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Leukemia rates two to three times higher in children born near fracking
Children born near fracking and other “unconventional” drilling sites are at two to three times greater risk of developing childhood leukemia, according to new research.
The study, published in the journal Environmental Health Perspectives, compared proximity of homes to unconventional oil and gas development (UOGD) sites and risk of the most common form of childhood leukemia, acute lymphoblastic leukemia (ALL).
Researchers looked at 405 children aged 2-7 diagnosed with ALL in Pennsylvania from 2009 to 2017. These children were compared to a control group of 2,080 without the disease matched on the year of birth.
“Unconventional oil and gas development can both use and release chemicals that have been linked to cancer,” study coauthor Nicole Deziel, PhD, of the Yale School of Public Health, New Haven, Conn., said in a statement . She noted that the possibility that children living in close proximity to such sites are “exposed to these chemical carcinogens is a major public health concern.”
About 17 million Americans live within a half-mile of active oil and gas production, according to the Oil & Gas Threat Map, Common Dreams reports. That number includes 4 million children.
The Yale study also found that drinking water could be an important pathway of exposure to oil- and gas-related chemicals used in the UOGD methods of extraction.
Researchers used a new metric that measures exposure to contaminated drinking water and distance to a well. They were able to identify UOGD-affected wells that fell within watersheds where children and their families likely obtained their water.
“Previous health studies have found links between proximity to oil and gas drilling and various children’s health outcomes,” said Dr. Deziel. “This study is among the few to focus on drinking water specifically and the first to apply a novel metric designed to capture potential exposure through this pathway.”
A version of this article first appeared on WebMD.com.
Children born near fracking and other “unconventional” drilling sites are at two to three times greater risk of developing childhood leukemia, according to new research.
The study, published in the journal Environmental Health Perspectives, compared proximity of homes to unconventional oil and gas development (UOGD) sites and risk of the most common form of childhood leukemia, acute lymphoblastic leukemia (ALL).
Researchers looked at 405 children aged 2-7 diagnosed with ALL in Pennsylvania from 2009 to 2017. These children were compared to a control group of 2,080 without the disease matched on the year of birth.
“Unconventional oil and gas development can both use and release chemicals that have been linked to cancer,” study coauthor Nicole Deziel, PhD, of the Yale School of Public Health, New Haven, Conn., said in a statement . She noted that the possibility that children living in close proximity to such sites are “exposed to these chemical carcinogens is a major public health concern.”
About 17 million Americans live within a half-mile of active oil and gas production, according to the Oil & Gas Threat Map, Common Dreams reports. That number includes 4 million children.
The Yale study also found that drinking water could be an important pathway of exposure to oil- and gas-related chemicals used in the UOGD methods of extraction.
Researchers used a new metric that measures exposure to contaminated drinking water and distance to a well. They were able to identify UOGD-affected wells that fell within watersheds where children and their families likely obtained their water.
“Previous health studies have found links between proximity to oil and gas drilling and various children’s health outcomes,” said Dr. Deziel. “This study is among the few to focus on drinking water specifically and the first to apply a novel metric designed to capture potential exposure through this pathway.”
A version of this article first appeared on WebMD.com.
Children born near fracking and other “unconventional” drilling sites are at two to three times greater risk of developing childhood leukemia, according to new research.
The study, published in the journal Environmental Health Perspectives, compared proximity of homes to unconventional oil and gas development (UOGD) sites and risk of the most common form of childhood leukemia, acute lymphoblastic leukemia (ALL).
Researchers looked at 405 children aged 2-7 diagnosed with ALL in Pennsylvania from 2009 to 2017. These children were compared to a control group of 2,080 without the disease matched on the year of birth.
“Unconventional oil and gas development can both use and release chemicals that have been linked to cancer,” study coauthor Nicole Deziel, PhD, of the Yale School of Public Health, New Haven, Conn., said in a statement . She noted that the possibility that children living in close proximity to such sites are “exposed to these chemical carcinogens is a major public health concern.”
About 17 million Americans live within a half-mile of active oil and gas production, according to the Oil & Gas Threat Map, Common Dreams reports. That number includes 4 million children.
The Yale study also found that drinking water could be an important pathway of exposure to oil- and gas-related chemicals used in the UOGD methods of extraction.
Researchers used a new metric that measures exposure to contaminated drinking water and distance to a well. They were able to identify UOGD-affected wells that fell within watersheds where children and their families likely obtained their water.
“Previous health studies have found links between proximity to oil and gas drilling and various children’s health outcomes,” said Dr. Deziel. “This study is among the few to focus on drinking water specifically and the first to apply a novel metric designed to capture potential exposure through this pathway.”
A version of this article first appeared on WebMD.com.
Are artificial sweeteners really harmless?
New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.
Researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.
The study was published online in the journal Cell.
Gut reaction?
Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that these sweeteners affect the microbiome of mice in ways that could affect glycemic responses.
They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.
Each sweetener “significantly and distinctly” altered stool and oral microbiome, and two of them (saccharin and sucralose) significantly impaired glucose tolerance, the researchers reported.
“Importantly, by performing extensive fecal transplantation of human microbiomes into germ-free mice, we demonstrate a causal and individualized link between NNS-altered microbiomes and glucose intolerance developing in non–NNS-consuming recipient mice,” they said.
They noted that the effects of these sweeteners will likely vary from person to person because of the unique composition of an individual’s microbiome.
“We need to raise awareness of the fact that NNS are not inert to the human body as we originally believed. With that said, the clinical health implications of the changes they may elicit in humans remain unknown and merit future long-term studies,” Dr. Elinav said in a news release.
For now, Dr. Elinav said it’s his personal view that “drinking only water seems to be the best solution.”
Weighing the evidence
Several experts weighed in on the results in a statement from the U.K. nonprofit organization, Science Media Centre.
Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).
“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Dr. Mellor says.
Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, concurs, saying “this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals.”
The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.
“Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a ‘stepping stone’ allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet,” Dr. Mellor suggests.
Kevin McConway, PhD, with the Open University, Milton Keynes, England, said it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.
“But exactly what the health consequences of all this, if any, might be is a subject for future research,” Dr. McConway added.
Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth (England) agrees.
“We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small,” she says.
The International Sweeteners Association also weighs in, saying, “No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes.”
They add “a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota.”
Nevertheless, Dr. Redfern says the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer-term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”
The study had no specific funding. Dr. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Dr. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Dr. Barrett, Dr. McConway, and Dr. Redfern report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This article was updated 8/29/22.
New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.
Researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.
The study was published online in the journal Cell.
Gut reaction?
Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that these sweeteners affect the microbiome of mice in ways that could affect glycemic responses.
They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.
Each sweetener “significantly and distinctly” altered stool and oral microbiome, and two of them (saccharin and sucralose) significantly impaired glucose tolerance, the researchers reported.
“Importantly, by performing extensive fecal transplantation of human microbiomes into germ-free mice, we demonstrate a causal and individualized link between NNS-altered microbiomes and glucose intolerance developing in non–NNS-consuming recipient mice,” they said.
They noted that the effects of these sweeteners will likely vary from person to person because of the unique composition of an individual’s microbiome.
“We need to raise awareness of the fact that NNS are not inert to the human body as we originally believed. With that said, the clinical health implications of the changes they may elicit in humans remain unknown and merit future long-term studies,” Dr. Elinav said in a news release.
For now, Dr. Elinav said it’s his personal view that “drinking only water seems to be the best solution.”
Weighing the evidence
Several experts weighed in on the results in a statement from the U.K. nonprofit organization, Science Media Centre.
Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).
“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Dr. Mellor says.
Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, concurs, saying “this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals.”
The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.
“Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a ‘stepping stone’ allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet,” Dr. Mellor suggests.
Kevin McConway, PhD, with the Open University, Milton Keynes, England, said it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.
“But exactly what the health consequences of all this, if any, might be is a subject for future research,” Dr. McConway added.
Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth (England) agrees.
“We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small,” she says.
The International Sweeteners Association also weighs in, saying, “No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes.”
They add “a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota.”
Nevertheless, Dr. Redfern says the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer-term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”
The study had no specific funding. Dr. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Dr. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Dr. Barrett, Dr. McConway, and Dr. Redfern report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This article was updated 8/29/22.
New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.
Researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.
The study was published online in the journal Cell.
Gut reaction?
Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that these sweeteners affect the microbiome of mice in ways that could affect glycemic responses.
They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.
Each sweetener “significantly and distinctly” altered stool and oral microbiome, and two of them (saccharin and sucralose) significantly impaired glucose tolerance, the researchers reported.
“Importantly, by performing extensive fecal transplantation of human microbiomes into germ-free mice, we demonstrate a causal and individualized link between NNS-altered microbiomes and glucose intolerance developing in non–NNS-consuming recipient mice,” they said.
They noted that the effects of these sweeteners will likely vary from person to person because of the unique composition of an individual’s microbiome.
“We need to raise awareness of the fact that NNS are not inert to the human body as we originally believed. With that said, the clinical health implications of the changes they may elicit in humans remain unknown and merit future long-term studies,” Dr. Elinav said in a news release.
For now, Dr. Elinav said it’s his personal view that “drinking only water seems to be the best solution.”
Weighing the evidence
Several experts weighed in on the results in a statement from the U.K. nonprofit organization, Science Media Centre.
Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).
“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Dr. Mellor says.
Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, concurs, saying “this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals.”
The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.
“Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a ‘stepping stone’ allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet,” Dr. Mellor suggests.
Kevin McConway, PhD, with the Open University, Milton Keynes, England, said it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.
“But exactly what the health consequences of all this, if any, might be is a subject for future research,” Dr. McConway added.
Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth (England) agrees.
“We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small,” she says.
The International Sweeteners Association also weighs in, saying, “No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes.”
They add “a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota.”
Nevertheless, Dr. Redfern says the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer-term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”
The study had no specific funding. Dr. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Dr. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Dr. Barrett, Dr. McConway, and Dr. Redfern report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This article was updated 8/29/22.
Lung adverse effects in patients taking trastuzumab deruxtecan
although the benefit-to-risk relationship with use of the drug is still positive, say researchers who report a review of early clinical trials with the drug.
T-DXd is a monoclonal antibody that targets HER2. It is approved for use in HER2-positive breast, gastric, and lung cancers.
In the new study, investigators analyzed data from early clinical trials that involved patients with advanced cancers who had been heavily pretreated. They found an incidence of just over 15% for interstitial lung disease (ILD)/pneumonitis associated with the drug. Most patients (77.4%) had grade 1 or 2 ILD, but 2.2% of patients had grade 5 ILD.
“Interstitial lung disease is a known risk factor in patients treated with antibody conjugates for cancer,” commented lead author Charles Powell, MD, Icahn School of Medicine at Mount Sinai, New York. This adverse effect can lead to lung fibrosis and can become severe, life threatening, and even fatal, the authors warned.
The authors also discussed management of the event, which involves corticosteroids, and recommended that any patient who develops ILD of grade 3 or higher be hospitalized.
Close monitoring and proactive management may reduce the risk of ILD, they suggested.
Indeed, the incidence of this adverse effect was lower in a later phase 3 trial of the drug (10.5% in the DESTINY-Breast03 trial) and that the adverse events were less severe in this patient population (none of these events were of grade 4 or 5).
“Increased knowledge ... and implementation of ILD/pneumonitis monitoring, diagnosis, and management guidelines” may have resulted in this adverse effect being identified early and treated before it progressed, they commented.
ILD is highlighted in a boxed warning on the product label.
The study was published online in ESMO Open.
In their review, the investigators evaluated nine early-stage monotherapy clinical trials (phases 1 and 2) involving a total of 1,150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%, other cancers, 3.0%).
These patients had advanced cancer and had been heavily pretreated with a median of four prior lines of therapy. They received one or more doses of at least 5.4 mg/kg of T-DXd.
Nearly half of the cohort were treated for more than 6 months. A total of 276 potential ILD/pneumonitis events were sent for adjudication; of those, 85% were adjudicated as ILD/pneumonitis.
The overall incidence of adjudicated ILD/pneumonitis events was 15.4%; most were low-grade events. Some 87% of patients experienced their first ILD event within 12 months of treatment. The median time to experiencing an ILD/pneumonitis event was 5.4 months.
Some of the patients who developed grade 1 ILD/pneumonitis were treated and the adverse event resolved. These patients were then rechallenged with the drug. Only 3 of the 47 rechallenged patients experienced recurrence of ILD/pneumonitis, the authors noted.
“Rechallenge with T-DXd after complete resolution of grade 1 events is possible and warrants further investigation,” they commented. They cautioned, however, that rechallenge is not recommended for all patients, at least not for those with grade 2 or higher ILD/pneumonitis.
Overall, the authors concluded that the “benefit-risk of T-DXd treatment is positive,” but they warned that some patients may be at increased risk of developing ILD/pneumonitis
Baseline factors that increase the risk of developing an ILD/pneumonitis event include the following: being younger than 65 years, receiving a T-DXd dose of more than6.4 mg/kg, having a baseline oxygen saturation level of less than 95%, having moderate to severe renal impairment, and having lung comorbidities. In addition, patients who had initially been diagnosed with cancer more than 4 years before receiving the drug were at higher risk of developing ILD/pneumonitis.
“Using learnings from the early clinical trials experience, physician education and patient management protocols were revised and disseminated by the study sponsors [and] more recent trial data in earlier lines of therapy has demonstrated lower rates of ILD events, suggesting close monitoring and proactive management of ILD/pneumonitis is warranted for all patients,” Dr. Powell said in a statement.
The T-DXd clinical trials were sponsored by AstraZeneca and Daiichi Sankyo. Dr. Powell has received fees from Daiichi Sankyo, AstraZeneca, and Voluntis.
A version of this article first appeared on Medscape.com.
although the benefit-to-risk relationship with use of the drug is still positive, say researchers who report a review of early clinical trials with the drug.
T-DXd is a monoclonal antibody that targets HER2. It is approved for use in HER2-positive breast, gastric, and lung cancers.
In the new study, investigators analyzed data from early clinical trials that involved patients with advanced cancers who had been heavily pretreated. They found an incidence of just over 15% for interstitial lung disease (ILD)/pneumonitis associated with the drug. Most patients (77.4%) had grade 1 or 2 ILD, but 2.2% of patients had grade 5 ILD.
“Interstitial lung disease is a known risk factor in patients treated with antibody conjugates for cancer,” commented lead author Charles Powell, MD, Icahn School of Medicine at Mount Sinai, New York. This adverse effect can lead to lung fibrosis and can become severe, life threatening, and even fatal, the authors warned.
The authors also discussed management of the event, which involves corticosteroids, and recommended that any patient who develops ILD of grade 3 or higher be hospitalized.
Close monitoring and proactive management may reduce the risk of ILD, they suggested.
Indeed, the incidence of this adverse effect was lower in a later phase 3 trial of the drug (10.5% in the DESTINY-Breast03 trial) and that the adverse events were less severe in this patient population (none of these events were of grade 4 or 5).
“Increased knowledge ... and implementation of ILD/pneumonitis monitoring, diagnosis, and management guidelines” may have resulted in this adverse effect being identified early and treated before it progressed, they commented.
ILD is highlighted in a boxed warning on the product label.
The study was published online in ESMO Open.
In their review, the investigators evaluated nine early-stage monotherapy clinical trials (phases 1 and 2) involving a total of 1,150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%, other cancers, 3.0%).
These patients had advanced cancer and had been heavily pretreated with a median of four prior lines of therapy. They received one or more doses of at least 5.4 mg/kg of T-DXd.
Nearly half of the cohort were treated for more than 6 months. A total of 276 potential ILD/pneumonitis events were sent for adjudication; of those, 85% were adjudicated as ILD/pneumonitis.
The overall incidence of adjudicated ILD/pneumonitis events was 15.4%; most were low-grade events. Some 87% of patients experienced their first ILD event within 12 months of treatment. The median time to experiencing an ILD/pneumonitis event was 5.4 months.
Some of the patients who developed grade 1 ILD/pneumonitis were treated and the adverse event resolved. These patients were then rechallenged with the drug. Only 3 of the 47 rechallenged patients experienced recurrence of ILD/pneumonitis, the authors noted.
“Rechallenge with T-DXd after complete resolution of grade 1 events is possible and warrants further investigation,” they commented. They cautioned, however, that rechallenge is not recommended for all patients, at least not for those with grade 2 or higher ILD/pneumonitis.
Overall, the authors concluded that the “benefit-risk of T-DXd treatment is positive,” but they warned that some patients may be at increased risk of developing ILD/pneumonitis
Baseline factors that increase the risk of developing an ILD/pneumonitis event include the following: being younger than 65 years, receiving a T-DXd dose of more than6.4 mg/kg, having a baseline oxygen saturation level of less than 95%, having moderate to severe renal impairment, and having lung comorbidities. In addition, patients who had initially been diagnosed with cancer more than 4 years before receiving the drug were at higher risk of developing ILD/pneumonitis.
“Using learnings from the early clinical trials experience, physician education and patient management protocols were revised and disseminated by the study sponsors [and] more recent trial data in earlier lines of therapy has demonstrated lower rates of ILD events, suggesting close monitoring and proactive management of ILD/pneumonitis is warranted for all patients,” Dr. Powell said in a statement.
The T-DXd clinical trials were sponsored by AstraZeneca and Daiichi Sankyo. Dr. Powell has received fees from Daiichi Sankyo, AstraZeneca, and Voluntis.
A version of this article first appeared on Medscape.com.
although the benefit-to-risk relationship with use of the drug is still positive, say researchers who report a review of early clinical trials with the drug.
T-DXd is a monoclonal antibody that targets HER2. It is approved for use in HER2-positive breast, gastric, and lung cancers.
In the new study, investigators analyzed data from early clinical trials that involved patients with advanced cancers who had been heavily pretreated. They found an incidence of just over 15% for interstitial lung disease (ILD)/pneumonitis associated with the drug. Most patients (77.4%) had grade 1 or 2 ILD, but 2.2% of patients had grade 5 ILD.
“Interstitial lung disease is a known risk factor in patients treated with antibody conjugates for cancer,” commented lead author Charles Powell, MD, Icahn School of Medicine at Mount Sinai, New York. This adverse effect can lead to lung fibrosis and can become severe, life threatening, and even fatal, the authors warned.
The authors also discussed management of the event, which involves corticosteroids, and recommended that any patient who develops ILD of grade 3 or higher be hospitalized.
Close monitoring and proactive management may reduce the risk of ILD, they suggested.
Indeed, the incidence of this adverse effect was lower in a later phase 3 trial of the drug (10.5% in the DESTINY-Breast03 trial) and that the adverse events were less severe in this patient population (none of these events were of grade 4 or 5).
“Increased knowledge ... and implementation of ILD/pneumonitis monitoring, diagnosis, and management guidelines” may have resulted in this adverse effect being identified early and treated before it progressed, they commented.
ILD is highlighted in a boxed warning on the product label.
The study was published online in ESMO Open.
In their review, the investigators evaluated nine early-stage monotherapy clinical trials (phases 1 and 2) involving a total of 1,150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%, other cancers, 3.0%).
These patients had advanced cancer and had been heavily pretreated with a median of four prior lines of therapy. They received one or more doses of at least 5.4 mg/kg of T-DXd.
Nearly half of the cohort were treated for more than 6 months. A total of 276 potential ILD/pneumonitis events were sent for adjudication; of those, 85% were adjudicated as ILD/pneumonitis.
The overall incidence of adjudicated ILD/pneumonitis events was 15.4%; most were low-grade events. Some 87% of patients experienced their first ILD event within 12 months of treatment. The median time to experiencing an ILD/pneumonitis event was 5.4 months.
Some of the patients who developed grade 1 ILD/pneumonitis were treated and the adverse event resolved. These patients were then rechallenged with the drug. Only 3 of the 47 rechallenged patients experienced recurrence of ILD/pneumonitis, the authors noted.
“Rechallenge with T-DXd after complete resolution of grade 1 events is possible and warrants further investigation,” they commented. They cautioned, however, that rechallenge is not recommended for all patients, at least not for those with grade 2 or higher ILD/pneumonitis.
Overall, the authors concluded that the “benefit-risk of T-DXd treatment is positive,” but they warned that some patients may be at increased risk of developing ILD/pneumonitis
Baseline factors that increase the risk of developing an ILD/pneumonitis event include the following: being younger than 65 years, receiving a T-DXd dose of more than6.4 mg/kg, having a baseline oxygen saturation level of less than 95%, having moderate to severe renal impairment, and having lung comorbidities. In addition, patients who had initially been diagnosed with cancer more than 4 years before receiving the drug were at higher risk of developing ILD/pneumonitis.
“Using learnings from the early clinical trials experience, physician education and patient management protocols were revised and disseminated by the study sponsors [and] more recent trial data in earlier lines of therapy has demonstrated lower rates of ILD events, suggesting close monitoring and proactive management of ILD/pneumonitis is warranted for all patients,” Dr. Powell said in a statement.
The T-DXd clinical trials were sponsored by AstraZeneca and Daiichi Sankyo. Dr. Powell has received fees from Daiichi Sankyo, AstraZeneca, and Voluntis.
A version of this article first appeared on Medscape.com.
FROM ESMO OPEN
The ‘great dynamism’ of radiation oncology
The field of radiation oncology has rapidly evolved in recent years, thanks in large part to findings from randomized clinical trials (RCTs) that have helped shift therapeutic standards, a review of the literature shows.
Highlights from this research reveal how high-tech radiotherapy, such as hypofractionation and stereotactic body radiotherapy, has improved care for many patients, how personalized radiotherapy using image-based guidance has helped tailor treatments, and how endpoints that focus on quality of life and patient satisfaction are emerging.
For instance, Charles B. Simone II, MD, FACRO, who was not involved in the current work, pointed to “a proliferation of trials assessing hypofractionation in the curative setting and stereotactic body radiation therapy in the curative and poly- and oligometastatic settings that have allowed for increased patient convenience and dose intensification, respectively.”
Dr. Simone, chief medical officer, New York Proton Center, Memorial Sloan Kettering Cancer Center, also noted that the first personalized radiotherapy trials using imaging and biological markers have “the profound potential to individualize treatment and improve patient outcomes.”
The review was published in the European Journal of Cancer.
An evolving field
Given the fast-changing landscape for cancer therapeutics and a deluge of research studies, the authors wanted to understand the most notable advances established in recent trials as well as caveats to some approaches and emerging areas to watch.
In the review, Sophie Espenel, MD, from the department of radiation oncology, Gustave Roussy Cancer Campus, Villejuif, France, and colleagues identified 1,347 radiotherapy RCTs that were conducted from January 2018 to December 2021. Of these, the authors selected 110 large phase 2 or 3 RCTs that contained data showing practice-changing or emerging concepts.
Overall, the studies showed “great dynamism” in radiation oncology research and covered a wide range of radiotherapy practices, according to Dr. Espenel and coauthors.
A central area of research has focused on radioimmunotherapy, an approach that aims to enhance the antitumor immune response. One RCT in the preoperative setting showed, for instance, that concurrent stereotactic body radiotherapy delivered at 24 Gy over eight fractions, along with the anti–PD-L1 agent durvalumab, increased major pathologic complete response rates almost eightfold in comparison with durvalumab alone for patients with early-stage lung cancer (53.3% vs. 6.7%).
Although promising, not all trials that evaluated a concurrent chemoradiotherapy-immunotherapy strategy showed positive results. One RCT of locally advanced head and neck squamous cell carcinoma, for instance, found that median progression-free survival was not reached when adding the anti–PD-L1 avelumab to chemoradiotherapy. In addition, trials in the metastatic setting have shown conflicting results, the authors note.
Another topic of interest is that of newer radiosensitizers. A trial that evaluated high-risk locoregionally advanced head and neck squamous cell carcinoma highlighted the efficacy of xevinapant, a pro-apoptotic agent that inhibits apoptosis proteins. Xevinapant was used for the first time in conjunction with a standard high-dose cisplatin chemoradiotherapy. In this study, locoregional control at 18 months was achieved for 54% of patients who received xevinapant vs. 33% of those who received standard care. The toxicity profiles were similar.
