disclosures: Amgen supported the trial. Dr. Vermorken reported participating in advisory boards for and receiving honoraria from Amgen, Merck-Serono, Lilly, Boehringer-Ingelheim, and Sanofi-Aventis. Several of his coinvestigators reported financial relationships with Amgen. Dr. Posner disclosed consulting for several pharmaceutical companies.
Pemetrexed/Cisplatin Combo Stumbles in Advanced Head and Neck Cancer
MILAN – The combination of pemetrexed and cisplatin failed to extend overall survival of recurrent or metastatic squamous cell carcinoma of the head and neck significantly in a pivotal phase III trial.
The primary end point of median overall survival was 7.3 months with pemetrexed injection (Alimta) plus cisplatin, and 6.3 months with cisplatin plus placebo. The 1-month difference was not statistically significant (hazard ratio, 0.87; P = .082), Dr. Susan G. Urba said at the annual congress of the European Society for Medical Oncology.
Median progression-free survival also was similar at 3.6 months in the experimental arm vs. 2.8 months in the control arm (HR, 0.88; P = .166), as was response rate (12% vs. 8%; P = .061).
The data were disappointing enough for pemetrexed maker Eli Lilly & Co. to subsequently announce it is forgoing plans to submit marketing authorization applications for pemetrexed in squamous cell carcinoma of the head and neck with the Food and Drug Administration and the European Medicines Agency.
Pemetrexed has shown single-agent activity in head and neck cancer. It is FDA approved for several indications in nonsquamous non–small cell lung cancer and malignant pleural mesothelioma.
The 795-patient trial, described as the largest trial conducted to date in this setting, did provide some good news.
A planned subgroup analysis showed that patients with an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, which represented 87% of the total population, derived a survival advantage with pemetrexed plus cisplatin, said Dr. Urba of the cancer center at the University of Michigan in Ann Arbor.
In this subpopulation, median overall survival significantly increased from 6.7 months with cisplatin alone to 8.4 months with combination therapy (P = .026). Response rate also improved from 9% to 14%, respectively (P = .033).
Patients with oropharyngeal cancers, who accounted for 24% of the study population, also experienced an overall survival advantage with pemetrexed plus cisplatin, compared with cisplatin alone (9.9 months vs. 6.1 months; P = .002), she said.
A further analysis among good-performance-status patients suggested that those with prior platinum therapy may also benefit from combination therapy.
When asked during a discussion of the paper whether the combination therapy should be introduced into clinical practice, Dr. Urba responded, “If I was in my clinic at home and had a good-performance-status patient, would I consider using this regimen? Yes, I would.
“I think we certainly see that it was well tolerated for a group of patients who can tolerate double combination chemotherapy. And I also think that in this group of patients with head and neck cancer ... even response rate and shrinking tumors for some period of time [are] very important because it can really impact quality of life.”
In all, 41% of pemetrexed/cisplatin patients and 22% of controls experienced at least one serious potentially drug-related grade 3 or 4 adverse event, with bone marrow toxicity, febrile neutropenia, and fatigue significantly more common in the experimental arm. There were 13 deaths that were possibly related to study drugs in the combination arm and 1 in the control arm. Upon review, 3 of the 13 deaths were considered not related to pemetrexed/cisplatin, Dr. Urba said.
Invited discussant Dr. Marshall Posner said the duet of pemetrexed and cisplatin is active, and the activity is consistent with other duets in this particular class of drugs.
He suggested that the target population will probably be good performance status patients, at least for now, as well as oropharynx cases and perhaps patients with prior cisplatin exposure.
“This may be most effective in the setting of postprimary platinum therapy, and may provide a different spectrum of toxicities for those patients who would be intolerant of 5-fluorouracil or taxane-induced toxicity,” said Dr. Posner, medical director of the head and neck oncology program and cancer clinical trials office at Mount Sinai Medical Center in New York City.
Investigators at 113 sites in 20 countries randomized 398 patients to pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2, both every 21 days for up to six cycles, and 397 patients to the same cisplatin regimen plus placebo. Their median age was 57 years. About 90% of patients had been previously treated for their head and neck cancer, half had received prior platinum-based therapy, and 60% had distant metastases. No prior treatment for metastatic disease was allowed.
Eli Lilly supported the study. Dr. Urba and seven coauthors reported no conflicts of interest. Two coauthors were Lilly employees with stock ownership. Dr. Posner disclosed consulting with several pharmaceutical companies, but not with Lilly.
MILAN – The combination of pemetrexed and cisplatin failed to extend overall survival of recurrent or metastatic squamous cell carcinoma of the head and neck significantly in a pivotal phase III trial.
The primary end point of median overall survival was 7.3 months with pemetrexed injection (Alimta) plus cisplatin, and 6.3 months with cisplatin plus placebo. The 1-month difference was not statistically significant (hazard ratio, 0.87; P = .082), Dr. Susan G. Urba said at the annual congress of the European Society for Medical Oncology.
Median progression-free survival also was similar at 3.6 months in the experimental arm vs. 2.8 months in the control arm (HR, 0.88; P = .166), as was response rate (12% vs. 8%; P = .061).
The data were disappointing enough for pemetrexed maker Eli Lilly & Co. to subsequently announce it is forgoing plans to submit marketing authorization applications for pemetrexed in squamous cell carcinoma of the head and neck with the Food and Drug Administration and the European Medicines Agency.
Pemetrexed has shown single-agent activity in head and neck cancer. It is FDA approved for several indications in nonsquamous non–small cell lung cancer and malignant pleural mesothelioma.
The 795-patient trial, described as the largest trial conducted to date in this setting, did provide some good news.
A planned subgroup analysis showed that patients with an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, which represented 87% of the total population, derived a survival advantage with pemetrexed plus cisplatin, said Dr. Urba of the cancer center at the University of Michigan in Ann Arbor.
In this subpopulation, median overall survival significantly increased from 6.7 months with cisplatin alone to 8.4 months with combination therapy (P = .026). Response rate also improved from 9% to 14%, respectively (P = .033).
Patients with oropharyngeal cancers, who accounted for 24% of the study population, also experienced an overall survival advantage with pemetrexed plus cisplatin, compared with cisplatin alone (9.9 months vs. 6.1 months; P = .002), she said.
A further analysis among good-performance-status patients suggested that those with prior platinum therapy may also benefit from combination therapy.
When asked during a discussion of the paper whether the combination therapy should be introduced into clinical practice, Dr. Urba responded, “If I was in my clinic at home and had a good-performance-status patient, would I consider using this regimen? Yes, I would.
“I think we certainly see that it was well tolerated for a group of patients who can tolerate double combination chemotherapy. And I also think that in this group of patients with head and neck cancer ... even response rate and shrinking tumors for some period of time [are] very important because it can really impact quality of life.”
In all, 41% of pemetrexed/cisplatin patients and 22% of controls experienced at least one serious potentially drug-related grade 3 or 4 adverse event, with bone marrow toxicity, febrile neutropenia, and fatigue significantly more common in the experimental arm. There were 13 deaths that were possibly related to study drugs in the combination arm and 1 in the control arm. Upon review, 3 of the 13 deaths were considered not related to pemetrexed/cisplatin, Dr. Urba said.
