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Rare pediatric cancers persist 63 years after nuclear accident
Chernobyl. Fukushima. Three Mile Island.
The world knows these names all too well because of accidents there: complete or partial meltdowns of nuclear reactors that released massive amounts of cancer-causing radiation into the air, soil, and water.
The Santa Susana Field Lab is far less well-known, but no less infamous for what took place at this former rocket engine and nuclear energy test site just 28 miles northwest of downtown Los Angeles.
In July 1959, an accident involving one of 10 experimental nuclear reactors at the SSFL site released a cloud of harmful radiation and toxic chemicals over the surrounding area, including Simi Valley, San Gabriel Valley, Chatsworth, and Canoga Park. The small reactor had no containment vessel.
This accident resulted in a release of radioactive iodine estimated to be as much as 250 times that of the partial meltdown that would occur 2 decades later at Three Mile Island, a much larger commercial reactor that had a containment vessel.
Decades-long cover-up
In 1959, the public knew nothing about what happened at the site.
According to John Pace, then an employee at SSFL, the accident was covered up. Mr. Pace recounted the cover-up in the documentary “In the Dark of the Valley,” which first aired in November 2021 on MSNBC.
In fact, the accident at SSFL remained under wraps for 2 decades, according to Daniel Hirsch, former director of the Program on Environmental and Nuclear Policy at the University of California, Santa Cruz, and now president of Committee to Bridge the Gap, a nuclear policy nongovernmental organization.
“Students working with me while I was teaching at UCLA in 1979 uncovered these Atomic Energy Commission reports from Atomics International,” he said in an interview. “We had to order the documents from the annex to the UCLA Engineering Library. They were stored offsite, and it took a few days, and when we got them, we opened them up, and there were these fold-out photographs of the fuel [rods]. As we folded out the photographs further, we saw one photo with an arrow labeled ‘longitudinal cracks,’ and then other arrows showing other kinds of cracks, and then another arrow labeled ‘melted blob.’ ”
Mr. Hirsch and his students found that other accidents had occurred at SSFL, including a fuel fabrication system that leached plutonium, fires in a “hot” lab where irradiated nuclear fuel from around the United States was handled, and open-air burn pits where radioactive and toxic chemical wastes were illegally torched.
According to the Committee to Bridge the Gap, when the 2,800-acre SSFL site was being developed under the name Rocketdyne by aircraft maker North American Aviation, the area was sparsely populated, with nearly as many grazing animals as people in its hills and valleys.
North American Aviation later became part of Rockwell International, which in turn sold its aerospace and defense business units to the Boeing Company in 1996. Boeing, now in charge of the site and the cleanup efforts, is doing everything in its power to shirk or diminish its responsibility, Mr. Hirsch and other critics say.
Parents against SSFL
Today, more than 150,000 people live within 5 miles of SSFL, and more than half a million live within 10 miles.
Melissa Bumstead is one of those residents. She and her family live 3.7 miles from the Santa Susana site. When her toddler Grace was diagnosed with a rare form of leukemia in 2014, doctors told Ms. Bumstead there were no known links between her daughter’s cancer and environmental contamination.
But during Grace’s treatment at Children’s Hospital Los Angeles, her mother began meeting other parents who lived near her and had children facing equally rare cancers.
Lauren Hammersley, whose daughter Hazel was diagnosed with a rare brain tumor called neuroblastoma at age 2, lived about 10 miles from Ms. Bumstead on the other side of a mountain and just over 4 miles from SSFL.
On her street alone, Ms. Bumstead discovered three cases of pediatric cancer, including two children in adjacent homes who had the same rare brain tumor as Hazel Hammersley.
As Ms. Bumstead told Los Angeles National Public Radio station KCRW in 2021, “I started to panic because I knew that childhood cancer is extremely rare. There’s only 15,000 new cases every year out of 72 million children in America. So, the chance of knowing your neighbors, especially at an internationally renowned hospital like Children’s Hospital Los Angeles – we knew something wasn’t right.”
After a relapse of her tumor, Hazel died in 2018, a few months after her seventh birthday.
Cancer clusters
Hoping to understand why their kids were getting so sick, Ms. Bumstead and the other parents formed a Facebook group. They plotted their homes on Google Maps and found that they all lived within roughly 10 miles of one another. It would take another year for them to realize that the SSFL site was at the center of the circle.
Once they realized that being close to SSFL could be their common thread, Ms. Bumstead and parents in her group began to gradually piece together the story, linking unusual or unexplained illnesses in their families to potential radiation or toxic chemical exposures from the lab.
“What really convinced me that this was absolutely a problem was when I learned about the epidemiological study by Dr. Hal Morgenstern that found that residents living within 2 miles of the Santa Susana Field Lab actually had a 60% higher cancer incidence rate and that over 1,500 workers have been diagnosed with cancer just from the Santa Susana Field Lab,” she told KCRW.
In 2015, Ms. Bumstead and other parents formed Parents Against Santa Susana Field Lab to hold SSFL site owner Boeing accountable for radiologic and toxic contamination and to ensure that Boeing cleans the site and surrounding areas. The group “seeks to reduce, to the greatest extent possible, the number of local families who have to hear the words, ‘Your child has cancer.’ ”
No longer quite so rare
Dr. Morgenstern, now retired from the University of Michigan, declined to be interviewed for this article. But as he and colleagues reported to the Centers for Disease Control and Prevention’s Agency for Toxic Substances and Disease Registry in 2007, there were strong signs of a link between contamination of the site and cancer.
The researchers compared cancer rates of adults living within 2 miles and 2-5 miles from SSFL with those of adults living more than 5 miles away, in Ventura and Los Angeles counties. They found that from 1988 through 1995, residents living within 2 miles of SSFL had a 60% higher rate of cancers than the control group. These included cancers of the thyroid, oral and nasal cavities, pharynx, larynx, esophagus, and bladder, as well as blood cancers such as leukemia, lymphoma, and multiple myeloma.
In separate studies, the investigators found higher rates of certain cancers among workers at SSFL who were exposed to radiation and to hydrazine, a chemical in rocket fuel.
In an interview, Dr. Saro Armenian, a pediatric hematologist-oncologist who was not involved in the studies, said the 60% increase in cancer incidence, which translated into a 1.6-fold increase in risk, merits more investigation.
“In epidemiologic studies, a 1.6-fold risk is actually a pretty strong signal because typically, most signals that you get are somewhere around 1.1- to 1.2-fold increased risk,” noted Dr. Armenian, a specialist in pediatric cancer survivorship and outcomes at City of Hope National Medical Center in Duarte, Calif.
However, Dr. Thomas Mack, former director of the Los Angeles County Cancer Surveillance Program, contends that there is insufficient evidence to support a direct link between the 1959 reactor accident and recent incident cancers. Dr. Mack is currently a professor of preventive medicine and pathology at the University of Southern California in Los Angeles.
“I have evaluated concerns about local excesses of cancer at least 100 times, usually from county residents, but for a while I represented the CDC and the California cancer registry,” Dr. Mack said, in response to an emailed request for comment.
“So far I have seen no evidence of carcinogenic radionucleotides or chemical carcinogens from Santa Susana found in any meaningful amount in any nearby community, but if someone has such evidence that would constitute evidence, that needs a response,” Dr. Mack added.
Boeing and California
Boeing has said problems at SSFL were not responsible for the high cancer rates among children in the community.
In April 2007, in a statement opposing a bill before the California State Legislature that would compel Boeing to pay for SSFL site cleanup, the company said that “in contrast to the accusations made against The Boeing Company that falsely claim increased cancer rates in the communities surrounding SSFL, a recent study conducted by the University of Michigan School of Public Health just concluded the opposite.”
Yet as Dr. Morgenstern wrote in 2007 to California state Sen. Joe Simitian, then chair of the Committee on Environmental Quality: “For the period 1996 through 2002, we found that the incidence rate of thyroid cancer was more than 60% greater among residents living within 2 miles of SSFL than for residents living more than 5 miles from SSFL. The magnitude and consistency of the thyroid finding for both periods is especially provocative because of evidence from other studies linking thyroid cancer with environmental exposures originating at SSFL and found in the surrounding communities.”
Boeing chose to ignore the results and instead focused on the methods used in the study, where the authors acknowledged that they measured distance from the site rather than environmental exposures and thus could not conclusively link excess cancer rates to exposures arising from SSFL.
But Dr. Morgenstern emphasized the conclusion of the report: “Despite the methodologic limitations of this study, the findings suggest there may be elevated incidence rates of certain cancers near SSFL that have been linked in previous studies with hazardous substances used at Rocketdyne, some of which have been observed or projected to exist offsite.”
Failure to come clean
In 2008, a law that set standards for cleanup of the site was passed. But the law was overturned in 2014 after a legal challenge by Boeing.
That left in place a 2007 order of consent between Boeing, NASA, the U.S. Department of Energy, and the California Department of Toxic Substances Control (DTSC) that required cleanup of SSFL to a much less stringent standard.
As of last year, Boeing and DTSC had begun confidential, nonbinding agreements regarding the 2007 order of consent, according to Parents Against SSFL.
Among the contaminants lingering at the site are radioactive particles, chemical compounds, heavy metals, and polluted water.
“In fact, over 300 contaminants of concern have been found at the site, and they are refusing to clean it,” Mr. Hirsch said. “This company releases large amounts of carcinogens, and perhaps significant numbers of people get sick with cancer, and the company doesn’t go to prison. They get more federal contracts.”
A version of this article first appeared on WebMD.com.
April 20, 2022 – Editor’s note: This article has been updated to include an interview with Dr. Thomas Mack, former director of the Los Angeles County Cancer Surveillance Program, who contends that there is insufficient evidence to support a direct link between the 1959 reactor accident and recent incident cancers.
Chernobyl. Fukushima. Three Mile Island.
The world knows these names all too well because of accidents there: complete or partial meltdowns of nuclear reactors that released massive amounts of cancer-causing radiation into the air, soil, and water.
The Santa Susana Field Lab is far less well-known, but no less infamous for what took place at this former rocket engine and nuclear energy test site just 28 miles northwest of downtown Los Angeles.
In July 1959, an accident involving one of 10 experimental nuclear reactors at the SSFL site released a cloud of harmful radiation and toxic chemicals over the surrounding area, including Simi Valley, San Gabriel Valley, Chatsworth, and Canoga Park. The small reactor had no containment vessel.
This accident resulted in a release of radioactive iodine estimated to be as much as 250 times that of the partial meltdown that would occur 2 decades later at Three Mile Island, a much larger commercial reactor that had a containment vessel.
Decades-long cover-up
In 1959, the public knew nothing about what happened at the site.
According to John Pace, then an employee at SSFL, the accident was covered up. Mr. Pace recounted the cover-up in the documentary “In the Dark of the Valley,” which first aired in November 2021 on MSNBC.
In fact, the accident at SSFL remained under wraps for 2 decades, according to Daniel Hirsch, former director of the Program on Environmental and Nuclear Policy at the University of California, Santa Cruz, and now president of Committee to Bridge the Gap, a nuclear policy nongovernmental organization.
“Students working with me while I was teaching at UCLA in 1979 uncovered these Atomic Energy Commission reports from Atomics International,” he said in an interview. “We had to order the documents from the annex to the UCLA Engineering Library. They were stored offsite, and it took a few days, and when we got them, we opened them up, and there were these fold-out photographs of the fuel [rods]. As we folded out the photographs further, we saw one photo with an arrow labeled ‘longitudinal cracks,’ and then other arrows showing other kinds of cracks, and then another arrow labeled ‘melted blob.’ ”
Mr. Hirsch and his students found that other accidents had occurred at SSFL, including a fuel fabrication system that leached plutonium, fires in a “hot” lab where irradiated nuclear fuel from around the United States was handled, and open-air burn pits where radioactive and toxic chemical wastes were illegally torched.
According to the Committee to Bridge the Gap, when the 2,800-acre SSFL site was being developed under the name Rocketdyne by aircraft maker North American Aviation, the area was sparsely populated, with nearly as many grazing animals as people in its hills and valleys.
North American Aviation later became part of Rockwell International, which in turn sold its aerospace and defense business units to the Boeing Company in 1996. Boeing, now in charge of the site and the cleanup efforts, is doing everything in its power to shirk or diminish its responsibility, Mr. Hirsch and other critics say.
Parents against SSFL
Today, more than 150,000 people live within 5 miles of SSFL, and more than half a million live within 10 miles.
Melissa Bumstead is one of those residents. She and her family live 3.7 miles from the Santa Susana site. When her toddler Grace was diagnosed with a rare form of leukemia in 2014, doctors told Ms. Bumstead there were no known links between her daughter’s cancer and environmental contamination.
But during Grace’s treatment at Children’s Hospital Los Angeles, her mother began meeting other parents who lived near her and had children facing equally rare cancers.
Lauren Hammersley, whose daughter Hazel was diagnosed with a rare brain tumor called neuroblastoma at age 2, lived about 10 miles from Ms. Bumstead on the other side of a mountain and just over 4 miles from SSFL.
On her street alone, Ms. Bumstead discovered three cases of pediatric cancer, including two children in adjacent homes who had the same rare brain tumor as Hazel Hammersley.
As Ms. Bumstead told Los Angeles National Public Radio station KCRW in 2021, “I started to panic because I knew that childhood cancer is extremely rare. There’s only 15,000 new cases every year out of 72 million children in America. So, the chance of knowing your neighbors, especially at an internationally renowned hospital like Children’s Hospital Los Angeles – we knew something wasn’t right.”
After a relapse of her tumor, Hazel died in 2018, a few months after her seventh birthday.
Cancer clusters
Hoping to understand why their kids were getting so sick, Ms. Bumstead and the other parents formed a Facebook group. They plotted their homes on Google Maps and found that they all lived within roughly 10 miles of one another. It would take another year for them to realize that the SSFL site was at the center of the circle.
Once they realized that being close to SSFL could be their common thread, Ms. Bumstead and parents in her group began to gradually piece together the story, linking unusual or unexplained illnesses in their families to potential radiation or toxic chemical exposures from the lab.
“What really convinced me that this was absolutely a problem was when I learned about the epidemiological study by Dr. Hal Morgenstern that found that residents living within 2 miles of the Santa Susana Field Lab actually had a 60% higher cancer incidence rate and that over 1,500 workers have been diagnosed with cancer just from the Santa Susana Field Lab,” she told KCRW.
In 2015, Ms. Bumstead and other parents formed Parents Against Santa Susana Field Lab to hold SSFL site owner Boeing accountable for radiologic and toxic contamination and to ensure that Boeing cleans the site and surrounding areas. The group “seeks to reduce, to the greatest extent possible, the number of local families who have to hear the words, ‘Your child has cancer.’ ”
No longer quite so rare
Dr. Morgenstern, now retired from the University of Michigan, declined to be interviewed for this article. But as he and colleagues reported to the Centers for Disease Control and Prevention’s Agency for Toxic Substances and Disease Registry in 2007, there were strong signs of a link between contamination of the site and cancer.
The researchers compared cancer rates of adults living within 2 miles and 2-5 miles from SSFL with those of adults living more than 5 miles away, in Ventura and Los Angeles counties. They found that from 1988 through 1995, residents living within 2 miles of SSFL had a 60% higher rate of cancers than the control group. These included cancers of the thyroid, oral and nasal cavities, pharynx, larynx, esophagus, and bladder, as well as blood cancers such as leukemia, lymphoma, and multiple myeloma.