The use of high-tech radiotherapy is gaining ground. It allows patients to receive more targeted treatments at lower doses and in shorter time frames. One trial found, for instance, that a more hypofractionated adjuvant whole breast approach, using 26 Gy in five fractions over a week, is as effective and safe as 40 Gy in 15 fractions over 3 weeks. The researchers found that there was no difference in the incidence of locoregional relapses, disease-free survival, and overall survival between the regimens.
Dr. Simone also noted that advanced treatment modalities, such as intensity-modulated radiotherapy, stereotactic radiosurgery, and proton therapy, have the potential to improve patient-reported adverse events and clinical outcomes. “I have seen this both in my clinical practice and in several recent publications,” he says.
Personalization of radiotherapy is also an emerging area that may allow for more tailored treatments with improved outcomes. The authors highlighted a study that found that PMSA PET-CT was better than conventional CT for accurately staging prostate cancer. This approach was also less expensive and led to less radiation exposure.
On the basis of this research, “PMSA PET-CT has since become the [standard of care] for prostate cancer staging,” the authors explain.
Dr. Espenel and colleagues note that as patients survive longer, quality of life and patient satisfaction are increasingly becoming endpoints in RCTs. Experts are focusing more attention on sequelae of treatments and advances in technology that can spare critical organs from radiation and reduce overall treatment time.
Shared decision-making is becoming increasingly possible in many cases as well. For example, with some clinical trials that involved different treatment modalities, outcomes were equivalent, but toxicity profiles differed, allowing patients to choose therapeutic options tailored to their preferences.
Overall, these data demonstrate “a great dynamism of radiation oncology research in most primary tumor types,” the researchers write.
The study received no outside financial support. The authors have disclosed no relevant financial relationships. Dr. Simone is chair of the American Society for Radiation Oncology Lung Resource Panel and the American Society for Radiation Oncology Veteran Affairs Radiation Oncology Quality Surveillance Blue Ribbon Lung Panel and has received honorarium from Varian Medical Systems.
A version of this article first appeared on Medscape.com.
The field of radiation oncology has rapidly evolved in recent years, thanks in large part to findings from randomized clinical trials (RCTs) that have helped shift therapeutic standards, a review of the literature shows.
Highlights from this research reveal how high-tech radiotherapy, such as hypofractionation and stereotactic body radiotherapy, has improved care for many patients, how personalized radiotherapy using image-based guidance has helped tailor treatments, and how endpoints that focus on quality of life and patient satisfaction are emerging.
For instance, Charles B. Simone II, MD, FACRO, who was not involved in the current work, pointed to “a proliferation of trials assessing hypofractionation in the curative setting and stereotactic body radiation therapy in the curative and poly- and oligometastatic settings that have allowed for increased patient convenience and dose intensification, respectively.”
Dr. Simone, chief medical officer, New York Proton Center, Memorial Sloan Kettering Cancer Center, also noted that the first personalized radiotherapy trials using imaging and biological markers have “the profound potential to individualize treatment and improve patient outcomes.”
The review was published in the European Journal of Cancer.
An evolving field
Given the fast-changing landscape for cancer therapeutics and a deluge of research studies, the authors wanted to understand the most notable advances established in recent trials as well as caveats to some approaches and emerging areas to watch.
In the review, Sophie Espenel, MD, from the department of radiation oncology, Gustave Roussy Cancer Campus, Villejuif, France, and colleagues identified 1,347 radiotherapy RCTs that were conducted from January 2018 to December 2021. Of these, the authors selected 110 large phase 2 or 3 RCTs that contained data showing practice-changing or emerging concepts.
Overall, the studies showed “great dynamism” in radiation oncology research and covered a wide range of radiotherapy practices, according to Dr. Espenel and coauthors.
A central area of research has focused on radioimmunotherapy, an approach that aims to enhance the antitumor immune response. One RCT in the preoperative setting showed, for instance, that concurrent stereotactic body radiotherapy delivered at 24 Gy over eight fractions, along with the anti–PD-L1 agent durvalumab, increased major pathologic complete response rates almost eightfold in comparison with durvalumab alone for patients with early-stage lung cancer (53.3% vs. 6.7%).
Although promising, not all trials that evaluated a concurrent chemoradiotherapy-immunotherapy strategy showed positive results. One RCT of locally advanced head and neck squamous cell carcinoma, for instance, found that median progression-free survival was not reached when adding the anti–PD-L1 avelumab to chemoradiotherapy. In addition, trials in the metastatic setting have shown conflicting results, the authors note.
Another topic of interest is that of newer radiosensitizers. A trial that evaluated high-risk locoregionally advanced head and neck squamous cell carcinoma highlighted the efficacy of xevinapant, a pro-apoptotic agent that inhibits apoptosis proteins. Xevinapant was used for the first time in conjunction with a standard high-dose cisplatin chemoradiotherapy. In this study, locoregional control at 18 months was achieved for 54% of patients who received xevinapant vs. 33% of those who received standard care. The toxicity profiles were similar.
The use of high-tech radiotherapy is gaining ground. It allows patients to receive more targeted treatments at lower doses and in shorter time frames. One trial found, for instance, that a more hypofractionated adjuvant whole breast approach, using 26 Gy in five fractions over a week, is as effective and safe as 40 Gy in 15 fractions over 3 weeks. The researchers found that there was no difference in the incidence of locoregional relapses, disease-free survival, and overall survival between the regimens.
Dr. Simone also noted that advanced treatment modalities, such as intensity-modulated radiotherapy, stereotactic radiosurgery, and proton therapy, have the potential to improve patient-reported adverse events and clinical outcomes. “I have seen this both in my clinical practice and in several recent publications,” he says.
Personalization of radiotherapy is also an emerging area that may allow for more tailored treatments with improved outcomes. The authors highlighted a study that found that PMSA PET-CT was better than conventional CT for accurately staging prostate cancer. This approach was also less expensive and led to less radiation exposure.
On the basis of this research, “PMSA PET-CT has since become the [standard of care] for prostate cancer staging,” the authors explain.
Dr. Espenel and colleagues note that as patients survive longer, quality of life and patient satisfaction are increasingly becoming endpoints in RCTs. Experts are focusing more attention on sequelae of treatments and advances in technology that can spare critical organs from radiation and reduce overall treatment time.
Shared decision-making is becoming increasingly possible in many cases as well. For example, with some clinical trials that involved different treatment modalities, outcomes were equivalent, but toxicity profiles differed, allowing patients to choose therapeutic options tailored to their preferences.
Overall, these data demonstrate “a great dynamism of radiation oncology research in most primary tumor types,” the researchers write.
The study received no outside financial support. The authors have disclosed no relevant financial relationships. Dr. Simone is chair of the American Society for Radiation Oncology Lung Resource Panel and the American Society for Radiation Oncology Veteran Affairs Radiation Oncology Quality Surveillance Blue Ribbon Lung Panel and has received honorarium from Varian Medical Systems.
A version of this article first appeared on Medscape.com.
The field of radiation oncology has rapidly evolved in recent years, thanks in large part to findings from randomized clinical trials (RCTs) that have helped shift therapeutic standards, a review of the literature shows.
Highlights from this research reveal how high-tech radiotherapy, such as hypofractionation and stereotactic body radiotherapy, has improved care for many patients, how personalized radiotherapy using image-based guidance has helped tailor treatments, and how endpoints that focus on quality of life and patient satisfaction are emerging.
For instance, Charles B. Simone II, MD, FACRO, who was not involved in the current work, pointed to “a proliferation of trials assessing hypofractionation in the curative setting and stereotactic body radiation therapy in the curative and poly- and oligometastatic settings that have allowed for increased patient convenience and dose intensification, respectively.”
Dr. Simone, chief medical officer, New York Proton Center, Memorial Sloan Kettering Cancer Center, also noted that the first personalized radiotherapy trials using imaging and biological markers have “the profound potential to individualize treatment and improve patient outcomes.”
The review was published in the European Journal of Cancer.
An evolving field
Given the fast-changing landscape for cancer therapeutics and a deluge of research studies, the authors wanted to understand the most notable advances established in recent trials as well as caveats to some approaches and emerging areas to watch.
In the review, Sophie Espenel, MD, from the department of radiation oncology, Gustave Roussy Cancer Campus, Villejuif, France, and colleagues identified 1,347 radiotherapy RCTs that were conducted from January 2018 to December 2021. Of these, the authors selected 110 large phase 2 or 3 RCTs that contained data showing practice-changing or emerging concepts.
Overall, the studies showed “great dynamism” in radiation oncology research and covered a wide range of radiotherapy practices, according to Dr. Espenel and coauthors.
A central area of research has focused on radioimmunotherapy, an approach that aims to enhance the antitumor immune response. One RCT in the preoperative setting showed, for instance, that concurrent stereotactic body radiotherapy delivered at 24 Gy over eight fractions, along with the anti–PD-L1 agent durvalumab, increased major pathologic complete response rates almost eightfold in comparison with durvalumab alone for patients with early-stage lung cancer (53.3% vs. 6.7%).
Although promising, not all trials that evaluated a concurrent chemoradiotherapy-immunotherapy strategy showed positive results. One RCT of locally advanced head and neck squamous cell carcinoma, for instance, found that median progression-free survival was not reached when adding the anti–PD-L1 avelumab to chemoradiotherapy. In addition, trials in the metastatic setting have shown conflicting results, the authors note.
Another topic of interest is that of newer radiosensitizers. A trial that evaluated high-risk locoregionally advanced head and neck squamous cell carcinoma highlighted the efficacy of xevinapant, a pro-apoptotic agent that inhibits apoptosis proteins. Xevinapant was used for the first time in conjunction with a standard high-dose cisplatin chemoradiotherapy. In this study, locoregional control at 18 months was achieved for 54% of patients who received xevinapant vs. 33% of those who received standard care. The toxicity profiles were similar.
The use of high-tech radiotherapy is gaining ground. It allows patients to receive more targeted treatments at lower doses and in shorter time frames. One trial found, for instance, that a more hypofractionated adjuvant whole breast approach, using 26 Gy in five fractions over a week, is as effective and safe as 40 Gy in 15 fractions over 3 weeks. The researchers found that there was no difference in the incidence of locoregional relapses, disease-free survival, and overall survival between the regimens.
Dr. Simone also noted that advanced treatment modalities, such as intensity-modulated radiotherapy, stereotactic radiosurgery, and proton therapy, have the potential to improve patient-reported adverse events and clinical outcomes. “I have seen this both in my clinical practice and in several recent publications,” he says.
Personalization of radiotherapy is also an emerging area that may allow for more tailored treatments with improved outcomes. The authors highlighted a study that found that PMSA PET-CT was better than conventional CT for accurately staging prostate cancer. This approach was also less expensive and led to less radiation exposure.
On the basis of this research, “PMSA PET-CT has since become the [standard of care] for prostate cancer staging,” the authors explain.
Dr. Espenel and colleagues note that as patients survive longer, quality of life and patient satisfaction are increasingly becoming endpoints in RCTs. Experts are focusing more attention on sequelae of treatments and advances in technology that can spare critical organs from radiation and reduce overall treatment time.
Shared decision-making is becoming increasingly possible in many cases as well. For example, with some clinical trials that involved different treatment modalities, outcomes were equivalent, but toxicity profiles differed, allowing patients to choose therapeutic options tailored to their preferences.
Overall, these data demonstrate “a great dynamism of radiation oncology research in most primary tumor types,” the researchers write.
The study received no outside financial support. The authors have disclosed no relevant financial relationships. Dr. Simone is chair of the American Society for Radiation Oncology Lung Resource Panel and the American Society for Radiation Oncology Veteran Affairs Radiation Oncology Quality Surveillance Blue Ribbon Lung Panel and has received honorarium from Varian Medical Systems.
A version of this article first appeared on Medscape.com.
FROM THE EUROPEAN JOURNAL OF CANCER
AML’s seasonal peak suggests viral or environmental etiology
Most diagnoses of acute myeloid leukemia (AML) are made during January. This finding strongly implies that seasonal factors, such as infectious agents or environmental triggers, influence the development or proliferation of the disease, which points to prevention opportunities. This was the conclusion of an international study led by a team from the Jiménez Díaz Foundation University Hospital Health Research Institute (IIS-FJD) in Madrid, in collaboration with colleagues from the University of Bristol, England. Their work was published in the British Journal of Haematology.
The study’s aim was to investigate the potential seasonal and long-term trends in AML diagnosis in an overall population and in subgroups according to sex and age. To do so, the researchers examined 26,472 cases of AML diagnosed in Spain between 2004 and 2015. They found seasonality in the diagnosis of this type of leukemia. This “could point to there being an underlying seasonal etiology at play,” noted one of the main authors of the study, Juan Manuel Alonso, MD, a physician in the IIS-FJD’s department of hematology and hemotherapy.
“The environmental triggers involved could be radiation, pollution, allergens, or infectious agents like viruses. We’re leaning toward viruses, because there are already distinct solid tumor and hematologic cancers that are caused by them and because, in the winter months, there’s an increased incidence of cancers due to viral infections,” Dr. Alonso said in an interview. “The etiological mechanism should be different from that exerted by chronic viral pressure, because here we’re dealing with an acute and aggressive disease that probably needs a short incubation period.”
Various hypotheses
In an interview, David Martínez, MD, a hematologist at La Fe University Hospital in Valencia, Spain, described the research as “an extremely well done and much-discussed study on AML, a disease that appears to be diagnosed more frequently at a certain time of year – namely, January.
“There’s no clear explanation for this finding,” Dr. Martínez said. “Several possible reasons have been put forward and are being talked about. The one that seems to hold the most water is the hypothesis that infectious agents and environmental factors may have a greater influence. This is because the idea that they’re involved in neoplastic diseases is nothing new. In fact, there are a lot of publications and a good amount of scientific evidence that link viral infections and environmental factors with the development of oncologic diseases.”
AML is a rare disease yet is responsible for many cancer-related deaths. Mutations that cause AML can occur due to an inherited mutant gene or exposure to certain carcinogens, such as chemotherapy, radiotherapy, ionizing radiation, tobacco, and benzene. These findings are broadly similar to those of a large U.S.-based study by Calip et al., who found a peak of adult AML diagnoses during December and January from 1992 to 2008. Previous smaller studies have provided conflicting evidence, likely due to lower power or to the use of less advanced statistical approaches.
Seasonal factors involved?
Demonstration of seasonal variation in the occurrence of AML would, firstly, provide supportive evidence of etiology by seasonal factors, such as infectious agents or environmental factors, and, secondly, focus research onto the etiologic role of such factors.
The current study used population-based data on cases of AML occurring in Spain from a nationwide hospital discharge registry for the years 2004 to 2015. “This is, to our knowledge, the largest study aimed at investigating the potential seasonal and long-term trends in AML incidence in an overall population and in subgroups according to sex and age while employing novel statistical models with serial dependence for discrete-valued time series,” wrote the researchers.
They extracted information from the register of each case about the date of admission, discharge date, the anonymous identifier for each patient, International Classification of Diseases (ICD)–9 codes, sex, and date of birth, from which they derived age groups as described for the at-risk population. For patients hospitalized on more than one occasion, only the record corresponding to their first diagnosis of AML was selected.
AML cases per month were standardized to months of equal length.
Age/sex-standardized monthly incidence rates of AML were calculated using the census of Spanish population in 2010 as a “standard” population. Age-standardized and sex-standardized monthly incidence rates of AML were calculated.
Nine separate time-series decompositions were performed as an initial exploratory analysis on the monthly incidence rates of AML using data for all cases and data for each sex and age group. Nine separate Poisson generalized linear autoregressive moving average (GLARMA) models were fitted to evaluate the temporal dynamics in AML incidence using data for all cases, and data for each sex and age group.
Long-term trend
A total of 26,472 patients with a first diagnosis of active AML were hospitalized in Spain and registered at the country’s Minimum Basic Data Set (CMBD) during 2004-2015. In the end, there were 26,475 patients in the study population; a greater proportion of cases were male (56.0%), and the median age at diagnosis was 67 years.
Seasonal and trend decomposition using Loess decomposition of the incidence rates observed in the overall population exhibited seasonal fluctuation with a peak in January. A slight upward trend was apparent from visual inspection with an upturn in early 2005 and a downturn at the end of 2013. As for the differences by sex groups and age groups, Dr. Alonso said, “For both sexes and in age groups 5-19, 20-49, and 50-64 years, we found that the results were identical to those found in the overall population.”
The final model included an upward linear long-term trend, as well as the variables monthly seasonality and December 2015. The estimated monthly long-term trend implies that the monthly incidence rates of AML diagnoses annually increased by 0.4% (95% confidence interval [CI], 0.2%-0.6%; P = .0011), given that the other covariates are held constant.
January displayed the highest incidence rate of AML, with a minimum average difference of 7%, when compared with February (95% CI, 2%-12%; P = .0143) and a maximum average difference of 16%, compared with November (95% CI, 11%-21%; P < .0001) and August (95% CI, 10%-21%; P < .0001).
The incidence rate of AML for December 2015 was 0.43 (95% CI, 0.34-0.54; P < .0001) times the average incidence rate for the rest of the study period.
Potential role of viruses
“We have to keep in mind that infectious agents (viral infections) and environmental factors (allergens) don’t disappear in the warmer months,” Dr. Martínez added. “There are just other viruses and different factors. We don’t know the role or the weight that each one of the factors has, either individually or specifically, in the development of AML. In addition, we know that AML is a very heterogeneous disease and that various factors, including genetic ones, can be involved in its etiopathogenesis.”
With respect to the stem cell theory in this leukemia, Dr. Alonso emphasized that, “in theory, the virus could fit into it with no problem. That said, any other environmental agent could also produce the described phenomenon where the rapid proliferation of quiescent leukemic stem cells is stimulated, thereby hastening the diagnosis.”
“Should the etiological factor be found,” Dr. Martínez noted, “we can try to reduce exposure and thereby decrease the incidence of AML. On the other hand, discovering how the environmental factor stimulates the proliferation of quiescent leukemic [stem] cells could enhance our knowledge about the regulation of that.”
As to whether there is evidence for the involvement of infections in other hematologic malignancies, Dr. Martínez reported, “This has already been seen. And this study shows other examples (Epstein-Barr virus and human T-cell lymphotropic virus type 1 with lymphomas), and there could also be Helicobacter pylori and lymphomas.”
Outside of hematology, human papillomavirus has been associated with cervical cancer, tobacco with lung cancer, sun with skin cancer, and diet with the development of some solid neoplasms.
“The study speaks about the concept of a latency period. To accept the idea that a factor or virus that’s more prevalent in winter produces, on its own, AML in a few weeks or months means accepting the idea of a very short latency period – something that’s not usually the case. For that, another explanation is given: An abnormal immune response or that a seasonal infectious agent can be capable of promoting leukemogenesis. These are also hypotheses to be explored in the future,” suggested Dr. Martínez.
New research network
Several potential limitations of this study should be considered. One limitation is that AML cases were obtained from the CMBD registry as defined by ICD-9, and no other AML classifications were available. Another limitation is that information on the date of onset of clinical symptoms was not available for analysis. In addition, a further limitation related to the source of their data may have led the researchers to underestimate the incidence rates of AML in older patients, as only hospitalized patients were captured in their study.
As for continuing the research, the results make it necessary to carry out complementary epidemiologic studies that will examine the association between seasonal risk factors and the increased diagnosis of AML during winter months.
To go forward, the first step would be to secure funding. For this purpose, a network is being put together featuring collaborators from other world-renowned research groups that are at the top of their respective disciplines. Through this network, they hope to be able to apply together for public research grants from countries in Europe and elsewhere as well as to establish collaborations with various companies in the private sector.
“This could open up new therapeutic avenues in the future, as we could try to force leukemic stem cells to divide, thereby reducing the resistance that the standard treatments usually demonstrate,” Dr. Alonso concluded.
Dr. Alonso received research funding from Incyte, Pfizer International, and Astellas Pharma outside the present work. Dr. Martínez disclosed no relevant financial relationships.
This article was translated from the Medscape Spanish edition. A version of the article appeared on Medscape.com.
Most diagnoses of acute myeloid leukemia (AML) are made during January. This finding strongly implies that seasonal factors, such as infectious agents or environmental triggers, influence the development or proliferation of the disease, which points to prevention opportunities. This was the conclusion of an international study led by a team from the Jiménez Díaz Foundation University Hospital Health Research Institute (IIS-FJD) in Madrid, in collaboration with colleagues from the University of Bristol, England. Their work was published in the British Journal of Haematology.
The study’s aim was to investigate the potential seasonal and long-term trends in AML diagnosis in an overall population and in subgroups according to sex and age. To do so, the researchers examined 26,472 cases of AML diagnosed in Spain between 2004 and 2015. They found seasonality in the diagnosis of this type of leukemia. This “could point to there being an underlying seasonal etiology at play,” noted one of the main authors of the study, Juan Manuel Alonso, MD, a physician in the IIS-FJD’s department of hematology and hemotherapy.
“The environmental triggers involved could be radiation, pollution, allergens, or infectious agents like viruses. We’re leaning toward viruses, because there are already distinct solid tumor and hematologic cancers that are caused by them and because, in the winter months, there’s an increased incidence of cancers due to viral infections,” Dr. Alonso said in an interview. “The etiological mechanism should be different from that exerted by chronic viral pressure, because here we’re dealing with an acute and aggressive disease that probably needs a short incubation period.”
Various hypotheses
In an interview, David Martínez, MD, a hematologist at La Fe University Hospital in Valencia, Spain, described the research as “an extremely well done and much-discussed study on AML, a disease that appears to be diagnosed more frequently at a certain time of year – namely, January.
“There’s no clear explanation for this finding,” Dr. Martínez said. “Several possible reasons have been put forward and are being talked about. The one that seems to hold the most water is the hypothesis that infectious agents and environmental factors may have a greater influence. This is because the idea that they’re involved in neoplastic diseases is nothing new. In fact, there are a lot of publications and a good amount of scientific evidence that link viral infections and environmental factors with the development of oncologic diseases.”
AML is a rare disease yet is responsible for many cancer-related deaths. Mutations that cause AML can occur due to an inherited mutant gene or exposure to certain carcinogens, such as chemotherapy, radiotherapy, ionizing radiation, tobacco, and benzene. These findings are broadly similar to those of a large U.S.-based study by Calip et al., who found a peak of adult AML diagnoses during December and January from 1992 to 2008. Previous smaller studies have provided conflicting evidence, likely due to lower power or to the use of less advanced statistical approaches.
Seasonal factors involved?
Demonstration of seasonal variation in the occurrence of AML would, firstly, provide supportive evidence of etiology by seasonal factors, such as infectious agents or environmental factors, and, secondly, focus research onto the etiologic role of such factors.
The current study used population-based data on cases of AML occurring in Spain from a nationwide hospital discharge registry for the years 2004 to 2015. “This is, to our knowledge, the largest study aimed at investigating the potential seasonal and long-term trends in AML incidence in an overall population and in subgroups according to sex and age while employing novel statistical models with serial dependence for discrete-valued time series,” wrote the researchers.
They extracted information from the register of each case about the date of admission, discharge date, the anonymous identifier for each patient, International Classification of Diseases (ICD)–9 codes, sex, and date of birth, from which they derived age groups as described for the at-risk population. For patients hospitalized on more than one occasion, only the record corresponding to their first diagnosis of AML was selected.
AML cases per month were standardized to months of equal length.
Age/sex-standardized monthly incidence rates of AML were calculated using the census of Spanish population in 2010 as a “standard” population. Age-standardized and sex-standardized monthly incidence rates of AML were calculated.
Nine separate time-series decompositions were performed as an initial exploratory analysis on the monthly incidence rates of AML using data for all cases and data for each sex and age group. Nine separate Poisson generalized linear autoregressive moving average (GLARMA) models were fitted to evaluate the temporal dynamics in AML incidence using data for all cases, and data for each sex and age group.
Long-term trend
A total of 26,472 patients with a first diagnosis of active AML were hospitalized in Spain and registered at the country’s Minimum Basic Data Set (CMBD) during 2004-2015. In the end, there were 26,475 patients in the study population; a greater proportion of cases were male (56.0%), and the median age at diagnosis was 67 years.