Invited discussant Dr. Marshall Posner said the duet of pemetrexed and cisplatin is active, and the activity is consistent with other duets in this particular class of drugs.
He suggested that the target population will probably be good performance status patients, at least for now, as well as oropharynx cases and perhaps patients with prior cisplatin exposure.
“This may be most effective in the setting of postprimary platinum therapy, and may provide a different spectrum of toxicities for those patients who would be intolerant of 5-fluorouracil or taxane-induced toxicity,” said Dr. Posner, medical director of the head and neck oncology program and cancer clinical trials office at Mount Sinai Medical Center in New York City.
Investigators at 113 sites in 20 countries randomized 398 patients to pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2, both every 21 days for up to six cycles, and 397 patients to the same cisplatin regimen plus placebo. Their median age was 57 years. About 90% of patients had been previously treated for their head and neck cancer, half had received prior platinum-based therapy, and 60% had distant metastases. No prior treatment for metastatic disease was allowed.
Eli Lilly supported the study. Dr. Urba and seven coauthors reported no conflicts of interest. Two coauthors were Lilly employees with stock ownership. Dr. Posner disclosed consulting with several pharmaceutical companies, but not with Lilly.
MILAN – The combination of pemetrexed and cisplatin failed to extend overall survival of recurrent or metastatic squamous cell carcinoma of the head and neck significantly in a pivotal phase III trial.
The primary end point of median overall survival was 7.3 months with pemetrexed injection (Alimta) plus cisplatin, and 6.3 months with cisplatin plus placebo. The 1-month difference was not statistically significant (hazard ratio, 0.87; P = .082), Dr. Susan G. Urba said at the annual congress of the European Society for Medical Oncology.
Median progression-free survival also was similar at 3.6 months in the experimental arm vs. 2.8 months in the control arm (HR, 0.88; P = .166), as was response rate (12% vs. 8%; P = .061).
The data were disappointing enough for pemetrexed maker Eli Lilly & Co. to subsequently announce it is forgoing plans to submit marketing authorization applications for pemetrexed in squamous cell carcinoma of the head and neck with the Food and Drug Administration and the European Medicines Agency.
Pemetrexed has shown single-agent activity in head and neck cancer. It is FDA approved for several indications in nonsquamous non–small cell lung cancer and malignant pleural mesothelioma.
The 795-patient trial, described as the largest trial conducted to date in this setting, did provide some good news.
A planned subgroup analysis showed that patients with an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, which represented 87% of the total population, derived a survival advantage with pemetrexed plus cisplatin, said Dr. Urba of the cancer center at the University of Michigan in Ann Arbor.
In this subpopulation, median overall survival significantly increased from 6.7 months with cisplatin alone to 8.4 months with combination therapy (P = .026). Response rate also improved from 9% to 14%, respectively (P = .033).
Patients with oropharyngeal cancers, who accounted for 24% of the study population, also experienced an overall survival advantage with pemetrexed plus cisplatin, compared with cisplatin alone (9.9 months vs. 6.1 months; P = .002), she said.
A further analysis among good-performance-status patients suggested that those with prior platinum therapy may also benefit from combination therapy.
When asked during a discussion of the paper whether the combination therapy should be introduced into clinical practice, Dr. Urba responded, “If I was in my clinic at home and had a good-performance-status patient, would I consider using this regimen? Yes, I would.
“I think we certainly see that it was well tolerated for a group of patients who can tolerate double combination chemotherapy. And I also think that in this group of patients with head and neck cancer ... even response rate and shrinking tumors for some period of time [are] very important because it can really impact quality of life.”
In all, 41% of pemetrexed/cisplatin patients and 22% of controls experienced at least one serious potentially drug-related grade 3 or 4 adverse event, with bone marrow toxicity, febrile neutropenia, and fatigue significantly more common in the experimental arm. There were 13 deaths that were possibly related to study drugs in the combination arm and 1 in the control arm. Upon review, 3 of the 13 deaths were considered not related to pemetrexed/cisplatin, Dr. Urba said.
Invited discussant Dr. Marshall Posner said the duet of pemetrexed and cisplatin is active, and the activity is consistent with other duets in this particular class of drugs.
He suggested that the target population will probably be good performance status patients, at least for now, as well as oropharynx cases and perhaps patients with prior cisplatin exposure.
“This may be most effective in the setting of postprimary platinum therapy, and may provide a different spectrum of toxicities for those patients who would be intolerant of 5-fluorouracil or taxane-induced toxicity,” said Dr. Posner, medical director of the head and neck oncology program and cancer clinical trials office at Mount Sinai Medical Center in New York City.
Investigators at 113 sites in 20 countries randomized 398 patients to pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2, both every 21 days for up to six cycles, and 397 patients to the same cisplatin regimen plus placebo. Their median age was 57 years. About 90% of patients had been previously treated for their head and neck cancer, half had received prior platinum-based therapy, and 60% had distant metastases. No prior treatment for metastatic disease was allowed.
Eli Lilly supported the study. Dr. Urba and seven coauthors reported no conflicts of interest. Two coauthors were Lilly employees with stock ownership. Dr. Posner disclosed consulting with several pharmaceutical companies, but not with Lilly.
Major Finding: The primary end point of median overall survival was improved but not significantly at 7.3 months with pemetrexed injection plus cisplatin and 6.3 months with cisplatin plus and placebo (P = .082; HR, 0.87).
Data Source: International, randomized, double-blind, phase III trial in 795 patients with metastatic or recurrent squamous cell carcinoma of the head and neck.
Disclosures: Eli Lilly supported the study. Dr. Urba and seven coauthors reported no conflicts of interest. Two coauthors were Lilly employees with stock ownership. Dr. Posner disclosed consulting with several pharmaceutical companies, but not with Lilly.
Overall Survival Advantage Eludes Afatinib in NSCLC
MILAN – The investigational oral agent afatinib tripled median progression-free survival, but failed to extend overall survival in the third- and fourth-line setting of non–small cell lung cancer in the LUX-Lung 1 trial.
The primary outcome of median overall survival was 10.78 months for afatinib plus best supportive care and 11.96 months for best supportive care plus placebo (hazard ratio, 1.07; log-rank P = .74), Dr. Vincent Miller reported from a late-breaking abstract during the presidential symposium at the annual congress of the European Society for Medical Oncology.
Median progression-free survival by independent review increased from 1.1 months in the placebo arm to 3.3 months in the afatinib arm (HR, 0.38; log rank P less than .0001). A robust and consistent benefit was seen across all subgroups, he said. The disease control rate also tripled with afatinib.
LUX-Lung 1 compared afatinib 50 mg once daily plus best supportive care vs. best supportive care plus placebo in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib (Tarceva) or gefitinib (Iressa).
Afatinib, also known as BIBW 2992, is an irreversible TKI that is highly specific for EGFR and HER2, and has shown preclinical activity against EGFR-mutant tumors that also possess the T790M mutation.