In separate studies, the investigators found higher rates of certain cancers among workers at SSFL who were exposed to radiation and to hydrazine, a chemical in rocket fuel.
In an interview, Dr. Saro Armenian, a pediatric hematologist-oncologist who was not involved in the studies, said the 60% increase in cancer incidence, which translated into a 1.6-fold increase in risk, merits more investigation.
“In epidemiologic studies, a 1.6-fold risk is actually a pretty strong signal because typically, most signals that you get are somewhere around 1.1- to 1.2-fold increased risk,” noted Dr. Armenian, a specialist in pediatric cancer survivorship and outcomes at City of Hope National Medical Center in Duarte, Calif.
However, Dr. Thomas Mack, former director of the Los Angeles County Cancer Surveillance Program, contends that there is insufficient evidence to support a direct link between the 1959 reactor accident and recent incident cancers. Dr. Mack is currently a professor of preventive medicine and pathology at the University of Southern California in Los Angeles.
“I have evaluated concerns about local excesses of cancer at least 100 times, usually from county residents, but for a while I represented the CDC and the California cancer registry,” Dr. Mack said, in response to an emailed request for comment.
“So far I have seen no evidence of carcinogenic radionucleotides or chemical carcinogens from Santa Susana found in any meaningful amount in any nearby community, but if someone has such evidence that would constitute evidence, that needs a response,” Dr. Mack added.
Boeing and California
Boeing has said problems at SSFL were not responsible for the high cancer rates among children in the community.
In April 2007, in a statement opposing a bill before the California State Legislature that would compel Boeing to pay for SSFL site cleanup, the company said that “in contrast to the accusations made against The Boeing Company that falsely claim increased cancer rates in the communities surrounding SSFL, a recent study conducted by the University of Michigan School of Public Health just concluded the opposite.”
Yet as Dr. Morgenstern wrote in 2007 to California state Sen. Joe Simitian, then chair of the Committee on Environmental Quality: “For the period 1996 through 2002, we found that the incidence rate of thyroid cancer was more than 60% greater among residents living within 2 miles of SSFL than for residents living more than 5 miles from SSFL. The magnitude and consistency of the thyroid finding for both periods is especially provocative because of evidence from other studies linking thyroid cancer with environmental exposures originating at SSFL and found in the surrounding communities.”
Boeing chose to ignore the results and instead focused on the methods used in the study, where the authors acknowledged that they measured distance from the site rather than environmental exposures and thus could not conclusively link excess cancer rates to exposures arising from SSFL.
But Dr. Morgenstern emphasized the conclusion of the report: “Despite the methodologic limitations of this study, the findings suggest there may be elevated incidence rates of certain cancers near SSFL that have been linked in previous studies with hazardous substances used at Rocketdyne, some of which have been observed or projected to exist offsite.”
Failure to come clean
In 2008, a law that set standards for cleanup of the site was passed. But the law was overturned in 2014 after a legal challenge by Boeing.
That left in place a 2007 order of consent between Boeing, NASA, the U.S. Department of Energy, and the California Department of Toxic Substances Control (DTSC) that required cleanup of SSFL to a much less stringent standard.
As of last year, Boeing and DTSC had begun confidential, nonbinding agreements regarding the 2007 order of consent, according to Parents Against SSFL.
Among the contaminants lingering at the site are radioactive particles, chemical compounds, heavy metals, and polluted water.
“In fact, over 300 contaminants of concern have been found at the site, and they are refusing to clean it,” Mr. Hirsch said. “This company releases large amounts of carcinogens, and perhaps significant numbers of people get sick with cancer, and the company doesn’t go to prison. They get more federal contracts.”
A version of this article first appeared on WebMD.com.
April 20, 2022 – Editor’s note: This article has been updated to include an interview with Dr. Thomas Mack, former director of the Los Angeles County Cancer Surveillance Program, who contends that there is insufficient evidence to support a direct link between the 1959 reactor accident and recent incident cancers.
Chernobyl. Fukushima. Three Mile Island.
The world knows these names all too well because of accidents there: complete or partial meltdowns of nuclear reactors that released massive amounts of cancer-causing radiation into the air, soil, and water.
The Santa Susana Field Lab is far less well-known, but no less infamous for what took place at this former rocket engine and nuclear energy test site just 28 miles northwest of downtown Los Angeles.
In July 1959, an accident involving one of 10 experimental nuclear reactors at the SSFL site released a cloud of harmful radiation and toxic chemicals over the surrounding area, including Simi Valley, San Gabriel Valley, Chatsworth, and Canoga Park. The small reactor had no containment vessel.
This accident resulted in a release of radioactive iodine estimated to be as much as 250 times that of the partial meltdown that would occur 2 decades later at Three Mile Island, a much larger commercial reactor that had a containment vessel.
Decades-long cover-up
In 1959, the public knew nothing about what happened at the site.
According to John Pace, then an employee at SSFL, the accident was covered up. Mr. Pace recounted the cover-up in the documentary “In the Dark of the Valley,” which first aired in November 2021 on MSNBC.
In fact, the accident at SSFL remained under wraps for 2 decades, according to Daniel Hirsch, former director of the Program on Environmental and Nuclear Policy at the University of California, Santa Cruz, and now president of Committee to Bridge the Gap, a nuclear policy nongovernmental organization.
“Students working with me while I was teaching at UCLA in 1979 uncovered these Atomic Energy Commission reports from Atomics International,” he said in an interview. “We had to order the documents from the annex to the UCLA Engineering Library. They were stored offsite, and it took a few days, and when we got them, we opened them up, and there were these fold-out photographs of the fuel [rods]. As we folded out the photographs further, we saw one photo with an arrow labeled ‘longitudinal cracks,’ and then other arrows showing other kinds of cracks, and then another arrow labeled ‘melted blob.’ ”
Mr. Hirsch and his students found that other accidents had occurred at SSFL, including a fuel fabrication system that leached plutonium, fires in a “hot” lab where irradiated nuclear fuel from around the United States was handled, and open-air burn pits where radioactive and toxic chemical wastes were illegally torched.
According to the Committee to Bridge the Gap, when the 2,800-acre SSFL site was being developed under the name Rocketdyne by aircraft maker North American Aviation, the area was sparsely populated, with nearly as many grazing animals as people in its hills and valleys.
North American Aviation later became part of Rockwell International, which in turn sold its aerospace and defense business units to the Boeing Company in 1996. Boeing, now in charge of the site and the cleanup efforts, is doing everything in its power to shirk or diminish its responsibility, Mr. Hirsch and other critics say.
Parents against SSFL
Today, more than 150,000 people live within 5 miles of SSFL, and more than half a million live within 10 miles.
Melissa Bumstead is one of those residents. She and her family live 3.7 miles from the Santa Susana site. When her toddler Grace was diagnosed with a rare form of leukemia in 2014, doctors told Ms. Bumstead there were no known links between her daughter’s cancer and environmental contamination.
But during Grace’s treatment at Children’s Hospital Los Angeles, her mother began meeting other parents who lived near her and had children facing equally rare cancers.
Lauren Hammersley, whose daughter Hazel was diagnosed with a rare brain tumor called neuroblastoma at age 2, lived about 10 miles from Ms. Bumstead on the other side of a mountain and just over 4 miles from SSFL.
On her street alone, Ms. Bumstead discovered three cases of pediatric cancer, including two children in adjacent homes who had the same rare brain tumor as Hazel Hammersley.
As Ms. Bumstead told Los Angeles National Public Radio station KCRW in 2021, “I started to panic because I knew that childhood cancer is extremely rare. There’s only 15,000 new cases every year out of 72 million children in America. So, the chance of knowing your neighbors, especially at an internationally renowned hospital like Children’s Hospital Los Angeles – we knew something wasn’t right.”
After a relapse of her tumor, Hazel died in 2018, a few months after her seventh birthday.
Cancer clusters
Hoping to understand why their kids were getting so sick, Ms. Bumstead and the other parents formed a Facebook group. They plotted their homes on Google Maps and found that they all lived within roughly 10 miles of one another. It would take another year for them to realize that the SSFL site was at the center of the circle.
Once they realized that being close to SSFL could be their common thread, Ms. Bumstead and parents in her group began to gradually piece together the story, linking unusual or unexplained illnesses in their families to potential radiation or toxic chemical exposures from the lab.
“What really convinced me that this was absolutely a problem was when I learned about the epidemiological study by Dr. Hal Morgenstern that found that residents living within 2 miles of the Santa Susana Field Lab actually had a 60% higher cancer incidence rate and that over 1,500 workers have been diagnosed with cancer just from the Santa Susana Field Lab,” she told KCRW.
In 2015, Ms. Bumstead and other parents formed Parents Against Santa Susana Field Lab to hold SSFL site owner Boeing accountable for radiologic and toxic contamination and to ensure that Boeing cleans the site and surrounding areas. The group “seeks to reduce, to the greatest extent possible, the number of local families who have to hear the words, ‘Your child has cancer.’ ”
No longer quite so rare
Dr. Morgenstern, now retired from the University of Michigan, declined to be interviewed for this article. But as he and colleagues reported to the Centers for Disease Control and Prevention’s Agency for Toxic Substances and Disease Registry in 2007, there were strong signs of a link between contamination of the site and cancer.
The researchers compared cancer rates of adults living within 2 miles and 2-5 miles from SSFL with those of adults living more than 5 miles away, in Ventura and Los Angeles counties. They found that from 1988 through 1995, residents living within 2 miles of SSFL had a 60% higher rate of cancers than the control group. These included cancers of the thyroid, oral and nasal cavities, pharynx, larynx, esophagus, and bladder, as well as blood cancers such as leukemia, lymphoma, and multiple myeloma.
In separate studies, the investigators found higher rates of certain cancers among workers at SSFL who were exposed to radiation and to hydrazine, a chemical in rocket fuel.
In an interview, Dr. Saro Armenian, a pediatric hematologist-oncologist who was not involved in the studies, said the 60% increase in cancer incidence, which translated into a 1.6-fold increase in risk, merits more investigation.
“In epidemiologic studies, a 1.6-fold risk is actually a pretty strong signal because typically, most signals that you get are somewhere around 1.1- to 1.2-fold increased risk,” noted Dr. Armenian, a specialist in pediatric cancer survivorship and outcomes at City of Hope National Medical Center in Duarte, Calif.
However, Dr. Thomas Mack, former director of the Los Angeles County Cancer Surveillance Program, contends that there is insufficient evidence to support a direct link between the 1959 reactor accident and recent incident cancers. Dr. Mack is currently a professor of preventive medicine and pathology at the University of Southern California in Los Angeles.
“I have evaluated concerns about local excesses of cancer at least 100 times, usually from county residents, but for a while I represented the CDC and the California cancer registry,” Dr. Mack said, in response to an emailed request for comment.
“So far I have seen no evidence of carcinogenic radionucleotides or chemical carcinogens from Santa Susana found in any meaningful amount in any nearby community, but if someone has such evidence that would constitute evidence, that needs a response,” Dr. Mack added.
Boeing and California
Boeing has said problems at SSFL were not responsible for the high cancer rates among children in the community.
In April 2007, in a statement opposing a bill before the California State Legislature that would compel Boeing to pay for SSFL site cleanup, the company said that “in contrast to the accusations made against The Boeing Company that falsely claim increased cancer rates in the communities surrounding SSFL, a recent study conducted by the University of Michigan School of Public Health just concluded the opposite.”
Yet as Dr. Morgenstern wrote in 2007 to California state Sen. Joe Simitian, then chair of the Committee on Environmental Quality: “For the period 1996 through 2002, we found that the incidence rate of thyroid cancer was more than 60% greater among residents living within 2 miles of SSFL than for residents living more than 5 miles from SSFL. The magnitude and consistency of the thyroid finding for both periods is especially provocative because of evidence from other studies linking thyroid cancer with environmental exposures originating at SSFL and found in the surrounding communities.”
Boeing chose to ignore the results and instead focused on the methods used in the study, where the authors acknowledged that they measured distance from the site rather than environmental exposures and thus could not conclusively link excess cancer rates to exposures arising from SSFL.
But Dr. Morgenstern emphasized the conclusion of the report: “Despite the methodologic limitations of this study, the findings suggest there may be elevated incidence rates of certain cancers near SSFL that have been linked in previous studies with hazardous substances used at Rocketdyne, some of which have been observed or projected to exist offsite.”
Failure to come clean
In 2008, a law that set standards for cleanup of the site was passed. But the law was overturned in 2014 after a legal challenge by Boeing.
That left in place a 2007 order of consent between Boeing, NASA, the U.S. Department of Energy, and the California Department of Toxic Substances Control (DTSC) that required cleanup of SSFL to a much less stringent standard.
As of last year, Boeing and DTSC had begun confidential, nonbinding agreements regarding the 2007 order of consent, according to Parents Against SSFL.
Among the contaminants lingering at the site are radioactive particles, chemical compounds, heavy metals, and polluted water.
“In fact, over 300 contaminants of concern have been found at the site, and they are refusing to clean it,” Mr. Hirsch said. “This company releases large amounts of carcinogens, and perhaps significant numbers of people get sick with cancer, and the company doesn’t go to prison. They get more federal contracts.”
A version of this article first appeared on WebMD.com.
April 20, 2022 – Editor’s note: This article has been updated to include an interview with Dr. Thomas Mack, former director of the Los Angeles County Cancer Surveillance Program, who contends that there is insufficient evidence to support a direct link between the 1959 reactor accident and recent incident cancers.
New gene signals for asthma-COPD overlap identified
A large-scale analysis of the genetic underpinnings of the overlap between asthma and chronic obstructive pulmonary disease (COPD) has identified eight novel signals that may be linked to inflammation and worse asthma outcomes, according to an international team of investigators.
They conducted a genome-wide association study (GWAS) of 8,068 individuals with asthma-COPD overlap (ACO) and 40,360 controls with either asthma or COPD alone and identified genetic variants that could predispose patients to ACO.
The findings by Catherine John, MBBChir, from the University of Leicester, England, and colleagues from Europe, the United States, and Canada were published online in Chest.
“Our study contributes to understanding the genetic landscape of asthma and COPD at the population level,” explained coauthor Lystra P. Hayden, MD, from Brigham and Women’s Hospital and Harvard Medical School, Boston, in an email.
“It provides evidence for shared genetic influence ranging from variants implicated in asthma to those implicated in fixed airflow obstruction and specifically those which influence an intermediate phenotype with features of both, which was the focus of this investigation,” she wrote.
Although the study does not provide sufficient evidence to support patient-level genetic testing for these variants, “it does suggest potential common biological mechanisms underpinning both asthma and COPD, which in the future could inform treatments of people displaying features of both conditions,” Dr. Hayden said.
Asthma and COPD are distinct conditions but share certain features, such as airflow obstruction, inflammation, and cytokine profiles. Recent studies have suggested that patients with features of both conditions – ACO – have worse outcomes than those with either condition alone.
The authors note that recent guidelines from the Global Initiative for Chronic Obstructive Lung Disease “emphasize that asthma and COPD are different conditions but may coexist in the same patient.”
“One of the things that genetics can do is to see if there is a genetic basis to the etiology of both of these conditions,” said coauthor Sina A. Gharib, MD, professor of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle.
“Are these both just the same disease manifesting differently, or are they two really different diseases? That’s an ongoing controversy, and I don’t think this paper or any other paper that I’ve seen really settles this,” he said in an interview.
He noted that most genetic studies of asthma tend to exclude patients with COPD, and vice versa, because the complexity of the respective phenotypes can make it difficult to draw strong conclusions about genetic contributions to disease etiology.