Seasonal and trend decomposition using Loess decomposition of the incidence rates observed in the overall population exhibited seasonal fluctuation with a peak in January. A slight upward trend was apparent from visual inspection with an upturn in early 2005 and a downturn at the end of 2013. As for the differences by sex groups and age groups, Dr. Alonso said, “For both sexes and in age groups 5-19, 20-49, and 50-64 years, we found that the results were identical to those found in the overall population.”
The final model included an upward linear long-term trend, as well as the variables monthly seasonality and December 2015. The estimated monthly long-term trend implies that the monthly incidence rates of AML diagnoses annually increased by 0.4% (95% confidence interval [CI], 0.2%-0.6%; P = .0011), given that the other covariates are held constant.
January displayed the highest incidence rate of AML, with a minimum average difference of 7%, when compared with February (95% CI, 2%-12%; P = .0143) and a maximum average difference of 16%, compared with November (95% CI, 11%-21%; P < .0001) and August (95% CI, 10%-21%; P < .0001).
The incidence rate of AML for December 2015 was 0.43 (95% CI, 0.34-0.54; P < .0001) times the average incidence rate for the rest of the study period.
Potential role of viruses
“We have to keep in mind that infectious agents (viral infections) and environmental factors (allergens) don’t disappear in the warmer months,” Dr. Martínez added. “There are just other viruses and different factors. We don’t know the role or the weight that each one of the factors has, either individually or specifically, in the development of AML. In addition, we know that AML is a very heterogeneous disease and that various factors, including genetic ones, can be involved in its etiopathogenesis.”
With respect to the stem cell theory in this leukemia, Dr. Alonso emphasized that, “in theory, the virus could fit into it with no problem. That said, any other environmental agent could also produce the described phenomenon where the rapid proliferation of quiescent leukemic stem cells is stimulated, thereby hastening the diagnosis.”
“Should the etiological factor be found,” Dr. Martínez noted, “we can try to reduce exposure and thereby decrease the incidence of AML. On the other hand, discovering how the environmental factor stimulates the proliferation of quiescent leukemic [stem] cells could enhance our knowledge about the regulation of that.”
As to whether there is evidence for the involvement of infections in other hematologic malignancies, Dr. Martínez reported, “This has already been seen. And this study shows other examples (Epstein-Barr virus and human T-cell lymphotropic virus type 1 with lymphomas), and there could also be Helicobacter pylori and lymphomas.”
Outside of hematology, human papillomavirus has been associated with cervical cancer, tobacco with lung cancer, sun with skin cancer, and diet with the development of some solid neoplasms.
“The study speaks about the concept of a latency period. To accept the idea that a factor or virus that’s more prevalent in winter produces, on its own, AML in a few weeks or months means accepting the idea of a very short latency period – something that’s not usually the case. For that, another explanation is given: An abnormal immune response or that a seasonal infectious agent can be capable of promoting leukemogenesis. These are also hypotheses to be explored in the future,” suggested Dr. Martínez.
New research network
Several potential limitations of this study should be considered. One limitation is that AML cases were obtained from the CMBD registry as defined by ICD-9, and no other AML classifications were available. Another limitation is that information on the date of onset of clinical symptoms was not available for analysis. In addition, a further limitation related to the source of their data may have led the researchers to underestimate the incidence rates of AML in older patients, as only hospitalized patients were captured in their study.
As for continuing the research, the results make it necessary to carry out complementary epidemiologic studies that will examine the association between seasonal risk factors and the increased diagnosis of AML during winter months.
To go forward, the first step would be to secure funding. For this purpose, a network is being put together featuring collaborators from other world-renowned research groups that are at the top of their respective disciplines. Through this network, they hope to be able to apply together for public research grants from countries in Europe and elsewhere as well as to establish collaborations with various companies in the private sector.
“This could open up new therapeutic avenues in the future, as we could try to force leukemic stem cells to divide, thereby reducing the resistance that the standard treatments usually demonstrate,” Dr. Alonso concluded.
Dr. Alonso received research funding from Incyte, Pfizer International, and Astellas Pharma outside the present work. Dr. Martínez disclosed no relevant financial relationships.
This article was translated from the Medscape Spanish edition. A version of the article appeared on Medscape.com.
Most diagnoses of acute myeloid leukemia (AML) are made during January. This finding strongly implies that seasonal factors, such as infectious agents or environmental triggers, influence the development or proliferation of the disease, which points to prevention opportunities. This was the conclusion of an international study led by a team from the Jiménez Díaz Foundation University Hospital Health Research Institute (IIS-FJD) in Madrid, in collaboration with colleagues from the University of Bristol, England. Their work was published in the British Journal of Haematology.
The study’s aim was to investigate the potential seasonal and long-term trends in AML diagnosis in an overall population and in subgroups according to sex and age. To do so, the researchers examined 26,472 cases of AML diagnosed in Spain between 2004 and 2015. They found seasonality in the diagnosis of this type of leukemia. This “could point to there being an underlying seasonal etiology at play,” noted one of the main authors of the study, Juan Manuel Alonso, MD, a physician in the IIS-FJD’s department of hematology and hemotherapy.
“The environmental triggers involved could be radiation, pollution, allergens, or infectious agents like viruses. We’re leaning toward viruses, because there are already distinct solid tumor and hematologic cancers that are caused by them and because, in the winter months, there’s an increased incidence of cancers due to viral infections,” Dr. Alonso said in an interview. “The etiological mechanism should be different from that exerted by chronic viral pressure, because here we’re dealing with an acute and aggressive disease that probably needs a short incubation period.”
Various hypotheses
In an interview, David Martínez, MD, a hematologist at La Fe University Hospital in Valencia, Spain, described the research as “an extremely well done and much-discussed study on AML, a disease that appears to be diagnosed more frequently at a certain time of year – namely, January.
“There’s no clear explanation for this finding,” Dr. Martínez said. “Several possible reasons have been put forward and are being talked about. The one that seems to hold the most water is the hypothesis that infectious agents and environmental factors may have a greater influence. This is because the idea that they’re involved in neoplastic diseases is nothing new. In fact, there are a lot of publications and a good amount of scientific evidence that link viral infections and environmental factors with the development of oncologic diseases.”
AML is a rare disease yet is responsible for many cancer-related deaths. Mutations that cause AML can occur due to an inherited mutant gene or exposure to certain carcinogens, such as chemotherapy, radiotherapy, ionizing radiation, tobacco, and benzene. These findings are broadly similar to those of a large U.S.-based study by Calip et al., who found a peak of adult AML diagnoses during December and January from 1992 to 2008. Previous smaller studies have provided conflicting evidence, likely due to lower power or to the use of less advanced statistical approaches.
Seasonal factors involved?
Demonstration of seasonal variation in the occurrence of AML would, firstly, provide supportive evidence of etiology by seasonal factors, such as infectious agents or environmental factors, and, secondly, focus research onto the etiologic role of such factors.
The current study used population-based data on cases of AML occurring in Spain from a nationwide hospital discharge registry for the years 2004 to 2015. “This is, to our knowledge, the largest study aimed at investigating the potential seasonal and long-term trends in AML incidence in an overall population and in subgroups according to sex and age while employing novel statistical models with serial dependence for discrete-valued time series,” wrote the researchers.
They extracted information from the register of each case about the date of admission, discharge date, the anonymous identifier for each patient, International Classification of Diseases (ICD)–9 codes, sex, and date of birth, from which they derived age groups as described for the at-risk population. For patients hospitalized on more than one occasion, only the record corresponding to their first diagnosis of AML was selected.
AML cases per month were standardized to months of equal length.
Age/sex-standardized monthly incidence rates of AML were calculated using the census of Spanish population in 2010 as a “standard” population. Age-standardized and sex-standardized monthly incidence rates of AML were calculated.
Nine separate time-series decompositions were performed as an initial exploratory analysis on the monthly incidence rates of AML using data for all cases and data for each sex and age group. Nine separate Poisson generalized linear autoregressive moving average (GLARMA) models were fitted to evaluate the temporal dynamics in AML incidence using data for all cases, and data for each sex and age group.
Long-term trend
A total of 26,472 patients with a first diagnosis of active AML were hospitalized in Spain and registered at the country’s Minimum Basic Data Set (CMBD) during 2004-2015. In the end, there were 26,475 patients in the study population; a greater proportion of cases were male (56.0%), and the median age at diagnosis was 67 years.
Seasonal and trend decomposition using Loess decomposition of the incidence rates observed in the overall population exhibited seasonal fluctuation with a peak in January. A slight upward trend was apparent from visual inspection with an upturn in early 2005 and a downturn at the end of 2013. As for the differences by sex groups and age groups, Dr. Alonso said, “For both sexes and in age groups 5-19, 20-49, and 50-64 years, we found that the results were identical to those found in the overall population.”
The final model included an upward linear long-term trend, as well as the variables monthly seasonality and December 2015. The estimated monthly long-term trend implies that the monthly incidence rates of AML diagnoses annually increased by 0.4% (95% confidence interval [CI], 0.2%-0.6%; P = .0011), given that the other covariates are held constant.
January displayed the highest incidence rate of AML, with a minimum average difference of 7%, when compared with February (95% CI, 2%-12%; P = .0143) and a maximum average difference of 16%, compared with November (95% CI, 11%-21%; P < .0001) and August (95% CI, 10%-21%; P < .0001).
The incidence rate of AML for December 2015 was 0.43 (95% CI, 0.34-0.54; P < .0001) times the average incidence rate for the rest of the study period.
Potential role of viruses
“We have to keep in mind that infectious agents (viral infections) and environmental factors (allergens) don’t disappear in the warmer months,” Dr. Martínez added. “There are just other viruses and different factors. We don’t know the role or the weight that each one of the factors has, either individually or specifically, in the development of AML. In addition, we know that AML is a very heterogeneous disease and that various factors, including genetic ones, can be involved in its etiopathogenesis.”
With respect to the stem cell theory in this leukemia, Dr. Alonso emphasized that, “in theory, the virus could fit into it with no problem. That said, any other environmental agent could also produce the described phenomenon where the rapid proliferation of quiescent leukemic stem cells is stimulated, thereby hastening the diagnosis.”
“Should the etiological factor be found,” Dr. Martínez noted, “we can try to reduce exposure and thereby decrease the incidence of AML. On the other hand, discovering how the environmental factor stimulates the proliferation of quiescent leukemic [stem] cells could enhance our knowledge about the regulation of that.”
As to whether there is evidence for the involvement of infections in other hematologic malignancies, Dr. Martínez reported, “This has already been seen. And this study shows other examples (Epstein-Barr virus and human T-cell lymphotropic virus type 1 with lymphomas), and there could also be Helicobacter pylori and lymphomas.”
Outside of hematology, human papillomavirus has been associated with cervical cancer, tobacco with lung cancer, sun with skin cancer, and diet with the development of some solid neoplasms.
“The study speaks about the concept of a latency period. To accept the idea that a factor or virus that’s more prevalent in winter produces, on its own, AML in a few weeks or months means accepting the idea of a very short latency period – something that’s not usually the case. For that, another explanation is given: An abnormal immune response or that a seasonal infectious agent can be capable of promoting leukemogenesis. These are also hypotheses to be explored in the future,” suggested Dr. Martínez.
New research network
Several potential limitations of this study should be considered. One limitation is that AML cases were obtained from the CMBD registry as defined by ICD-9, and no other AML classifications were available. Another limitation is that information on the date of onset of clinical symptoms was not available for analysis. In addition, a further limitation related to the source of their data may have led the researchers to underestimate the incidence rates of AML in older patients, as only hospitalized patients were captured in their study.
As for continuing the research, the results make it necessary to carry out complementary epidemiologic studies that will examine the association between seasonal risk factors and the increased diagnosis of AML during winter months.
To go forward, the first step would be to secure funding. For this purpose, a network is being put together featuring collaborators from other world-renowned research groups that are at the top of their respective disciplines. Through this network, they hope to be able to apply together for public research grants from countries in Europe and elsewhere as well as to establish collaborations with various companies in the private sector.
“This could open up new therapeutic avenues in the future, as we could try to force leukemic stem cells to divide, thereby reducing the resistance that the standard treatments usually demonstrate,” Dr. Alonso concluded.
Dr. Alonso received research funding from Incyte, Pfizer International, and Astellas Pharma outside the present work. Dr. Martínez disclosed no relevant financial relationships.
This article was translated from the Medscape Spanish edition. A version of the article appeared on Medscape.com.
FROM THE BRITISH JOURNAL OF HEMATOLOGY
Annual PSA screening important for Black men
, new data suggest.
The data come from a review of 45,834 veterans (aged 55-69 years) who had been diagnosed with prostate cancer. About one-third of these men self-identified as non-Hispanic Black, and the rest were White.
During the study period (2004-2017), 2,465 men (5.4%) died of the disease.
The review found that annual prostate-specific antigen (PSA) screening significantly reduced the risk of dying from prostate cancer among Black men but not White men.
The study was published online in JAMA Oncology.
“These results may be biologically plausible because a shorter screening interval may be valuable for detecting aggressive disease, which is more common in Black men,” say investigators, led by University of California, San Diego, radiation oncology resident Michael Sherer, MD.
“Given that Black men are younger at diagnosis and have worse prostate cancer survival compared with White men,” more intensive screening recommendations “may benefit Black patients,” they write.
The study “conclusions are reasonable,” said Christopher Wallis, MD, PhD, a urologic oncologist at Mount Sinai Hospital in Toronto, when asked for comment.
Annual screening may well have “a greater potential to benefit” Black men, he said. “While we would ideally see randomized data supporting this, those data are unlikely to ever be forthcoming. Thus, this study provides a strong rationale to support the recommendations from many guideline panels (including those from the American Urological Association) that Black men, in the context of shared decision-making, may benefit more from PSA-based prostate cancer screening than the population at large,” he added.
Overall, the findings could help inform screening discussions with Black men, the investigators comments. In its most recent guidance, the U.S. Preventive Services Task Force recommends shared decision-making regarding PSA screening for men aged 55-69 years.
Similar screening frequency
For their study, the team reviewed Veterans Health Administration data to assess PSA screening patterns – which they categorized as no screening, less than annual screening, or annual screening – in the 5 years leading up to diagnosis.
They then correlated screening behaviors with the subsequent risk of dying from prostate cancer.
Overall, the reduction in risk of prostate cancer–specific mortality (PCSM) associated with screening was similar among Black men (subdistribution hazard ratio, 0.56; P = .001) and White men (sHR, 0.58; P = .001).
However, on multivariable regression, annual screening, in comparison with some screening, was associated with a significant reduction in the risk of dying from prostate cancer only among Black men (sHR, 0.65; P = .02), not among White men (sHR, 0.91; P = .35).
The cumulative incidence of PCSM among Black men was 4.7% with annual screening but 7.3% with only some screening.
Among White men, the cumulative incidence of PCSM with annual screening was 5.9% vs. 6.9% with less than annual screening.
Screening frequency was similar between Black men and White men. Black men were younger on average (61.8 vs. 63.1 years) and had slightly higher PSA levels at diagnosis but were not more likely to have regional or metastatic disease.
No funding was reported for this study. The investigators have disclosed no relevant financial relationships. Dr. Wallis has received personal fees from Janssen Canada.
A version of this article first appeared on Medscape.com.
, new data suggest.
The data come from a review of 45,834 veterans (aged 55-69 years) who had been diagnosed with prostate cancer. About one-third of these men self-identified as non-Hispanic Black, and the rest were White.
During the study period (2004-2017), 2,465 men (5.4%) died of the disease.
The review found that annual prostate-specific antigen (PSA) screening significantly reduced the risk of dying from prostate cancer among Black men but not White men.
The study was published online in JAMA Oncology.
“These results may be biologically plausible because a shorter screening interval may be valuable for detecting aggressive disease, which is more common in Black men,” say investigators, led by University of California, San Diego, radiation oncology resident Michael Sherer, MD.
“Given that Black men are younger at diagnosis and have worse prostate cancer survival compared with White men,” more intensive screening recommendations “may benefit Black patients,” they write.
The study “conclusions are reasonable,” said Christopher Wallis, MD, PhD, a urologic oncologist at Mount Sinai Hospital in Toronto, when asked for comment.
Annual screening may well have “a greater potential to benefit” Black men, he said. “While we would ideally see randomized data supporting this, those data are unlikely to ever be forthcoming. Thus, this study provides a strong rationale to support the recommendations from many guideline panels (including those from the American Urological Association) that Black men, in the context of shared decision-making, may benefit more from PSA-based prostate cancer screening than the population at large,” he added.
Overall, the findings could help inform screening discussions with Black men, the investigators comments. In its most recent guidance, the U.S. Preventive Services Task Force recommends shared decision-making regarding PSA screening for men aged 55-69 years.
Similar screening frequency
For their study, the team reviewed Veterans Health Administration data to assess PSA screening patterns – which they categorized as no screening, less than annual screening, or annual screening – in the 5 years leading up to diagnosis.
They then correlated screening behaviors with the subsequent risk of dying from prostate cancer.
Overall, the reduction in risk of prostate cancer–specific mortality (PCSM) associated with screening was similar among Black men (subdistribution hazard ratio, 0.56; P = .001) and White men (sHR, 0.58; P = .001).
However, on multivariable regression, annual screening, in comparison with some screening, was associated with a significant reduction in the risk of dying from prostate cancer only among Black men (sHR, 0.65; P = .02), not among White men (sHR, 0.91; P = .35).
The cumulative incidence of PCSM among Black men was 4.7% with annual screening but 7.3% with only some screening.
Among White men, the cumulative incidence of PCSM with annual screening was 5.9% vs. 6.9% with less than annual screening.
Screening frequency was similar between Black men and White men. Black men were younger on average (61.8 vs. 63.1 years) and had slightly higher PSA levels at diagnosis but were not more likely to have regional or metastatic disease.
No funding was reported for this study. The investigators have disclosed no relevant financial relationships. Dr. Wallis has received personal fees from Janssen Canada.
A version of this article first appeared on Medscape.com.
, new data suggest.
The data come from a review of 45,834 veterans (aged 55-69 years) who had been diagnosed with prostate cancer. About one-third of these men self-identified as non-Hispanic Black, and the rest were White.
During the study period (2004-2017), 2,465 men (5.4%) died of the disease.
The review found that annual prostate-specific antigen (PSA) screening significantly reduced the risk of dying from prostate cancer among Black men but not White men.
The study was published online in JAMA Oncology.
“These results may be biologically plausible because a shorter screening interval may be valuable for detecting aggressive disease, which is more common in Black men,” say investigators, led by University of California, San Diego, radiation oncology resident Michael Sherer, MD.
“Given that Black men are younger at diagnosis and have worse prostate cancer survival compared with White men,” more intensive screening recommendations “may benefit Black patients,” they write.
The study “conclusions are reasonable,” said Christopher Wallis, MD, PhD, a urologic oncologist at Mount Sinai Hospital in Toronto, when asked for comment.
Annual screening may well have “a greater potential to benefit” Black men, he said. “While we would ideally see randomized data supporting this, those data are unlikely to ever be forthcoming. Thus, this study provides a strong rationale to support the recommendations from many guideline panels (including those from the American Urological Association) that Black men, in the context of shared decision-making, may benefit more from PSA-based prostate cancer screening than the population at large,” he added.
Overall, the findings could help inform screening discussions with Black men, the investigators comments. In its most recent guidance, the U.S. Preventive Services Task Force recommends shared decision-making regarding PSA screening for men aged 55-69 years.
Similar screening frequency
For their study, the team reviewed Veterans Health Administration data to assess PSA screening patterns – which they categorized as no screening, less than annual screening, or annual screening – in the 5 years leading up to diagnosis.
They then correlated screening behaviors with the subsequent risk of dying from prostate cancer.
Overall, the reduction in risk of prostate cancer–specific mortality (PCSM) associated with screening was similar among Black men (subdistribution hazard ratio, 0.56; P = .001) and White men (sHR, 0.58; P = .001).
However, on multivariable regression, annual screening, in comparison with some screening, was associated with a significant reduction in the risk of dying from prostate cancer only among Black men (sHR, 0.65; P = .02), not among White men (sHR, 0.91; P = .35).
The cumulative incidence of PCSM among Black men was 4.7% with annual screening but 7.3% with only some screening.
Among White men, the cumulative incidence of PCSM with annual screening was 5.9% vs. 6.9% with less than annual screening.
Screening frequency was similar between Black men and White men. Black men were younger on average (61.8 vs. 63.1 years) and had slightly higher PSA levels at diagnosis but were not more likely to have regional or metastatic disease.
No funding was reported for this study. The investigators have disclosed no relevant financial relationships. Dr. Wallis has received personal fees from Janssen Canada.
A version of this article first appeared on Medscape.com.
FROM JAMA ONCOLOGY
‘Obesity paradox’ in AFib challenged as mortality climbs with BMI
The relationship between body mass index (BMI) and all-cause mortality in patients with atrial fibrillation (AFib) is U-shaped, with the risk highest in those who are underweight or severely obese and lowest in patients defined simply as obese, a registry analysis suggests. It also showed a similar relationship between BMI and risk for new or worsening heart failure (HF).
Mortality bottomed out at a BMI of about 30-35 kg/m2, which suggests that mild obesity was protective, compared even with “normal-weight” or “overweight” BMI. Still, mortality went up sharply from there with rising BMI.
But higher BMI, a surrogate for obesity, apparently didn’t worsen outcomes by itself. The risk for death from any cause at higher obesity levels was found to depend a lot on related risk factors and comorbidities when the analysis controlled for conditions such as diabetes and hypertension.
The findings suggest an inverse relationship between BMI and all-cause mortality in AFib only for patients with BMI less than about 30. They therefore argue against any “obesity paradox” in AFib that posits consistently better survival with increasing levels of obesity, say researchers, based on their analysis of patients with new-onset AFib in the GARFIELD-AF registry.
“It’s common practice now for clinicians to discuss weight within a clinic setting when they’re talking to their AFib patients,” observed Christian Fielder Camm, BM, BCh, University of Oxford (England), and Royal Berkshire NHS Foundation Trust, Reading, England. So studies suggesting an inverse association between BMI and AFib-related risk can be a concern.
Such studies “seem to suggest that once you’ve got AFib, maintaining a high or very high BMI may in some way be protective – which is contrary to what would seem to make sense and certainly contrary to what our results have shown,” Dr. Camm told this news organization.
“I think that having further evidence now to suggest, actually, that greater BMI is associated with a greater risk of all-cause mortality and heart failure helps reframe that discussion at the physician-patient interaction level more clearly, and ensures that we’re able to talk to our patients appropriately about risks associated with BMI and atrial fibrillation,” said Dr. Camm, who is lead author on the analysis published in Open Heart.
“Obesity is a cause of most cardiovascular diseases, but [these] data would support that being overweight or having mild obesity does not increase the risk,” observed Carl J. Lavie, MD, of the John Ochsner Heart and Vascular Institute, New Orleans, La., and the Ochsner Clinical School at the University of Queensland, Brisbane, Australia.
“At a BMI of 40, it’s very important for them to lose weight for their long-term prognosis,” Dr. Lavie noted, but “at a BMI of 30, the important thing would be to prevent further weight gain. And if they could keep their BMI of 30, they should have a good prognosis. Their prognosis would be particularly good if they didn’t gain weight and put themselves in a more extreme obesity class that is associated with worse risk.”
The current analysis, Dr. Lavie said, “is way better than the AFFIRM study,” which yielded an obesity-paradox report on its patients with AFib about a dozen years ago. “It’s got more data, more numbers, more statistical power,” and breaks BMI into more categories.
That previous analysis based on the influential AFFIRM randomized trial separated its 4,060 patients with AFib into normal (BMI, 18.5-25), overweight (BMI, 25-30), and obese (BMI, > 30) categories, per the convention at the time. It concluded that “obese patients with atrial fibrillation appear to have better long-term outcomes than nonobese patients.”
Bleeding risk on oral anticoagulants
Also noteworthy in the current analysis, variation in BMI didn’t seem to affect mortality or risk for major bleeding or nonhemorrhagic stroke according to choice of oral anticoagulant – whether a new oral anticoagulant (NOAC) or a vitamin K antagonist (VKA).