Although the presence of EGFR-activating mutation in non–small cell lung cancer (NSCLC) confers sensitivity to EGFR TKIs, patients who are sensitive to gefitinib or erlotinib eventually progress, Dr. Miller explained. The T790NM mutation is the most common cause of resistance, detected in about half of such patients.
Despite the lack of overall survival benefit, he remained optimistic about the potential value of afatinib, noting that it induced objective regressions in a population with no or limited treatment options.
After at least 8 weeks of therapy, the disease control rate by independent review was significantly higher at 58% in the afatinib arm vs. 19% in the placebo arm (P less than .0001), said Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York City.
Just 0.5% of controls had an unconfirmed or confirmed partial response, compared with 13% and 7%, respectively, of afatinib patients (P less than .01 for both). Dr. Miller reported stable disease after at least 8 weeks of therapy in 51% of patients on afatinib vs. 18% on placebo. The median duration of confirmed response was 24 weeks.
“These results, I believe, are both clinically and statistically significant,” he said.
Patients receiving afatinib also reported significant improvements in prespecified lung cancer–related symptoms including cough, dyspnea, and pain.
The safety profile of afatinib was as expected, with diarrhea (17% with grade 3) and rash (14% with grade 3) predominating, Dr. Miller said. In all, 8% of patients discontinued afatinib because of a treatment-related adverse event, compared with 1% on placebo.
Serious treatment-related adverse events were reported in 10% of afatinib patients and 1% of placebo patients. Two deaths were considered attributable to afatinib: one cardiac syndrome with heart failure and one hepatic and renal failure, he said.
The median survival of nearly 1 year was unexpected and could be explained in part by subsequent therapy that was received by patients, as well as by inherently favorable biology in patients who have EGFR mutations, Dr. Miller said. In all, 68% of afatinib and 79% of placebo patients did so, with pemetrexed chemotherapy being the treatment of choice at 36% and 47%, respectively.
Dr. Miller said that the results of EGFR mutation profiling, including the presence or absence of T790M mutation, were not complete and would be reported at a later date.
Even without the EGFR data, invited discussant Dr. Jean-Charles Soria said the unprecedented survival time in both arms was probably related to the trial population’s being highly selected. Most notably, 100% had adenocarcinoma, 60% were East Asian (an ethnicity known to have higher EGFR mutation rates), 60% were never- or light smokers, and 25% had a performance status of 0, even in the third- and fourth-line setting.
“That’s not what we have in our clinical daily practice in Western cultures,” he said. “This is a population that was very sensitive to previous EGFR mutation.”
Overall survival also may have been confounded by the heavy use of subsequent treatments. “At the end of the day, they are comparing afatinib vs. further chemotherapy with pemetrexed,” said Dr. Soria, a professor of medicine and medical oncology at the Institut de Canc?rologie Gustave Roussy in Villejuif, France.
Dr. Miller has received honoraria for consulting and other support from Boehringer-Ingelheim, the study sponsor, as well as from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships including employment with Boehringer-Ingelheim. Prof. Soria receives consultancy fees from several companies including Boehringer-Ingelheim.
MILAN – The investigational oral agent afatinib tripled median progression-free survival, but failed to extend overall survival in the third- and fourth-line setting of non–small cell lung cancer in the LUX-Lung 1 trial.
The primary outcome of median overall survival was 10.78 months for afatinib plus best supportive care and 11.96 months for best supportive care plus placebo (hazard ratio, 1.07; log-rank P = .74), Dr. Vincent Miller reported from a late-breaking abstract during the presidential symposium at the annual congress of the European Society for Medical Oncology.
Median progression-free survival by independent review increased from 1.1 months in the placebo arm to 3.3 months in the afatinib arm (HR, 0.38; log rank P less than .0001). A robust and consistent benefit was seen across all subgroups, he said. The disease control rate also tripled with afatinib.
LUX-Lung 1 compared afatinib 50 mg once daily plus best supportive care vs. best supportive care plus placebo in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib (Tarceva) or gefitinib (Iressa).
Afatinib, also known as BIBW 2992, is an irreversible TKI that is highly specific for EGFR and HER2, and has shown preclinical activity against EGFR-mutant tumors that also possess the T790M mutation.
Although the presence of EGFR-activating mutation in non–small cell lung cancer (NSCLC) confers sensitivity to EGFR TKIs, patients who are sensitive to gefitinib or erlotinib eventually progress, Dr. Miller explained. The T790NM mutation is the most common cause of resistance, detected in about half of such patients.
Despite the lack of overall survival benefit, he remained optimistic about the potential value of afatinib, noting that it induced objective regressions in a population with no or limited treatment options.
After at least 8 weeks of therapy, the disease control rate by independent review was significantly higher at 58% in the afatinib arm vs. 19% in the placebo arm (P less than .0001), said Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York City.
Just 0.5% of controls had an unconfirmed or confirmed partial response, compared with 13% and 7%, respectively, of afatinib patients (P less than .01 for both). Dr. Miller reported stable disease after at least 8 weeks of therapy in 51% of patients on afatinib vs. 18% on placebo. The median duration of confirmed response was 24 weeks.
“These results, I believe, are both clinically and statistically significant,” he said.
Patients receiving afatinib also reported significant improvements in prespecified lung cancer–related symptoms including cough, dyspnea, and pain.
The safety profile of afatinib was as expected, with diarrhea (17% with grade 3) and rash (14% with grade 3) predominating, Dr. Miller said. In all, 8% of patients discontinued afatinib because of a treatment-related adverse event, compared with 1% on placebo.
Serious treatment-related adverse events were reported in 10% of afatinib patients and 1% of placebo patients. Two deaths were considered attributable to afatinib: one cardiac syndrome with heart failure and one hepatic and renal failure, he said.
The median survival of nearly 1 year was unexpected and could be explained in part by subsequent therapy that was received by patients, as well as by inherently favorable biology in patients who have EGFR mutations, Dr. Miller said. In all, 68% of afatinib and 79% of placebo patients did so, with pemetrexed chemotherapy being the treatment of choice at 36% and 47%, respectively.
Dr. Miller said that the results of EGFR mutation profiling, including the presence or absence of T790M mutation, were not complete and would be reported at a later date.
Even without the EGFR data, invited discussant Dr. Jean-Charles Soria said the unprecedented survival time in both arms was probably related to the trial population’s being highly selected. Most notably, 100% had adenocarcinoma, 60% were East Asian (an ethnicity known to have higher EGFR mutation rates), 60% were never- or light smokers, and 25% had a performance status of 0, even in the third- and fourth-line setting.
“That’s not what we have in our clinical daily practice in Western cultures,” he said. “This is a population that was very sensitive to previous EGFR mutation.”
Overall survival also may have been confounded by the heavy use of subsequent treatments. “At the end of the day, they are comparing afatinib vs. further chemotherapy with pemetrexed,” said Dr. Soria, a professor of medicine and medical oncology at the Institut de Canc?rologie Gustave Roussy in Villejuif, France.