Dr. Gharib’s group contributed data for the validation portion of the study.
Genetic study
The authors first drew data on the patients with ACO and controls from the UK Biobank and conducted a GWAS using a cutoff P value of less than 5x10-6 to identify “promising” signals that remained significant in analyses comparing patients with ACO with those with asthma alone and with COPD alone.
They then analyzed the variants in 12 independent cohorts and identified 31 variants they deemed to be worth a closer look.
“These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD or lung function,” they write.
The investigators also performed subgroup analyses stratified by age of asthma onset and by smoking status.
“We found that for the 31 ACO signals of interest examined, the effect sizes amongst cases with childhood-onset asthma were highly correlated to those with adult onset. Effect sizes in ever- and never-smokers were also closely correlated. Our study suggests that ACO is not due solely to smoking in people with asthma,” Dr. Hayden said.
In addition, they tested variants across a wide range of phenotypes and found that traits of eosinophil counts, atopy, and asthma were prominent.
“Our findings suggest a spectrum of shared genetic influences, from variants predominantly influencing asthma to those predominantly influencing fixed airflow obstruction. We focus on variants that tend towards an intermediate phenotype with features of both asthma and fixed airflow obstruction with pathways implicating innate and adaptive immunity and potentially bone development and signals for which the biology remains unclear,” they write.
While it’s still unclear whether ACO is a distinct entity unto itself, “we do seem to find some signals that seem to be uniquely displayed in this population that has diagnosis of asthma but also has a reduction in lung function that’s not reversible, which is what we see in COPD,” Dr. Gharib said.
Further exploration of the biology of ACO could lead to development of methods to prevent fixed airflow obstruction in patients with asthma, the authors conclude.
The study was supported by BREATHE, the Health Data Research Hub for Respiratory Health in partnership with SAIL Databank. Dr. Hayden and Dr. Gharib reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A large-scale analysis of the genetic underpinnings of the overlap between asthma and chronic obstructive pulmonary disease (COPD) has identified eight novel signals that may be linked to inflammation and worse asthma outcomes, according to an international team of investigators.
They conducted a genome-wide association study (GWAS) of 8,068 individuals with asthma-COPD overlap (ACO) and 40,360 controls with either asthma or COPD alone and identified genetic variants that could predispose patients to ACO.
The findings by Catherine John, MBBChir, from the University of Leicester, England, and colleagues from Europe, the United States, and Canada were published online in Chest.
“Our study contributes to understanding the genetic landscape of asthma and COPD at the population level,” explained coauthor Lystra P. Hayden, MD, from Brigham and Women’s Hospital and Harvard Medical School, Boston, in an email.
“It provides evidence for shared genetic influence ranging from variants implicated in asthma to those implicated in fixed airflow obstruction and specifically those which influence an intermediate phenotype with features of both, which was the focus of this investigation,” she wrote.
Although the study does not provide sufficient evidence to support patient-level genetic testing for these variants, “it does suggest potential common biological mechanisms underpinning both asthma and COPD, which in the future could inform treatments of people displaying features of both conditions,” Dr. Hayden said.
Asthma and COPD are distinct conditions but share certain features, such as airflow obstruction, inflammation, and cytokine profiles. Recent studies have suggested that patients with features of both conditions – ACO – have worse outcomes than those with either condition alone.
The authors note that recent guidelines from the Global Initiative for Chronic Obstructive Lung Disease “emphasize that asthma and COPD are different conditions but may coexist in the same patient.”
“One of the things that genetics can do is to see if there is a genetic basis to the etiology of both of these conditions,” said coauthor Sina A. Gharib, MD, professor of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle.
“Are these both just the same disease manifesting differently, or are they two really different diseases? That’s an ongoing controversy, and I don’t think this paper or any other paper that I’ve seen really settles this,” he said in an interview.
He noted that most genetic studies of asthma tend to exclude patients with COPD, and vice versa, because the complexity of the respective phenotypes can make it difficult to draw strong conclusions about genetic contributions to disease etiology.
Dr. Gharib’s group contributed data for the validation portion of the study.
Genetic study
The authors first drew data on the patients with ACO and controls from the UK Biobank and conducted a GWAS using a cutoff P value of less than 5x10-6 to identify “promising” signals that remained significant in analyses comparing patients with ACO with those with asthma alone and with COPD alone.
They then analyzed the variants in 12 independent cohorts and identified 31 variants they deemed to be worth a closer look.
“These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD or lung function,” they write.
The investigators also performed subgroup analyses stratified by age of asthma onset and by smoking status.
“We found that for the 31 ACO signals of interest examined, the effect sizes amongst cases with childhood-onset asthma were highly correlated to those with adult onset. Effect sizes in ever- and never-smokers were also closely correlated. Our study suggests that ACO is not due solely to smoking in people with asthma,” Dr. Hayden said.
In addition, they tested variants across a wide range of phenotypes and found that traits of eosinophil counts, atopy, and asthma were prominent.
“Our findings suggest a spectrum of shared genetic influences, from variants predominantly influencing asthma to those predominantly influencing fixed airflow obstruction. We focus on variants that tend towards an intermediate phenotype with features of both asthma and fixed airflow obstruction with pathways implicating innate and adaptive immunity and potentially bone development and signals for which the biology remains unclear,” they write.
While it’s still unclear whether ACO is a distinct entity unto itself, “we do seem to find some signals that seem to be uniquely displayed in this population that has diagnosis of asthma but also has a reduction in lung function that’s not reversible, which is what we see in COPD,” Dr. Gharib said.
Further exploration of the biology of ACO could lead to development of methods to prevent fixed airflow obstruction in patients with asthma, the authors conclude.
The study was supported by BREATHE, the Health Data Research Hub for Respiratory Health in partnership with SAIL Databank. Dr. Hayden and Dr. Gharib reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A large-scale analysis of the genetic underpinnings of the overlap between asthma and chronic obstructive pulmonary disease (COPD) has identified eight novel signals that may be linked to inflammation and worse asthma outcomes, according to an international team of investigators.
They conducted a genome-wide association study (GWAS) of 8,068 individuals with asthma-COPD overlap (ACO) and 40,360 controls with either asthma or COPD alone and identified genetic variants that could predispose patients to ACO.
The findings by Catherine John, MBBChir, from the University of Leicester, England, and colleagues from Europe, the United States, and Canada were published online in Chest.
“Our study contributes to understanding the genetic landscape of asthma and COPD at the population level,” explained coauthor Lystra P. Hayden, MD, from Brigham and Women’s Hospital and Harvard Medical School, Boston, in an email.
“It provides evidence for shared genetic influence ranging from variants implicated in asthma to those implicated in fixed airflow obstruction and specifically those which influence an intermediate phenotype with features of both, which was the focus of this investigation,” she wrote.
Although the study does not provide sufficient evidence to support patient-level genetic testing for these variants, “it does suggest potential common biological mechanisms underpinning both asthma and COPD, which in the future could inform treatments of people displaying features of both conditions,” Dr. Hayden said.
Asthma and COPD are distinct conditions but share certain features, such as airflow obstruction, inflammation, and cytokine profiles. Recent studies have suggested that patients with features of both conditions – ACO – have worse outcomes than those with either condition alone.
The authors note that recent guidelines from the Global Initiative for Chronic Obstructive Lung Disease “emphasize that asthma and COPD are different conditions but may coexist in the same patient.”
“One of the things that genetics can do is to see if there is a genetic basis to the etiology of both of these conditions,” said coauthor Sina A. Gharib, MD, professor of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle.
“Are these both just the same disease manifesting differently, or are they two really different diseases? That’s an ongoing controversy, and I don’t think this paper or any other paper that I’ve seen really settles this,” he said in an interview.
He noted that most genetic studies of asthma tend to exclude patients with COPD, and vice versa, because the complexity of the respective phenotypes can make it difficult to draw strong conclusions about genetic contributions to disease etiology.
Dr. Gharib’s group contributed data for the validation portion of the study.
Genetic study
The authors first drew data on the patients with ACO and controls from the UK Biobank and conducted a GWAS using a cutoff P value of less than 5x10-6 to identify “promising” signals that remained significant in analyses comparing patients with ACO with those with asthma alone and with COPD alone.
They then analyzed the variants in 12 independent cohorts and identified 31 variants they deemed to be worth a closer look.
“These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD or lung function,” they write.
The investigators also performed subgroup analyses stratified by age of asthma onset and by smoking status.
“We found that for the 31 ACO signals of interest examined, the effect sizes amongst cases with childhood-onset asthma were highly correlated to those with adult onset. Effect sizes in ever- and never-smokers were also closely correlated. Our study suggests that ACO is not due solely to smoking in people with asthma,” Dr. Hayden said.
In addition, they tested variants across a wide range of phenotypes and found that traits of eosinophil counts, atopy, and asthma were prominent.
“Our findings suggest a spectrum of shared genetic influences, from variants predominantly influencing asthma to those predominantly influencing fixed airflow obstruction. We focus on variants that tend towards an intermediate phenotype with features of both asthma and fixed airflow obstruction with pathways implicating innate and adaptive immunity and potentially bone development and signals for which the biology remains unclear,” they write.
While it’s still unclear whether ACO is a distinct entity unto itself, “we do seem to find some signals that seem to be uniquely displayed in this population that has diagnosis of asthma but also has a reduction in lung function that’s not reversible, which is what we see in COPD,” Dr. Gharib said.
Further exploration of the biology of ACO could lead to development of methods to prevent fixed airflow obstruction in patients with asthma, the authors conclude.
The study was supported by BREATHE, the Health Data Research Hub for Respiratory Health in partnership with SAIL Databank. Dr. Hayden and Dr. Gharib reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
High early recurrence rates with Merkel cell carcinoma
, and more than half of all patients with stage IV disease will have a recurrence within 1 year of definitive therapy, results of a new study show.
A study of 618 patients with MCC who were enrolled in a Seattle-based data repository shows that among all patients the 5-year recurrence rate was 40%. The risk of recurrence within the first year was 11% for patients with pathologic stage I disease, 33% for those with stage IIA/IIB disease, 45% for those with stage IIIB disease, and 58% for patients with pathologic stage IV MCC.
Approximately 95% of all recurrences happened within 3 years of the initial diagnosis, report Aubriana McEvoy, MD, from the University of Washington in Seattle, and colleagues.
“This cohort study indicates that the highest yield (and likely most cost-effective) time period for detecting MCC recurrence is 1-3 years after diagnosis,” they write in a study published online in JAMA Dermatology.
The estimated annual incidence of MCC in the United States in 2018 was 2,000 according to the American Cancer Society. The annual incidence rate is rising rapidly, however, and is estimated to reach 3,284 by 2025, McEvoy and colleagues write.
Although MCC is known to have high recurrence rates and is associated with a higher mortality rate than malignant melanoma, recurrence rate data are not captured by either the Surveillance, Epidemiology, and End Results (SEER) database or by the National Cancer Database. As a result, estimates of recurrence rates with MCC have been all over the map, ranging from 27% to 77%, depending on the population studied.
But as senior author Paul Nghiem, MD, PhD, professor and chair of dermatology at the University of Washington, Seattle, told this news organization, recurrence rates over time in their study were remarkably consistent.
“The biggest surprise to me was that, when we broke our nearly 20-year cohort into three 5- or 6-year chunks, every one of the groups had a 40% recurrence rate, within 1%. So we feel really confident that’s the right number,” he said.
Dr. Nghiem and colleagues report that, in contrast to patients with MCC, approximately 19% of patients with melanoma will have a recurrence, as will an estimated 5%-9% of patients with squamous cell carcinoma and 1%-10% of patients with basal cell carcinoma.
The fact that recurrence rates of MCC have remained stable over time despite presumed improvements in definitive therapy is disappointing, Dr. Nghiem acknowledged. He noted that it’s still unclear whether immunotherapy will have the same dramatic effect on survival rates for patients with MCC as it has for patients with malignant melanoma.
The high recurrence rates following definitive therapy for patients with early-stage disease was a novel finding, commented Shawn Demehri, MD, PhD, director of the high-risk skin cancer clinic at Massachusetts General Hospital in Boston.
“When you’re looking at patients with stage I or stage II, and they have definitive surgery but still have recurrences at a higher rate than melanoma, it brings home the point that these are among the most aggressive tumors of the skin,” he said in an interview.
The high recurrence rates seen with MCC are attributable to a variety of factors.
“This is a rare cancer of mostly older individuals with a lot of comorbidities, and also a cancer that, even though it is a primary cancer, might be detected a little later than even a melanoma primary tumor, just because of the nature of the neuroendocrine tumor cells,” he said.
Dr. Demehri was not involved in the study.
Prospective cohort
The study cohort consisted of 618 patients with MCC. The median age of the patients was 69, and 227 (37%) were women. The patients were enrolled within 6 months of their diagnosis in the prospective data repository from 2003 through 2019. Of this group, 223 had a recurrence of MCC.
As noted, there was a high risk of recurrence within 1 year, ranging from 11% for patients with pathologic stage I tumors to 58% for those with stage IV disease, and 95% of all recurrences occurred within 3 years of definitive therapy.
To get a better picture of the natural history of MCC recurrence, the investigators studied a cohort of patients with pathologically confirmed MCC who were prospectively enrolled from January 2003 through April 2019 in a data repository maintained at the University of Washington.
In addition to disease stage, factors associated with increased recurrence risk in univariable analyses include immunosuppression (hazard ratio, 2.4; P < .001), male sex (HR, 1.9; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; P = .001), and older age (HR, 1.1, P = .06 for each 10-year increase).
Of the 187 patients in the cohort who died during the study, 121 died from MCC. At 4 years after diagnosis, MCC-specific survival rates were 95% for patients with pathologic stage I, 84% with stage IIA/IIB, 80% with stage IIIA, 58% with stage IIIB, and 41% with stage IV.
Evidence supports close monitoring within the first 3 years for patients with stage I-II MCC. Local recurrence within or adjacent to the primary tumor scar was associated with a 5-year MCC-specific survival rate of 85%, compared with 88% of patients with stage I or II disease who did not have recurrences.
“Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage- and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest,” the authors wrote.
“If you’re a patient who has not had your cancer come back for 3, 4, or 5 years, you can really cut down on the intensity of your follow-up and scans,” Dr. Nghiem said.
“We do now have two excellent blood tests that are working very well, and we have really good ways to detect the cancer coming back early, and that’s important, because we have potentially curative therapies that tend to work better if you catch the cancer early,” he said.
The study was supported by the National Institutes of Health. Dr. Nghiem reported personal fees and institutional support outside the study from several companies and patents for Merkel cell therapies with the University of Washington and University of Denmark. Dr. Demehri has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, and more than half of all patients with stage IV disease will have a recurrence within 1 year of definitive therapy, results of a new study show.
A study of 618 patients with MCC who were enrolled in a Seattle-based data repository shows that among all patients the 5-year recurrence rate was 40%. The risk of recurrence within the first year was 11% for patients with pathologic stage I disease, 33% for those with stage IIA/IIB disease, 45% for those with stage IIIB disease, and 58% for patients with pathologic stage IV MCC.
Approximately 95% of all recurrences happened within 3 years of the initial diagnosis, report Aubriana McEvoy, MD, from the University of Washington in Seattle, and colleagues.
“This cohort study indicates that the highest yield (and likely most cost-effective) time period for detecting MCC recurrence is 1-3 years after diagnosis,” they write in a study published online in JAMA Dermatology.