“We saw that even in the obese and extremely obese group, all-cause mortality was lower in the group taking NOACs, compared with taking warfarin,” Dr. Camm observed, “which goes against the idea that we would need any kind of dose adjustments for increased BMI.”
Indeed, the report notes, use of NOACs, compared with VKA, was associated with a 23% drop in risk for death among patients who were either normal weight or overweight and also in those who were obese or extremely obese.
Those findings “are basically saying that the NOACs look better than warfarin regardless of weight,” agreed Dr. Lavie. “The problem is that the study is not very powered.”
Whereas the benefits of NOACs, compared to VKA, seem similar for patients with a BMI of 30 or 34, compared with a BMI of 23, for example, “none of the studies has many people with 50 BMI.” Many clinicians “feel uncomfortable giving the same dose of NOAC to somebody who has a 60 BMI,” he said. At least with warfarin, “you can check the INR [international normalized ratio].”
The current analysis included 40,482 patients with recently diagnosed AFib and at least one other stroke risk factor from among the registry’s more than 50,000 patients from 35 countries, enrolled from 2010 to 2016. They were followed for 2 years.
The 703 patients with BMI under 18.5 at AFib diagnosis were classified per World Health Organization definitions as underweight; the 13,095 with BMI 18.5-25 as normal weight; the 15,043 with BMI 25-30 as overweight; the 7,560 with BMI 30-35 as obese; and the 4,081 with BMI above 35 as extremely obese. Their ages averaged 71 years, and 55.6% were men.
BMI effects on different outcomes
Relationships between BMI and all-cause mortality and between BMI and new or worsening HF emerged as U-shaped, the risk climbing with both increasing and decreasing BMI. The nadir BMI for risk was about 30 in the case of mortality and about 25 for new or worsening HF.
The all-cause mortality risk rose by 32% for every 5 BMI points lower than a BMI of 30, and by 16% for every 5 BMI points higher than 30, in a partially adjusted analysis. The risk for new or worsening HF rose significantly with increasing but not decreasing BMI, and the reverse was observed for the endpoint of major bleeding.
The effect of BMI on all-cause mortality was “substantially attenuated” when the analysis was further adjusted with “likely mediators of any association between BMI and outcomes,” including hypertension, diabetes, HF, cerebrovascular events, and history of bleeding, Dr. Camm said.
That blunted BMI-mortality relationship, he said, “suggests that a lot of the effect is mediated through relatively traditional risk factors like hypertension and diabetes.”
The 2010 AFFIRM analysis by BMI, Dr. Lavie noted, “didn’t even look at the underweight; they actually threw them out.” Yet, such patients with AFib, who tend to be extremely frail or have chronic diseases or conditions other than the arrhythmia, are common. A take-home of the current study is that “the underweight with atrial fibrillation have a really bad prognosis.”
That message isn’t heard as much, he observed, “but is as important as saying that BMI 30 has the best prognosis. The worst prognosis is with the underweight or the really extreme obese.”
Dr. Camm discloses research funding from the British Heart Foundation. Disclosures for the other authors are in the report. Dr. Lavie has previously disclosed serving as a speaker and consultant for PAI Health and DSM Nutritional Products and is the author of “The Obesity Paradox: When Thinner Means Sicker and Heavier Means Healthier” (Avery, 2014).
A version of this article first appeared on Medscape.com.
The relationship between body mass index (BMI) and all-cause mortality in patients with atrial fibrillation (AFib) is U-shaped, with the risk highest in those who are underweight or severely obese and lowest in patients defined simply as obese, a registry analysis suggests. It also showed a similar relationship between BMI and risk for new or worsening heart failure (HF).
Mortality bottomed out at a BMI of about 30-35 kg/m2, which suggests that mild obesity was protective, compared even with “normal-weight” or “overweight” BMI. Still, mortality went up sharply from there with rising BMI.
But higher BMI, a surrogate for obesity, apparently didn’t worsen outcomes by itself. The risk for death from any cause at higher obesity levels was found to depend a lot on related risk factors and comorbidities when the analysis controlled for conditions such as diabetes and hypertension.
The findings suggest an inverse relationship between BMI and all-cause mortality in AFib only for patients with BMI less than about 30. They therefore argue against any “obesity paradox” in AFib that posits consistently better survival with increasing levels of obesity, say researchers, based on their analysis of patients with new-onset AFib in the GARFIELD-AF registry.
“It’s common practice now for clinicians to discuss weight within a clinic setting when they’re talking to their AFib patients,” observed Christian Fielder Camm, BM, BCh, University of Oxford (England), and Royal Berkshire NHS Foundation Trust, Reading, England. So studies suggesting an inverse association between BMI and AFib-related risk can be a concern.
Such studies “seem to suggest that once you’ve got AFib, maintaining a high or very high BMI may in some way be protective – which is contrary to what would seem to make sense and certainly contrary to what our results have shown,” Dr. Camm told this news organization.
“I think that having further evidence now to suggest, actually, that greater BMI is associated with a greater risk of all-cause mortality and heart failure helps reframe that discussion at the physician-patient interaction level more clearly, and ensures that we’re able to talk to our patients appropriately about risks associated with BMI and atrial fibrillation,” said Dr. Camm, who is lead author on the analysis published in Open Heart.
“Obesity is a cause of most cardiovascular diseases, but [these] data would support that being overweight or having mild obesity does not increase the risk,” observed Carl J. Lavie, MD, of the John Ochsner Heart and Vascular Institute, New Orleans, La., and the Ochsner Clinical School at the University of Queensland, Brisbane, Australia.
“At a BMI of 40, it’s very important for them to lose weight for their long-term prognosis,” Dr. Lavie noted, but “at a BMI of 30, the important thing would be to prevent further weight gain. And if they could keep their BMI of 30, they should have a good prognosis. Their prognosis would be particularly good if they didn’t gain weight and put themselves in a more extreme obesity class that is associated with worse risk.”
The current analysis, Dr. Lavie said, “is way better than the AFFIRM study,” which yielded an obesity-paradox report on its patients with AFib about a dozen years ago. “It’s got more data, more numbers, more statistical power,” and breaks BMI into more categories.
That previous analysis based on the influential AFFIRM randomized trial separated its 4,060 patients with AFib into normal (BMI, 18.5-25), overweight (BMI, 25-30), and obese (BMI, > 30) categories, per the convention at the time. It concluded that “obese patients with atrial fibrillation appear to have better long-term outcomes than nonobese patients.”
Bleeding risk on oral anticoagulants
Also noteworthy in the current analysis, variation in BMI didn’t seem to affect mortality or risk for major bleeding or nonhemorrhagic stroke according to choice of oral anticoagulant – whether a new oral anticoagulant (NOAC) or a vitamin K antagonist (VKA).
“We saw that even in the obese and extremely obese group, all-cause mortality was lower in the group taking NOACs, compared with taking warfarin,” Dr. Camm observed, “which goes against the idea that we would need any kind of dose adjustments for increased BMI.”
Indeed, the report notes, use of NOACs, compared with VKA, was associated with a 23% drop in risk for death among patients who were either normal weight or overweight and also in those who were obese or extremely obese.
Those findings “are basically saying that the NOACs look better than warfarin regardless of weight,” agreed Dr. Lavie. “The problem is that the study is not very powered.”
Whereas the benefits of NOACs, compared to VKA, seem similar for patients with a BMI of 30 or 34, compared with a BMI of 23, for example, “none of the studies has many people with 50 BMI.” Many clinicians “feel uncomfortable giving the same dose of NOAC to somebody who has a 60 BMI,” he said. At least with warfarin, “you can check the INR [international normalized ratio].”
The current analysis included 40,482 patients with recently diagnosed AFib and at least one other stroke risk factor from among the registry’s more than 50,000 patients from 35 countries, enrolled from 2010 to 2016. They were followed for 2 years.
The 703 patients with BMI under 18.5 at AFib diagnosis were classified per World Health Organization definitions as underweight; the 13,095 with BMI 18.5-25 as normal weight; the 15,043 with BMI 25-30 as overweight; the 7,560 with BMI 30-35 as obese; and the 4,081 with BMI above 35 as extremely obese. Their ages averaged 71 years, and 55.6% were men.
BMI effects on different outcomes
Relationships between BMI and all-cause mortality and between BMI and new or worsening HF emerged as U-shaped, the risk climbing with both increasing and decreasing BMI. The nadir BMI for risk was about 30 in the case of mortality and about 25 for new or worsening HF.
The all-cause mortality risk rose by 32% for every 5 BMI points lower than a BMI of 30, and by 16% for every 5 BMI points higher than 30, in a partially adjusted analysis. The risk for new or worsening HF rose significantly with increasing but not decreasing BMI, and the reverse was observed for the endpoint of major bleeding.
The effect of BMI on all-cause mortality was “substantially attenuated” when the analysis was further adjusted with “likely mediators of any association between BMI and outcomes,” including hypertension, diabetes, HF, cerebrovascular events, and history of bleeding, Dr. Camm said.
That blunted BMI-mortality relationship, he said, “suggests that a lot of the effect is mediated through relatively traditional risk factors like hypertension and diabetes.”
The 2010 AFFIRM analysis by BMI, Dr. Lavie noted, “didn’t even look at the underweight; they actually threw them out.” Yet, such patients with AFib, who tend to be extremely frail or have chronic diseases or conditions other than the arrhythmia, are common. A take-home of the current study is that “the underweight with atrial fibrillation have a really bad prognosis.”
That message isn’t heard as much, he observed, “but is as important as saying that BMI 30 has the best prognosis. The worst prognosis is with the underweight or the really extreme obese.”
Dr. Camm discloses research funding from the British Heart Foundation. Disclosures for the other authors are in the report. Dr. Lavie has previously disclosed serving as a speaker and consultant for PAI Health and DSM Nutritional Products and is the author of “The Obesity Paradox: When Thinner Means Sicker and Heavier Means Healthier” (Avery, 2014).
A version of this article first appeared on Medscape.com.
The relationship between body mass index (BMI) and all-cause mortality in patients with atrial fibrillation (AFib) is U-shaped, with the risk highest in those who are underweight or severely obese and lowest in patients defined simply as obese, a registry analysis suggests. It also showed a similar relationship between BMI and risk for new or worsening heart failure (HF).
Mortality bottomed out at a BMI of about 30-35 kg/m2, which suggests that mild obesity was protective, compared even with “normal-weight” or “overweight” BMI. Still, mortality went up sharply from there with rising BMI.
But higher BMI, a surrogate for obesity, apparently didn’t worsen outcomes by itself. The risk for death from any cause at higher obesity levels was found to depend a lot on related risk factors and comorbidities when the analysis controlled for conditions such as diabetes and hypertension.
The findings suggest an inverse relationship between BMI and all-cause mortality in AFib only for patients with BMI less than about 30. They therefore argue against any “obesity paradox” in AFib that posits consistently better survival with increasing levels of obesity, say researchers, based on their analysis of patients with new-onset AFib in the GARFIELD-AF registry.
“It’s common practice now for clinicians to discuss weight within a clinic setting when they’re talking to their AFib patients,” observed Christian Fielder Camm, BM, BCh, University of Oxford (England), and Royal Berkshire NHS Foundation Trust, Reading, England. So studies suggesting an inverse association between BMI and AFib-related risk can be a concern.
Such studies “seem to suggest that once you’ve got AFib, maintaining a high or very high BMI may in some way be protective – which is contrary to what would seem to make sense and certainly contrary to what our results have shown,” Dr. Camm told this news organization.
“I think that having further evidence now to suggest, actually, that greater BMI is associated with a greater risk of all-cause mortality and heart failure helps reframe that discussion at the physician-patient interaction level more clearly, and ensures that we’re able to talk to our patients appropriately about risks associated with BMI and atrial fibrillation,” said Dr. Camm, who is lead author on the analysis published in Open Heart.
“Obesity is a cause of most cardiovascular diseases, but [these] data would support that being overweight or having mild obesity does not increase the risk,” observed Carl J. Lavie, MD, of the John Ochsner Heart and Vascular Institute, New Orleans, La., and the Ochsner Clinical School at the University of Queensland, Brisbane, Australia.
“At a BMI of 40, it’s very important for them to lose weight for their long-term prognosis,” Dr. Lavie noted, but “at a BMI of 30, the important thing would be to prevent further weight gain. And if they could keep their BMI of 30, they should have a good prognosis. Their prognosis would be particularly good if they didn’t gain weight and put themselves in a more extreme obesity class that is associated with worse risk.”
The current analysis, Dr. Lavie said, “is way better than the AFFIRM study,” which yielded an obesity-paradox report on its patients with AFib about a dozen years ago. “It’s got more data, more numbers, more statistical power,” and breaks BMI into more categories.
That previous analysis based on the influential AFFIRM randomized trial separated its 4,060 patients with AFib into normal (BMI, 18.5-25), overweight (BMI, 25-30), and obese (BMI, > 30) categories, per the convention at the time. It concluded that “obese patients with atrial fibrillation appear to have better long-term outcomes than nonobese patients.”
Bleeding risk on oral anticoagulants
Also noteworthy in the current analysis, variation in BMI didn’t seem to affect mortality or risk for major bleeding or nonhemorrhagic stroke according to choice of oral anticoagulant – whether a new oral anticoagulant (NOAC) or a vitamin K antagonist (VKA).
“We saw that even in the obese and extremely obese group, all-cause mortality was lower in the group taking NOACs, compared with taking warfarin,” Dr. Camm observed, “which goes against the idea that we would need any kind of dose adjustments for increased BMI.”
Indeed, the report notes, use of NOACs, compared with VKA, was associated with a 23% drop in risk for death among patients who were either normal weight or overweight and also in those who were obese or extremely obese.
Those findings “are basically saying that the NOACs look better than warfarin regardless of weight,” agreed Dr. Lavie. “The problem is that the study is not very powered.”
Whereas the benefits of NOACs, compared to VKA, seem similar for patients with a BMI of 30 or 34, compared with a BMI of 23, for example, “none of the studies has many people with 50 BMI.” Many clinicians “feel uncomfortable giving the same dose of NOAC to somebody who has a 60 BMI,” he said. At least with warfarin, “you can check the INR [international normalized ratio].”
The current analysis included 40,482 patients with recently diagnosed AFib and at least one other stroke risk factor from among the registry’s more than 50,000 patients from 35 countries, enrolled from 2010 to 2016. They were followed for 2 years.
The 703 patients with BMI under 18.5 at AFib diagnosis were classified per World Health Organization definitions as underweight; the 13,095 with BMI 18.5-25 as normal weight; the 15,043 with BMI 25-30 as overweight; the 7,560 with BMI 30-35 as obese; and the 4,081 with BMI above 35 as extremely obese. Their ages averaged 71 years, and 55.6% were men.
BMI effects on different outcomes
Relationships between BMI and all-cause mortality and between BMI and new or worsening HF emerged as U-shaped, the risk climbing with both increasing and decreasing BMI. The nadir BMI for risk was about 30 in the case of mortality and about 25 for new or worsening HF.
The all-cause mortality risk rose by 32% for every 5 BMI points lower than a BMI of 30, and by 16% for every 5 BMI points higher than 30, in a partially adjusted analysis. The risk for new or worsening HF rose significantly with increasing but not decreasing BMI, and the reverse was observed for the endpoint of major bleeding.
The effect of BMI on all-cause mortality was “substantially attenuated” when the analysis was further adjusted with “likely mediators of any association between BMI and outcomes,” including hypertension, diabetes, HF, cerebrovascular events, and history of bleeding, Dr. Camm said.
That blunted BMI-mortality relationship, he said, “suggests that a lot of the effect is mediated through relatively traditional risk factors like hypertension and diabetes.”
The 2010 AFFIRM analysis by BMI, Dr. Lavie noted, “didn’t even look at the underweight; they actually threw them out.” Yet, such patients with AFib, who tend to be extremely frail or have chronic diseases or conditions other than the arrhythmia, are common. A take-home of the current study is that “the underweight with atrial fibrillation have a really bad prognosis.”
That message isn’t heard as much, he observed, “but is as important as saying that BMI 30 has the best prognosis. The worst prognosis is with the underweight or the really extreme obese.”
Dr. Camm discloses research funding from the British Heart Foundation. Disclosures for the other authors are in the report. Dr. Lavie has previously disclosed serving as a speaker and consultant for PAI Health and DSM Nutritional Products and is the author of “The Obesity Paradox: When Thinner Means Sicker and Heavier Means Healthier” (Avery, 2014).
A version of this article first appeared on Medscape.com.
FROM OPEN HEART
Safety Profile of Mutant EGFR-TK Inhibitors in Advanced Non–Small Cell Lung Cancer: A Meta-analysis
Lung cancer has been the leading cause of cancer-related mortality for decades. It is also predicted to remain as the leading cause of cancer-related mortality through 2030.1 Platinum-based chemotherapy, including carboplatin and paclitaxel, was introduced 3 decades ago and revolutionized the management of advanced non–small cell lung cancer (NSCLC). A more recent advancement has been mutant epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors.1 EGFR is a transmembrane protein that functions by transducing essential growth factor signaling from the extracellular milieu to the cell. As 60% of the advanced NSCLC expresses this receptor, blocking the mutant EGFR receptor was a groundbreaking development in the management of advanced NSCLC.2 Development of mutant EGFR-TK inhibitors has revolutionized the management of advanced NSCLC. This study was conducted to determine the safety profile of mutant EGFR-TK inhibitors in the management of advanced NSCLC.
Methods
This meta-analysis was conducted according to Cochrane Collaboration guidelines and reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The findings are summarized in the PRISMA flow diagram (Figure 1). Two authors (MZ and MM) performed a systematic literature search using databases such as MEDLINE (via PubMed), Embase, and Cochrane Library using the medical search terms and their respective entry words with the following search strategy: safety, “mutant EGFR-TK inhibitors,” advanced, “non–small cell,” “lung cancer,” “adverse effect,” and literature. Additionally, unpublished trials were identified from clinicaltrials.gov, and references of all pertinent articles were also scrutinized to ensure the inclusion of all relevant studies. The search was completed on June 1, 2021, and we only included studies available in English. Two authors (MM and MZ) independently screened the search results in a 2-step process based on predetermined inclusion/exclusion criteria. First, 890 articles were evaluated for relevance on title and abstract level, followed by full-text screening of the final list of 140 articles. Any disagreements were resolved by discussion or third-party review, and a total of 9 articles were included in the study.
The following eligibility criteria were used: original articles reporting adverse effects (AEs) of mutant EGFR-TK inhibitors in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy. All the patients included in the study had an EGFR mutation but randomly assigned to either treatment or control group. All articles with subjective data on mutant EGFR-TK inhibitors AEs in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy were included in the analysis. Only 9 articles qualified the aforementioned selection criteria for eligibility. All qualifying studies were nationwide inpatient or pooled clinical trials data. The reasons for exclusion of the other 71 articles were irrelevant (n = 31), duplicate (n = 13), reviews (n = 14), and poor data reporting (n = 12). Out of the 9 included studies, 9 studies showed correlation of AEs, including rash, diarrhea, nausea, and fatigue. Seven studies showed correlation of AEs including neutropenia, anorexia, and vomiting. Six studies showed correlation of anemia, cough, and stomatitis. Five studies showed correlation of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and leucopenia. Four studies showed correlation of fever between mutant EGFR-TK inhibitors and platinum-based chemotherapy.
The primary endpoints were reported AEs including rash, diarrhea, elevated ALT, elevated AST, stomatitis, nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever, respectively. Data on baseline characteristics and clinical outcomes were then extracted, and summary tables were created. Summary estimates of the clinical endpoints were then calculated with risk ratio (RR) and 95% confidence intervals (CIs) using the random-effects model. Heterogeneity between studies was examined with the Cochran Q I2 statistic which can be defined as low (25% to 50%), moderate (50% to 75%), or high (> 75%). Statistical analysis was performed using Comprehensive Meta-Analysis Software CMA Version 3.0.
Results
A total of 9 studies including 3415 patients (1775 in EGFR-TK inhibitor treatment group while 1640 patients in platinum-based chemotherapy control group) were included in the study. All 9 studies were phase III randomized control clinical trials conducted to compare the safety profile of mutant EGFR-TK inhibitors in patients with advanced NSCLC. Mean age was 61 years in both treatment and control groups. Further details on study and participant characteristics and safety profile including AEs are summarized in Tables 1 and 2. No evidence of publication bias was found.
Rash developed in 45.8% of patients in the treatment group receiving mutant EGFR-TK inhibitors vs only 5.6% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 7.38 with the 95% CI noted, which was statistically significant, confirming higher rash event rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 2).
Diarrhea occurred in 33.6% of patients in the mutant EGFR-TK inhibitors treatment group vs 13.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 2.63 and 95% CI was noted, which was statistically significant, confirming higher diarrheal rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 3).
Elevated ALT levels developed in 27.9% of patients in the treatment group receiving mutant EGFR-TK inhibitors compared with 15.1% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 1.37 and 95% CI was noted, which was statistically significant, confirming higher ALT levels in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 4).
Elevated AST levels occurred in 40.7% of patients in the mutant EGFR-TK inhibitors treatment group vs 12.8% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 1.77 and 95% CI was noted, which was statistically significant, confirming elevated AST levels in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 5).
Stomatitis developed in 17.2% of patients in the treatment group receiving mutant EGFR-TK inhibitors compared with 7.9% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 1.53 and 95% CI was noted, which was statistically significant, confirming higher stomatitis event rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 6).
Nausea occurred in 16.5% of patients in the mutant EGFR-TK inhibitors group vs 42.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.37 and 95% CI was noted, which was statistically significant, confirming higher nausea rates in patients receiving platinum-based chemotherapy compared with treatment group for their advanced NSCLC (Figure 7).
Leucopenia developed in 9.7% of patients in the mutant EGFR-TK inhibitors group compared with 51.3% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.18 and 95% CI was noted, which was statistically significant, confirming higher leucopenia incidence in patients receiving platinum-based chemotherapy compared with treatment group for their advanced NSCLC (Figure 8).
Fatigue was reported in 17% of patients in the mutant EGFR-TK inhibitors group compared with 29.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.59 and 95% CI was noted, which was statistically significant, confirming higher fatigue rates in patients receiving platinum-based chemotherapy compared with treatment group for their advanced NSCLC (Figure 9).
Neutropenia developed in 6.1% of patients in the mutant EGFR-TK inhibitors group vs 48.2% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.11 and 95% CI was noted, which was statistically significant, confirming higher neutropenia rates in patients receiving platinum-based chemotherapy compared with the treatment group for their advanced NSCLC (Figure 10).
Anorexia developed in 21.3% of patients in the mutant EGFR-TK inhibitors group vs 31.4% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.44 and 95% CI was noted, which was statistically significant, confirming higher anorexia rates in patients receiving platinum-based chemotherapy compared with the treatment group for their advanced NSCLC (Figure 11).
Anemia occurred in 8.7% of patients in the mutant EGFR-TK inhibitors group compared with 32.1% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.24 and 95% CI was noted, which was statistically significant, confirming higher anorexia rates in patients receiving platinum-based chemotherapy compared with treatment for their advanced NSCLC (Figure 12).
Cough was reported in 17.8% of patients in the mutant EGFR-TK inhibitors group compared with 18.9% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.99 and 95% CI was noted, which was statistically significant, confirming slightly higher cough rates in patients receiving platinum-based chemotherapy compared with treatment for their advanced NSCLC (Figure 13).
Vomiting developed in 11% of patients in the mutant EGFR-TK inhibitors group vs 30.1% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.35 and 95% CI was noted, which was statistically significant, confirming higher vomiting rates in patients receiving platinum-based chemotherapy compared with the treatment group for their advanced NSCLC (Figure 14).
Fever occurred in 5.6% of patients in the mutant EGFR-TK inhibitors group compared with 30.1% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.41 and 95% CI was noted, which was statistically significant, confirming higher fever rates in patients receiving platinum-based chemotherapy compared with the treatment group for their advanced NSCLC (Figure 15).