Dr. Miller has received honoraria for consulting and other support from Boehringer-Ingelheim, the study sponsor, as well as from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships including employment with Boehringer-Ingelheim. Prof. Soria receives consultancy fees from several companies including Boehringer-Ingelheim.
MILAN – The investigational oral agent afatinib tripled median progression-free survival, but failed to extend overall survival in the third- and fourth-line setting of non–small cell lung cancer in the LUX-Lung 1 trial.
The primary outcome of median overall survival was 10.78 months for afatinib plus best supportive care and 11.96 months for best supportive care plus placebo (hazard ratio, 1.07; log-rank P = .74), Dr. Vincent Miller reported from a late-breaking abstract during the presidential symposium at the annual congress of the European Society for Medical Oncology.
Median progression-free survival by independent review increased from 1.1 months in the placebo arm to 3.3 months in the afatinib arm (HR, 0.38; log rank P less than .0001). A robust and consistent benefit was seen across all subgroups, he said. The disease control rate also tripled with afatinib.
LUX-Lung 1 compared afatinib 50 mg once daily plus best supportive care vs. best supportive care plus placebo in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib (Tarceva) or gefitinib (Iressa).
Afatinib, also known as BIBW 2992, is an irreversible TKI that is highly specific for EGFR and HER2, and has shown preclinical activity against EGFR-mutant tumors that also possess the T790M mutation.
Although the presence of EGFR-activating mutation in non–small cell lung cancer (NSCLC) confers sensitivity to EGFR TKIs, patients who are sensitive to gefitinib or erlotinib eventually progress, Dr. Miller explained. The T790NM mutation is the most common cause of resistance, detected in about half of such patients.
Despite the lack of overall survival benefit, he remained optimistic about the potential value of afatinib, noting that it induced objective regressions in a population with no or limited treatment options.
After at least 8 weeks of therapy, the disease control rate by independent review was significantly higher at 58% in the afatinib arm vs. 19% in the placebo arm (P less than .0001), said Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York City.
Just 0.5% of controls had an unconfirmed or confirmed partial response, compared with 13% and 7%, respectively, of afatinib patients (P less than .01 for both). Dr. Miller reported stable disease after at least 8 weeks of therapy in 51% of patients on afatinib vs. 18% on placebo. The median duration of confirmed response was 24 weeks.
“These results, I believe, are both clinically and statistically significant,” he said.
Patients receiving afatinib also reported significant improvements in prespecified lung cancer–related symptoms including cough, dyspnea, and pain.
The safety profile of afatinib was as expected, with diarrhea (17% with grade 3) and rash (14% with grade 3) predominating, Dr. Miller said. In all, 8% of patients discontinued afatinib because of a treatment-related adverse event, compared with 1% on placebo.
Serious treatment-related adverse events were reported in 10% of afatinib patients and 1% of placebo patients. Two deaths were considered attributable to afatinib: one cardiac syndrome with heart failure and one hepatic and renal failure, he said.
The median survival of nearly 1 year was unexpected and could be explained in part by subsequent therapy that was received by patients, as well as by inherently favorable biology in patients who have EGFR mutations, Dr. Miller said. In all, 68% of afatinib and 79% of placebo patients did so, with pemetrexed chemotherapy being the treatment of choice at 36% and 47%, respectively.
Dr. Miller said that the results of EGFR mutation profiling, including the presence or absence of T790M mutation, were not complete and would be reported at a later date.
Even without the EGFR data, invited discussant Dr. Jean-Charles Soria said the unprecedented survival time in both arms was probably related to the trial population’s being highly selected. Most notably, 100% had adenocarcinoma, 60% were East Asian (an ethnicity known to have higher EGFR mutation rates), 60% were never- or light smokers, and 25% had a performance status of 0, even in the third- and fourth-line setting.
“That’s not what we have in our clinical daily practice in Western cultures,” he said. “This is a population that was very sensitive to previous EGFR mutation.”
Overall survival also may have been confounded by the heavy use of subsequent treatments. “At the end of the day, they are comparing afatinib vs. further chemotherapy with pemetrexed,” said Dr. Soria, a professor of medicine and medical oncology at the Institut de Canc?rologie Gustave Roussy in Villejuif, France.
Dr. Miller has received honoraria for consulting and other support from Boehringer-Ingelheim, the study sponsor, as well as from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships including employment with Boehringer-Ingelheim. Prof. Soria receives consultancy fees from several companies including Boehringer-Ingelheim.
Major Finding: Median overall survival was 10.78 months with afatinib plus best supportive care vs. 11.96 months for best supportive care plus placebo.
Data Source: Randomized, phase IIB/III LUX-Lung 1 trial in 585 patients with non–small cell lung cancer after treatment failure with one to two lines of chemotherapy and erlotinib or gefitinib.
Disclosures: Dr. Miller has received honoraria for consulting and other support from Boehringer-Ingelheim, the study sponsor, as well as from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships including employment with Boehringer-Ingelheim. Prof. Soria receives consultancy fees from several companies including Boehringer-Ingelheim.
Targeting Met Delays Progression in Advanced NSCLC
MILAN – Adding the targeted investigational agent MetMAb to erlotinib improved survival in a select group of patients who were being treated for advanced non–small cell lung cancer in a phase II trial.
The risk of disease progression and death was nearly halved when patients with high expression of the Met receptor targeted by MetMAb received the novel agent plus erlotinib (Tarceva). High Met expression was associated with a worse outcome in patients who were treated with erlotinib alone.
“These results support further testing of MetMAb in lung cancer, and highlight the importance of diagnostic development,” said lead author Dr. David Spigel, director of lung cancer research at the Sarah Cannon Research Institute in Nashville, Tenn.
MetMAb is a selective monovalent monoclonal antibody that blocks hepatocyte growth factor (HGF) from activating the Met signaling pathway. Met is amplified, mutated, and overexpressed in many tumors. Its expression is associated with worse prognosis in many cancers, including non–small cell lung cancer (NSCLC), Dr. Spigel explained. Met activation is also implicated in resistance to tyrosine kinase inhibitors such as erlotinib and gefitinib (Iressa) in patients with activating epidermal growth factor receptor (EGFR) mutations.
There is a strong rationale for combining MetMAb with erlotinib, Dr. Spigel said. Met activation by HGF decreases the sensitivity to erlotinib. “When you add MetMAb, that sensitivity to erlotinib is restored,” he said.
The phase II, double-blind trial evenly randomized 128 patients who required second- or third-line therapy for NSCLC of all histologies to MetMAb 15 mg/kg intravenously every 3 weeks plus daily oral erlotinib 150 mg or daily erlotinib plus IV placebo. In all, 23 patients in the placebo group crossed over at progression to MetMAb.
Adequate tissue for Met evaluation by immunohistochemistry was available from 121 patients. Of these, 51% in the control arm and 56.5% in the experimental arm were “Met high,” defined as at least 50% tumor cells with a staining intensity of 2+ or 3+ on a 0-3 scale, Dr. Spigel said. “Met low” was defined as no expression or 1+ expression. Of 112 evaluable patients, a KRAS mutation was present in 23% of patients in both arms, and an EGFR mutation in 11% of the control arm and in 12.5% of the experimental arm.