The estimated annual incidence of MCC in the United States in 2018 was 2,000 according to the American Cancer Society. The annual incidence rate is rising rapidly, however, and is estimated to reach 3,284 by 2025, McEvoy and colleagues write.
Although MCC is known to have high recurrence rates and is associated with a higher mortality rate than malignant melanoma, recurrence rate data are not captured by either the Surveillance, Epidemiology, and End Results (SEER) database or by the National Cancer Database. As a result, estimates of recurrence rates with MCC have been all over the map, ranging from 27% to 77%, depending on the population studied.
But as senior author Paul Nghiem, MD, PhD, professor and chair of dermatology at the University of Washington, Seattle, told this news organization, recurrence rates over time in their study were remarkably consistent.
“The biggest surprise to me was that, when we broke our nearly 20-year cohort into three 5- or 6-year chunks, every one of the groups had a 40% recurrence rate, within 1%. So we feel really confident that’s the right number,” he said.
Dr. Nghiem and colleagues report that, in contrast to patients with MCC, approximately 19% of patients with melanoma will have a recurrence, as will an estimated 5%-9% of patients with squamous cell carcinoma and 1%-10% of patients with basal cell carcinoma.
The fact that recurrence rates of MCC have remained stable over time despite presumed improvements in definitive therapy is disappointing, Dr. Nghiem acknowledged. He noted that it’s still unclear whether immunotherapy will have the same dramatic effect on survival rates for patients with MCC as it has for patients with malignant melanoma.
The high recurrence rates following definitive therapy for patients with early-stage disease was a novel finding, commented Shawn Demehri, MD, PhD, director of the high-risk skin cancer clinic at Massachusetts General Hospital in Boston.
“When you’re looking at patients with stage I or stage II, and they have definitive surgery but still have recurrences at a higher rate than melanoma, it brings home the point that these are among the most aggressive tumors of the skin,” he said in an interview.
The high recurrence rates seen with MCC are attributable to a variety of factors.
“This is a rare cancer of mostly older individuals with a lot of comorbidities, and also a cancer that, even though it is a primary cancer, might be detected a little later than even a melanoma primary tumor, just because of the nature of the neuroendocrine tumor cells,” he said.
Dr. Demehri was not involved in the study.
Prospective cohort
The study cohort consisted of 618 patients with MCC. The median age of the patients was 69, and 227 (37%) were women. The patients were enrolled within 6 months of their diagnosis in the prospective data repository from 2003 through 2019. Of this group, 223 had a recurrence of MCC.
As noted, there was a high risk of recurrence within 1 year, ranging from 11% for patients with pathologic stage I tumors to 58% for those with stage IV disease, and 95% of all recurrences occurred within 3 years of definitive therapy.
To get a better picture of the natural history of MCC recurrence, the investigators studied a cohort of patients with pathologically confirmed MCC who were prospectively enrolled from January 2003 through April 2019 in a data repository maintained at the University of Washington.
In addition to disease stage, factors associated with increased recurrence risk in univariable analyses include immunosuppression (hazard ratio, 2.4; P < .001), male sex (HR, 1.9; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; P = .001), and older age (HR, 1.1, P = .06 for each 10-year increase).
Of the 187 patients in the cohort who died during the study, 121 died from MCC. At 4 years after diagnosis, MCC-specific survival rates were 95% for patients with pathologic stage I, 84% with stage IIA/IIB, 80% with stage IIIA, 58% with stage IIIB, and 41% with stage IV.
Evidence supports close monitoring within the first 3 years for patients with stage I-II MCC. Local recurrence within or adjacent to the primary tumor scar was associated with a 5-year MCC-specific survival rate of 85%, compared with 88% of patients with stage I or II disease who did not have recurrences.
“Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage- and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest,” the authors wrote.
“If you’re a patient who has not had your cancer come back for 3, 4, or 5 years, you can really cut down on the intensity of your follow-up and scans,” Dr. Nghiem said.
“We do now have two excellent blood tests that are working very well, and we have really good ways to detect the cancer coming back early, and that’s important, because we have potentially curative therapies that tend to work better if you catch the cancer early,” he said.
The study was supported by the National Institutes of Health. Dr. Nghiem reported personal fees and institutional support outside the study from several companies and patents for Merkel cell therapies with the University of Washington and University of Denmark. Dr. Demehri has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, and more than half of all patients with stage IV disease will have a recurrence within 1 year of definitive therapy, results of a new study show.
A study of 618 patients with MCC who were enrolled in a Seattle-based data repository shows that among all patients the 5-year recurrence rate was 40%. The risk of recurrence within the first year was 11% for patients with pathologic stage I disease, 33% for those with stage IIA/IIB disease, 45% for those with stage IIIB disease, and 58% for patients with pathologic stage IV MCC.
Approximately 95% of all recurrences happened within 3 years of the initial diagnosis, report Aubriana McEvoy, MD, from the University of Washington in Seattle, and colleagues.
“This cohort study indicates that the highest yield (and likely most cost-effective) time period for detecting MCC recurrence is 1-3 years after diagnosis,” they write in a study published online in JAMA Dermatology.
The estimated annual incidence of MCC in the United States in 2018 was 2,000 according to the American Cancer Society. The annual incidence rate is rising rapidly, however, and is estimated to reach 3,284 by 2025, McEvoy and colleagues write.
Although MCC is known to have high recurrence rates and is associated with a higher mortality rate than malignant melanoma, recurrence rate data are not captured by either the Surveillance, Epidemiology, and End Results (SEER) database or by the National Cancer Database. As a result, estimates of recurrence rates with MCC have been all over the map, ranging from 27% to 77%, depending on the population studied.
But as senior author Paul Nghiem, MD, PhD, professor and chair of dermatology at the University of Washington, Seattle, told this news organization, recurrence rates over time in their study were remarkably consistent.
“The biggest surprise to me was that, when we broke our nearly 20-year cohort into three 5- or 6-year chunks, every one of the groups had a 40% recurrence rate, within 1%. So we feel really confident that’s the right number,” he said.
Dr. Nghiem and colleagues report that, in contrast to patients with MCC, approximately 19% of patients with melanoma will have a recurrence, as will an estimated 5%-9% of patients with squamous cell carcinoma and 1%-10% of patients with basal cell carcinoma.
The fact that recurrence rates of MCC have remained stable over time despite presumed improvements in definitive therapy is disappointing, Dr. Nghiem acknowledged. He noted that it’s still unclear whether immunotherapy will have the same dramatic effect on survival rates for patients with MCC as it has for patients with malignant melanoma.
The high recurrence rates following definitive therapy for patients with early-stage disease was a novel finding, commented Shawn Demehri, MD, PhD, director of the high-risk skin cancer clinic at Massachusetts General Hospital in Boston.
“When you’re looking at patients with stage I or stage II, and they have definitive surgery but still have recurrences at a higher rate than melanoma, it brings home the point that these are among the most aggressive tumors of the skin,” he said in an interview.
The high recurrence rates seen with MCC are attributable to a variety of factors.
“This is a rare cancer of mostly older individuals with a lot of comorbidities, and also a cancer that, even though it is a primary cancer, might be detected a little later than even a melanoma primary tumor, just because of the nature of the neuroendocrine tumor cells,” he said.
Dr. Demehri was not involved in the study.
Prospective cohort
The study cohort consisted of 618 patients with MCC. The median age of the patients was 69, and 227 (37%) were women. The patients were enrolled within 6 months of their diagnosis in the prospective data repository from 2003 through 2019. Of this group, 223 had a recurrence of MCC.
As noted, there was a high risk of recurrence within 1 year, ranging from 11% for patients with pathologic stage I tumors to 58% for those with stage IV disease, and 95% of all recurrences occurred within 3 years of definitive therapy.
To get a better picture of the natural history of MCC recurrence, the investigators studied a cohort of patients with pathologically confirmed MCC who were prospectively enrolled from January 2003 through April 2019 in a data repository maintained at the University of Washington.
In addition to disease stage, factors associated with increased recurrence risk in univariable analyses include immunosuppression (hazard ratio, 2.4; P < .001), male sex (HR, 1.9; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; P = .001), and older age (HR, 1.1, P = .06 for each 10-year increase).
Of the 187 patients in the cohort who died during the study, 121 died from MCC. At 4 years after diagnosis, MCC-specific survival rates were 95% for patients with pathologic stage I, 84% with stage IIA/IIB, 80% with stage IIIA, 58% with stage IIIB, and 41% with stage IV.
Evidence supports close monitoring within the first 3 years for patients with stage I-II MCC. Local recurrence within or adjacent to the primary tumor scar was associated with a 5-year MCC-specific survival rate of 85%, compared with 88% of patients with stage I or II disease who did not have recurrences.
“Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage- and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest,” the authors wrote.
“If you’re a patient who has not had your cancer come back for 3, 4, or 5 years, you can really cut down on the intensity of your follow-up and scans,” Dr. Nghiem said.
“We do now have two excellent blood tests that are working very well, and we have really good ways to detect the cancer coming back early, and that’s important, because we have potentially curative therapies that tend to work better if you catch the cancer early,” he said.
The study was supported by the National Institutes of Health. Dr. Nghiem reported personal fees and institutional support outside the study from several companies and patents for Merkel cell therapies with the University of Washington and University of Denmark. Dr. Demehri has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA DERMATOLOGY
New hemophilia treatments: ‘Our cup runneth over’
It’s a problem many clinicians would love to have: A whole variety of new or emerging therapeutic options to use in the care of their patients.
In a session titled “Hemophilia Update: Our Cup Runneth Over,” presented at the 2021 annual meeting of the American Society of Hematology, .
Factor concentrates
Prophylaxis – as opposed to episodic treatment – is the standard of care in the use of factor concentrates in patients with hemophilia, said Ming Y. Lim, MB BChir, from the University of Utah in Salt Lake City.
“Effective prophylaxis is an ongoing collaborative effort that relies on shared decision-making between the patient and the clinician,” she told the audience.
As the complexity of therapeutic options, including gene therapy, continues to increase “it is critical that both patients and clinicians are actively involved in this collaborative process to optimize treatment and overall patient outcomes,” she added.
Historically, clinicians who treat patients with hemophilia aimed for trough levels of factor concentrates of at least 1% to prevent spontaneous joint bleeding. But as updated World Federation of Hemophilia (WFH) guidelines now recommend, trough levels should be sufficient to prevent spontaneous bleeding based on the individual patient’s bleeding phenotype and activity levels, starting in the range between 3% and 5%, and going higher as necessary.
“The appropriate target trough level is that at which a person with hemophilia experiences zero bleeds while pursuing an active or sedentary lifestyle,” she said.
The choice of factor concentrates between standard and extended half-life products will depend on multiple factors, including availability, patient and provider preferences, cost, and access to assays for monitoring extended half-life products.
The prolonged action of extended half-life products translates into dosing twice per week or every 3 days for factor VIII concentrates, and every 7-14 days for factor IX concentrates.
“All available extended half-life products have been shown to be efficacious in the prevention and treatment of bleeds, with no evidence for any clinical safety issues,” Dr. Lim said.
There are theoretical concerns, however, regarding the lifelong use of PEGylated clotting factor concentrates, leading to some variations in the regulatory approval for some PEGylated product intended for bleeding prophylaxis in children with hemophilia, she noted.
The pharmacokinetics of prophylaxis with factor concentrates can vary according to age, body mass, blood type, and von Willebrand factor levels, so WFH guidelines recommend pharmacokinetic assessment of people with hemophilia for optimization of prophylaxis, she said.
Factor mimetic and rebalancing therapies
With the commercial availability of one factor mimetic for treatment of hemophilia A and with other factor mimetics and rebalancing therapies such as fitusiran in the works, it raises the question, “Is this the beginning of the end of the use of factor?” said Alice Ma, MD, FACP, of the University of North Carolina in Chapel Hill.
Factors that may determine the answer to that question include the convenience of subcutaneous administration of factor VIII mimetics compared with intravenous delivery of factor concentrates, relative cost of factors versus nonfactor products, and safety.
She reviewed the current state of alternatives to factor concentrates, including the factor mimetic emicizumab (Hemlibra), which was approved by the Food and Drug Administration in 2018 for bleeding prophylaxis in patients with hemophilia A with inhibitors, and is currently the only FDA-approved and licensed agent in its class.
Although emicizumab is widely regarded as a major advance, there are still unanswered clinical questions about its long-term use, Dr. Ma said. It is unknown, for example, whether it can prevent inhibitor development in previously untreated patients, and whether it can prevent intracranial hemorrhage in early years of life prior to the start of traditional prophylaxis.
It’s also unknown whether the factor VIII mimetic activity of emicizumab provides the same physiological benefits of coagulation factors, and the mechanism of thrombotic adverse events seen with this agent is still unclear, she added.
Other factor VIII mimetics in the pipeline include Mim8, which is being developed in Denmark by Novo Nordisk; this is a next-generation bispecific antibody with enhanced activity over emicizumab in both mouse models and in vitro hemophilia A assays. There are also two others bispecific antibodies designed to generate thrombin in preclinical development: BS-027125 (Bioverativ, U.S.) and NIBX-2101 (Takeda, Japan).
One of the most promising rebalancing factors in development is fitusiran, a small interfering RNA molecule that targets mRNA encoding antithrombin. As reported during ASH 2021, fitusiran was associated with an approximately 90% reduction in annualized bleeding rates in patients with hemophilia A and hemophilia B, both with inhibitors, in two clinical trials. It was described at the meeting “as a great leap forward” in the treatment of hemophilia.
However, during its clinical development fitusiran has been consistently associated with thrombotic complications, Dr. Ma noted.
Also in development are several drugs targeted against tissue factor pathway inhibitor (TFPI), an anticoagulant protein that inhibits early phases of the procoagulant response. These agents included marstacimab (Pfizer, U.S.) which has been reported to normalize coagulation in plasma from hemophilia patients ex vivo and is currently being evaluated in patients with hemophilia A and B. There is also MG1113 (Green Cross Corporation, South Korea), a monoclonal antibody currently being tested in healthy volunteers, and BAX499 (Takeda), an aptamer derived from recombinant human TFPI that has been shown to inhibit TFPI in vitro and in vivo. However, development of this agent is on hold due to bleeding in study subjects, Dr. Ma noted.
“It is really notable that none of the replacements of factor have been free of thrombotic side effects,” Dr. Ma said. “And so I think it shows that you mess with Mother Nature at your peril. If you poke at the hemostasis-thrombosis arm and reduce antithrombotic proteins, and something triggers bleeding and you start to treat with a therapy for hemorrhage, it’s not a surprise that the first patient treated with fitusiran had a thrombosis, and I think we were just not potentially savvy enough to predict that.”
Considerable optimism over gene therapy
“There is now repeated proof of concept success for hemophilia A and B gene therapy. I think this supports the considerable optimism that’s really driving this field,” said Lindsey A. George, MD, of the University of Pennsylvania and Children’s Hospital of Philadelphia.
She reviewed adeno-associated virus (AAV) vector and AAV-mediated gene transfer approaches for hemophilia A and B.
There are currently four clinical trials of gene therapy for patients with hemophilia B, and five for patients with hemophilia A.
Because AAV efficiently targets the liver, most safety considerations about systemic AAV-mediated gene therapy are focused around potential hepatotoxicity, Dr. George said.
“Thankfully, short-term safety in the context of hemophilia has really been quite good,” she said.