Discussion
Despite the advancement in the treatment of metastatic NSCLC, lung cancer stays as most common cause of cancer-related death in North America and European countries, as patients usually have an advanced disease at the time of diagnosis.3 In the past, platinum-based chemotherapy remained the standard of care for most of the patients affected with advanced NSCLC, but the higher recurrence rate and increase in frequency and intensity of AEs with platinum-based chemotherapy led to the development of targeted therapy for NSCLC, one of which includes
Smoking is the most common reversible risk factor associated with lung cancer. The EURTAC trial was the first perspective study in this regard, which compared safety and efficacy of mutant EGFR-TK inhibitors with platinum-based chemotherapy. Results analyzed in this study were in favor of mutant EGFR-TK inhibitors except in the group of former smokers.5 On the contrary, the OPTIMAL trial showed results in favor of mutant EGFR-TK inhibitors both in active and former smokers; this trial also confirmed the efficacy of mutant EGFR-TK inhibitors in European and Asian populations, confirming the rationale for routine testing of EGFR mutation in all the patients being diagnosed with advanced NSCLC.6 Similarly, osimertinib is one of the most recent mutant EGFR-TK inhibitors developed for the treatment of advanced NSCLC in patients with EGFR-positive receptors.
According to the FLAURA trial, patients receiving osimertinib showed significantly longer progression-free survival compared with platinum-based chemotherapy and early mutant EGFR-TK inhibitors. Median progression-free survival was noted to be 18.9 months, which showed 54% lower risk of disease progression in the treatment group receiving osimertinib.7 The ARCHER study emphasized a significant improvement in overall survival as well as progression-free survival among a patient population receiving dacomitinib compared with platinum-based chemotherapy.8,9
Being a potent targeted therapy, mutant EGFR-TK inhibitors do come with some AEs including diarrhea, which was seen in 33.6% of the patients receiving mutant EGFR-TK inhibitors in our study vs 53% in the chemotherapy group, as was observed in the study conducted by Pless and colleagues.10 Similarly, only 16.5% of patients receiving mutant EGFR-TK inhibitors developed nausea compared with 66% being observed in patients receiving chemotherapy. Correspondingly, only a small fraction of patients (9.7%) receiving mutant EGFR-TK inhibitors developed leucopenia, which was 10 times less reported in mutant EGFR-TK inhibitors compared with patients receiving chemotherapy having a percentage of 100%. A similar trend was reported for neutropenia and anemia in mutant EGFR-TK inhibitors with an incidence of 6.1% and 8.7%, compared with the platinum-based chemotherapy group in which the incidence was found to be 80% and 100%, respectively. It was concluded that platinum-based chemotherapy had played a vital role in the treatment of advanced NSCLC but at an expense of serious and severe AEs which led to discontinuation or withdrawal of treatment, leading to relapse and recurrence of lung cancer.10,11
Zhong and colleagues conducted a phase 2 randomized clinical trial comparing mutant EGFR-TK inhibitors with platinum-based chemotherapy. They concluded that in patients receiving platinum-based chemotherapy, incidence of rash, vomiting, anorexia, neutropenia, and nausea were 29.4%, 47%, 41.2%, 55.8%, and 32.4% compared with 45.8%, 11%, 21.3%, 6.1%, and 16.5%, respectively, reported in patients receiving mutant EGFR-TK inhibitors for their advanced NSCLC.12
Another study was conducted in 2019 by Noronha and colleagues to determine the impact of platinum-based chemotherapy combined with gefitinib on patients with advanced NSCLC.13 They concluded that 70% of the patients receiving combination treatment developed rash, which was significantly higher compared with 45.8% patients receiving the mutant EGFR-TK inhibitors alone in our study. Also, 56% of patients receiving combination therapy developed diarrhea vs 33.6% of patients receiving mutant EGFR-TK inhibitors only. Similarly, 96% of patients in the combination therapy group developed some degree of anemia compared with only 8.7% patients in the mutant EGFR-TK inhibitors group included in our study. In the same way, neutropenia was observed in 55% of patients receiving combination therapy vs 6.1% in patients receiving mutant EGFR-TK inhibitors solely. They concluded that mutant EGFR-TK inhibitors when combined with platinum-based chemotherapy increase the incidence of AEs of chemotherapy by many folds.13,14
Kato and colleagues conducted a study to determine the impact on AEs when erlotinib was combined with anti–vascular endothelial growth factor (VEGF) inhibitors like bevacizumab, they stated that 98.7% of patient in combination therapy developed rash, the incidence of which was only 45.8% in patients receiving mutant EGFR-TK inhibitors as was observed in our study. Similar trends were noticed with other AEs, including diarrhea, fatigue, nausea, and elevated liver enzymes.15
With the latest advancements in the management of advanced NSCLC, nivolumab, a programmed death ligand 1 (PD-L1) inhibitor, was developed and either used as monotherapy in patients with PD-L1 expression or was combined with platinum-based chemotherapy regardless of PD-L1 expression.16,17 Patients expressing lower PD-L1 levels were not omitted from receiving nivolumab as no significant difference was noted in progression-free span and overall survival in patients receiving nivolumab irrespective of PD-L1 levels.15 Rash developed in 17% of patients after receiving nivolumab vs 45.8% patients being observed in our study. A similar trend was observed with diarrhea as only 17% of the population receiving nivolumab developed diarrhea compared with 33.6% of the population receiving mutant EGFR-TK inhibitors in our study. Likewise, only 9.9% of the patients receiving nivolumab developed nausea as an AE compared with 16.5% being observed in mutant EGFR-TK inhibitors in our study. Also, fatigue was observed in 14.4% of the population receiving nivolumab vs 17% observed in patients receiving mutant EGFR-TK inhibitors as was noticed in our study.7,8
Rizvi and colleagues conducted a study on the role of nivolumab when combined with platinum-based chemotherapy in patients with advanced NSCLC and reported that 40% of patients included in the study developed rash compared with 45.8% reported in mutant EGFR-TK inhibitors in our study. Similarly, only 13% of patients in the nivolumab group developed diarrhea vs 33.6% cases reported in the mutant EGFR-TK inhibitors group included in our study. Also, 7% of patients in the nivolumab group developed elevated ALT levels vs 27.9% of patients receiving mutant EGFR-TK inhibitors included in our study, concluding that addition of immune checkpoint inhibitors like nivolumab to platinum-based chemotherapy does not increase the frequency of AEs.18
Conclusions
Our study focused on the safety profile of mutant EGFR-TK inhibitors vs platinum-based chemotherapy in the treatment of advanced NSCLC. Mutant EGFR-TK inhibitors are safer than platinum-based chemotherapy when compared for nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever. On the other end, mutant EGFR-TK inhibitors cause slightly higher AEs, including rash, diarrhea, elevated AST and ALT levels, and stomatitis. However, considering that the development of mutant EGFR-TK inhibitors laid a foundation of targeted therapy, we recommend continuing using mutant EGFR-TK inhibitors in patients with advanced NSCLC especially in patients having mutant EGFR receptors. AEs caused by mutant EGFR-TK inhibitors are significant but are usually tolerable and can be avoided by reducing the dosage of it with each cycle or by skipping or delaying the dose until the patient is symptomatic.
1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913-2921. doi:10.1158/0008-5472.CAN-14-0155
2. da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49-69. doi:10.1146/annurev-pathol-011110-130206
3. Sgambato A, Casaluce F, Maione P, et al. The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation. Curr Med Chem. 2012;19(20):3337-3352. doi:10.2174/092986712801215973
4. Rossi A, Di Maio M. Platinum-based chemotherapy in advanced non–small-cell lung cancer: optimal number of treatment cycles. Expert Rev Anticancer Ther. 2016;16(6):653-660. doi:10.1586/14737140.2016.1170596
5. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non–small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246. doi:10.1016/S1470-2045(11)70393-X
6. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non–small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742. doi:10.1016/S1470-2045(11)70184-X
7. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
8. Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non–small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018;36(22):2244-2250. doi:10.1200/JCO.2018.78.7994
9. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957. doi:10.1056/NEJMoa0810699
10. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non–small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386(9998):1049-1056. doi:10.1016/S0140-6736(15)60294-X
11. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non–small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol. 1995;13(8):1880-1892. doi:10.1200/JCO.1995.13.8.1880
12. Zhong WZ, Chen KN, Chen C, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of Stage IIIA-N2 EGFR-mutant non–small-cell lung cancer (EMERGING-CTONG 1103): a randomized phase II study. J Clin Oncol. 2019;37(25):2235-2245. doi:10.1200/JCO.19.00075
13. Noronha V, Patil VM, Joshi A, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol. 2020;38(2):124-136. doi:10.1200/JCO.19.01154
14. Noronha V, Prabhash K, Thavamani A, et al. EGFR mutations in Indian lung cancer patients: clinical correlation and outcome to EGFR targeted therapy. PLoS One. 2013;8(4):e61561. Published 2013 Apr 19. doi:10.1371/journal.pone.0061561
15. Kato T, Seto T, Nishio M, et al. Erlotinib plus bevacizumab phase ll study in patients with advanced non–small-cell lung cancer (JO25567): updated safety results. Drug Saf. 2018;41(2):229-237. doi:10.1007/s40264-017-0596-0
16. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231
17. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946
18. Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non–small-cell lung cancer. J Clin Oncol. 2016;34(25):2969-2979. doi:10.1200/JCO.2016.66.9861
19. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC: final overall survival analysis of CTONG1104 Phase III Trial. J Clin Oncol. 2021;39(7):713-722. doi:10.1200/JCO.20.01820
20. Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830-838. doi:10.1016/S1470-2045(15)00026-1
21. Shi YK, Wang L, Han BH, et al. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017;28(10):2443-2450. doi:10.1093/annonc/mdx359
22. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomized trial. Lancet Oncol. 2015;16(8):990-998 doi:10.1016/S1470-2045(15)00121-7
23. Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013;31(27):3320-3326. doi:10.1200/JCO.2013.51.1816
24. Sun JM, Lee KH, Kim SW, et al. Gefitinib versus pemetrexed as second-line treatment in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012;118(24):6234-6242. doi:10.1200/JCO.2013.51.1816
25. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol. 2010;11(2):121-128. doi:10.1016/S1470-2045(09)70364-X
26. Lee DH, Park K, Kim JH, Lee JS, et al. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010;16(4):1307-1314. doi:10.1158/1078-0432.CCR-09-1903
27. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomized phase III trial. Lancet. 2008;22;372(9652):1809-1818. doi:10.1016/S0140-6736(08)61758-4
Lung cancer has been the leading cause of cancer-related mortality for decades. It is also predicted to remain as the leading cause of cancer-related mortality through 2030.1 Platinum-based chemotherapy, including carboplatin and paclitaxel, was introduced 3 decades ago and revolutionized the management of advanced non–small cell lung cancer (NSCLC). A more recent advancement has been mutant epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors.1 EGFR is a transmembrane protein that functions by transducing essential growth factor signaling from the extracellular milieu to the cell. As 60% of the advanced NSCLC expresses this receptor, blocking the mutant EGFR receptor was a groundbreaking development in the management of advanced NSCLC.2 Development of mutant EGFR-TK inhibitors has revolutionized the management of advanced NSCLC. This study was conducted to determine the safety profile of mutant EGFR-TK inhibitors in the management of advanced NSCLC.
Methods
This meta-analysis was conducted according to Cochrane Collaboration guidelines and reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The findings are summarized in the PRISMA flow diagram (Figure 1). Two authors (MZ and MM) performed a systematic literature search using databases such as MEDLINE (via PubMed), Embase, and Cochrane Library using the medical search terms and their respective entry words with the following search strategy: safety, “mutant EGFR-TK inhibitors,” advanced, “non–small cell,” “lung cancer,” “adverse effect,” and literature. Additionally, unpublished trials were identified from clinicaltrials.gov, and references of all pertinent articles were also scrutinized to ensure the inclusion of all relevant studies. The search was completed on June 1, 2021, and we only included studies available in English. Two authors (MM and MZ) independently screened the search results in a 2-step process based on predetermined inclusion/exclusion criteria. First, 890 articles were evaluated for relevance on title and abstract level, followed by full-text screening of the final list of 140 articles. Any disagreements were resolved by discussion or third-party review, and a total of 9 articles were included in the study.
The following eligibility criteria were used: original articles reporting adverse effects (AEs) of mutant EGFR-TK inhibitors in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy. All the patients included in the study had an EGFR mutation but randomly assigned to either treatment or control group. All articles with subjective data on mutant EGFR-TK inhibitors AEs in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy were included in the analysis. Only 9 articles qualified the aforementioned selection criteria for eligibility. All qualifying studies were nationwide inpatient or pooled clinical trials data. The reasons for exclusion of the other 71 articles were irrelevant (n = 31), duplicate (n = 13), reviews (n = 14), and poor data reporting (n = 12). Out of the 9 included studies, 9 studies showed correlation of AEs, including rash, diarrhea, nausea, and fatigue. Seven studies showed correlation of AEs including neutropenia, anorexia, and vomiting. Six studies showed correlation of anemia, cough, and stomatitis. Five studies showed correlation of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and leucopenia. Four studies showed correlation of fever between mutant EGFR-TK inhibitors and platinum-based chemotherapy.
The primary endpoints were reported AEs including rash, diarrhea, elevated ALT, elevated AST, stomatitis, nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever, respectively. Data on baseline characteristics and clinical outcomes were then extracted, and summary tables were created. Summary estimates of the clinical endpoints were then calculated with risk ratio (RR) and 95% confidence intervals (CIs) using the random-effects model. Heterogeneity between studies was examined with the Cochran Q I2 statistic which can be defined as low (25% to 50%), moderate (50% to 75%), or high (> 75%). Statistical analysis was performed using Comprehensive Meta-Analysis Software CMA Version 3.0.
Results
A total of 9 studies including 3415 patients (1775 in EGFR-TK inhibitor treatment group while 1640 patients in platinum-based chemotherapy control group) were included in the study. All 9 studies were phase III randomized control clinical trials conducted to compare the safety profile of mutant EGFR-TK inhibitors in patients with advanced NSCLC. Mean age was 61 years in both treatment and control groups. Further details on study and participant characteristics and safety profile including AEs are summarized in Tables 1 and 2. No evidence of publication bias was found.
Rash developed in 45.8% of patients in the treatment group receiving mutant EGFR-TK inhibitors vs only 5.6% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 7.38 with the 95% CI noted, which was statistically significant, confirming higher rash event rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 2).
Diarrhea occurred in 33.6% of patients in the mutant EGFR-TK inhibitors treatment group vs 13.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 2.63 and 95% CI was noted, which was statistically significant, confirming higher diarrheal rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 3).
Elevated ALT levels developed in 27.9% of patients in the treatment group receiving mutant EGFR-TK inhibitors compared with 15.1% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 1.37 and 95% CI was noted, which was statistically significant, confirming higher ALT levels in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 4).
Elevated AST levels occurred in 40.7% of patients in the mutant EGFR-TK inhibitors treatment group vs 12.8% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 1.77 and 95% CI was noted, which was statistically significant, confirming elevated AST levels in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 5).
Stomatitis developed in 17.2% of patients in the treatment group receiving mutant EGFR-TK inhibitors compared with 7.9% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 1.53 and 95% CI was noted, which was statistically significant, confirming higher stomatitis event rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 6).
Nausea occurred in 16.5% of patients in the mutant EGFR-TK inhibitors group vs 42.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.37 and 95% CI was noted, which was statistically significant, confirming higher nausea rates in patients receiving platinum-based chemotherapy compared with treatment group for their advanced NSCLC (Figure 7).
Leucopenia developed in 9.7% of patients in the mutant EGFR-TK inhibitors group compared with 51.3% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.18 and 95% CI was noted, which was statistically significant, confirming higher leucopenia incidence in patients receiving platinum-based chemotherapy compared with treatment group for their advanced NSCLC (Figure 8).
Fatigue was reported in 17% of patients in the mutant EGFR-TK inhibitors group compared with 29.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.59 and 95% CI was noted, which was statistically significant, confirming higher fatigue rates in patients receiving platinum-based chemotherapy compared with treatment group for their advanced NSCLC (Figure 9).
Neutropenia developed in 6.1% of patients in the mutant EGFR-TK inhibitors group vs 48.2% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.11 and 95% CI was noted, which was statistically significant, confirming higher neutropenia rates in patients receiving platinum-based chemotherapy compared with the treatment group for their advanced NSCLC (Figure 10).
Anorexia developed in 21.3% of patients in the mutant EGFR-TK inhibitors group vs 31.4% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.44 and 95% CI was noted, which was statistically significant, confirming higher anorexia rates in patients receiving platinum-based chemotherapy compared with the treatment group for their advanced NSCLC (Figure 11).
Anemia occurred in 8.7% of patients in the mutant EGFR-TK inhibitors group compared with 32.1% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.24 and 95% CI was noted, which was statistically significant, confirming higher anorexia rates in patients receiving platinum-based chemotherapy compared with treatment for their advanced NSCLC (Figure 12).
Cough was reported in 17.8% of patients in the mutant EGFR-TK inhibitors group compared with 18.9% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.99 and 95% CI was noted, which was statistically significant, confirming slightly higher cough rates in patients receiving platinum-based chemotherapy compared with treatment for their advanced NSCLC (Figure 13).
Vomiting developed in 11% of patients in the mutant EGFR-TK inhibitors group vs 30.1% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.35 and 95% CI was noted, which was statistically significant, confirming higher vomiting rates in patients receiving platinum-based chemotherapy compared with the treatment group for their advanced NSCLC (Figure 14).
Fever occurred in 5.6% of patients in the mutant EGFR-TK inhibitors group compared with 30.1% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.41 and 95% CI was noted, which was statistically significant, confirming higher fever rates in patients receiving platinum-based chemotherapy compared with the treatment group for their advanced NSCLC (Figure 15).
Discussion
Despite the advancement in the treatment of metastatic NSCLC, lung cancer stays as most common cause of cancer-related death in North America and European countries, as patients usually have an advanced disease at the time of diagnosis.3 In the past, platinum-based chemotherapy remained the standard of care for most of the patients affected with advanced NSCLC, but the higher recurrence rate and increase in frequency and intensity of AEs with platinum-based chemotherapy led to the development of targeted therapy for NSCLC, one of which includes
Smoking is the most common reversible risk factor associated with lung cancer. The EURTAC trial was the first perspective study in this regard, which compared safety and efficacy of mutant EGFR-TK inhibitors with platinum-based chemotherapy. Results analyzed in this study were in favor of mutant EGFR-TK inhibitors except in the group of former smokers.5 On the contrary, the OPTIMAL trial showed results in favor of mutant EGFR-TK inhibitors both in active and former smokers; this trial also confirmed the efficacy of mutant EGFR-TK inhibitors in European and Asian populations, confirming the rationale for routine testing of EGFR mutation in all the patients being diagnosed with advanced NSCLC.6 Similarly, osimertinib is one of the most recent mutant EGFR-TK inhibitors developed for the treatment of advanced NSCLC in patients with EGFR-positive receptors.
According to the FLAURA trial, patients receiving osimertinib showed significantly longer progression-free survival compared with platinum-based chemotherapy and early mutant EGFR-TK inhibitors. Median progression-free survival was noted to be 18.9 months, which showed 54% lower risk of disease progression in the treatment group receiving osimertinib.7 The ARCHER study emphasized a significant improvement in overall survival as well as progression-free survival among a patient population receiving dacomitinib compared with platinum-based chemotherapy.8,9
Being a potent targeted therapy, mutant EGFR-TK inhibitors do come with some AEs including diarrhea, which was seen in 33.6% of the patients receiving mutant EGFR-TK inhibitors in our study vs 53% in the chemotherapy group, as was observed in the study conducted by Pless and colleagues.10 Similarly, only 16.5% of patients receiving mutant EGFR-TK inhibitors developed nausea compared with 66% being observed in patients receiving chemotherapy. Correspondingly, only a small fraction of patients (9.7%) receiving mutant EGFR-TK inhibitors developed leucopenia, which was 10 times less reported in mutant EGFR-TK inhibitors compared with patients receiving chemotherapy having a percentage of 100%. A similar trend was reported for neutropenia and anemia in mutant EGFR-TK inhibitors with an incidence of 6.1% and 8.7%, compared with the platinum-based chemotherapy group in which the incidence was found to be 80% and 100%, respectively. It was concluded that platinum-based chemotherapy had played a vital role in the treatment of advanced NSCLC but at an expense of serious and severe AEs which led to discontinuation or withdrawal of treatment, leading to relapse and recurrence of lung cancer.10,11
Zhong and colleagues conducted a phase 2 randomized clinical trial comparing mutant EGFR-TK inhibitors with platinum-based chemotherapy. They concluded that in patients receiving platinum-based chemotherapy, incidence of rash, vomiting, anorexia, neutropenia, and nausea were 29.4%, 47%, 41.2%, 55.8%, and 32.4% compared with 45.8%, 11%, 21.3%, 6.1%, and 16.5%, respectively, reported in patients receiving mutant EGFR-TK inhibitors for their advanced NSCLC.12
Another study was conducted in 2019 by Noronha and colleagues to determine the impact of platinum-based chemotherapy combined with gefitinib on patients with advanced NSCLC.13 They concluded that 70% of the patients receiving combination treatment developed rash, which was significantly higher compared with 45.8% patients receiving the mutant EGFR-TK inhibitors alone in our study. Also, 56% of patients receiving combination therapy developed diarrhea vs 33.6% of patients receiving mutant EGFR-TK inhibitors only. Similarly, 96% of patients in the combination therapy group developed some degree of anemia compared with only 8.7% patients in the mutant EGFR-TK inhibitors group included in our study. In the same way, neutropenia was observed in 55% of patients receiving combination therapy vs 6.1% in patients receiving mutant EGFR-TK inhibitors solely. They concluded that mutant EGFR-TK inhibitors when combined with platinum-based chemotherapy increase the incidence of AEs of chemotherapy by many folds.13,14
Kato and colleagues conducted a study to determine the impact on AEs when erlotinib was combined with anti–vascular endothelial growth factor (VEGF) inhibitors like bevacizumab, they stated that 98.7% of patient in combination therapy developed rash, the incidence of which was only 45.8% in patients receiving mutant EGFR-TK inhibitors as was observed in our study. Similar trends were noticed with other AEs, including diarrhea, fatigue, nausea, and elevated liver enzymes.15
With the latest advancements in the management of advanced NSCLC, nivolumab, a programmed death ligand 1 (PD-L1) inhibitor, was developed and either used as monotherapy in patients with PD-L1 expression or was combined with platinum-based chemotherapy regardless of PD-L1 expression.16,17 Patients expressing lower PD-L1 levels were not omitted from receiving nivolumab as no significant difference was noted in progression-free span and overall survival in patients receiving nivolumab irrespective of PD-L1 levels.15 Rash developed in 17% of patients after receiving nivolumab vs 45.8% patients being observed in our study. A similar trend was observed with diarrhea as only 17% of the population receiving nivolumab developed diarrhea compared with 33.6% of the population receiving mutant EGFR-TK inhibitors in our study. Likewise, only 9.9% of the patients receiving nivolumab developed nausea as an AE compared with 16.5% being observed in mutant EGFR-TK inhibitors in our study. Also, fatigue was observed in 14.4% of the population receiving nivolumab vs 17% observed in patients receiving mutant EGFR-TK inhibitors as was noticed in our study.7,8
Rizvi and colleagues conducted a study on the role of nivolumab when combined with platinum-based chemotherapy in patients with advanced NSCLC and reported that 40% of patients included in the study developed rash compared with 45.8% reported in mutant EGFR-TK inhibitors in our study. Similarly, only 13% of patients in the nivolumab group developed diarrhea vs 33.6% cases reported in the mutant EGFR-TK inhibitors group included in our study. Also, 7% of patients in the nivolumab group developed elevated ALT levels vs 27.9% of patients receiving mutant EGFR-TK inhibitors included in our study, concluding that addition of immune checkpoint inhibitors like nivolumab to platinum-based chemotherapy does not increase the frequency of AEs.18
Conclusions
Our study focused on the safety profile of mutant EGFR-TK inhibitors vs platinum-based chemotherapy in the treatment of advanced NSCLC. Mutant EGFR-TK inhibitors are safer than platinum-based chemotherapy when compared for nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever. On the other end, mutant EGFR-TK inhibitors cause slightly higher AEs, including rash, diarrhea, elevated AST and ALT levels, and stomatitis. However, considering that the development of mutant EGFR-TK inhibitors laid a foundation of targeted therapy, we recommend continuing using mutant EGFR-TK inhibitors in patients with advanced NSCLC especially in patients having mutant EGFR receptors. AEs caused by mutant EGFR-TK inhibitors are significant but are usually tolerable and can be avoided by reducing the dosage of it with each cycle or by skipping or delaying the dose until the patient is symptomatic.