In the overall intent-to-treat population, the primary end point of median progression-free survival reached 11.1 weeks for erlotinib and placebo and 9.6 weeks for MetMAb and erlotinib (hazard ratio, 1.09; log-rank P = .69,), suggesting no advantage with MetMAb, Dr. Spigel said. This also was true for median overall survival at 8.2 months and 7.1 months, respectively (HR, 1.09; log-rank P = .76).
When the researchers looked only at the Met-high group, however, median progression-free survival increased from 6.4 weeks with erlotinib and placebo to 12.4 weeks with combination therapy (HR, 0.56; log-rank P = .054). What is also impressive, he added, is that this translated into an overall survival hazard ratio of 0.55 (7.4 months vs. 7.7 months; log rank P = .11).
The Met-low group, however, did worse with the combination of MetMAb and erlotinib, even though patients with low Met expression in general do better, Dr. Spigel said. Progression-free survival was 6.0 weeks with MetMAb vs. 11.4 weeks with placebo (HR, 2.01; log-rank P = .03) and overall survival 5.5 months vs. 9.2 months (HR, 3.02; log-rank P = .02).
The reason for this negative outcome is unclear, but the obvious speculation is that MetMAb must be interfering with erlotinib’s effectiveness, Dr. Spigel said during a discussion of the paper. “We know that there is a lot of crosstalk between these pathways, the EGFR and Met pathway[s], but I think at this point, it’s just speculation,” he said.
The worse outcome in Met-low patients who were treated with MetMAb and erlotinib could not be explained by adverse safety events. With the exception of peripheral edema, the overall toxicity for MetMAb appeared to be similar to that of erlotinib and placebo, Dr. Spigel said. The incidence of grade 3 and 4 rash, diarrhea, and fatigue were higher in the Met-high subgroup group who was treated with MetMAb, whereas the incidence of pneumonia was higher in the Met-low group receiving MetMAb. No grade 5 events occurred.
In additional analyses, the selective benefit of MetMAb and erlotinib was not observed in other subgroups including nonsquamous histology and EGFR or KRAS mutations.
Dr. Luis Paz-Ares, who was invited to discuss the paper, said that it was strange to see the negative response in patients with low Met expression, but that this has been seen in other trials with targeted agents.
He said that the results warrant further exploration, that future phase II and III trials should be conducted in selected populations, and that they should validate the Met scoring used in the current trial.
Finally, “c-Met inhibition is a potentially valuable intervention in lung cancer treatment,” said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocio in Seville, Spain. He reminded the audience to collect tissue samples of their patients, pointing out that the current trial would have been negative without them.
“Tissue is the issue,” he said.
Dr. Spigel is a nonpaid consultant to Genentech Inc., the study sponsor. Three of his coinvestigators are Genentech employees. Dr. Paz-Ares is an adviser to Astra-Zeneca.
MILAN – Adding the targeted investigational agent MetMAb to erlotinib improved survival in a select group of patients who were being treated for advanced non–small cell lung cancer in a phase II trial.
The risk of disease progression and death was nearly halved when patients with high expression of the Met receptor targeted by MetMAb received the novel agent plus erlotinib (Tarceva). High Met expression was associated with a worse outcome in patients who were treated with erlotinib alone.
“These results support further testing of MetMAb in lung cancer, and highlight the importance of diagnostic development,” said lead author Dr. David Spigel, director of lung cancer research at the Sarah Cannon Research Institute in Nashville, Tenn.
MetMAb is a selective monovalent monoclonal antibody that blocks hepatocyte growth factor (HGF) from activating the Met signaling pathway. Met is amplified, mutated, and overexpressed in many tumors. Its expression is associated with worse prognosis in many cancers, including non–small cell lung cancer (NSCLC), Dr. Spigel explained. Met activation is also implicated in resistance to tyrosine kinase inhibitors such as erlotinib and gefitinib (Iressa) in patients with activating epidermal growth factor receptor (EGFR) mutations.
There is a strong rationale for combining MetMAb with erlotinib, Dr. Spigel said. Met activation by HGF decreases the sensitivity to erlotinib. “When you add MetMAb, that sensitivity to erlotinib is restored,” he said.
The phase II, double-blind trial evenly randomized 128 patients who required second- or third-line therapy for NSCLC of all histologies to MetMAb 15 mg/kg intravenously every 3 weeks plus daily oral erlotinib 150 mg or daily erlotinib plus IV placebo. In all, 23 patients in the placebo group crossed over at progression to MetMAb.
Adequate tissue for Met evaluation by immunohistochemistry was available from 121 patients. Of these, 51% in the control arm and 56.5% in the experimental arm were “Met high,” defined as at least 50% tumor cells with a staining intensity of 2+ or 3+ on a 0-3 scale, Dr. Spigel said. “Met low” was defined as no expression or 1+ expression. Of 112 evaluable patients, a KRAS mutation was present in 23% of patients in both arms, and an EGFR mutation in 11% of the control arm and in 12.5% of the experimental arm.
In the overall intent-to-treat population, the primary end point of median progression-free survival reached 11.1 weeks for erlotinib and placebo and 9.6 weeks for MetMAb and erlotinib (hazard ratio, 1.09; log-rank P = .69,), suggesting no advantage with MetMAb, Dr. Spigel said. This also was true for median overall survival at 8.2 months and 7.1 months, respectively (HR, 1.09; log-rank P = .76).
When the researchers looked only at the Met-high group, however, median progression-free survival increased from 6.4 weeks with erlotinib and placebo to 12.4 weeks with combination therapy (HR, 0.56; log-rank P = .054). What is also impressive, he added, is that this translated into an overall survival hazard ratio of 0.55 (7.4 months vs. 7.7 months; log rank P = .11).
The Met-low group, however, did worse with the combination of MetMAb and erlotinib, even though patients with low Met expression in general do better, Dr. Spigel said. Progression-free survival was 6.0 weeks with MetMAb vs. 11.4 weeks with placebo (HR, 2.01; log-rank P = .03) and overall survival 5.5 months vs. 9.2 months (HR, 3.02; log-rank P = .02).
The reason for this negative outcome is unclear, but the obvious speculation is that MetMAb must be interfering with erlotinib’s effectiveness, Dr. Spigel said during a discussion of the paper. “We know that there is a lot of crosstalk between these pathways, the EGFR and Met pathway[s], but I think at this point, it’s just speculation,” he said.
The worse outcome in Met-low patients who were treated with MetMAb and erlotinib could not be explained by adverse safety events. With the exception of peripheral edema, the overall toxicity for MetMAb appeared to be similar to that of erlotinib and placebo, Dr. Spigel said. The incidence of grade 3 and 4 rash, diarrhea, and fatigue were higher in the Met-high subgroup group who was treated with MetMAb, whereas the incidence of pneumonia was higher in the Met-low group receiving MetMAb. No grade 5 events occurred.
In additional analyses, the selective benefit of MetMAb and erlotinib was not observed in other subgroups including nonsquamous histology and EGFR or KRAS mutations.