Patients who undergo gene therapy for hemophilia are typically monitored twice weekly for 3 months for evidence of a capsid-specific CD8 T cell response, also called a capsid immune response. This presents with transient transaminase elevations (primarily ALT) and a decline in factor VIII and factor IX activity.
In clinical trials for patients with hemophilia, the capsid immune response has limited the efficacy of the therapy in the short term, but has not been a major cause for safety concerns. It is typically managed with glucocorticoids or other immunomodulating agents such as mycophenolate mofetil or tacrolimus.
There have also been reported cases of transaminase elevations without evidence of a capsid immune response, which warrants further investigation, she added.
Regarding efficacy, she noted that across clinical trials, the observed annualized bleeding rate has been less than 1%, despite heterogeneity of vectors and dosing used.
“That’s obviously quite optimistic for the field, but it also sort of raises the point that the heterogeneity at which we’re achieving the same phenotypic observations deserves a bit of a deeper dive,” she said.
Although hemophilia B gene transfer appears to be durable, the same cannot be said as yet for hemophilia A.
In canine models for hemophilia A and B, factor VIII and factor IX expression have been demonstrated for 8-10 years post vector, and in humans factor IX expression in patients with hemophilia B has been reported for up to 8 years.
In contrast, in the three hemophilia A trials in which patients have been followed for a minimum of 2 years, there was an approximately 40% loss of transgene vector from year 1 to year 2 with two vectors, but not a third.
Potential explanations for the loss of expression seen include an unfolded protein response, promoter silence, and an ongoing undetected or unmitigated immune response to AAV or to the transgene.
Regarding the future of gene therapy, Dr. George said that “we anticipate that there will be licensed vectors in the very near future, and predicted that gene therapy “will fulfill its promise to alter the paradigm of hemophilia care.”
Dr. Lim disclosed honoraria from several companies and travel support from Novo Nordisk. Dr. Ma disclosed honoraria and research funding from Takeda. Dr. George disclosed FVIII-QQ patents and royalties, research funding from AskBio, and consulting activities/advisory board participation with others.
A version of this article first appeared on Medscape.com.
It’s a problem many clinicians would love to have: A whole variety of new or emerging therapeutic options to use in the care of their patients.
In a session titled “Hemophilia Update: Our Cup Runneth Over,” presented at the 2021 annual meeting of the American Society of Hematology, .
Factor concentrates
Prophylaxis – as opposed to episodic treatment – is the standard of care in the use of factor concentrates in patients with hemophilia, said Ming Y. Lim, MB BChir, from the University of Utah in Salt Lake City.
“Effective prophylaxis is an ongoing collaborative effort that relies on shared decision-making between the patient and the clinician,” she told the audience.
As the complexity of therapeutic options, including gene therapy, continues to increase “it is critical that both patients and clinicians are actively involved in this collaborative process to optimize treatment and overall patient outcomes,” she added.
Historically, clinicians who treat patients with hemophilia aimed for trough levels of factor concentrates of at least 1% to prevent spontaneous joint bleeding. But as updated World Federation of Hemophilia (WFH) guidelines now recommend, trough levels should be sufficient to prevent spontaneous bleeding based on the individual patient’s bleeding phenotype and activity levels, starting in the range between 3% and 5%, and going higher as necessary.
“The appropriate target trough level is that at which a person with hemophilia experiences zero bleeds while pursuing an active or sedentary lifestyle,” she said.
The choice of factor concentrates between standard and extended half-life products will depend on multiple factors, including availability, patient and provider preferences, cost, and access to assays for monitoring extended half-life products.
The prolonged action of extended half-life products translates into dosing twice per week or every 3 days for factor VIII concentrates, and every 7-14 days for factor IX concentrates.
“All available extended half-life products have been shown to be efficacious in the prevention and treatment of bleeds, with no evidence for any clinical safety issues,” Dr. Lim said.
There are theoretical concerns, however, regarding the lifelong use of PEGylated clotting factor concentrates, leading to some variations in the regulatory approval for some PEGylated product intended for bleeding prophylaxis in children with hemophilia, she noted.
The pharmacokinetics of prophylaxis with factor concentrates can vary according to age, body mass, blood type, and von Willebrand factor levels, so WFH guidelines recommend pharmacokinetic assessment of people with hemophilia for optimization of prophylaxis, she said.
Factor mimetic and rebalancing therapies
With the commercial availability of one factor mimetic for treatment of hemophilia A and with other factor mimetics and rebalancing therapies such as fitusiran in the works, it raises the question, “Is this the beginning of the end of the use of factor?” said Alice Ma, MD, FACP, of the University of North Carolina in Chapel Hill.
Factors that may determine the answer to that question include the convenience of subcutaneous administration of factor VIII mimetics compared with intravenous delivery of factor concentrates, relative cost of factors versus nonfactor products, and safety.
She reviewed the current state of alternatives to factor concentrates, including the factor mimetic emicizumab (Hemlibra), which was approved by the Food and Drug Administration in 2018 for bleeding prophylaxis in patients with hemophilia A with inhibitors, and is currently the only FDA-approved and licensed agent in its class.
Although emicizumab is widely regarded as a major advance, there are still unanswered clinical questions about its long-term use, Dr. Ma said. It is unknown, for example, whether it can prevent inhibitor development in previously untreated patients, and whether it can prevent intracranial hemorrhage in early years of life prior to the start of traditional prophylaxis.
It’s also unknown whether the factor VIII mimetic activity of emicizumab provides the same physiological benefits of coagulation factors, and the mechanism of thrombotic adverse events seen with this agent is still unclear, she added.
Other factor VIII mimetics in the pipeline include Mim8, which is being developed in Denmark by Novo Nordisk; this is a next-generation bispecific antibody with enhanced activity over emicizumab in both mouse models and in vitro hemophilia A assays. There are also two others bispecific antibodies designed to generate thrombin in preclinical development: BS-027125 (Bioverativ, U.S.) and NIBX-2101 (Takeda, Japan).
One of the most promising rebalancing factors in development is fitusiran, a small interfering RNA molecule that targets mRNA encoding antithrombin. As reported during ASH 2021, fitusiran was associated with an approximately 90% reduction in annualized bleeding rates in patients with hemophilia A and hemophilia B, both with inhibitors, in two clinical trials. It was described at the meeting “as a great leap forward” in the treatment of hemophilia.
However, during its clinical development fitusiran has been consistently associated with thrombotic complications, Dr. Ma noted.
Also in development are several drugs targeted against tissue factor pathway inhibitor (TFPI), an anticoagulant protein that inhibits early phases of the procoagulant response. These agents included marstacimab (Pfizer, U.S.) which has been reported to normalize coagulation in plasma from hemophilia patients ex vivo and is currently being evaluated in patients with hemophilia A and B. There is also MG1113 (Green Cross Corporation, South Korea), a monoclonal antibody currently being tested in healthy volunteers, and BAX499 (Takeda), an aptamer derived from recombinant human TFPI that has been shown to inhibit TFPI in vitro and in vivo. However, development of this agent is on hold due to bleeding in study subjects, Dr. Ma noted.
“It is really notable that none of the replacements of factor have been free of thrombotic side effects,” Dr. Ma said. “And so I think it shows that you mess with Mother Nature at your peril. If you poke at the hemostasis-thrombosis arm and reduce antithrombotic proteins, and something triggers bleeding and you start to treat with a therapy for hemorrhage, it’s not a surprise that the first patient treated with fitusiran had a thrombosis, and I think we were just not potentially savvy enough to predict that.”
Considerable optimism over gene therapy
“There is now repeated proof of concept success for hemophilia A and B gene therapy. I think this supports the considerable optimism that’s really driving this field,” said Lindsey A. George, MD, of the University of Pennsylvania and Children’s Hospital of Philadelphia.
She reviewed adeno-associated virus (AAV) vector and AAV-mediated gene transfer approaches for hemophilia A and B.
There are currently four clinical trials of gene therapy for patients with hemophilia B, and five for patients with hemophilia A.
Because AAV efficiently targets the liver, most safety considerations about systemic AAV-mediated gene therapy are focused around potential hepatotoxicity, Dr. George said.
“Thankfully, short-term safety in the context of hemophilia has really been quite good,” she said.
Patients who undergo gene therapy for hemophilia are typically monitored twice weekly for 3 months for evidence of a capsid-specific CD8 T cell response, also called a capsid immune response. This presents with transient transaminase elevations (primarily ALT) and a decline in factor VIII and factor IX activity.
In clinical trials for patients with hemophilia, the capsid immune response has limited the efficacy of the therapy in the short term, but has not been a major cause for safety concerns. It is typically managed with glucocorticoids or other immunomodulating agents such as mycophenolate mofetil or tacrolimus.
There have also been reported cases of transaminase elevations without evidence of a capsid immune response, which warrants further investigation, she added.
Regarding efficacy, she noted that across clinical trials, the observed annualized bleeding rate has been less than 1%, despite heterogeneity of vectors and dosing used.
“That’s obviously quite optimistic for the field, but it also sort of raises the point that the heterogeneity at which we’re achieving the same phenotypic observations deserves a bit of a deeper dive,” she said.
Although hemophilia B gene transfer appears to be durable, the same cannot be said as yet for hemophilia A.
In canine models for hemophilia A and B, factor VIII and factor IX expression have been demonstrated for 8-10 years post vector, and in humans factor IX expression in patients with hemophilia B has been reported for up to 8 years.
In contrast, in the three hemophilia A trials in which patients have been followed for a minimum of 2 years, there was an approximately 40% loss of transgene vector from year 1 to year 2 with two vectors, but not a third.
Potential explanations for the loss of expression seen include an unfolded protein response, promoter silence, and an ongoing undetected or unmitigated immune response to AAV or to the transgene.
Regarding the future of gene therapy, Dr. George said that “we anticipate that there will be licensed vectors in the very near future, and predicted that gene therapy “will fulfill its promise to alter the paradigm of hemophilia care.”
Dr. Lim disclosed honoraria from several companies and travel support from Novo Nordisk. Dr. Ma disclosed honoraria and research funding from Takeda. Dr. George disclosed FVIII-QQ patents and royalties, research funding from AskBio, and consulting activities/advisory board participation with others.
A version of this article first appeared on Medscape.com.
It’s a problem many clinicians would love to have: A whole variety of new or emerging therapeutic options to use in the care of their patients.
In a session titled “Hemophilia Update: Our Cup Runneth Over,” presented at the 2021 annual meeting of the American Society of Hematology, .
Factor concentrates
Prophylaxis – as opposed to episodic treatment – is the standard of care in the use of factor concentrates in patients with hemophilia, said Ming Y. Lim, MB BChir, from the University of Utah in Salt Lake City.
“Effective prophylaxis is an ongoing collaborative effort that relies on shared decision-making between the patient and the clinician,” she told the audience.
As the complexity of therapeutic options, including gene therapy, continues to increase “it is critical that both patients and clinicians are actively involved in this collaborative process to optimize treatment and overall patient outcomes,” she added.
Historically, clinicians who treat patients with hemophilia aimed for trough levels of factor concentrates of at least 1% to prevent spontaneous joint bleeding. But as updated World Federation of Hemophilia (WFH) guidelines now recommend, trough levels should be sufficient to prevent spontaneous bleeding based on the individual patient’s bleeding phenotype and activity levels, starting in the range between 3% and 5%, and going higher as necessary.
“The appropriate target trough level is that at which a person with hemophilia experiences zero bleeds while pursuing an active or sedentary lifestyle,” she said.
The choice of factor concentrates between standard and extended half-life products will depend on multiple factors, including availability, patient and provider preferences, cost, and access to assays for monitoring extended half-life products.
The prolonged action of extended half-life products translates into dosing twice per week or every 3 days for factor VIII concentrates, and every 7-14 days for factor IX concentrates.
“All available extended half-life products have been shown to be efficacious in the prevention and treatment of bleeds, with no evidence for any clinical safety issues,” Dr. Lim said.
There are theoretical concerns, however, regarding the lifelong use of PEGylated clotting factor concentrates, leading to some variations in the regulatory approval for some PEGylated product intended for bleeding prophylaxis in children with hemophilia, she noted.
The pharmacokinetics of prophylaxis with factor concentrates can vary according to age, body mass, blood type, and von Willebrand factor levels, so WFH guidelines recommend pharmacokinetic assessment of people with hemophilia for optimization of prophylaxis, she said.
Factor mimetic and rebalancing therapies
With the commercial availability of one factor mimetic for treatment of hemophilia A and with other factor mimetics and rebalancing therapies such as fitusiran in the works, it raises the question, “Is this the beginning of the end of the use of factor?” said Alice Ma, MD, FACP, of the University of North Carolina in Chapel Hill.
Factors that may determine the answer to that question include the convenience of subcutaneous administration of factor VIII mimetics compared with intravenous delivery of factor concentrates, relative cost of factors versus nonfactor products, and safety.
She reviewed the current state of alternatives to factor concentrates, including the factor mimetic emicizumab (Hemlibra), which was approved by the Food and Drug Administration in 2018 for bleeding prophylaxis in patients with hemophilia A with inhibitors, and is currently the only FDA-approved and licensed agent in its class.
Although emicizumab is widely regarded as a major advance, there are still unanswered clinical questions about its long-term use, Dr. Ma said. It is unknown, for example, whether it can prevent inhibitor development in previously untreated patients, and whether it can prevent intracranial hemorrhage in early years of life prior to the start of traditional prophylaxis.
It’s also unknown whether the factor VIII mimetic activity of emicizumab provides the same physiological benefits of coagulation factors, and the mechanism of thrombotic adverse events seen with this agent is still unclear, she added.
Other factor VIII mimetics in the pipeline include Mim8, which is being developed in Denmark by Novo Nordisk; this is a next-generation bispecific antibody with enhanced activity over emicizumab in both mouse models and in vitro hemophilia A assays. There are also two others bispecific antibodies designed to generate thrombin in preclinical development: BS-027125 (Bioverativ, U.S.) and NIBX-2101 (Takeda, Japan).
One of the most promising rebalancing factors in development is fitusiran, a small interfering RNA molecule that targets mRNA encoding antithrombin. As reported during ASH 2021, fitusiran was associated with an approximately 90% reduction in annualized bleeding rates in patients with hemophilia A and hemophilia B, both with inhibitors, in two clinical trials. It was described at the meeting “as a great leap forward” in the treatment of hemophilia.
However, during its clinical development fitusiran has been consistently associated with thrombotic complications, Dr. Ma noted.
Also in development are several drugs targeted against tissue factor pathway inhibitor (TFPI), an anticoagulant protein that inhibits early phases of the procoagulant response. These agents included marstacimab (Pfizer, U.S.) which has been reported to normalize coagulation in plasma from hemophilia patients ex vivo and is currently being evaluated in patients with hemophilia A and B. There is also MG1113 (Green Cross Corporation, South Korea), a monoclonal antibody currently being tested in healthy volunteers, and BAX499 (Takeda), an aptamer derived from recombinant human TFPI that has been shown to inhibit TFPI in vitro and in vivo. However, development of this agent is on hold due to bleeding in study subjects, Dr. Ma noted.
“It is really notable that none of the replacements of factor have been free of thrombotic side effects,” Dr. Ma said. “And so I think it shows that you mess with Mother Nature at your peril. If you poke at the hemostasis-thrombosis arm and reduce antithrombotic proteins, and something triggers bleeding and you start to treat with a therapy for hemorrhage, it’s not a surprise that the first patient treated with fitusiran had a thrombosis, and I think we were just not potentially savvy enough to predict that.”