Lung cancer has been the leading cause of cancer-related mortality for decades. It is also predicted to remain as the leading cause of cancer-related mortality through 2030.1 Platinum-based chemotherapy, including carboplatin and paclitaxel, was introduced 3 decades ago and revolutionized the management of advanced non–small cell lung cancer (NSCLC). A more recent advancement has been mutant epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors.1 EGFR is a transmembrane protein that functions by transducing essential growth factor signaling from the extracellular milieu to the cell. As 60% of the advanced NSCLC expresses this receptor, blocking the mutant EGFR receptor was a groundbreaking development in the management of advanced NSCLC.2 Development of mutant EGFR-TK inhibitors has revolutionized the management of advanced NSCLC. This study was conducted to determine the safety profile of mutant EGFR-TK inhibitors in the management of advanced NSCLC.
Methods
This meta-analysis was conducted according to Cochrane Collaboration guidelines and reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The findings are summarized in the PRISMA flow diagram (Figure 1). Two authors (MZ and MM) performed a systematic literature search using databases such as MEDLINE (via PubMed), Embase, and Cochrane Library using the medical search terms and their respective entry words with the following search strategy: safety, “mutant EGFR-TK inhibitors,” advanced, “non–small cell,” “lung cancer,” “adverse effect,” and literature. Additionally, unpublished trials were identified from clinicaltrials.gov, and references of all pertinent articles were also scrutinized to ensure the inclusion of all relevant studies. The search was completed on June 1, 2021, and we only included studies available in English. Two authors (MM and MZ) independently screened the search results in a 2-step process based on predetermined inclusion/exclusion criteria. First, 890 articles were evaluated for relevance on title and abstract level, followed by full-text screening of the final list of 140 articles. Any disagreements were resolved by discussion or third-party review, and a total of 9 articles were included in the study.
The following eligibility criteria were used: original articles reporting adverse effects (AEs) of mutant EGFR-TK inhibitors in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy. All the patients included in the study had an EGFR mutation but randomly assigned to either treatment or control group. All articles with subjective data on mutant EGFR-TK inhibitors AEs in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy were included in the analysis. Only 9 articles qualified the aforementioned selection criteria for eligibility. All qualifying studies were nationwide inpatient or pooled clinical trials data. The reasons for exclusion of the other 71 articles were irrelevant (n = 31), duplicate (n = 13), reviews (n = 14), and poor data reporting (n = 12). Out of the 9 included studies, 9 studies showed correlation of AEs, including rash, diarrhea, nausea, and fatigue. Seven studies showed correlation of AEs including neutropenia, anorexia, and vomiting. Six studies showed correlation of anemia, cough, and stomatitis. Five studies showed correlation of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and leucopenia. Four studies showed correlation of fever between mutant EGFR-TK inhibitors and platinum-based chemotherapy.
The primary endpoints were reported AEs including rash, diarrhea, elevated ALT, elevated AST, stomatitis, nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever, respectively. Data on baseline characteristics and clinical outcomes were then extracted, and summary tables were created. Summary estimates of the clinical endpoints were then calculated with risk ratio (RR) and 95% confidence intervals (CIs) using the random-effects model. Heterogeneity between studies was examined with the Cochran Q I2 statistic which can be defined as low (25% to 50%), moderate (50% to 75%), or high (> 75%). Statistical analysis was performed using Comprehensive Meta-Analysis Software CMA Version 3.0.
Results
A total of 9 studies including 3415 patients (1775 in EGFR-TK inhibitor treatment group while 1640 patients in platinum-based chemotherapy control group) were included in the study. All 9 studies were phase III randomized control clinical trials conducted to compare the safety profile of mutant EGFR-TK inhibitors in patients with advanced NSCLC. Mean age was 61 years in both treatment and control groups. Further details on study and participant characteristics and safety profile including AEs are summarized in Tables 1 and 2. No evidence of publication bias was found.
Rash developed in 45.8% of patients in the treatment group receiving mutant EGFR-TK inhibitors vs only 5.6% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 7.38 with the 95% CI noted, which was statistically significant, confirming higher rash event rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 2).
Diarrhea occurred in 33.6% of patients in the mutant EGFR-TK inhibitors treatment group vs 13.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 2.63 and 95% CI was noted, which was statistically significant, confirming higher diarrheal rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 3).
Elevated ALT levels developed in 27.9% of patients in the treatment group receiving mutant EGFR-TK inhibitors compared with 15.1% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 1.37 and 95% CI was noted, which was statistically significant, confirming higher ALT levels in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 4).
Elevated AST levels occurred in 40.7% of patients in the mutant EGFR-TK inhibitors treatment group vs 12.8% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 1.77 and 95% CI was noted, which was statistically significant, confirming elevated AST levels in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 5).
Stomatitis developed in 17.2% of patients in the treatment group receiving mutant EGFR-TK inhibitors compared with 7.9% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 1.53 and 95% CI was noted, which was statistically significant, confirming higher stomatitis event rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 6).
Nausea occurred in 16.5% of patients in the mutant EGFR-TK inhibitors group vs 42.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.37 and 95% CI was noted, which was statistically significant, confirming higher nausea rates in patients receiving platinum-based chemotherapy compared with treatment group for their advanced NSCLC (Figure 7).
Leucopenia developed in 9.7% of patients in the mutant EGFR-TK inhibitors group compared with 51.3% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.18 and 95% CI was noted, which was statistically significant, confirming higher leucopenia incidence in patients receiving platinum-based chemotherapy compared with treatment group for their advanced NSCLC (Figure 8).
Fatigue was reported in 17% of patients in the mutant EGFR-TK inhibitors group compared with 29.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.59 and 95% CI was noted, which was statistically significant, confirming higher fatigue rates in patients receiving platinum-based chemotherapy compared with treatment group for their advanced NSCLC (Figure 9).
Neutropenia developed in 6.1% of patients in the mutant EGFR-TK inhibitors group vs 48.2% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.11 and 95% CI was noted, which was statistically significant, confirming higher neutropenia rates in patients receiving platinum-based chemotherapy compared with the treatment group for their advanced NSCLC (Figure 10).
Anorexia developed in 21.3% of patients in the mutant EGFR-TK inhibitors group vs 31.4% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.44 and 95% CI was noted, which was statistically significant, confirming higher anorexia rates in patients receiving platinum-based chemotherapy compared with the treatment group for their advanced NSCLC (Figure 11).
Anemia occurred in 8.7% of patients in the mutant EGFR-TK inhibitors group compared with 32.1% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.24 and 95% CI was noted, which was statistically significant, confirming higher anorexia rates in patients receiving platinum-based chemotherapy compared with treatment for their advanced NSCLC (Figure 12).
Cough was reported in 17.8% of patients in the mutant EGFR-TK inhibitors group compared with 18.9% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.99 and 95% CI was noted, which was statistically significant, confirming slightly higher cough rates in patients receiving platinum-based chemotherapy compared with treatment for their advanced NSCLC (Figure 13).
Vomiting developed in 11% of patients in the mutant EGFR-TK inhibitors group vs 30.1% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.35 and 95% CI was noted, which was statistically significant, confirming higher vomiting rates in patients receiving platinum-based chemotherapy compared with the treatment group for their advanced NSCLC (Figure 14).
Fever occurred in 5.6% of patients in the mutant EGFR-TK inhibitors group compared with 30.1% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 0.41 and 95% CI was noted, which was statistically significant, confirming higher fever rates in patients receiving platinum-based chemotherapy compared with the treatment group for their advanced NSCLC (Figure 15).
Discussion
Despite the advancement in the treatment of metastatic NSCLC, lung cancer stays as most common cause of cancer-related death in North America and European countries, as patients usually have an advanced disease at the time of diagnosis.3 In the past, platinum-based chemotherapy remained the standard of care for most of the patients affected with advanced NSCLC, but the higher recurrence rate and increase in frequency and intensity of AEs with platinum-based chemotherapy led to the development of targeted therapy for NSCLC, one of which includes
Smoking is the most common reversible risk factor associated with lung cancer. The EURTAC trial was the first perspective study in this regard, which compared safety and efficacy of mutant EGFR-TK inhibitors with platinum-based chemotherapy. Results analyzed in this study were in favor of mutant EGFR-TK inhibitors except in the group of former smokers.5 On the contrary, the OPTIMAL trial showed results in favor of mutant EGFR-TK inhibitors both in active and former smokers; this trial also confirmed the efficacy of mutant EGFR-TK inhibitors in European and Asian populations, confirming the rationale for routine testing of EGFR mutation in all the patients being diagnosed with advanced NSCLC.6 Similarly, osimertinib is one of the most recent mutant EGFR-TK inhibitors developed for the treatment of advanced NSCLC in patients with EGFR-positive receptors.
According to the FLAURA trial, patients receiving osimertinib showed significantly longer progression-free survival compared with platinum-based chemotherapy and early mutant EGFR-TK inhibitors. Median progression-free survival was noted to be 18.9 months, which showed 54% lower risk of disease progression in the treatment group receiving osimertinib.7 The ARCHER study emphasized a significant improvement in overall survival as well as progression-free survival among a patient population receiving dacomitinib compared with platinum-based chemotherapy.8,9
Being a potent targeted therapy, mutant EGFR-TK inhibitors do come with some AEs including diarrhea, which was seen in 33.6% of the patients receiving mutant EGFR-TK inhibitors in our study vs 53% in the chemotherapy group, as was observed in the study conducted by Pless and colleagues.10 Similarly, only 16.5% of patients receiving mutant EGFR-TK inhibitors developed nausea compared with 66% being observed in patients receiving chemotherapy. Correspondingly, only a small fraction of patients (9.7%) receiving mutant EGFR-TK inhibitors developed leucopenia, which was 10 times less reported in mutant EGFR-TK inhibitors compared with patients receiving chemotherapy having a percentage of 100%. A similar trend was reported for neutropenia and anemia in mutant EGFR-TK inhibitors with an incidence of 6.1% and 8.7%, compared with the platinum-based chemotherapy group in which the incidence was found to be 80% and 100%, respectively. It was concluded that platinum-based chemotherapy had played a vital role in the treatment of advanced NSCLC but at an expense of serious and severe AEs which led to discontinuation or withdrawal of treatment, leading to relapse and recurrence of lung cancer.10,11
Zhong and colleagues conducted a phase 2 randomized clinical trial comparing mutant EGFR-TK inhibitors with platinum-based chemotherapy. They concluded that in patients receiving platinum-based chemotherapy, incidence of rash, vomiting, anorexia, neutropenia, and nausea were 29.4%, 47%, 41.2%, 55.8%, and 32.4% compared with 45.8%, 11%, 21.3%, 6.1%, and 16.5%, respectively, reported in patients receiving mutant EGFR-TK inhibitors for their advanced NSCLC.12
Another study was conducted in 2019 by Noronha and colleagues to determine the impact of platinum-based chemotherapy combined with gefitinib on patients with advanced NSCLC.13 They concluded that 70% of the patients receiving combination treatment developed rash, which was significantly higher compared with 45.8% patients receiving the mutant EGFR-TK inhibitors alone in our study. Also, 56% of patients receiving combination therapy developed diarrhea vs 33.6% of patients receiving mutant EGFR-TK inhibitors only. Similarly, 96% of patients in the combination therapy group developed some degree of anemia compared with only 8.7% patients in the mutant EGFR-TK inhibitors group included in our study. In the same way, neutropenia was observed in 55% of patients receiving combination therapy vs 6.1% in patients receiving mutant EGFR-TK inhibitors solely. They concluded that mutant EGFR-TK inhibitors when combined with platinum-based chemotherapy increase the incidence of AEs of chemotherapy by many folds.13,14
Kato and colleagues conducted a study to determine the impact on AEs when erlotinib was combined with anti–vascular endothelial growth factor (VEGF) inhibitors like bevacizumab, they stated that 98.7% of patient in combination therapy developed rash, the incidence of which was only 45.8% in patients receiving mutant EGFR-TK inhibitors as was observed in our study. Similar trends were noticed with other AEs, including diarrhea, fatigue, nausea, and elevated liver enzymes.15
With the latest advancements in the management of advanced NSCLC, nivolumab, a programmed death ligand 1 (PD-L1) inhibitor, was developed and either used as monotherapy in patients with PD-L1 expression or was combined with platinum-based chemotherapy regardless of PD-L1 expression.16,17 Patients expressing lower PD-L1 levels were not omitted from receiving nivolumab as no significant difference was noted in progression-free span and overall survival in patients receiving nivolumab irrespective of PD-L1 levels.15 Rash developed in 17% of patients after receiving nivolumab vs 45.8% patients being observed in our study. A similar trend was observed with diarrhea as only 17% of the population receiving nivolumab developed diarrhea compared with 33.6% of the population receiving mutant EGFR-TK inhibitors in our study. Likewise, only 9.9% of the patients receiving nivolumab developed nausea as an AE compared with 16.5% being observed in mutant EGFR-TK inhibitors in our study. Also, fatigue was observed in 14.4% of the population receiving nivolumab vs 17% observed in patients receiving mutant EGFR-TK inhibitors as was noticed in our study.7,8
Rizvi and colleagues conducted a study on the role of nivolumab when combined with platinum-based chemotherapy in patients with advanced NSCLC and reported that 40% of patients included in the study developed rash compared with 45.8% reported in mutant EGFR-TK inhibitors in our study. Similarly, only 13% of patients in the nivolumab group developed diarrhea vs 33.6% cases reported in the mutant EGFR-TK inhibitors group included in our study. Also, 7% of patients in the nivolumab group developed elevated ALT levels vs 27.9% of patients receiving mutant EGFR-TK inhibitors included in our study, concluding that addition of immune checkpoint inhibitors like nivolumab to platinum-based chemotherapy does not increase the frequency of AEs.18
Conclusions
Our study focused on the safety profile of mutant EGFR-TK inhibitors vs platinum-based chemotherapy in the treatment of advanced NSCLC. Mutant EGFR-TK inhibitors are safer than platinum-based chemotherapy when compared for nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever. On the other end, mutant EGFR-TK inhibitors cause slightly higher AEs, including rash, diarrhea, elevated AST and ALT levels, and stomatitis. However, considering that the development of mutant EGFR-TK inhibitors laid a foundation of targeted therapy, we recommend continuing using mutant EGFR-TK inhibitors in patients with advanced NSCLC especially in patients having mutant EGFR receptors. AEs caused by mutant EGFR-TK inhibitors are significant but are usually tolerable and can be avoided by reducing the dosage of it with each cycle or by skipping or delaying the dose until the patient is symptomatic.
1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913-2921. doi:10.1158/0008-5472.CAN-14-0155
2. da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49-69. doi:10.1146/annurev-pathol-011110-130206
3. Sgambato A, Casaluce F, Maione P, et al. The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation. Curr Med Chem. 2012;19(20):3337-3352. doi:10.2174/092986712801215973
4. Rossi A, Di Maio M. Platinum-based chemotherapy in advanced non–small-cell lung cancer: optimal number of treatment cycles. Expert Rev Anticancer Ther. 2016;16(6):653-660. doi:10.1586/14737140.2016.1170596
5. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non–small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246. doi:10.1016/S1470-2045(11)70393-X
6. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non–small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742. doi:10.1016/S1470-2045(11)70184-X
7. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
8. Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non–small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018;36(22):2244-2250. doi:10.1200/JCO.2018.78.7994
9. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957. doi:10.1056/NEJMoa0810699
10. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non–small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386(9998):1049-1056. doi:10.1016/S0140-6736(15)60294-X
11. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non–small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol. 1995;13(8):1880-1892. doi:10.1200/JCO.1995.13.8.1880
12. Zhong WZ, Chen KN, Chen C, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of Stage IIIA-N2 EGFR-mutant non–small-cell lung cancer (EMERGING-CTONG 1103): a randomized phase II study. J Clin Oncol. 2019;37(25):2235-2245. doi:10.1200/JCO.19.00075
13. Noronha V, Patil VM, Joshi A, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol. 2020;38(2):124-136. doi:10.1200/JCO.19.01154
14. Noronha V, Prabhash K, Thavamani A, et al. EGFR mutations in Indian lung cancer patients: clinical correlation and outcome to EGFR targeted therapy. PLoS One. 2013;8(4):e61561. Published 2013 Apr 19. doi:10.1371/journal.pone.0061561
15. Kato T, Seto T, Nishio M, et al. Erlotinib plus bevacizumab phase ll study in patients with advanced non–small-cell lung cancer (JO25567): updated safety results. Drug Saf. 2018;41(2):229-237. doi:10.1007/s40264-017-0596-0
16. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231
17. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946
18. Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non–small-cell lung cancer. J Clin Oncol. 2016;34(25):2969-2979. doi:10.1200/JCO.2016.66.9861
19. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC: final overall survival analysis of CTONG1104 Phase III Trial. J Clin Oncol. 2021;39(7):713-722. doi:10.1200/JCO.20.01820
20. Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830-838. doi:10.1016/S1470-2045(15)00026-1
21. Shi YK, Wang L, Han BH, et al. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017;28(10):2443-2450. doi:10.1093/annonc/mdx359
22. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomized trial. Lancet Oncol. 2015;16(8):990-998 doi:10.1016/S1470-2045(15)00121-7
23. Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013;31(27):3320-3326. doi:10.1200/JCO.2013.51.1816
24. Sun JM, Lee KH, Kim SW, et al. Gefitinib versus pemetrexed as second-line treatment in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012;118(24):6234-6242. doi:10.1200/JCO.2013.51.1816
25. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol. 2010;11(2):121-128. doi:10.1016/S1470-2045(09)70364-X
26. Lee DH, Park K, Kim JH, Lee JS, et al. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010;16(4):1307-1314. doi:10.1158/1078-0432.CCR-09-1903
27. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomized phase III trial. Lancet. 2008;22;372(9652):1809-1818. doi:10.1016/S0140-6736(08)61758-4
1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913-2921. doi:10.1158/0008-5472.CAN-14-0155
2. da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49-69. doi:10.1146/annurev-pathol-011110-130206
3. Sgambato A, Casaluce F, Maione P, et al. The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation. Curr Med Chem. 2012;19(20):3337-3352. doi:10.2174/092986712801215973
4. Rossi A, Di Maio M. Platinum-based chemotherapy in advanced non–small-cell lung cancer: optimal number of treatment cycles. Expert Rev Anticancer Ther. 2016;16(6):653-660. doi:10.1586/14737140.2016.1170596
5. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non–small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246. doi:10.1016/S1470-2045(11)70393-X
6. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non–small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742. doi:10.1016/S1470-2045(11)70184-X
7. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
8. Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non–small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018;36(22):2244-2250. doi:10.1200/JCO.2018.78.7994
9. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957. doi:10.1056/NEJMoa0810699
10. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non–small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386(9998):1049-1056. doi:10.1016/S0140-6736(15)60294-X
11. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non–small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol. 1995;13(8):1880-1892. doi:10.1200/JCO.1995.13.8.1880
12. Zhong WZ, Chen KN, Chen C, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of Stage IIIA-N2 EGFR-mutant non–small-cell lung cancer (EMERGING-CTONG 1103): a randomized phase II study. J Clin Oncol. 2019;37(25):2235-2245. doi:10.1200/JCO.19.00075
13. Noronha V, Patil VM, Joshi A, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol. 2020;38(2):124-136. doi:10.1200/JCO.19.01154
14. Noronha V, Prabhash K, Thavamani A, et al. EGFR mutations in Indian lung cancer patients: clinical correlation and outcome to EGFR targeted therapy. PLoS One. 2013;8(4):e61561. Published 2013 Apr 19. doi:10.1371/journal.pone.0061561
15. Kato T, Seto T, Nishio M, et al. Erlotinib plus bevacizumab phase ll study in patients with advanced non–small-cell lung cancer (JO25567): updated safety results. Drug Saf. 2018;41(2):229-237. doi:10.1007/s40264-017-0596-0
16. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231
17. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946
18. Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non–small-cell lung cancer. J Clin Oncol. 2016;34(25):2969-2979. doi:10.1200/JCO.2016.66.9861
19. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC: final overall survival analysis of CTONG1104 Phase III Trial. J Clin Oncol. 2021;39(7):713-722. doi:10.1200/JCO.20.01820
20. Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830-838. doi:10.1016/S1470-2045(15)00026-1
21. Shi YK, Wang L, Han BH, et al. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017;28(10):2443-2450. doi:10.1093/annonc/mdx359
22. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomized trial. Lancet Oncol. 2015;16(8):990-998 doi:10.1016/S1470-2045(15)00121-7
23. Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013;31(27):3320-3326. doi:10.1200/JCO.2013.51.1816
24. Sun JM, Lee KH, Kim SW, et al. Gefitinib versus pemetrexed as second-line treatment in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012;118(24):6234-6242. doi:10.1200/JCO.2013.51.1816
25. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol. 2010;11(2):121-128. doi:10.1016/S1470-2045(09)70364-X
26. Lee DH, Park K, Kim JH, Lee JS, et al. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010;16(4):1307-1314. doi:10.1158/1078-0432.CCR-09-1903
27. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomized phase III trial. Lancet. 2008;22;372(9652):1809-1818. doi:10.1016/S0140-6736(08)61758-4
Obesity drug shortage triggers frustrations, workarounds
The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the U.S. Food and Drug Administration approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continue to date, frustrating patients and their health care providers.
The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a “game changer” for treating people with obesity because of semaglutide’s proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug’s pivotal clinical trials.
But during the months following semaglutide’s approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.
A manufacturing glitch shut down the primary location for production of U.S.-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in U.S. pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand have dramatically limited Ozempic availability in Australia.)
‘Unprecedented demand’ for Wegovy derailed when plant went offline
The supply side for Wegovy became so hopelessly broken that just months after U.S. sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.
Novo Nordisk’s financial report for the second quarter of 2022, released on Aug. 3, said the company “expects to make all Wegovy dose strengths available in the United States towards the end of 2022.”
A Dear Health Care Provider letter that Novo Nordisk posted on its U.S. Wegovy website last spring cited “unprecedented demand” that exceeded every prior product launch in the company’s history. It forced Novo Nordisk to pull the plug on all U.S. promotion of Wegovy and compelled the company to ask U.S. clinicians to halt new patient starts.
“I stopped offering Wegovy to new patients” since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan, Ann Arbor. “It’s very frustrating to not have patients [with obesity] receive the optimal treatment available.” Although she adds that she tries to match obesity treatments to each patient’s clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.
“It was a disastrous rollout,” says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia, Charlottesville. “It’s frustrating to know that the treatment is there but not being able to use it,” she said in an interview.
“I had about 800 patients on Wegovy” when the supply dropped earlier this year, and “I couldn’t handle the volume of messages that I got from patients,” recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center, Boston. “It was painful,” she said in an interview.
“Frustrating and chaotic,” is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
The liraglutide/Saxenda workaround
The upshot is that people with obesity and their health care providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.
Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).
Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.
Results from the head-to-head STEP 8 trial, published in JAMA, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
A ‘reasonable’ evidence base, but more work
Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, “would be reasonably evidence-based medicine,” said Dr. Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a “handful” of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.
“No prospective study has looked at this transition,” but dose equivalence tables exist based on expert opinion, noted Dr. Oshman, as in this 2020 report.
Dr. Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the “destination” Wegovy doses that has remained generally available during the shortage. But Dr. Varney’s experience is that only half of her patients made the changeover smoothly, with the others having “severe gastrointestinal distress,” including vomiting, she notes.
Dr. Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn’t been easy.
“It’s more work and more prior authorizations. It’s harder and adds a layer of stress,” but, Dr. Fitch adds, “people are willing to work on it because the weight loss is worth it.”