Dr. Luis Paz-Ares, who was invited to discuss the paper, said that it was strange to see the negative response in patients with low Met expression, but that this has been seen in other trials with targeted agents.
He said that the results warrant further exploration, that future phase II and III trials should be conducted in selected populations, and that they should validate the Met scoring used in the current trial.
Finally, “c-Met inhibition is a potentially valuable intervention in lung cancer treatment,” said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocio in Seville, Spain. He reminded the audience to collect tissue samples of their patients, pointing out that the current trial would have been negative without them.
“Tissue is the issue,” he said.
Dr. Spigel is a nonpaid consultant to Genentech Inc., the study sponsor. Three of his coinvestigators are Genentech employees. Dr. Paz-Ares is an adviser to Astra-Zeneca.
MILAN – Adding the targeted investigational agent MetMAb to erlotinib improved survival in a select group of patients who were being treated for advanced non–small cell lung cancer in a phase II trial.
The risk of disease progression and death was nearly halved when patients with high expression of the Met receptor targeted by MetMAb received the novel agent plus erlotinib (Tarceva). High Met expression was associated with a worse outcome in patients who were treated with erlotinib alone.
“These results support further testing of MetMAb in lung cancer, and highlight the importance of diagnostic development,” said lead author Dr. David Spigel, director of lung cancer research at the Sarah Cannon Research Institute in Nashville, Tenn.
MetMAb is a selective monovalent monoclonal antibody that blocks hepatocyte growth factor (HGF) from activating the Met signaling pathway. Met is amplified, mutated, and overexpressed in many tumors. Its expression is associated with worse prognosis in many cancers, including non–small cell lung cancer (NSCLC), Dr. Spigel explained. Met activation is also implicated in resistance to tyrosine kinase inhibitors such as erlotinib and gefitinib (Iressa) in patients with activating epidermal growth factor receptor (EGFR) mutations.
There is a strong rationale for combining MetMAb with erlotinib, Dr. Spigel said. Met activation by HGF decreases the sensitivity to erlotinib. “When you add MetMAb, that sensitivity to erlotinib is restored,” he said.
The phase II, double-blind trial evenly randomized 128 patients who required second- or third-line therapy for NSCLC of all histologies to MetMAb 15 mg/kg intravenously every 3 weeks plus daily oral erlotinib 150 mg or daily erlotinib plus IV placebo. In all, 23 patients in the placebo group crossed over at progression to MetMAb.
Adequate tissue for Met evaluation by immunohistochemistry was available from 121 patients. Of these, 51% in the control arm and 56.5% in the experimental arm were “Met high,” defined as at least 50% tumor cells with a staining intensity of 2+ or 3+ on a 0-3 scale, Dr. Spigel said. “Met low” was defined as no expression or 1+ expression. Of 112 evaluable patients, a KRAS mutation was present in 23% of patients in both arms, and an EGFR mutation in 11% of the control arm and in 12.5% of the experimental arm.
In the overall intent-to-treat population, the primary end point of median progression-free survival reached 11.1 weeks for erlotinib and placebo and 9.6 weeks for MetMAb and erlotinib (hazard ratio, 1.09; log-rank P = .69,), suggesting no advantage with MetMAb, Dr. Spigel said. This also was true for median overall survival at 8.2 months and 7.1 months, respectively (HR, 1.09; log-rank P = .76).
When the researchers looked only at the Met-high group, however, median progression-free survival increased from 6.4 weeks with erlotinib and placebo to 12.4 weeks with combination therapy (HR, 0.56; log-rank P = .054). What is also impressive, he added, is that this translated into an overall survival hazard ratio of 0.55 (7.4 months vs. 7.7 months; log rank P = .11).
The Met-low group, however, did worse with the combination of MetMAb and erlotinib, even though patients with low Met expression in general do better, Dr. Spigel said. Progression-free survival was 6.0 weeks with MetMAb vs. 11.4 weeks with placebo (HR, 2.01; log-rank P = .03) and overall survival 5.5 months vs. 9.2 months (HR, 3.02; log-rank P = .02).
The reason for this negative outcome is unclear, but the obvious speculation is that MetMAb must be interfering with erlotinib’s effectiveness, Dr. Spigel said during a discussion of the paper. “We know that there is a lot of crosstalk between these pathways, the EGFR and Met pathway[s], but I think at this point, it’s just speculation,” he said.
The worse outcome in Met-low patients who were treated with MetMAb and erlotinib could not be explained by adverse safety events. With the exception of peripheral edema, the overall toxicity for MetMAb appeared to be similar to that of erlotinib and placebo, Dr. Spigel said. The incidence of grade 3 and 4 rash, diarrhea, and fatigue were higher in the Met-high subgroup group who was treated with MetMAb, whereas the incidence of pneumonia was higher in the Met-low group receiving MetMAb. No grade 5 events occurred.
In additional analyses, the selective benefit of MetMAb and erlotinib was not observed in other subgroups including nonsquamous histology and EGFR or KRAS mutations.
Dr. Luis Paz-Ares, who was invited to discuss the paper, said that it was strange to see the negative response in patients with low Met expression, but that this has been seen in other trials with targeted agents.
He said that the results warrant further exploration, that future phase II and III trials should be conducted in selected populations, and that they should validate the Met scoring used in the current trial.
Finally, “c-Met inhibition is a potentially valuable intervention in lung cancer treatment,” said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocio in Seville, Spain. He reminded the audience to collect tissue samples of their patients, pointing out that the current trial would have been negative without them.
“Tissue is the issue,” he said.
Dr. Spigel is a nonpaid consultant to Genentech Inc., the study sponsor. Three of his coinvestigators are Genentech employees. Dr. Paz-Ares is an adviser to Astra-Zeneca.
Targeting Met Delays Progression in Advanced NSCLC
MILAN – Adding the targeted investigational agent MetMAb to erlotinib improved survival in a select group of patients who were being treated for advanced non–small cell lung cancer in a phase II trial.
The risk of disease progression and death was nearly halved when patients with high expression of the Met receptor targeted by MetMAb received the novel agent plus erlotinib (Tarceva). High Met expression was associated with a worse outcome in patients who were treated with erlotinib alone.
“These results support further testing of MetMAb in lung cancer, and highlight the importance of diagnostic development,” said lead author Dr. David Spigel, director of lung cancer research at the Sarah Cannon Research Institute in Nashville, Tenn.
MetMAb is a selective monovalent monoclonal antibody that blocks hepatocyte growth factor (HGF) from activating the Met signaling pathway. Met is amplified, mutated, and overexpressed in many tumors. Its expression is associated with worse prognosis in many cancers, including non–small cell lung cancer (NSCLC), Dr. Spigel explained. Met activation is also implicated in resistance to tyrosine kinase inhibitors such as erlotinib and gefitinib (Iressa) in patients with activating epidermal growth factor receptor (EGFR) mutations.
There is a strong rationale for combining MetMAb with erlotinib, Dr. Spigel said. Met activation by HGF decreases the sensitivity to erlotinib. “When you add MetMAb, that sensitivity to erlotinib is restored,” he said.