Considerable optimism over gene therapy
“There is now repeated proof of concept success for hemophilia A and B gene therapy. I think this supports the considerable optimism that’s really driving this field,” said Lindsey A. George, MD, of the University of Pennsylvania and Children’s Hospital of Philadelphia.
She reviewed adeno-associated virus (AAV) vector and AAV-mediated gene transfer approaches for hemophilia A and B.
There are currently four clinical trials of gene therapy for patients with hemophilia B, and five for patients with hemophilia A.
Because AAV efficiently targets the liver, most safety considerations about systemic AAV-mediated gene therapy are focused around potential hepatotoxicity, Dr. George said.
“Thankfully, short-term safety in the context of hemophilia has really been quite good,” she said.
Patients who undergo gene therapy for hemophilia are typically monitored twice weekly for 3 months for evidence of a capsid-specific CD8 T cell response, also called a capsid immune response. This presents with transient transaminase elevations (primarily ALT) and a decline in factor VIII and factor IX activity.
In clinical trials for patients with hemophilia, the capsid immune response has limited the efficacy of the therapy in the short term, but has not been a major cause for safety concerns. It is typically managed with glucocorticoids or other immunomodulating agents such as mycophenolate mofetil or tacrolimus.
There have also been reported cases of transaminase elevations without evidence of a capsid immune response, which warrants further investigation, she added.
Regarding efficacy, she noted that across clinical trials, the observed annualized bleeding rate has been less than 1%, despite heterogeneity of vectors and dosing used.
“That’s obviously quite optimistic for the field, but it also sort of raises the point that the heterogeneity at which we’re achieving the same phenotypic observations deserves a bit of a deeper dive,” she said.
Although hemophilia B gene transfer appears to be durable, the same cannot be said as yet for hemophilia A.
In canine models for hemophilia A and B, factor VIII and factor IX expression have been demonstrated for 8-10 years post vector, and in humans factor IX expression in patients with hemophilia B has been reported for up to 8 years.
In contrast, in the three hemophilia A trials in which patients have been followed for a minimum of 2 years, there was an approximately 40% loss of transgene vector from year 1 to year 2 with two vectors, but not a third.
Potential explanations for the loss of expression seen include an unfolded protein response, promoter silence, and an ongoing undetected or unmitigated immune response to AAV or to the transgene.
Regarding the future of gene therapy, Dr. George said that “we anticipate that there will be licensed vectors in the very near future, and predicted that gene therapy “will fulfill its promise to alter the paradigm of hemophilia care.”
Dr. Lim disclosed honoraria from several companies and travel support from Novo Nordisk. Dr. Ma disclosed honoraria and research funding from Takeda. Dr. George disclosed FVIII-QQ patents and royalties, research funding from AskBio, and consulting activities/advisory board participation with others.
A version of this article first appeared on Medscape.com.
REPORTING FROM ASH 2021
Handle with care: Managing IBD in older patients
As the saying goes: "Age is a case of mind over matter: If you don't mind, it don't matter."
But for older patients with inflammatory bowel disease (IBD) and the clinicians who treat them, it’s hard to ignore the complications that aging can bring, such as comorbidities, functional limitations, and polypharmacy, said Nana Bernasko, CRNP, DNP, WHNP-BC, a nurse practitioner in the department of gastroenterology at Penn State Milton S. Hershey Medical Center in Hershey, Pa.
“We are seeing a large number of patients in our clinics that are being diagnosed later on in life,” she said in an oral presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Between 10% and 30% of all patients with IBD are older than 60, and roughly 10%-15% of patients with IBD are diagnosed after age 60, she said.
The diagnosis of IBD is often delayed in older patients as well, with an estimated 60% of patients initially given an incorrect or incomplete diagnosis that may lead to significant delays in the initiation of appropriate therapy, she said.
Differential diagnoses for IBD in older patients include diverticulitis, ischemic colitis, infectious colitis, and radiation colitis.
Bharati Kochar, MD, MS, from the Crohn’s and Colitis Center at Massachusetts General Hospital in Boston, who was not involved in the presentation, agreed that older adults need special handling.
“The management of IBD in older adults is challenging for a number of reasons, but primarily because until very recently, we have not invested in understanding how IBD should be optimally managed at older ages,” she said in an interview.
“Additionally, like in all fields, older adults with IBD are disproportionately under-represented in clinical trials, meaning that we have less rigorous data guiding the management of older adults,” she added.
Clinical presentations
Older adults tend to differ in clinical presentation, compared with younger adults, Dr. Bernasko said.
For example, among patients with Crohn’s disease, rectal bleeding is a more common symptom among older adults, whereas diarrhea and weight loss are more common among younger adults.
Disease location may also differ, with more senior adults having predominantly colonic disease (L2 according to the Montreal Classification of IBD), compared with more prevalent ileocolonic disease (L3) among their more junior counterparts. And although both generations of patients have inflammatory behavior (B1) at diagnosis, younger patients have more prevalent structuring (B2) and penetrating disease (B3), Dr. Bernasko noted.
Among patients with ulcerative colitis, rectal bleeding, abdominal pain, and extraintestinal manifestations are more common among the younger set, whereas left-sided colitis is more common among older patients. In addition, extensive ulcerative colitis (E3) is more common in younger patients, compared with older patients.
Management considerations
Dr. Kochar noted that “older adults have higher baseline risks for all adverse events – like infections, malignancies, polypharmacy, procedural complications – than younger adults, so any additional risk conferred by treatments seem amplified, but that should not mean that we should avoid effectively treating older adults. It should mean we need to invest in understanding how to best mitigate those risks.”
While younger patients are sometimes on multiple medications prior to starting on IBD therapy, polypharmacy is common among the older set, who may be taking drugs for diabetes, hypertension, prostate disease, and so on.
“There’s just so much going on in terms of their medical background to start off with, so many medications, and then we’re adding more things to it,” Dr. Bernasko said.
She echoed Dr. Kochar in noting that older patients as a subgroup are under-represented in clinical trials, making it difficult to know what treatment approaches may work best for them.
In addition, older patients are at higher risk for malignancies, and for complications from surgery.
Medication adherence in older patients is frequently compromised by memory issues, she added, noting that “I can’t tell you enough how sometimes our older patients forget to take their medications.”
Other challenges for the management of older patients with IBD included psychosocial issues, cognitive decline, and malnutrition.
Medications and adverse events
Dr. Bernasko also discussed specific medications and potential adverse events and drug interactions in older patients.
For example, aminosalicylic acids (5-ASA) are associated with higher risk for nephrotoxicity and pancreatitis in older patients and can interact with thiopurines to cause leukopenia.
Steroids are associated with elevated risk for osteopenia, myopathy, cataracts, glaucoma, diabetes, and hypertension, and can interact with thiazide and loop diuretics to cause hypokalemia.
Methotrexate use in this population is linked to pancytopenia and hepatotoxicity, and it can interact with NSAIDs and multiple antibiotics to cause decreased renal secretion.
Thiopurines in older patients are associated with increased risk for leukopenia, myelosuppression, non-Hodgkin lymphoma, skin cancer, pancreatitis, and hepatotoxicity, and drugs in this class interact with allopurinol and angiotensin-converting enzyme inhibitors to increase risk for myelosuppression. Additionally, warfarin can inhibit the efficacy of thiopurines, and when these drugs are used in combination with tumor necrosis factor (TNF)–alpha inhibitors they can further increase risk of malignancy through immunosuppression.
Cyclosporine is associated with worsening hypertension and renal insufficiency among older patients.
TNF-alpha inhibitors are associated with increased risk for tuberculosis; hepatitis B; and fungal infections, malignant lymphoma, and New York Heart Association class 3 or 4 heart failure.
Ciprofloxacin in older patients with IBD has been linked to tendinopathy and increased risk for Clostridioides difficile infections. Metronidazole increases the likelihood of peripheral neuropathy in these patients.
Colon cancer screening
“When it comes to colon cancer screening, definitely assess the risk prior to doing this,” Dr. Bernasko recommended. “Weigh all the risks and benefits. Why are we doing this for these elderly patients, because there are definitely risks associated with this.”
Older patients with IBD may have difficulty with bowel prep and are at elevated risk, compared with younger patients, for cardiopulmonary complications, perforation, adverse events from sedation, and procedural complications, she cautioned.
“When it comes to our elderly patients, you want to focus on a more personalized approach – not all older people present the same way in terms of comorbidities or medications,” Dr. Bernasko advised in her summary.
Dr. Bernasko and Dr. Kochar reported having no relevant conflicts of interest to disclose. Dr. Kochar is a member of the board of editors for GI & Hepatology News.
This article was updated 2/18/22.
As the saying goes: "Age is a case of mind over matter: If you don't mind, it don't matter."
But for older patients with inflammatory bowel disease (IBD) and the clinicians who treat them, it’s hard to ignore the complications that aging can bring, such as comorbidities, functional limitations, and polypharmacy, said Nana Bernasko, CRNP, DNP, WHNP-BC, a nurse practitioner in the department of gastroenterology at Penn State Milton S. Hershey Medical Center in Hershey, Pa.
“We are seeing a large number of patients in our clinics that are being diagnosed later on in life,” she said in an oral presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Between 10% and 30% of all patients with IBD are older than 60, and roughly 10%-15% of patients with IBD are diagnosed after age 60, she said.
The diagnosis of IBD is often delayed in older patients as well, with an estimated 60% of patients initially given an incorrect or incomplete diagnosis that may lead to significant delays in the initiation of appropriate therapy, she said.
Differential diagnoses for IBD in older patients include diverticulitis, ischemic colitis, infectious colitis, and radiation colitis.
Bharati Kochar, MD, MS, from the Crohn’s and Colitis Center at Massachusetts General Hospital in Boston, who was not involved in the presentation, agreed that older adults need special handling.
“The management of IBD in older adults is challenging for a number of reasons, but primarily because until very recently, we have not invested in understanding how IBD should be optimally managed at older ages,” she said in an interview.
“Additionally, like in all fields, older adults with IBD are disproportionately under-represented in clinical trials, meaning that we have less rigorous data guiding the management of older adults,” she added.
Clinical presentations
Older adults tend to differ in clinical presentation, compared with younger adults, Dr. Bernasko said.
For example, among patients with Crohn’s disease, rectal bleeding is a more common symptom among older adults, whereas diarrhea and weight loss are more common among younger adults.
Disease location may also differ, with more senior adults having predominantly colonic disease (L2 according to the Montreal Classification of IBD), compared with more prevalent ileocolonic disease (L3) among their more junior counterparts. And although both generations of patients have inflammatory behavior (B1) at diagnosis, younger patients have more prevalent structuring (B2) and penetrating disease (B3), Dr. Bernasko noted.
Among patients with ulcerative colitis, rectal bleeding, abdominal pain, and extraintestinal manifestations are more common among the younger set, whereas left-sided colitis is more common among older patients. In addition, extensive ulcerative colitis (E3) is more common in younger patients, compared with older patients.
Management considerations
Dr. Kochar noted that “older adults have higher baseline risks for all adverse events – like infections, malignancies, polypharmacy, procedural complications – than younger adults, so any additional risk conferred by treatments seem amplified, but that should not mean that we should avoid effectively treating older adults. It should mean we need to invest in understanding how to best mitigate those risks.”
While younger patients are sometimes on multiple medications prior to starting on IBD therapy, polypharmacy is common among the older set, who may be taking drugs for diabetes, hypertension, prostate disease, and so on.
“There’s just so much going on in terms of their medical background to start off with, so many medications, and then we’re adding more things to it,” Dr. Bernasko said.
She echoed Dr. Kochar in noting that older patients as a subgroup are under-represented in clinical trials, making it difficult to know what treatment approaches may work best for them.
In addition, older patients are at higher risk for malignancies, and for complications from surgery.
Medication adherence in older patients is frequently compromised by memory issues, she added, noting that “I can’t tell you enough how sometimes our older patients forget to take their medications.”
Other challenges for the management of older patients with IBD included psychosocial issues, cognitive decline, and malnutrition.
Medications and adverse events
Dr. Bernasko also discussed specific medications and potential adverse events and drug interactions in older patients.
For example, aminosalicylic acids (5-ASA) are associated with higher risk for nephrotoxicity and pancreatitis in older patients and can interact with thiopurines to cause leukopenia.
Steroids are associated with elevated risk for osteopenia, myopathy, cataracts, glaucoma, diabetes, and hypertension, and can interact with thiazide and loop diuretics to cause hypokalemia.
Methotrexate use in this population is linked to pancytopenia and hepatotoxicity, and it can interact with NSAIDs and multiple antibiotics to cause decreased renal secretion.
Thiopurines in older patients are associated with increased risk for leukopenia, myelosuppression, non-Hodgkin lymphoma, skin cancer, pancreatitis, and hepatotoxicity, and drugs in this class interact with allopurinol and angiotensin-converting enzyme inhibitors to increase risk for myelosuppression. Additionally, warfarin can inhibit the efficacy of thiopurines, and when these drugs are used in combination with tumor necrosis factor (TNF)–alpha inhibitors they can further increase risk of malignancy through immunosuppression.
Cyclosporine is associated with worsening hypertension and renal insufficiency among older patients.
TNF-alpha inhibitors are associated with increased risk for tuberculosis; hepatitis B; and fungal infections, malignant lymphoma, and New York Heart Association class 3 or 4 heart failure.
Ciprofloxacin in older patients with IBD has been linked to tendinopathy and increased risk for Clostridioides difficile infections. Metronidazole increases the likelihood of peripheral neuropathy in these patients.
Colon cancer screening
“When it comes to colon cancer screening, definitely assess the risk prior to doing this,” Dr. Bernasko recommended. “Weigh all the risks and benefits. Why are we doing this for these elderly patients, because there are definitely risks associated with this.”
Older patients with IBD may have difficulty with bowel prep and are at elevated risk, compared with younger patients, for cardiopulmonary complications, perforation, adverse events from sedation, and procedural complications, she cautioned.
“When it comes to our elderly patients, you want to focus on a more personalized approach – not all older people present the same way in terms of comorbidities or medications,” Dr. Bernasko advised in her summary.
Dr. Bernasko and Dr. Kochar reported having no relevant conflicts of interest to disclose. Dr. Kochar is a member of the board of editors for GI & Hepatology News.
This article was updated 2/18/22.
As the saying goes: "Age is a case of mind over matter: If you don't mind, it don't matter."
But for older patients with inflammatory bowel disease (IBD) and the clinicians who treat them, it’s hard to ignore the complications that aging can bring, such as comorbidities, functional limitations, and polypharmacy, said Nana Bernasko, CRNP, DNP, WHNP-BC, a nurse practitioner in the department of gastroenterology at Penn State Milton S. Hershey Medical Center in Hershey, Pa.
“We are seeing a large number of patients in our clinics that are being diagnosed later on in life,” she said in an oral presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Between 10% and 30% of all patients with IBD are older than 60, and roughly 10%-15% of patients with IBD are diagnosed after age 60, she said.
The diagnosis of IBD is often delayed in older patients as well, with an estimated 60% of patients initially given an incorrect or incomplete diagnosis that may lead to significant delays in the initiation of appropriate therapy, she said.
Differential diagnoses for IBD in older patients include diverticulitis, ischemic colitis, infectious colitis, and radiation colitis.
Bharati Kochar, MD, MS, from the Crohn’s and Colitis Center at Massachusetts General Hospital in Boston, who was not involved in the presentation, agreed that older adults need special handling.
“The management of IBD in older adults is challenging for a number of reasons, but primarily because until very recently, we have not invested in understanding how IBD should be optimally managed at older ages,” she said in an interview.