The liraglutide to semaglutide shuffle is “doable,” says Dr. Rizo, “but I’m looking forward to not having to do it and being able to just start Wegovy.”
The tirzepatide coupon program works ‘off label’ for obesity
Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.
Soon after approval, Lilly, the company that markets tirzepatide, started a U.S. coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.
Novo Nordisk offered U.S. patients with commercial insurance a similar discount when Wegovy first hit the U.S. market in 2021, but the program closed down once the supply shortage began.
Despite tirzepatide’s current approval only for type 2 diabetes, Dr. Varney has been successfully prescribing it to patients without diabetes off-label for weight loss.
“The coupons still work even when tirzepatide is used off-label,” she notes. And while the drug’s rollout is still only a couple of months old, so far, it’s gone “beautifully” with no hints of supply issues, she says.
But a major drawback to relying on an introductory coupon program that makes these agents affordable to patients is their ability to maintain treatment once the discounts inevitably end.
“We try to only prescribe agents that patients can continue to access,” says Dr. Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.
Many commercial U.S. insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.
Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study that tracked people who stopped taking semaglutide.
Dr. Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the “donut hole” in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
Even more workarounds
Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Dr. Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Dr. Oshman.
Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the U.S. price, she says, but is “still too high for many of my patients.”
Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.
“Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it’s not something that people should do,” says Dr. Fitch.
“Compounding pharmacies have no FDA regulation. People don’t know what they’re getting. It’s dangerous,” agrees Dr. Varney. Physicians who refer people for privately compounded semaglutide “are taking advantage of desperate people,” she adds.
Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to the weight loss medication stem from more systemic issues in the United States health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.
“We need to make obesity treatment a standard benefit, and not something that can be carved out,” says Dr. Fitch. People with obesity “deserve access to effective treatments for their disease,” she declares.
Dr. Oshman, Dr. Varney, and Dr. Rizo have reported no relevant financial relationships. Dr. Fitch has reported being an advisor to Jenny Craig.
A version of this article first appeared on Medscape.com.
The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the U.S. Food and Drug Administration approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continue to date, frustrating patients and their health care providers.
The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a “game changer” for treating people with obesity because of semaglutide’s proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug’s pivotal clinical trials.
But during the months following semaglutide’s approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.
A manufacturing glitch shut down the primary location for production of U.S.-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in U.S. pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand have dramatically limited Ozempic availability in Australia.)
‘Unprecedented demand’ for Wegovy derailed when plant went offline
The supply side for Wegovy became so hopelessly broken that just months after U.S. sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.
Novo Nordisk’s financial report for the second quarter of 2022, released on Aug. 3, said the company “expects to make all Wegovy dose strengths available in the United States towards the end of 2022.”
A Dear Health Care Provider letter that Novo Nordisk posted on its U.S. Wegovy website last spring cited “unprecedented demand” that exceeded every prior product launch in the company’s history. It forced Novo Nordisk to pull the plug on all U.S. promotion of Wegovy and compelled the company to ask U.S. clinicians to halt new patient starts.
“I stopped offering Wegovy to new patients” since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan, Ann Arbor. “It’s very frustrating to not have patients [with obesity] receive the optimal treatment available.” Although she adds that she tries to match obesity treatments to each patient’s clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.
“It was a disastrous rollout,” says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia, Charlottesville. “It’s frustrating to know that the treatment is there but not being able to use it,” she said in an interview.
“I had about 800 patients on Wegovy” when the supply dropped earlier this year, and “I couldn’t handle the volume of messages that I got from patients,” recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center, Boston. “It was painful,” she said in an interview.
“Frustrating and chaotic,” is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
The liraglutide/Saxenda workaround
The upshot is that people with obesity and their health care providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.
Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).
Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.
Results from the head-to-head STEP 8 trial, published in JAMA, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
A ‘reasonable’ evidence base, but more work
Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, “would be reasonably evidence-based medicine,” said Dr. Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a “handful” of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.
“No prospective study has looked at this transition,” but dose equivalence tables exist based on expert opinion, noted Dr. Oshman, as in this 2020 report.
Dr. Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the “destination” Wegovy doses that has remained generally available during the shortage. But Dr. Varney’s experience is that only half of her patients made the changeover smoothly, with the others having “severe gastrointestinal distress,” including vomiting, she notes.
Dr. Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn’t been easy.
“It’s more work and more prior authorizations. It’s harder and adds a layer of stress,” but, Dr. Fitch adds, “people are willing to work on it because the weight loss is worth it.”
The liraglutide to semaglutide shuffle is “doable,” says Dr. Rizo, “but I’m looking forward to not having to do it and being able to just start Wegovy.”
The tirzepatide coupon program works ‘off label’ for obesity
Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.
Soon after approval, Lilly, the company that markets tirzepatide, started a U.S. coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.
Novo Nordisk offered U.S. patients with commercial insurance a similar discount when Wegovy first hit the U.S. market in 2021, but the program closed down once the supply shortage began.
Despite tirzepatide’s current approval only for type 2 diabetes, Dr. Varney has been successfully prescribing it to patients without diabetes off-label for weight loss.
“The coupons still work even when tirzepatide is used off-label,” she notes. And while the drug’s rollout is still only a couple of months old, so far, it’s gone “beautifully” with no hints of supply issues, she says.
But a major drawback to relying on an introductory coupon program that makes these agents affordable to patients is their ability to maintain treatment once the discounts inevitably end.
“We try to only prescribe agents that patients can continue to access,” says Dr. Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.
Many commercial U.S. insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.
Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study that tracked people who stopped taking semaglutide.
Dr. Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the “donut hole” in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
Even more workarounds
Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Dr. Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Dr. Oshman.
Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the U.S. price, she says, but is “still too high for many of my patients.”
Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.
“Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it’s not something that people should do,” says Dr. Fitch.
“Compounding pharmacies have no FDA regulation. People don’t know what they’re getting. It’s dangerous,” agrees Dr. Varney. Physicians who refer people for privately compounded semaglutide “are taking advantage of desperate people,” she adds.
Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to the weight loss medication stem from more systemic issues in the United States health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.
“We need to make obesity treatment a standard benefit, and not something that can be carved out,” says Dr. Fitch. People with obesity “deserve access to effective treatments for their disease,” she declares.
Dr. Oshman, Dr. Varney, and Dr. Rizo have reported no relevant financial relationships. Dr. Fitch has reported being an advisor to Jenny Craig.
A version of this article first appeared on Medscape.com.
The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the U.S. Food and Drug Administration approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continue to date, frustrating patients and their health care providers.
The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a “game changer” for treating people with obesity because of semaglutide’s proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug’s pivotal clinical trials.
But during the months following semaglutide’s approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.
A manufacturing glitch shut down the primary location for production of U.S.-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in U.S. pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand have dramatically limited Ozempic availability in Australia.)
‘Unprecedented demand’ for Wegovy derailed when plant went offline
The supply side for Wegovy became so hopelessly broken that just months after U.S. sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.
Novo Nordisk’s financial report for the second quarter of 2022, released on Aug. 3, said the company “expects to make all Wegovy dose strengths available in the United States towards the end of 2022.”
A Dear Health Care Provider letter that Novo Nordisk posted on its U.S. Wegovy website last spring cited “unprecedented demand” that exceeded every prior product launch in the company’s history. It forced Novo Nordisk to pull the plug on all U.S. promotion of Wegovy and compelled the company to ask U.S. clinicians to halt new patient starts.
“I stopped offering Wegovy to new patients” since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan, Ann Arbor. “It’s very frustrating to not have patients [with obesity] receive the optimal treatment available.” Although she adds that she tries to match obesity treatments to each patient’s clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.
“It was a disastrous rollout,” says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia, Charlottesville. “It’s frustrating to know that the treatment is there but not being able to use it,” she said in an interview.
“I had about 800 patients on Wegovy” when the supply dropped earlier this year, and “I couldn’t handle the volume of messages that I got from patients,” recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center, Boston. “It was painful,” she said in an interview.
“Frustrating and chaotic,” is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
The liraglutide/Saxenda workaround
The upshot is that people with obesity and their health care providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.
Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).
Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.
Results from the head-to-head STEP 8 trial, published in JAMA, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
A ‘reasonable’ evidence base, but more work
Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, “would be reasonably evidence-based medicine,” said Dr. Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a “handful” of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.
“No prospective study has looked at this transition,” but dose equivalence tables exist based on expert opinion, noted Dr. Oshman, as in this 2020 report.
Dr. Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the “destination” Wegovy doses that has remained generally available during the shortage. But Dr. Varney’s experience is that only half of her patients made the changeover smoothly, with the others having “severe gastrointestinal distress,” including vomiting, she notes.
Dr. Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn’t been easy.
“It’s more work and more prior authorizations. It’s harder and adds a layer of stress,” but, Dr. Fitch adds, “people are willing to work on it because the weight loss is worth it.”
The liraglutide to semaglutide shuffle is “doable,” says Dr. Rizo, “but I’m looking forward to not having to do it and being able to just start Wegovy.”
The tirzepatide coupon program works ‘off label’ for obesity
Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.
Soon after approval, Lilly, the company that markets tirzepatide, started a U.S. coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.
Novo Nordisk offered U.S. patients with commercial insurance a similar discount when Wegovy first hit the U.S. market in 2021, but the program closed down once the supply shortage began.
Despite tirzepatide’s current approval only for type 2 diabetes, Dr. Varney has been successfully prescribing it to patients without diabetes off-label for weight loss.
“The coupons still work even when tirzepatide is used off-label,” she notes. And while the drug’s rollout is still only a couple of months old, so far, it’s gone “beautifully” with no hints of supply issues, she says.
But a major drawback to relying on an introductory coupon program that makes these agents affordable to patients is their ability to maintain treatment once the discounts inevitably end.
“We try to only prescribe agents that patients can continue to access,” says Dr. Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.
Many commercial U.S. insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.
Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study that tracked people who stopped taking semaglutide.
Dr. Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the “donut hole” in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
Even more workarounds
Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Dr. Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Dr. Oshman.
Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the U.S. price, she says, but is “still too high for many of my patients.”
Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.
“Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it’s not something that people should do,” says Dr. Fitch.
“Compounding pharmacies have no FDA regulation. People don’t know what they’re getting. It’s dangerous,” agrees Dr. Varney. Physicians who refer people for privately compounded semaglutide “are taking advantage of desperate people,” she adds.
Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to the weight loss medication stem from more systemic issues in the United States health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.
“We need to make obesity treatment a standard benefit, and not something that can be carved out,” says Dr. Fitch. People with obesity “deserve access to effective treatments for their disease,” she declares.
Dr. Oshman, Dr. Varney, and Dr. Rizo have reported no relevant financial relationships. Dr. Fitch has reported being an advisor to Jenny Craig.
A version of this article first appeared on Medscape.com.
The Effect of Race on Outcomes in Veterans With Hepatocellular Carcinoma at a Single Center
Hepatocellular carcinoma (HCC) is the sixth most common and third most deadly malignancy worldwide, carrying a mean survival rate without treatment of 6 to 20 months depending on stage.1 Fifty-seven percent of patients with liver cancer are diagnosed with regional or distant metastatic disease that carries 5-year relative survival rates of 10.7% and 3.1%, respectively.2 HCC arises most commonly from liver cirrhosis due to chronic hepatocyte injury, which may be mediated by viral hepatitis, alcoholism, and metabolic disease. Other less common causes include autoimmune disease, exposure to environmental hazards, and certain genetic diseases, such as α-1 antitrypsin deficiency and Wilson disease.
Multiple staging systems for HCC exist that incorporate some variation of the following features: size and invasion of the tumor, distant metastases, and liver function. Stage-directed treatments for HCC include ablation, embolization, resection, transplant, and systemic therapy, such as tyrosine kinase inhibitors, immunotherapies, and monoclonal antibodies. In addition to tumor/node/metastasis (TNM) staging, α-fetoprotein (AFP) is a diagnostic marker with prognostic value in HCC with higher levels correlating to higher tumor burden and a worse prognosis. With treatment, the 5-year survival rate for early stage HCC ranges from 60% to 80% but decreases significantly with higher stages.1 HCC screening in at-risk populations has accounted for > 40% of diagnoses since the practice became widely adopted, and earlier recognition has led to an improvement in survival even when adjusting for lead time bias.3
Systemic therapy for advanced disease continues to improve. Sorafenib remained the standard first-line systemic therapy since it was introduced in 2008.4 First-line therapy improved with immunotherapies. The phase 3 IMBrave150 trial comparing atezolizumab plus bevacizumab to sorafenib showed a median overall survival (OS) > 19 months with 7.7% of patients achieving a complete response.5 HIMALAYA, another phase 3 trial set for publication later this year, also reported promising results when a priming dose of the CTLA-4 inhibitor tremelimumab followed by durvalumab was compared with sorafenib.6
There has been a rise in incidence of HCC in the United States across all races and ethnicities, though Black, Hispanic, and Asian patients remain disproportionately affected. Subsequently, identifying causative biologic, socioeconomic, and cultural factors, as well as implicit bias in health care continues to be a topic of great interest.7-9 Using Surveillance, Epidemiology, and End Results (SEER) data, a number of large studies have found that Black patients with HCC were more likely to present with an advanced stage, less likely to receive curative intent treatment, and had significantly reduced survival compared with that of White patients.1,7-9 An analysis of 1117 patients by Rich and colleagues noted a 34% increased risk of death for Black patients with HCC compared with that of White patients, and other studies have shown about a 50% reduction in rate of liver transplantation for Black patients.10-12 Our study aimed to investigate potential disparities in incidence, etiology, AFP level at diagnosis, and outcomes of HCC in Black and White veterans managed at the Memphis Veterans Affairs Medical Center (VAMC) in Tennessee.
Methods
A single center retrospective chart review was conducted at the Memphis VAMC using the Computerized Patient Record System (CPRS) and the International Statistical Classification of Diseases, Tenth Revision (ICD-10) code C22.0 for HCC. Initial results were manually refined by prespecified criteria. Patients were included if they were diagnosed with HCC and received HCC treatment at the Memphis VAMC. Patients were excluded if HCC was not diagnosed histologically or clinically by imaging characteristics and AFP level, if the patient’s primary treatment was not provided at the Memphis VAMC, if they were lost to follow-up, or if race was not specified as either Black or White.
The following patient variables were examined: age, sex, comorbidities (alcohol or substance use disorder, cirrhosis, HIV), tumor stage, AFP, method of diagnosis, first-line treatments, systemic treatment, surgical options offered, and mortality. Staging was based on the American Joint Committee on Cancer TNM staging for HCC.13 Surgical options were recorded as resection or transplant. Patients who were offered treatment but lost to follow-up were excluded from the analysis.
Data Analysis
Our primary endpoint was identifying differences in OS among Memphis VAMC patients with HCC related to race. Kaplan-Meier analysis was used to investigate differences in OS and cumulative hazard ratio (HR) for death. Cox regression multivariate analysis further evaluated discrepancies among investigated patient variables, including age, race, alcohol, tobacco, or illicit drug use, HIV coinfection, and cirrhosis. Treatment factors were further defined by first-line treatment, systemic therapy, surgical resection, and transplant. χ2 analysis was used to investigate differences in treatment modalities.
Results
We identified 227 veterans, 95 Black and 132 White, between 2009 and 2021 meeting criteria for primary HCC treated at the Memphis VAMC. This study did not show a significant difference in OS between White and Black veterans (P = .24). Kaplan-Meier assessment showed OS was 1247 days (41 months) for Black veterans compared with 1032 days (34 months) for White veterans (Figure; Table 1).
Additionally, no significant difference was found between veterans for age or stage at diagnosis when stratified by race. The mean age of diagnosis for both groups was 65 years (P = .09). The mean TNM staging was 1.7 for White veterans vs 1.8 for Black veterans (P = .57). There was a significant increase in the AFP level at diagnosis for Black veterans (P = .001) (Table 2).
The most common initial treatment for both groups was transarterial chemoembolization and radiofrequency ablation with 68% of White and 64% of Black veterans receiving this therapy. There was no significant difference between who received systemic therapy.
However, we found significant differences by race for some forms of treatment. In our analysis, significant differences existed between those who did not receive any form of treatment as well as who received surgical resection and transplant. Among Black veterans, 11.6% received no treatment vs 6.1% for White veterans (P = .001). Only 2.1% of Black veterans underwent surgical resection vs 8.3% of White veterans (P = .046). Similarly, 13 (9.8%) White veterans vs 3 (3.2%) Black veterans received orthotopic liver transplantation (P = .052) in our cohort (eAppendix available at doi:10.12788/fp.0304). We found no differences in patient characteristics affecting OS, including alcohol use, tobacco use, illicit drug use, HIV coinfection, or liver cirrhosis (Table 3).
Discussion
In this retrospective analysis, Black veterans with HCC did not experience a statistically significant decrease in OS compared with that of White veterans despite some differences in therapy offered. Other studies have found that surgery was less frequently recommended to Black patients across multiple cancer types, and in most cases this carried a negative impact on OS.8,10,11,14,15 A number of other studies have demonstrated a greater percentage of Black patients receiving no treatment, although these studies are often based on SEER data, which captures only cancer-directed surgery and no other methods of treatment. Inequities in patient factors like insurance and socioeconomic status as well as willingness to receive certain treatments are often cited as major influences in health care disparities, but systemic and clinician factors like hospital volume, clinician expertise, specialist availability, and implicit racial bias all affect outcomes.16 One benefit of our study was that CPRS provided a centralized recording of all treatments received. Interestingly, the treatment discrepancy in our study was not attributable to a statistically significant difference in tumor stage at presentation. There should be no misconception that US Department of Veterans Affairs patients are less affected by socioeconomic inequities, though still this suggests clinician and systemic factors were significant drivers behind our findings.
This study did not intend to determine differences in incidence of HCC by race, although many studies have shown an age-adjusted incidence of HCC among Black and Hispanic patients up to twice that of White patients.1,8-10 Notably, the rate of orthotopic liver transplantation in this study was low regardless of race compared with that of other larger studies of patients with HCC.12,15 Discrepancies in HCC care among White and Black patients have been suggested to stem from a variety of influences, including access to early diagnosis and treatment of hepatitis C virus, comorbid conditions, as well as complex socioeconomic factors. It also has been shown that oncologists’ implicit racial bias has a negative impact on patients’ perceived quality of communication, their confidence in the recommended treatment, and the understood difficulty of the treatment by the patient and should be considered as a contributor to health disparities.17,18
Studies evaluating survival in HCC using SEER data generally stratify disease by localized, regional, or distant metastasis. For our study, TNM staging provided a more accurate assessment of the disease and reduced the chances that broader staging definitions could obscure differences in treatment choices. Future studies could be improved by stratifying patients by variables impacting treatment choice, such as Child-Pugh score or Barcelona Clinic Liver Cancer staging. Our study demonstrated a statistically significant difference in AFP level between White and Black veterans. This has been observed in prior studies as well, and while no specific cause has been identified, it suggests differences in tumor biologic features across different races. In addition, we found that an elevated AFP level at the time of diagnosis (defined as > 400) correlates with a worsened OS (HR, 1.36; P = .01).
Limitations
This study has several limitations, notably the number of veterans eligible for analysis at a single institution. A larger cohort would be needed to evaluate for statistically significant differences in outcomes by race. Additionally, our study did not account for therapy that was offered to but not pursued by the patient, and this would be useful to determine whether patient or practitioner factors were the more significant influence on the type of therapy received.
Conclusions
This study demonstrated a statistically significant difference in the rate of resection and liver transplantation between White and Black veterans at a single institution, although no difference in OS was observed. This discrepancy was not explained by differences in tumor staging. Additional, larger studies will be useful in clarifying the biologic, cultural, and socioeconomic drivers in HCC treatment and mortality.
Acknowledgments
The authors thank Lorri Reaves, Memphis Veterans Affairs Medical Center, Department of Hepatology.
1. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27(9):1485-1491. doi:10.1200/JCO.2008.20.7753
2. Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Accessed July 8, 2022. https://seer.cancer.gov/archive/csr/1975_2012/results_merged/sect_14_liver_bile.pdf#page=8
3. Singal AG, Mittal S, Yerokun OA, et al. Hepatocellular carcinoma screening associated with early tumor detection and improved survival among patients with cirrhosis in the US. Am J Med. 2017;130(9):1099-1106.e1. doi:10.1016/j.amjmed.2017.01.021
4. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857
5. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745
6. Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022;40(suppl 4):379. doi:10.1200/JCO.2022.40.4_suppl.379
7. Franco RA, Fan Y, Jarosek S, Bae S, Galbraith J. Racial and geographic disparities in hepatocellular carcinoma outcomes. Am J Prev Med. 2018;55(5)(suppl 1):S40-S48. doi:10.1016/j.amepre.2018.05.030
8. Ha J, Yan M, Aguilar M, et al. Race/ethnicity-specific disparities in hepatocellular carcinoma stage at diagnosis and its impact on receipt of curative therapies. J Clin Gastroenterol. 2016;50(5):423-430. doi:10.1097/MCG.0000000000000448
9. Wong R, Corley DA. Racial and ethnic variations in hepatocellular carcinoma incidence within the United States. Am J Med. 2008;121(6):525-531. doi:10.1016/j.amjmed.2008.03.005
10. Rich NE, Hester C, Odewole M, et al. Racial and ethnic differences in presentation and outcomes of hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2019;17(3):551-559.e1. doi:10.1016/j.cgh.2018.05.039
11. Peters NA, Javed AA, He J, Wolfgang CL, Weiss MJ. Association of socioeconomics, surgical therapy, and survival of early stage hepatocellular carcinoma. J Surg Res. 2017;210:253-260. doi:10.1016/j.jss.2016.11.042
12. Wong RJ, Devaki P, Nguyen L, Cheung R, Nguyen MH. Ethnic disparities and liver transplantation rates in hepatocellular carcinoma patients in the recent era: results from the Surveillance, Epidemiology, and End Results registry. Liver Transpl. 2014;20(5):528-535. doi:10.1002/lt.23820
13. Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y, Makuuchi M. Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan. Ann Surg. 2007;245(6):909-922. doi:10.1097/01.sla.0000254368.65878.da.
14. Harrison LE, Reichman T, Koneru B, et al. Racial discrepancies in the outcome of patients with hepatocellular carcinoma. Arch Surg. 2004;139(9):992-996. doi:10.1001/archsurg.139.9.992
15. Sloane D, Chen H, Howell C. Racial disparity in primary hepatocellular carcinoma: tumor stage at presentation, surgical treatment and survival. J Natl Med Assoc. 2006;98(12):1934-1939.
16. Haider AH, Scott VK, Rehman KA, et al. Racial disparities in surgical care and outcomes in the United States: a comprehensive review of patient, provider, and systemic factors. J Am Coll Surg. 2013;216(3):482-92.e12. doi:10.1016/j.jamcollsurg.2012.11.014
17. Cooper LA, Roter DL, Carson KA, et al. The associations of clinicians’ implicit attitudes about race with medical visit communication and patient ratings of interpersonal care. Am J Public Health. 2012;102(5):979-987. doi:10.2105/AJPH.2011.300558
18. Penner LA, Dovidio JF, Gonzalez R, et al. The effects of oncologist implicit racial bias in racially discordant oncology interactions. J Clin Oncol. 2016;34(24):2874-2880. doi:10.1200/JCO.2015.66.3658
Hepatocellular carcinoma (HCC) is the sixth most common and third most deadly malignancy worldwide, carrying a mean survival rate without treatment of 6 to 20 months depending on stage.1 Fifty-seven percent of patients with liver cancer are diagnosed with regional or distant metastatic disease that carries 5-year relative survival rates of 10.7% and 3.1%, respectively.2 HCC arises most commonly from liver cirrhosis due to chronic hepatocyte injury, which may be mediated by viral hepatitis, alcoholism, and metabolic disease. Other less common causes include autoimmune disease, exposure to environmental hazards, and certain genetic diseases, such as α-1 antitrypsin deficiency and Wilson disease.