The phase II, double-blind trial evenly randomized 128 patients who required second- or third-line therapy for NSCLC of all histologies to MetMAb 15 mg/kg intravenously every 3 weeks plus daily oral erlotinib 150 mg or daily erlotinib plus IV placebo. In all, 23 patients in the placebo group crossed over at progression to MetMAb.
Adequate tissue for Met evaluation by immunohistochemistry was available from 121 patients. Of these, 51% in the control arm and 56.5% in the experimental arm were “Met high,” defined as at least 50% tumor cells with a staining intensity of 2+ or 3+ on a 0-3 scale, Dr. Spigel said. “Met low” was defined as no expression or 1+ expression. Of 112 evaluable patients, a KRAS mutation was present in 23% of patients in both arms, and an EGFR mutation in 11% of the control arm and in 12.5% of the experimental arm.
In the overall intent-to-treat population, the primary end point of median progression-free survival reached 11.1 weeks for erlotinib and placebo and 9.6 weeks for MetMAb and erlotinib (hazard ratio, 1.09; log-rank P = .69,), suggesting no advantage with MetMAb, Dr. Spigel said. This also was true for median overall survival at 8.2 months and 7.1 months, respectively (HR, 1.09; log-rank P = .76).
When the researchers looked only at the Met-high group, however, median progression-free survival increased from 6.4 weeks with erlotinib and placebo to 12.4 weeks with combination therapy (HR, 0.56; log-rank P = .054). What is also impressive, he added, is that this translated into an overall survival hazard ratio of 0.55 (7.4 months vs. 7.7 months; log rank P = .11).
The Met-low group, however, did worse with the combination of MetMAb and erlotinib, even though patients with low Met expression in general do better, Dr. Spigel said. Progression-free survival was 6.0 weeks with MetMAb vs. 11.4 weeks with placebo (HR, 2.01; log-rank P = .03) and overall survival 5.5 months vs. 9.2 months (HR, 3.02; log-rank P = .02).
The reason for this negative outcome is unclear, but the obvious speculation is that MetMAb must be interfering with erlotinib’s effectiveness, Dr. Spigel said during a discussion of the paper. “We know that there is a lot of crosstalk between these pathways, the EGFR and Met pathway[s], but I think at this point, it’s just speculation,” he said.
The worse outcome in Met-low patients who were treated with MetMAb and erlotinib could not be explained by adverse safety events. With the exception of peripheral edema, the overall toxicity for MetMAb appeared to be similar to that of erlotinib and placebo, Dr. Spigel said. The incidence of grade 3 and 4 rash, diarrhea, and fatigue were higher in the Met-high subgroup group who was treated with MetMAb, whereas the incidence of pneumonia was higher in the Met-low group receiving MetMAb. No grade 5 events occurred.
In additional analyses, the selective benefit of MetMAb and erlotinib was not observed in other subgroups including nonsquamous histology and EGFR or KRAS mutations.
Dr. Luis Paz-Ares, who was invited to discuss the paper, said that it was strange to see the negative response in patients with low Met expression, but that this has been seen in other trials with targeted agents.
He said that the results warrant further exploration, that future phase II and III trials should be conducted in selected populations, and that they should validate the Met scoring used in the current trial.
Finally, “c-Met inhibition is a potentially valuable intervention in lung cancer treatment,” said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocio in Seville, Spain. He reminded the audience to collect tissue samples of their patients, pointing out that the current trial would have been negative without them.
“Tissue is the issue,” he said.
Dr. Spigel is a nonpaid consultant to Genentech Inc., the study sponsor. Three of his coinvestigators are Genentech employees. Dr. Paz-Ares is an adviser to Astra-Zeneca.
MILAN – Adding the targeted investigational agent MetMAb to erlotinib improved survival in a select group of patients who were being treated for advanced non–small cell lung cancer in a phase II trial.
The risk of disease progression and death was nearly halved when patients with high expression of the Met receptor targeted by MetMAb received the novel agent plus erlotinib (Tarceva). High Met expression was associated with a worse outcome in patients who were treated with erlotinib alone.
“These results support further testing of MetMAb in lung cancer, and highlight the importance of diagnostic development,” said lead author Dr. David Spigel, director of lung cancer research at the Sarah Cannon Research Institute in Nashville, Tenn.
MetMAb is a selective monovalent monoclonal antibody that blocks hepatocyte growth factor (HGF) from activating the Met signaling pathway. Met is amplified, mutated, and overexpressed in many tumors. Its expression is associated with worse prognosis in many cancers, including non–small cell lung cancer (NSCLC), Dr. Spigel explained. Met activation is also implicated in resistance to tyrosine kinase inhibitors such as erlotinib and gefitinib (Iressa) in patients with activating epidermal growth factor receptor (EGFR) mutations.
There is a strong rationale for combining MetMAb with erlotinib, Dr. Spigel said. Met activation by HGF decreases the sensitivity to erlotinib. “When you add MetMAb, that sensitivity to erlotinib is restored,” he said.
The phase II, double-blind trial evenly randomized 128 patients who required second- or third-line therapy for NSCLC of all histologies to MetMAb 15 mg/kg intravenously every 3 weeks plus daily oral erlotinib 150 mg or daily erlotinib plus IV placebo. In all, 23 patients in the placebo group crossed over at progression to MetMAb.
Adequate tissue for Met evaluation by immunohistochemistry was available from 121 patients. Of these, 51% in the control arm and 56.5% in the experimental arm were “Met high,” defined as at least 50% tumor cells with a staining intensity of 2+ or 3+ on a 0-3 scale, Dr. Spigel said. “Met low” was defined as no expression or 1+ expression. Of 112 evaluable patients, a KRAS mutation was present in 23% of patients in both arms, and an EGFR mutation in 11% of the control arm and in 12.5% of the experimental arm.
In the overall intent-to-treat population, the primary end point of median progression-free survival reached 11.1 weeks for erlotinib and placebo and 9.6 weeks for MetMAb and erlotinib (hazard ratio, 1.09; log-rank P = .69,), suggesting no advantage with MetMAb, Dr. Spigel said. This also was true for median overall survival at 8.2 months and 7.1 months, respectively (HR, 1.09; log-rank P = .76).
When the researchers looked only at the Met-high group, however, median progression-free survival increased from 6.4 weeks with erlotinib and placebo to 12.4 weeks with combination therapy (HR, 0.56; log-rank P = .054). What is also impressive, he added, is that this translated into an overall survival hazard ratio of 0.55 (7.4 months vs. 7.7 months; log rank P = .11).
The Met-low group, however, did worse with the combination of MetMAb and erlotinib, even though patients with low Met expression in general do better, Dr. Spigel said. Progression-free survival was 6.0 weeks with MetMAb vs. 11.4 weeks with placebo (HR, 2.01; log-rank P = .03) and overall survival 5.5 months vs. 9.2 months (HR, 3.02; log-rank P = .02).