“Additionally, like in all fields, older adults with IBD are disproportionately under-represented in clinical trials, meaning that we have less rigorous data guiding the management of older adults,” she added.
Clinical presentations
Older adults tend to differ in clinical presentation, compared with younger adults, Dr. Bernasko said.
For example, among patients with Crohn’s disease, rectal bleeding is a more common symptom among older adults, whereas diarrhea and weight loss are more common among younger adults.
Disease location may also differ, with more senior adults having predominantly colonic disease (L2 according to the Montreal Classification of IBD), compared with more prevalent ileocolonic disease (L3) among their more junior counterparts. And although both generations of patients have inflammatory behavior (B1) at diagnosis, younger patients have more prevalent structuring (B2) and penetrating disease (B3), Dr. Bernasko noted.
Among patients with ulcerative colitis, rectal bleeding, abdominal pain, and extraintestinal manifestations are more common among the younger set, whereas left-sided colitis is more common among older patients. In addition, extensive ulcerative colitis (E3) is more common in younger patients, compared with older patients.
Management considerations
Dr. Kochar noted that “older adults have higher baseline risks for all adverse events – like infections, malignancies, polypharmacy, procedural complications – than younger adults, so any additional risk conferred by treatments seem amplified, but that should not mean that we should avoid effectively treating older adults. It should mean we need to invest in understanding how to best mitigate those risks.”
While younger patients are sometimes on multiple medications prior to starting on IBD therapy, polypharmacy is common among the older set, who may be taking drugs for diabetes, hypertension, prostate disease, and so on.
“There’s just so much going on in terms of their medical background to start off with, so many medications, and then we’re adding more things to it,” Dr. Bernasko said.
She echoed Dr. Kochar in noting that older patients as a subgroup are under-represented in clinical trials, making it difficult to know what treatment approaches may work best for them.
In addition, older patients are at higher risk for malignancies, and for complications from surgery.
Medication adherence in older patients is frequently compromised by memory issues, she added, noting that “I can’t tell you enough how sometimes our older patients forget to take their medications.”
Other challenges for the management of older patients with IBD included psychosocial issues, cognitive decline, and malnutrition.
Medications and adverse events
Dr. Bernasko also discussed specific medications and potential adverse events and drug interactions in older patients.
For example, aminosalicylic acids (5-ASA) are associated with higher risk for nephrotoxicity and pancreatitis in older patients and can interact with thiopurines to cause leukopenia.
Steroids are associated with elevated risk for osteopenia, myopathy, cataracts, glaucoma, diabetes, and hypertension, and can interact with thiazide and loop diuretics to cause hypokalemia.
Methotrexate use in this population is linked to pancytopenia and hepatotoxicity, and it can interact with NSAIDs and multiple antibiotics to cause decreased renal secretion.
Thiopurines in older patients are associated with increased risk for leukopenia, myelosuppression, non-Hodgkin lymphoma, skin cancer, pancreatitis, and hepatotoxicity, and drugs in this class interact with allopurinol and angiotensin-converting enzyme inhibitors to increase risk for myelosuppression. Additionally, warfarin can inhibit the efficacy of thiopurines, and when these drugs are used in combination with tumor necrosis factor (TNF)–alpha inhibitors they can further increase risk of malignancy through immunosuppression.
Cyclosporine is associated with worsening hypertension and renal insufficiency among older patients.
TNF-alpha inhibitors are associated with increased risk for tuberculosis; hepatitis B; and fungal infections, malignant lymphoma, and New York Heart Association class 3 or 4 heart failure.
Ciprofloxacin in older patients with IBD has been linked to tendinopathy and increased risk for Clostridioides difficile infections. Metronidazole increases the likelihood of peripheral neuropathy in these patients.
Colon cancer screening
“When it comes to colon cancer screening, definitely assess the risk prior to doing this,” Dr. Bernasko recommended. “Weigh all the risks and benefits. Why are we doing this for these elderly patients, because there are definitely risks associated with this.”
Older patients with IBD may have difficulty with bowel prep and are at elevated risk, compared with younger patients, for cardiopulmonary complications, perforation, adverse events from sedation, and procedural complications, she cautioned.
“When it comes to our elderly patients, you want to focus on a more personalized approach – not all older people present the same way in terms of comorbidities or medications,” Dr. Bernasko advised in her summary.
Dr. Bernasko and Dr. Kochar reported having no relevant conflicts of interest to disclose. Dr. Kochar is a member of the board of editors for GI & Hepatology News.
This article was updated 2/18/22.
FROM CROHN’S & COLITIS CONGRESS
Malnutrition common in patients with IBD
Malnutrition is common among patients with inflammatory bowel disease (IBD) and is associated with worse outcomes that can prolong hospitalizations and increase patients’ risk for death.
As many as 85% of inpatients with IBD may be malnourished, with the severity of malnutrition affected by disease activity, extent, and duration, said Kelly Issokson, MS, RD, CNSC, clinical nutrition coordinator in the IBD program in the division of gastroenterology at Cedars-Sinai Medical Center, Los Angeles.
“Malnutrition is a severe complication of IBD, and it should not be overlooked,” she said during an oral presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
In patients with IBD, malabsorption, enteric losses, inadequate intake, and side effects of medical therapy can all lead to malnutrition, which in turn is an independent risk factor for venous thromboembolic events, nonelective surgery, longer hospital stays, and increased mortality.
In addition, malnutrition in IBD increases risk for infection and sepsis, and for perioperative complications, and can more than double the cost of care, compared with adequately nourished IBD patients, she said.
Ms. Issokson cited a definition of malnutrition from the American Society of Parenteral and Enteral Nutrition as “an acute or chronic state of overnutrition or undernutrition with or without inflammatory activity that has led to a change in body composition and diminished function.”
Lab findings of low albumin, low prealbumin, or isolated metrics such as weight loss or change in body mass index do not constitute malnutrition and should not be used to diagnosis it, Ms. Issokson cautioned.
Patients at low risk for malnutrition have no unintentional weight loss, are eating well, have minimal or no dietary restrictions, and no wasting. In contrast, high-risk patients have unintentional weight loss, decreased appetite and/or food intake, restrict multiple foods, or show signs of wasting.
Screening
“Nutrition screening is the first step in diagnosing a patient with malnutrition. This is a process of identifying individuals who may be at nutrition risk and benefit from assessment from a registered dietitian,” Ms. Issokson said.
The Malnutrition Screening Tool is quick, easy to administer, and requires minimal training. It can be used to screen adults for malnutrition regardless of age, medical history, or setting, she said.
The two-item instrument asks, “Have you recently lost weight without trying?” with a “no” scored as 0 and a “yes” scored as 2. The second question is, “Have you been eating poorly because of decreased appetite, with a “no” equal to 0 and a “yes” equal to 1. Patients with a score of 0 or 1 are not at risk, whereas patients with scores of 2 or 3 are deemed to be at risk for malnutrition and require further assessment by a dietitian.
Assessment
Assessment for malnutrition involves a variety of factors, including anthropometric factors such as weight and BMI changes; biochemical markers such as fat-soluble vitamins, water-soluble vitamins, minerals, and urinary sodium; symptoms such as decreased appetite, abdominal pain, cramping or bloating, diarrhea, or urgency or obstructive symptoms; and body composition measures such as handgrip strength, biochemical impedance analysis, skinfold thickness, bone mineral density, and muscle mass.
Other nutritional assessment tools may include 24-hour recall of nutrition intake, diet history, and questions about eating behaviors, food allergies or intolerances, and cultural or religious food preferences.
Assessing food security is also important, especially during the current pandemic, Ms. Issokson emphasized.
“Is your patient running out of food? Do they have money to purchase food? Are they able to go to the grocery store to buy food? This is essential to know when you’re developing a nutrition plan,” she said.
A nutrition-focused physical exam should include assessment of skin manifestation, secondary to malnutrition or malabsorption, such as dry skin, delayed wound healing, stomatitis, scurvy, seborrheic dermatitis, bleeding, and periorificial and acral dermatitis or alopecia.
Diagnosis
Currently available malnutrition criteria have not been validated for use in patients with IBD, and further studies are needed to affirm their applicability to this population, Ms. Issokson said.
The Academy of Nutrition and Dietetics–American Society for Parenteral and Enteral Nutrition (AND-ASPEN) malnutrition criteria require measures of weight loss, energy intake, subcutaneous fat loss, subcutaneous muscle loss, general or local fluid accumulation, and handgrip strength to determine whether a patient is moderately or severely malnourished.
Ms. Issokson said that she finds the European Society for Clinical Nutrition and Metabolism Global Leadership Initiative on Malnutrition (ESPEN GLIM) criteria somewhat easier to use for diagnosis, as they consist of phenotypic and etiologic criteria, with patients who meet at least one of each being considered malnourished.
“When identified, document malnutrition, and of course intervene appropriately by referring to a dietitian providing education and supporting the patient to help them optimize their nutrition and improve their outcomes,” she concluded.
In a discussion following the session, panelist Neha Shah, MPH, RD, CNSC, a dietitian and health education specialist at the University of California, San Francisco, commented on the importance of malnutrition assessment in patients with IBD being considered for surgery.
Patients should be screened for malnutrition, and if they have a positive screen, “should be automatically referred to a registered dietitian specializing in IBD for a nutrition assessment,” she said.
“Certainly, a nutritional assessment, as Kelly has highlighted really well, will encompass an evaluation of various areas of health – patient history, food and nutrition history, changing anthropometrics, alterations in labs – and certainly going into further nutrition history with net food intolerance, intake from each food group, portions, access, support, culture, eating environment, skills in the kitchen, relationship with diet.”
Ms. Issokson is a board member of the Crohn’s & Colitis Foundation and a digital advisory board member of Avant Healthcare. Ms. Shah had no disclosures.
Malnutrition is common among patients with inflammatory bowel disease (IBD) and is associated with worse outcomes that can prolong hospitalizations and increase patients’ risk for death.
As many as 85% of inpatients with IBD may be malnourished, with the severity of malnutrition affected by disease activity, extent, and duration, said Kelly Issokson, MS, RD, CNSC, clinical nutrition coordinator in the IBD program in the division of gastroenterology at Cedars-Sinai Medical Center, Los Angeles.
“Malnutrition is a severe complication of IBD, and it should not be overlooked,” she said during an oral presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
In patients with IBD, malabsorption, enteric losses, inadequate intake, and side effects of medical therapy can all lead to malnutrition, which in turn is an independent risk factor for venous thromboembolic events, nonelective surgery, longer hospital stays, and increased mortality.
In addition, malnutrition in IBD increases risk for infection and sepsis, and for perioperative complications, and can more than double the cost of care, compared with adequately nourished IBD patients, she said.
Ms. Issokson cited a definition of malnutrition from the American Society of Parenteral and Enteral Nutrition as “an acute or chronic state of overnutrition or undernutrition with or without inflammatory activity that has led to a change in body composition and diminished function.”
Lab findings of low albumin, low prealbumin, or isolated metrics such as weight loss or change in body mass index do not constitute malnutrition and should not be used to diagnosis it, Ms. Issokson cautioned.
Patients at low risk for malnutrition have no unintentional weight loss, are eating well, have minimal or no dietary restrictions, and no wasting. In contrast, high-risk patients have unintentional weight loss, decreased appetite and/or food intake, restrict multiple foods, or show signs of wasting.
Screening
“Nutrition screening is the first step in diagnosing a patient with malnutrition. This is a process of identifying individuals who may be at nutrition risk and benefit from assessment from a registered dietitian,” Ms. Issokson said.
The Malnutrition Screening Tool is quick, easy to administer, and requires minimal training. It can be used to screen adults for malnutrition regardless of age, medical history, or setting, she said.
The two-item instrument asks, “Have you recently lost weight without trying?” with a “no” scored as 0 and a “yes” scored as 2. The second question is, “Have you been eating poorly because of decreased appetite, with a “no” equal to 0 and a “yes” equal to 1. Patients with a score of 0 or 1 are not at risk, whereas patients with scores of 2 or 3 are deemed to be at risk for malnutrition and require further assessment by a dietitian.
Assessment
Assessment for malnutrition involves a variety of factors, including anthropometric factors such as weight and BMI changes; biochemical markers such as fat-soluble vitamins, water-soluble vitamins, minerals, and urinary sodium; symptoms such as decreased appetite, abdominal pain, cramping or bloating, diarrhea, or urgency or obstructive symptoms; and body composition measures such as handgrip strength, biochemical impedance analysis, skinfold thickness, bone mineral density, and muscle mass.
Other nutritional assessment tools may include 24-hour recall of nutrition intake, diet history, and questions about eating behaviors, food allergies or intolerances, and cultural or religious food preferences.
Assessing food security is also important, especially during the current pandemic, Ms. Issokson emphasized.
“Is your patient running out of food? Do they have money to purchase food? Are they able to go to the grocery store to buy food? This is essential to know when you’re developing a nutrition plan,” she said.
A nutrition-focused physical exam should include assessment of skin manifestation, secondary to malnutrition or malabsorption, such as dry skin, delayed wound healing, stomatitis, scurvy, seborrheic dermatitis, bleeding, and periorificial and acral dermatitis or alopecia.
Diagnosis
Currently available malnutrition criteria have not been validated for use in patients with IBD, and further studies are needed to affirm their applicability to this population, Ms. Issokson said.
The Academy of Nutrition and Dietetics–American Society for Parenteral and Enteral Nutrition (AND-ASPEN) malnutrition criteria require measures of weight loss, energy intake, subcutaneous fat loss, subcutaneous muscle loss, general or local fluid accumulation, and handgrip strength to determine whether a patient is moderately or severely malnourished.
Ms. Issokson said that she finds the European Society for Clinical Nutrition and Metabolism Global Leadership Initiative on Malnutrition (ESPEN GLIM) criteria somewhat easier to use for diagnosis, as they consist of phenotypic and etiologic criteria, with patients who meet at least one of each being considered malnourished.
“When identified, document malnutrition, and of course intervene appropriately by referring to a dietitian providing education and supporting the patient to help them optimize their nutrition and improve their outcomes,” she concluded.
In a discussion following the session, panelist Neha Shah, MPH, RD, CNSC, a dietitian and health education specialist at the University of California, San Francisco, commented on the importance of malnutrition assessment in patients with IBD being considered for surgery.
Patients should be screened for malnutrition, and if they have a positive screen, “should be automatically referred to a registered dietitian specializing in IBD for a nutrition assessment,” she said.
“Certainly, a nutritional assessment, as Kelly has highlighted really well, will encompass an evaluation of various areas of health – patient history, food and nutrition history, changing anthropometrics, alterations in labs – and certainly going into further nutrition history with net food intolerance, intake from each food group, portions, access, support, culture, eating environment, skills in the kitchen, relationship with diet.”
Ms. Issokson is a board member of the Crohn’s & Colitis Foundation and a digital advisory board member of Avant Healthcare. Ms. Shah had no disclosures.
Malnutrition is common among patients with inflammatory bowel disease (IBD) and is associated with worse outcomes that can prolong hospitalizations and increase patients’ risk for death.
As many as 85% of inpatients with IBD may be malnourished, with the severity of malnutrition affected by disease activity, extent, and duration, said Kelly Issokson, MS, RD, CNSC, clinical nutrition coordinator in the IBD program in the division of gastroenterology at Cedars-Sinai Medical Center, Los Angeles.