Multiple staging systems for HCC exist that incorporate some variation of the following features: size and invasion of the tumor, distant metastases, and liver function. Stage-directed treatments for HCC include ablation, embolization, resection, transplant, and systemic therapy, such as tyrosine kinase inhibitors, immunotherapies, and monoclonal antibodies. In addition to tumor/node/metastasis (TNM) staging, α-fetoprotein (AFP) is a diagnostic marker with prognostic value in HCC with higher levels correlating to higher tumor burden and a worse prognosis. With treatment, the 5-year survival rate for early stage HCC ranges from 60% to 80% but decreases significantly with higher stages.1 HCC screening in at-risk populations has accounted for > 40% of diagnoses since the practice became widely adopted, and earlier recognition has led to an improvement in survival even when adjusting for lead time bias.3
Systemic therapy for advanced disease continues to improve. Sorafenib remained the standard first-line systemic therapy since it was introduced in 2008.4 First-line therapy improved with immunotherapies. The phase 3 IMBrave150 trial comparing atezolizumab plus bevacizumab to sorafenib showed a median overall survival (OS) > 19 months with 7.7% of patients achieving a complete response.5 HIMALAYA, another phase 3 trial set for publication later this year, also reported promising results when a priming dose of the CTLA-4 inhibitor tremelimumab followed by durvalumab was compared with sorafenib.6
There has been a rise in incidence of HCC in the United States across all races and ethnicities, though Black, Hispanic, and Asian patients remain disproportionately affected. Subsequently, identifying causative biologic, socioeconomic, and cultural factors, as well as implicit bias in health care continues to be a topic of great interest.7-9 Using Surveillance, Epidemiology, and End Results (SEER) data, a number of large studies have found that Black patients with HCC were more likely to present with an advanced stage, less likely to receive curative intent treatment, and had significantly reduced survival compared with that of White patients.1,7-9 An analysis of 1117 patients by Rich and colleagues noted a 34% increased risk of death for Black patients with HCC compared with that of White patients, and other studies have shown about a 50% reduction in rate of liver transplantation for Black patients.10-12 Our study aimed to investigate potential disparities in incidence, etiology, AFP level at diagnosis, and outcomes of HCC in Black and White veterans managed at the Memphis Veterans Affairs Medical Center (VAMC) in Tennessee.
Methods
A single center retrospective chart review was conducted at the Memphis VAMC using the Computerized Patient Record System (CPRS) and the International Statistical Classification of Diseases, Tenth Revision (ICD-10) code C22.0 for HCC. Initial results were manually refined by prespecified criteria. Patients were included if they were diagnosed with HCC and received HCC treatment at the Memphis VAMC. Patients were excluded if HCC was not diagnosed histologically or clinically by imaging characteristics and AFP level, if the patient’s primary treatment was not provided at the Memphis VAMC, if they were lost to follow-up, or if race was not specified as either Black or White.
The following patient variables were examined: age, sex, comorbidities (alcohol or substance use disorder, cirrhosis, HIV), tumor stage, AFP, method of diagnosis, first-line treatments, systemic treatment, surgical options offered, and mortality. Staging was based on the American Joint Committee on Cancer TNM staging for HCC.13 Surgical options were recorded as resection or transplant. Patients who were offered treatment but lost to follow-up were excluded from the analysis.
Data Analysis
Our primary endpoint was identifying differences in OS among Memphis VAMC patients with HCC related to race. Kaplan-Meier analysis was used to investigate differences in OS and cumulative hazard ratio (HR) for death. Cox regression multivariate analysis further evaluated discrepancies among investigated patient variables, including age, race, alcohol, tobacco, or illicit drug use, HIV coinfection, and cirrhosis. Treatment factors were further defined by first-line treatment, systemic therapy, surgical resection, and transplant. χ2 analysis was used to investigate differences in treatment modalities.
Results
We identified 227 veterans, 95 Black and 132 White, between 2009 and 2021 meeting criteria for primary HCC treated at the Memphis VAMC. This study did not show a significant difference in OS between White and Black veterans (P = .24). Kaplan-Meier assessment showed OS was 1247 days (41 months) for Black veterans compared with 1032 days (34 months) for White veterans (Figure; Table 1).
Additionally, no significant difference was found between veterans for age or stage at diagnosis when stratified by race. The mean age of diagnosis for both groups was 65 years (P = .09). The mean TNM staging was 1.7 for White veterans vs 1.8 for Black veterans (P = .57). There was a significant increase in the AFP level at diagnosis for Black veterans (P = .001) (Table 2).
The most common initial treatment for both groups was transarterial chemoembolization and radiofrequency ablation with 68% of White and 64% of Black veterans receiving this therapy. There was no significant difference between who received systemic therapy.
However, we found significant differences by race for some forms of treatment. In our analysis, significant differences existed between those who did not receive any form of treatment as well as who received surgical resection and transplant. Among Black veterans, 11.6% received no treatment vs 6.1% for White veterans (P = .001). Only 2.1% of Black veterans underwent surgical resection vs 8.3% of White veterans (P = .046). Similarly, 13 (9.8%) White veterans vs 3 (3.2%) Black veterans received orthotopic liver transplantation (P = .052) in our cohort (eAppendix available at doi:10.12788/fp.0304). We found no differences in patient characteristics affecting OS, including alcohol use, tobacco use, illicit drug use, HIV coinfection, or liver cirrhosis (Table 3).
Discussion
In this retrospective analysis, Black veterans with HCC did not experience a statistically significant decrease in OS compared with that of White veterans despite some differences in therapy offered. Other studies have found that surgery was less frequently recommended to Black patients across multiple cancer types, and in most cases this carried a negative impact on OS.8,10,11,14,15 A number of other studies have demonstrated a greater percentage of Black patients receiving no treatment, although these studies are often based on SEER data, which captures only cancer-directed surgery and no other methods of treatment. Inequities in patient factors like insurance and socioeconomic status as well as willingness to receive certain treatments are often cited as major influences in health care disparities, but systemic and clinician factors like hospital volume, clinician expertise, specialist availability, and implicit racial bias all affect outcomes.16 One benefit of our study was that CPRS provided a centralized recording of all treatments received. Interestingly, the treatment discrepancy in our study was not attributable to a statistically significant difference in tumor stage at presentation. There should be no misconception that US Department of Veterans Affairs patients are less affected by socioeconomic inequities, though still this suggests clinician and systemic factors were significant drivers behind our findings.
This study did not intend to determine differences in incidence of HCC by race, although many studies have shown an age-adjusted incidence of HCC among Black and Hispanic patients up to twice that of White patients.1,8-10 Notably, the rate of orthotopic liver transplantation in this study was low regardless of race compared with that of other larger studies of patients with HCC.12,15 Discrepancies in HCC care among White and Black patients have been suggested to stem from a variety of influences, including access to early diagnosis and treatment of hepatitis C virus, comorbid conditions, as well as complex socioeconomic factors. It also has been shown that oncologists’ implicit racial bias has a negative impact on patients’ perceived quality of communication, their confidence in the recommended treatment, and the understood difficulty of the treatment by the patient and should be considered as a contributor to health disparities.17,18
Studies evaluating survival in HCC using SEER data generally stratify disease by localized, regional, or distant metastasis. For our study, TNM staging provided a more accurate assessment of the disease and reduced the chances that broader staging definitions could obscure differences in treatment choices. Future studies could be improved by stratifying patients by variables impacting treatment choice, such as Child-Pugh score or Barcelona Clinic Liver Cancer staging. Our study demonstrated a statistically significant difference in AFP level between White and Black veterans. This has been observed in prior studies as well, and while no specific cause has been identified, it suggests differences in tumor biologic features across different races. In addition, we found that an elevated AFP level at the time of diagnosis (defined as > 400) correlates with a worsened OS (HR, 1.36; P = .01).
Limitations
This study has several limitations, notably the number of veterans eligible for analysis at a single institution. A larger cohort would be needed to evaluate for statistically significant differences in outcomes by race. Additionally, our study did not account for therapy that was offered to but not pursued by the patient, and this would be useful to determine whether patient or practitioner factors were the more significant influence on the type of therapy received.
Conclusions
This study demonstrated a statistically significant difference in the rate of resection and liver transplantation between White and Black veterans at a single institution, although no difference in OS was observed. This discrepancy was not explained by differences in tumor staging. Additional, larger studies will be useful in clarifying the biologic, cultural, and socioeconomic drivers in HCC treatment and mortality.
Acknowledgments
The authors thank Lorri Reaves, Memphis Veterans Affairs Medical Center, Department of Hepatology.
Hepatocellular carcinoma (HCC) is the sixth most common and third most deadly malignancy worldwide, carrying a mean survival rate without treatment of 6 to 20 months depending on stage.1 Fifty-seven percent of patients with liver cancer are diagnosed with regional or distant metastatic disease that carries 5-year relative survival rates of 10.7% and 3.1%, respectively.2 HCC arises most commonly from liver cirrhosis due to chronic hepatocyte injury, which may be mediated by viral hepatitis, alcoholism, and metabolic disease. Other less common causes include autoimmune disease, exposure to environmental hazards, and certain genetic diseases, such as α-1 antitrypsin deficiency and Wilson disease.
Multiple staging systems for HCC exist that incorporate some variation of the following features: size and invasion of the tumor, distant metastases, and liver function. Stage-directed treatments for HCC include ablation, embolization, resection, transplant, and systemic therapy, such as tyrosine kinase inhibitors, immunotherapies, and monoclonal antibodies. In addition to tumor/node/metastasis (TNM) staging, α-fetoprotein (AFP) is a diagnostic marker with prognostic value in HCC with higher levels correlating to higher tumor burden and a worse prognosis. With treatment, the 5-year survival rate for early stage HCC ranges from 60% to 80% but decreases significantly with higher stages.1 HCC screening in at-risk populations has accounted for > 40% of diagnoses since the practice became widely adopted, and earlier recognition has led to an improvement in survival even when adjusting for lead time bias.3
Systemic therapy for advanced disease continues to improve. Sorafenib remained the standard first-line systemic therapy since it was introduced in 2008.4 First-line therapy improved with immunotherapies. The phase 3 IMBrave150 trial comparing atezolizumab plus bevacizumab to sorafenib showed a median overall survival (OS) > 19 months with 7.7% of patients achieving a complete response.5 HIMALAYA, another phase 3 trial set for publication later this year, also reported promising results when a priming dose of the CTLA-4 inhibitor tremelimumab followed by durvalumab was compared with sorafenib.6
There has been a rise in incidence of HCC in the United States across all races and ethnicities, though Black, Hispanic, and Asian patients remain disproportionately affected. Subsequently, identifying causative biologic, socioeconomic, and cultural factors, as well as implicit bias in health care continues to be a topic of great interest.7-9 Using Surveillance, Epidemiology, and End Results (SEER) data, a number of large studies have found that Black patients with HCC were more likely to present with an advanced stage, less likely to receive curative intent treatment, and had significantly reduced survival compared with that of White patients.1,7-9 An analysis of 1117 patients by Rich and colleagues noted a 34% increased risk of death for Black patients with HCC compared with that of White patients, and other studies have shown about a 50% reduction in rate of liver transplantation for Black patients.10-12 Our study aimed to investigate potential disparities in incidence, etiology, AFP level at diagnosis, and outcomes of HCC in Black and White veterans managed at the Memphis Veterans Affairs Medical Center (VAMC) in Tennessee.
Methods
A single center retrospective chart review was conducted at the Memphis VAMC using the Computerized Patient Record System (CPRS) and the International Statistical Classification of Diseases, Tenth Revision (ICD-10) code C22.0 for HCC. Initial results were manually refined by prespecified criteria. Patients were included if they were diagnosed with HCC and received HCC treatment at the Memphis VAMC. Patients were excluded if HCC was not diagnosed histologically or clinically by imaging characteristics and AFP level, if the patient’s primary treatment was not provided at the Memphis VAMC, if they were lost to follow-up, or if race was not specified as either Black or White.
The following patient variables were examined: age, sex, comorbidities (alcohol or substance use disorder, cirrhosis, HIV), tumor stage, AFP, method of diagnosis, first-line treatments, systemic treatment, surgical options offered, and mortality. Staging was based on the American Joint Committee on Cancer TNM staging for HCC.13 Surgical options were recorded as resection or transplant. Patients who were offered treatment but lost to follow-up were excluded from the analysis.
Data Analysis
Our primary endpoint was identifying differences in OS among Memphis VAMC patients with HCC related to race. Kaplan-Meier analysis was used to investigate differences in OS and cumulative hazard ratio (HR) for death. Cox regression multivariate analysis further evaluated discrepancies among investigated patient variables, including age, race, alcohol, tobacco, or illicit drug use, HIV coinfection, and cirrhosis. Treatment factors were further defined by first-line treatment, systemic therapy, surgical resection, and transplant. χ2 analysis was used to investigate differences in treatment modalities.
Results
We identified 227 veterans, 95 Black and 132 White, between 2009 and 2021 meeting criteria for primary HCC treated at the Memphis VAMC. This study did not show a significant difference in OS between White and Black veterans (P = .24). Kaplan-Meier assessment showed OS was 1247 days (41 months) for Black veterans compared with 1032 days (34 months) for White veterans (Figure; Table 1).
Additionally, no significant difference was found between veterans for age or stage at diagnosis when stratified by race. The mean age of diagnosis for both groups was 65 years (P = .09). The mean TNM staging was 1.7 for White veterans vs 1.8 for Black veterans (P = .57). There was a significant increase in the AFP level at diagnosis for Black veterans (P = .001) (Table 2).
The most common initial treatment for both groups was transarterial chemoembolization and radiofrequency ablation with 68% of White and 64% of Black veterans receiving this therapy. There was no significant difference between who received systemic therapy.
However, we found significant differences by race for some forms of treatment. In our analysis, significant differences existed between those who did not receive any form of treatment as well as who received surgical resection and transplant. Among Black veterans, 11.6% received no treatment vs 6.1% for White veterans (P = .001). Only 2.1% of Black veterans underwent surgical resection vs 8.3% of White veterans (P = .046). Similarly, 13 (9.8%) White veterans vs 3 (3.2%) Black veterans received orthotopic liver transplantation (P = .052) in our cohort (eAppendix available at doi:10.12788/fp.0304). We found no differences in patient characteristics affecting OS, including alcohol use, tobacco use, illicit drug use, HIV coinfection, or liver cirrhosis (Table 3).
Discussion
In this retrospective analysis, Black veterans with HCC did not experience a statistically significant decrease in OS compared with that of White veterans despite some differences in therapy offered. Other studies have found that surgery was less frequently recommended to Black patients across multiple cancer types, and in most cases this carried a negative impact on OS.8,10,11,14,15 A number of other studies have demonstrated a greater percentage of Black patients receiving no treatment, although these studies are often based on SEER data, which captures only cancer-directed surgery and no other methods of treatment. Inequities in patient factors like insurance and socioeconomic status as well as willingness to receive certain treatments are often cited as major influences in health care disparities, but systemic and clinician factors like hospital volume, clinician expertise, specialist availability, and implicit racial bias all affect outcomes.16 One benefit of our study was that CPRS provided a centralized recording of all treatments received. Interestingly, the treatment discrepancy in our study was not attributable to a statistically significant difference in tumor stage at presentation. There should be no misconception that US Department of Veterans Affairs patients are less affected by socioeconomic inequities, though still this suggests clinician and systemic factors were significant drivers behind our findings.
This study did not intend to determine differences in incidence of HCC by race, although many studies have shown an age-adjusted incidence of HCC among Black and Hispanic patients up to twice that of White patients.1,8-10 Notably, the rate of orthotopic liver transplantation in this study was low regardless of race compared with that of other larger studies of patients with HCC.12,15 Discrepancies in HCC care among White and Black patients have been suggested to stem from a variety of influences, including access to early diagnosis and treatment of hepatitis C virus, comorbid conditions, as well as complex socioeconomic factors. It also has been shown that oncologists’ implicit racial bias has a negative impact on patients’ perceived quality of communication, their confidence in the recommended treatment, and the understood difficulty of the treatment by the patient and should be considered as a contributor to health disparities.17,18
Studies evaluating survival in HCC using SEER data generally stratify disease by localized, regional, or distant metastasis. For our study, TNM staging provided a more accurate assessment of the disease and reduced the chances that broader staging definitions could obscure differences in treatment choices. Future studies could be improved by stratifying patients by variables impacting treatment choice, such as Child-Pugh score or Barcelona Clinic Liver Cancer staging. Our study demonstrated a statistically significant difference in AFP level between White and Black veterans. This has been observed in prior studies as well, and while no specific cause has been identified, it suggests differences in tumor biologic features across different races. In addition, we found that an elevated AFP level at the time of diagnosis (defined as > 400) correlates with a worsened OS (HR, 1.36; P = .01).
Limitations
This study has several limitations, notably the number of veterans eligible for analysis at a single institution. A larger cohort would be needed to evaluate for statistically significant differences in outcomes by race. Additionally, our study did not account for therapy that was offered to but not pursued by the patient, and this would be useful to determine whether patient or practitioner factors were the more significant influence on the type of therapy received.
Conclusions
This study demonstrated a statistically significant difference in the rate of resection and liver transplantation between White and Black veterans at a single institution, although no difference in OS was observed. This discrepancy was not explained by differences in tumor staging. Additional, larger studies will be useful in clarifying the biologic, cultural, and socioeconomic drivers in HCC treatment and mortality.
Acknowledgments
The authors thank Lorri Reaves, Memphis Veterans Affairs Medical Center, Department of Hepatology.
1. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27(9):1485-1491. doi:10.1200/JCO.2008.20.7753
2. Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Accessed July 8, 2022. https://seer.cancer.gov/archive/csr/1975_2012/results_merged/sect_14_liver_bile.pdf#page=8
3. Singal AG, Mittal S, Yerokun OA, et al. Hepatocellular carcinoma screening associated with early tumor detection and improved survival among patients with cirrhosis in the US. Am J Med. 2017;130(9):1099-1106.e1. doi:10.1016/j.amjmed.2017.01.021
4. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857
5. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745
6. Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022;40(suppl 4):379. doi:10.1200/JCO.2022.40.4_suppl.379
7. Franco RA, Fan Y, Jarosek S, Bae S, Galbraith J. Racial and geographic disparities in hepatocellular carcinoma outcomes. Am J Prev Med. 2018;55(5)(suppl 1):S40-S48. doi:10.1016/j.amepre.2018.05.030
8. Ha J, Yan M, Aguilar M, et al. Race/ethnicity-specific disparities in hepatocellular carcinoma stage at diagnosis and its impact on receipt of curative therapies. J Clin Gastroenterol. 2016;50(5):423-430. doi:10.1097/MCG.0000000000000448
9. Wong R, Corley DA. Racial and ethnic variations in hepatocellular carcinoma incidence within the United States. Am J Med. 2008;121(6):525-531. doi:10.1016/j.amjmed.2008.03.005
10. Rich NE, Hester C, Odewole M, et al. Racial and ethnic differences in presentation and outcomes of hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2019;17(3):551-559.e1. doi:10.1016/j.cgh.2018.05.039
11. Peters NA, Javed AA, He J, Wolfgang CL, Weiss MJ. Association of socioeconomics, surgical therapy, and survival of early stage hepatocellular carcinoma. J Surg Res. 2017;210:253-260. doi:10.1016/j.jss.2016.11.042
12. Wong RJ, Devaki P, Nguyen L, Cheung R, Nguyen MH. Ethnic disparities and liver transplantation rates in hepatocellular carcinoma patients in the recent era: results from the Surveillance, Epidemiology, and End Results registry. Liver Transpl. 2014;20(5):528-535. doi:10.1002/lt.23820
13. Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y, Makuuchi M. Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan. Ann Surg. 2007;245(6):909-922. doi:10.1097/01.sla.0000254368.65878.da.
14. Harrison LE, Reichman T, Koneru B, et al. Racial discrepancies in the outcome of patients with hepatocellular carcinoma. Arch Surg. 2004;139(9):992-996. doi:10.1001/archsurg.139.9.992
15. Sloane D, Chen H, Howell C. Racial disparity in primary hepatocellular carcinoma: tumor stage at presentation, surgical treatment and survival. J Natl Med Assoc. 2006;98(12):1934-1939.
16. Haider AH, Scott VK, Rehman KA, et al. Racial disparities in surgical care and outcomes in the United States: a comprehensive review of patient, provider, and systemic factors. J Am Coll Surg. 2013;216(3):482-92.e12. doi:10.1016/j.jamcollsurg.2012.11.014
17. Cooper LA, Roter DL, Carson KA, et al. The associations of clinicians’ implicit attitudes about race with medical visit communication and patient ratings of interpersonal care. Am J Public Health. 2012;102(5):979-987. doi:10.2105/AJPH.2011.300558
18. Penner LA, Dovidio JF, Gonzalez R, et al. The effects of oncologist implicit racial bias in racially discordant oncology interactions. J Clin Oncol. 2016;34(24):2874-2880. doi:10.1200/JCO.2015.66.3658
1. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27(9):1485-1491. doi:10.1200/JCO.2008.20.7753
2. Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Accessed July 8, 2022. https://seer.cancer.gov/archive/csr/1975_2012/results_merged/sect_14_liver_bile.pdf#page=8
3. Singal AG, Mittal S, Yerokun OA, et al. Hepatocellular carcinoma screening associated with early tumor detection and improved survival among patients with cirrhosis in the US. Am J Med. 2017;130(9):1099-1106.e1. doi:10.1016/j.amjmed.2017.01.021
4. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857
5. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745
6. Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022;40(suppl 4):379. doi:10.1200/JCO.2022.40.4_suppl.379
7. Franco RA, Fan Y, Jarosek S, Bae S, Galbraith J. Racial and geographic disparities in hepatocellular carcinoma outcomes. Am J Prev Med. 2018;55(5)(suppl 1):S40-S48. doi:10.1016/j.amepre.2018.05.030
8. Ha J, Yan M, Aguilar M, et al. Race/ethnicity-specific disparities in hepatocellular carcinoma stage at diagnosis and its impact on receipt of curative therapies. J Clin Gastroenterol. 2016;50(5):423-430. doi:10.1097/MCG.0000000000000448
9. Wong R, Corley DA. Racial and ethnic variations in hepatocellular carcinoma incidence within the United States. Am J Med. 2008;121(6):525-531. doi:10.1016/j.amjmed.2008.03.005
10. Rich NE, Hester C, Odewole M, et al. Racial and ethnic differences in presentation and outcomes of hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2019;17(3):551-559.e1. doi:10.1016/j.cgh.2018.05.039
11. Peters NA, Javed AA, He J, Wolfgang CL, Weiss MJ. Association of socioeconomics, surgical therapy, and survival of early stage hepatocellular carcinoma. J Surg Res. 2017;210:253-260. doi:10.1016/j.jss.2016.11.042
12. Wong RJ, Devaki P, Nguyen L, Cheung R, Nguyen MH. Ethnic disparities and liver transplantation rates in hepatocellular carcinoma patients in the recent era: results from the Surveillance, Epidemiology, and End Results registry. Liver Transpl. 2014;20(5):528-535. doi:10.1002/lt.23820
13. Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y, Makuuchi M. Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan. Ann Surg. 2007;245(6):909-922. doi:10.1097/01.sla.0000254368.65878.da.
14. Harrison LE, Reichman T, Koneru B, et al. Racial discrepancies in the outcome of patients with hepatocellular carcinoma. Arch Surg. 2004;139(9):992-996. doi:10.1001/archsurg.139.9.992
15. Sloane D, Chen H, Howell C. Racial disparity in primary hepatocellular carcinoma: tumor stage at presentation, surgical treatment and survival. J Natl Med Assoc. 2006;98(12):1934-1939.
16. Haider AH, Scott VK, Rehman KA, et al. Racial disparities in surgical care and outcomes in the United States: a comprehensive review of patient, provider, and systemic factors. J Am Coll Surg. 2013;216(3):482-92.e12. doi:10.1016/j.jamcollsurg.2012.11.014
17. Cooper LA, Roter DL, Carson KA, et al. The associations of clinicians’ implicit attitudes about race with medical visit communication and patient ratings of interpersonal care. Am J Public Health. 2012;102(5):979-987. doi:10.2105/AJPH.2011.300558
18. Penner LA, Dovidio JF, Gonzalez R, et al. The effects of oncologist implicit racial bias in racially discordant oncology interactions. J Clin Oncol. 2016;34(24):2874-2880. doi:10.1200/JCO.2015.66.3658