The reason for this negative outcome is unclear, but the obvious speculation is that MetMAb must be interfering with erlotinib’s effectiveness, Dr. Spigel said during a discussion of the paper. “We know that there is a lot of crosstalk between these pathways, the EGFR and Met pathway[s], but I think at this point, it’s just speculation,” he said.
The worse outcome in Met-low patients who were treated with MetMAb and erlotinib could not be explained by adverse safety events. With the exception of peripheral edema, the overall toxicity for MetMAb appeared to be similar to that of erlotinib and placebo, Dr. Spigel said. The incidence of grade 3 and 4 rash, diarrhea, and fatigue were higher in the Met-high subgroup group who was treated with MetMAb, whereas the incidence of pneumonia was higher in the Met-low group receiving MetMAb. No grade 5 events occurred.
In additional analyses, the selective benefit of MetMAb and erlotinib was not observed in other subgroups including nonsquamous histology and EGFR or KRAS mutations.
Dr. Luis Paz-Ares, who was invited to discuss the paper, said that it was strange to see the negative response in patients with low Met expression, but that this has been seen in other trials with targeted agents.
He said that the results warrant further exploration, that future phase II and III trials should be conducted in selected populations, and that they should validate the Met scoring used in the current trial.
Finally, “c-Met inhibition is a potentially valuable intervention in lung cancer treatment,” said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocio in Seville, Spain. He reminded the audience to collect tissue samples of their patients, pointing out that the current trial would have been negative without them.
“Tissue is the issue,” he said.
Dr. Spigel is a nonpaid consultant to Genentech Inc., the study sponsor. Three of his coinvestigators are Genentech employees. Dr. Paz-Ares is an adviser to Astra-Zeneca.
MILAN – Adding the targeted investigational agent MetMAb to erlotinib improved survival in a select group of patients who were being treated for advanced non–small cell lung cancer in a phase II trial.
The risk of disease progression and death was nearly halved when patients with high expression of the Met receptor targeted by MetMAb received the novel agent plus erlotinib (Tarceva). High Met expression was associated with a worse outcome in patients who were treated with erlotinib alone.
“These results support further testing of MetMAb in lung cancer, and highlight the importance of diagnostic development,” said lead author Dr. David Spigel, director of lung cancer research at the Sarah Cannon Research Institute in Nashville, Tenn.
MetMAb is a selective monovalent monoclonal antibody that blocks hepatocyte growth factor (HGF) from activating the Met signaling pathway. Met is amplified, mutated, and overexpressed in many tumors. Its expression is associated with worse prognosis in many cancers, including non–small cell lung cancer (NSCLC), Dr. Spigel explained. Met activation is also implicated in resistance to tyrosine kinase inhibitors such as erlotinib and gefitinib (Iressa) in patients with activating epidermal growth factor receptor (EGFR) mutations.
There is a strong rationale for combining MetMAb with erlotinib, Dr. Spigel said. Met activation by HGF decreases the sensitivity to erlotinib. “When you add MetMAb, that sensitivity to erlotinib is restored,” he said.
The phase II, double-blind trial evenly randomized 128 patients who required second- or third-line therapy for NSCLC of all histologies to MetMAb 15 mg/kg intravenously every 3 weeks plus daily oral erlotinib 150 mg or daily erlotinib plus IV placebo. In all, 23 patients in the placebo group crossed over at progression to MetMAb.
Adequate tissue for Met evaluation by immunohistochemistry was available from 121 patients. Of these, 51% in the control arm and 56.5% in the experimental arm were “Met high,” defined as at least 50% tumor cells with a staining intensity of 2+ or 3+ on a 0-3 scale, Dr. Spigel said. “Met low” was defined as no expression or 1+ expression. Of 112 evaluable patients, a KRAS mutation was present in 23% of patients in both arms, and an EGFR mutation in 11% of the control arm and in 12.5% of the experimental arm.
In the overall intent-to-treat population, the primary end point of median progression-free survival reached 11.1 weeks for erlotinib and placebo and 9.6 weeks for MetMAb and erlotinib (hazard ratio, 1.09; log-rank P = .69,), suggesting no advantage with MetMAb, Dr. Spigel said. This also was true for median overall survival at 8.2 months and 7.1 months, respectively (HR, 1.09; log-rank P = .76).
When the researchers looked only at the Met-high group, however, median progression-free survival increased from 6.4 weeks with erlotinib and placebo to 12.4 weeks with combination therapy (HR, 0.56; log-rank P = .054). What is also impressive, he added, is that this translated into an overall survival hazard ratio of 0.55 (7.4 months vs. 7.7 months; log rank P = .11).
The Met-low group, however, did worse with the combination of MetMAb and erlotinib, even though patients with low Met expression in general do better, Dr. Spigel said. Progression-free survival was 6.0 weeks with MetMAb vs. 11.4 weeks with placebo (HR, 2.01; log-rank P = .03) and overall survival 5.5 months vs. 9.2 months (HR, 3.02; log-rank P = .02).
The reason for this negative outcome is unclear, but the obvious speculation is that MetMAb must be interfering with erlotinib’s effectiveness, Dr. Spigel said during a discussion of the paper. “We know that there is a lot of crosstalk between these pathways, the EGFR and Met pathway[s], but I think at this point, it’s just speculation,” he said.
The worse outcome in Met-low patients who were treated with MetMAb and erlotinib could not be explained by adverse safety events. With the exception of peripheral edema, the overall toxicity for MetMAb appeared to be similar to that of erlotinib and placebo, Dr. Spigel said. The incidence of grade 3 and 4 rash, diarrhea, and fatigue were higher in the Met-high subgroup group who was treated with MetMAb, whereas the incidence of pneumonia was higher in the Met-low group receiving MetMAb. No grade 5 events occurred.
In additional analyses, the selective benefit of MetMAb and erlotinib was not observed in other subgroups including nonsquamous histology and EGFR or KRAS mutations.
Dr. Luis Paz-Ares, who was invited to discuss the paper, said that it was strange to see the negative response in patients with low Met expression, but that this has been seen in other trials with targeted agents.
He said that the results warrant further exploration, that future phase II and III trials should be conducted in selected populations, and that they should validate the Met scoring used in the current trial.
Finally, “c-Met inhibition is a potentially valuable intervention in lung cancer treatment,” said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocio in Seville, Spain. He reminded the audience to collect tissue samples of their patients, pointing out that the current trial would have been negative without them.
“Tissue is the issue,” he said.
Dr. Spigel is a nonpaid consultant to Genentech Inc., the study sponsor. Three of his coinvestigators are Genentech employees. Dr. Paz-Ares is an adviser to Astra-Zeneca.
Major Finding: Median progression-free survival increased from 6.4 weeks with erlotinib and placebo to 12.4 weeks with the combination of erlotinib and MetMAb in patients with high expression of c-Met (HR, 0.56; log-rank P = .054).
Data Source: Randomized, double-blind, phase II trial in 128 patients with advanced NSCLC.
Disclosures: Dr. Spigel is a nonpaid consultant to Genentech, the study sponsor. Three of his coinvestigators are Genentech employees. Dr. Paz-Ares is an advisor to AstraZeneca.