“Malnutrition is a severe complication of IBD, and it should not be overlooked,” she said during an oral presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
In patients with IBD, malabsorption, enteric losses, inadequate intake, and side effects of medical therapy can all lead to malnutrition, which in turn is an independent risk factor for venous thromboembolic events, nonelective surgery, longer hospital stays, and increased mortality.
In addition, malnutrition in IBD increases risk for infection and sepsis, and for perioperative complications, and can more than double the cost of care, compared with adequately nourished IBD patients, she said.
Ms. Issokson cited a definition of malnutrition from the American Society of Parenteral and Enteral Nutrition as “an acute or chronic state of overnutrition or undernutrition with or without inflammatory activity that has led to a change in body composition and diminished function.”
Lab findings of low albumin, low prealbumin, or isolated metrics such as weight loss or change in body mass index do not constitute malnutrition and should not be used to diagnosis it, Ms. Issokson cautioned.
Patients at low risk for malnutrition have no unintentional weight loss, are eating well, have minimal or no dietary restrictions, and no wasting. In contrast, high-risk patients have unintentional weight loss, decreased appetite and/or food intake, restrict multiple foods, or show signs of wasting.
Screening
“Nutrition screening is the first step in diagnosing a patient with malnutrition. This is a process of identifying individuals who may be at nutrition risk and benefit from assessment from a registered dietitian,” Ms. Issokson said.
The Malnutrition Screening Tool is quick, easy to administer, and requires minimal training. It can be used to screen adults for malnutrition regardless of age, medical history, or setting, she said.
The two-item instrument asks, “Have you recently lost weight without trying?” with a “no” scored as 0 and a “yes” scored as 2. The second question is, “Have you been eating poorly because of decreased appetite, with a “no” equal to 0 and a “yes” equal to 1. Patients with a score of 0 or 1 are not at risk, whereas patients with scores of 2 or 3 are deemed to be at risk for malnutrition and require further assessment by a dietitian.
Assessment
Assessment for malnutrition involves a variety of factors, including anthropometric factors such as weight and BMI changes; biochemical markers such as fat-soluble vitamins, water-soluble vitamins, minerals, and urinary sodium; symptoms such as decreased appetite, abdominal pain, cramping or bloating, diarrhea, or urgency or obstructive symptoms; and body composition measures such as handgrip strength, biochemical impedance analysis, skinfold thickness, bone mineral density, and muscle mass.
Other nutritional assessment tools may include 24-hour recall of nutrition intake, diet history, and questions about eating behaviors, food allergies or intolerances, and cultural or religious food preferences.
Assessing food security is also important, especially during the current pandemic, Ms. Issokson emphasized.
“Is your patient running out of food? Do they have money to purchase food? Are they able to go to the grocery store to buy food? This is essential to know when you’re developing a nutrition plan,” she said.
A nutrition-focused physical exam should include assessment of skin manifestation, secondary to malnutrition or malabsorption, such as dry skin, delayed wound healing, stomatitis, scurvy, seborrheic dermatitis, bleeding, and periorificial and acral dermatitis or alopecia.
Diagnosis
Currently available malnutrition criteria have not been validated for use in patients with IBD, and further studies are needed to affirm their applicability to this population, Ms. Issokson said.
The Academy of Nutrition and Dietetics–American Society for Parenteral and Enteral Nutrition (AND-ASPEN) malnutrition criteria require measures of weight loss, energy intake, subcutaneous fat loss, subcutaneous muscle loss, general or local fluid accumulation, and handgrip strength to determine whether a patient is moderately or severely malnourished.
Ms. Issokson said that she finds the European Society for Clinical Nutrition and Metabolism Global Leadership Initiative on Malnutrition (ESPEN GLIM) criteria somewhat easier to use for diagnosis, as they consist of phenotypic and etiologic criteria, with patients who meet at least one of each being considered malnourished.
“When identified, document malnutrition, and of course intervene appropriately by referring to a dietitian providing education and supporting the patient to help them optimize their nutrition and improve their outcomes,” she concluded.
In a discussion following the session, panelist Neha Shah, MPH, RD, CNSC, a dietitian and health education specialist at the University of California, San Francisco, commented on the importance of malnutrition assessment in patients with IBD being considered for surgery.
Patients should be screened for malnutrition, and if they have a positive screen, “should be automatically referred to a registered dietitian specializing in IBD for a nutrition assessment,” she said.
“Certainly, a nutritional assessment, as Kelly has highlighted really well, will encompass an evaluation of various areas of health – patient history, food and nutrition history, changing anthropometrics, alterations in labs – and certainly going into further nutrition history with net food intolerance, intake from each food group, portions, access, support, culture, eating environment, skills in the kitchen, relationship with diet.”
Ms. Issokson is a board member of the Crohn’s & Colitis Foundation and a digital advisory board member of Avant Healthcare. Ms. Shah had no disclosures.
FROM THE CROHN’S & COLITIS CONGRESS
Breakthrough COVID-19 milder in vaccinated patients with IBD
Vaccination against SARS-CoV-2 appears to protect people with inflammatory bowel disease (IBD) from the more serious consequences of breakthrough COVID-19 infections, but results may vary by which vaccine was received, results of a small study suggest.
In a study of patients with IBD who had completed a primary vaccine series but went on to develop COVID-19, there were trends toward worse outcomes for patients who received a non-mRNA vaccine, older patients, and those who were on combination therapy rather than monotherapy, reported Emily Spiera, a medical student at the Icahn School of Medicine at Mount Sinai, New York.
“Overall, we saw that vaccinated patients who subsequently developed COVID-19 had low rates of hospitalization, severe COVID, and death,” she said in an oral abstract at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
The study was conducted before the highly infectious Omicron variant of SARS-CoV-2 became dominant, however, and the sample size of 88 patients, combined with a low number of study events, was too small for statistical significance to emerge for most measures, Ms. Spiera acknowledged.
Nonetheless, the findings support the protective benefit of vaccines in this population, said Freddy Caldera, DO, associate professor of gastroenterology at the University of Wisconsin–Madison, who was not involved in the study.
“In my mind, when we think about COVID vaccines, the whole goal is to prevent severe disease,” he said.
Dr. Caldera and colleagues conducted an earlier study of humoral immunogenicity of mRNA COVID-19 vaccines in 122 patients with IBD and 60 healthy controls, and found that all controls and 97% of patients with IBD developed antibodies, although antibody concentrations were lower in patients with IBD, compared with controls (P < .001). Those who received the mRNA-1273 (Moderna) COVID-19 had significantly higher antibody concentrations than those who received the Pfizer-BNT vaccine series (P < .001).
They also found that patients on immune-modifying therapy had lower antibody concentrations, compared with those who were not on such therapy, or those who received aminosalicylates or vedolizumab (Entyvio; P = .003).
The protective effect of vaccines in this population became even more apparent after patients received an additional vaccine dose.
“We actually have a study in preprint of what happens after a third dose, where everyone made antibodies,” he said. “What we tell patients is that vaccines work.”
SECURE-IBD data
The investigators at Mount Sinai, the University of North Carolina at Chapel Hill, and Tel Aviv University analyzed data from the Surveillance Epidemiology of Coronavirus Under Research Exclusion in Inflammatory Bowel Disease (SECURE-IBD) database, an international web-based registry that includes reports from 74 countries, with data reported by 48 U.S. states.
The study sample consisted of patients enrolled from Dec. 12, 2020, to Oct. 1, 2021, who had completed a primary vaccination series with either mRNA vaccines (Pfizer or Moderna) adenoviral vector-based vaccines (AstraZeneca, Sputnik, CanSino, or Janssen/Johnson & Johnson), or an inactivated SARS-CoV-2 vaccine (Sinovac).
Of 2,477 patients with COVID-19 infections reported to SECURE-IBD, 160 reported being vaccinated. Of this group, 53 were excluded because they were only partially vaccinated, and 19 were excluded because of missing data on either vaccine type, number of doses, or COVID-19 outcomes, leaving 88 patients with completed primary vaccination series at the time of COVID-19 infection.
The median patient age was 40.1 years. Nearly two-thirds of the patients had a diagnosis of Crohn’s disease, and slightly more than one-third has a diagnosis of ulcerative colitis. The patients came from 18 countries, with 45.3% of the sample in the United States.
A total of 58% of patients were on biologic monotherapy, with either a tumor necrosis factor antagonist, integrin antagonist, or anti–interleukin-12/13. In addition, 3.4% were on immunomodulator monotherapy, 21.6% were on combination therapy, and 5.7% were receiving corticosteroids.
Lower severity
COVID-19 severity was numerically but not significantly lower among the 88 vaccinated patients, with a rate of 5.7%, compared with 9.3% among 2,317 patients with COVID-19 infections in the database who were not vaccinated.
COVID-19 severity defined as a composite of ICU admission, need for mechanical ventilation and/or death was actually slightly higher among the vaccinated patients, with a rate of 3.4% versus 1.9% for nonvaccinated patients, but this difference was not statistically significant.
There was 1 death among vaccinated patients (1.1%) versus 29 among the unvaccinated (1.2%).
There were trends toward fewer hospitalizations and less-frequent severe COVID-19 infection among patients who received a mRNA vaccine, compared with other vaccine types, but again these differences did not reach statistical significance.
As noted before, there was a higher frequency of severe COVID-19 among patients on combination therapy than on monotherapy, but this difference too was not statistically significant.
As seen with COVID-19 in the general population older patients tended to have worse outcomes, with a mean age of 53 for patients requiring hospitalization, compared with 39 years for patients who stayed out of the hospital (P = .04), and a mean age of 59 among patients with severe COVID-19 infections, compared with 39 for patients with moderate or mild infections (P = .03).
Ms. Spiera described the case of the single vaccinated patient who died. The 63-year-old woman had moderately active Crohn’s disease treated with corticosteroids, adalimumab (Humira) and azathioprine at the time of COVID-19 infection. She had received the AstraZeneca adenoviral-based vaccine more than 30 days prior to infection. She was hospitalized and intubated, and died from gastrointestinal bleeding.
Ms. Spiera noted that, although the sample size was small, and only patients known to have COVID-19 were included, it is one of the largest cohorts to date of vaccinated patients with IBD who developed COVID-19. She said that the study supports prior studies showing that combination therapy and tumor necrosis factor antagonists may result in reduced immunity, and that mRNA vaccines may offer better protection against severe illness in this population.
The study was supported by a Digestive Disease Research Foundation Fellowship. Ms. Spiera and Dr. Caldera reported no relevant disclosures.
Vaccination against SARS-CoV-2 appears to protect people with inflammatory bowel disease (IBD) from the more serious consequences of breakthrough COVID-19 infections, but results may vary by which vaccine was received, results of a small study suggest.
In a study of patients with IBD who had completed a primary vaccine series but went on to develop COVID-19, there were trends toward worse outcomes for patients who received a non-mRNA vaccine, older patients, and those who were on combination therapy rather than monotherapy, reported Emily Spiera, a medical student at the Icahn School of Medicine at Mount Sinai, New York.
“Overall, we saw that vaccinated patients who subsequently developed COVID-19 had low rates of hospitalization, severe COVID, and death,” she said in an oral abstract at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
The study was conducted before the highly infectious Omicron variant of SARS-CoV-2 became dominant, however, and the sample size of 88 patients, combined with a low number of study events, was too small for statistical significance to emerge for most measures, Ms. Spiera acknowledged.
Nonetheless, the findings support the protective benefit of vaccines in this population, said Freddy Caldera, DO, associate professor of gastroenterology at the University of Wisconsin–Madison, who was not involved in the study.
“In my mind, when we think about COVID vaccines, the whole goal is to prevent severe disease,” he said.
Dr. Caldera and colleagues conducted an earlier study of humoral immunogenicity of mRNA COVID-19 vaccines in 122 patients with IBD and 60 healthy controls, and found that all controls and 97% of patients with IBD developed antibodies, although antibody concentrations were lower in patients with IBD, compared with controls (P < .001). Those who received the mRNA-1273 (Moderna) COVID-19 had significantly higher antibody concentrations than those who received the Pfizer-BNT vaccine series (P < .001).
They also found that patients on immune-modifying therapy had lower antibody concentrations, compared with those who were not on such therapy, or those who received aminosalicylates or vedolizumab (Entyvio; P = .003).
The protective effect of vaccines in this population became even more apparent after patients received an additional vaccine dose.
“We actually have a study in preprint of what happens after a third dose, where everyone made antibodies,” he said. “What we tell patients is that vaccines work.”
SECURE-IBD data
The investigators at Mount Sinai, the University of North Carolina at Chapel Hill, and Tel Aviv University analyzed data from the Surveillance Epidemiology of Coronavirus Under Research Exclusion in Inflammatory Bowel Disease (SECURE-IBD) database, an international web-based registry that includes reports from 74 countries, with data reported by 48 U.S. states.
The study sample consisted of patients enrolled from Dec. 12, 2020, to Oct. 1, 2021, who had completed a primary vaccination series with either mRNA vaccines (Pfizer or Moderna) adenoviral vector-based vaccines (AstraZeneca, Sputnik, CanSino, or Janssen/Johnson & Johnson), or an inactivated SARS-CoV-2 vaccine (Sinovac).
Of 2,477 patients with COVID-19 infections reported to SECURE-IBD, 160 reported being vaccinated. Of this group, 53 were excluded because they were only partially vaccinated, and 19 were excluded because of missing data on either vaccine type, number of doses, or COVID-19 outcomes, leaving 88 patients with completed primary vaccination series at the time of COVID-19 infection.
The median patient age was 40.1 years. Nearly two-thirds of the patients had a diagnosis of Crohn’s disease, and slightly more than one-third has a diagnosis of ulcerative colitis. The patients came from 18 countries, with 45.3% of the sample in the United States.
A total of 58% of patients were on biologic monotherapy, with either a tumor necrosis factor antagonist, integrin antagonist, or anti–interleukin-12/13. In addition, 3.4% were on immunomodulator monotherapy, 21.6% were on combination therapy, and 5.7% were receiving corticosteroids.
Lower severity
COVID-19 severity was numerically but not significantly lower among the 88 vaccinated patients, with a rate of 5.7%, compared with 9.3% among 2,317 patients with COVID-19 infections in the database who were not vaccinated.
COVID-19 severity defined as a composite of ICU admission, need for mechanical ventilation and/or death was actually slightly higher among the vaccinated patients, with a rate of 3.4% versus 1.9% for nonvaccinated patients, but this difference was not statistically significant.
There was 1 death among vaccinated patients (1.1%) versus 29 among the unvaccinated (1.2%).
There were trends toward fewer hospitalizations and less-frequent severe COVID-19 infection among patients who received a mRNA vaccine, compared with other vaccine types, but again these differences did not reach statistical significance.
As noted before, there was a higher frequency of severe COVID-19 among patients on combination therapy than on monotherapy, but this difference too was not statistically significant.
As seen with COVID-19 in the general population older patients tended to have worse outcomes, with a mean age of 53 for patients requiring hospitalization, compared with 39 years for patients who stayed out of the hospital (P = .04), and a mean age of 59 among patients with severe COVID-19 infections, compared with 39 for patients with moderate or mild infections (P = .03).
Ms. Spiera described the case of the single vaccinated patient who died. The 63-year-old woman had moderately active Crohn’s disease treated with corticosteroids, adalimumab (Humira) and azathioprine at the time of COVID-19 infection. She had received the AstraZeneca adenoviral-based vaccine more than 30 days prior to infection. She was hospitalized and intubated, and died from gastrointestinal bleeding.
Ms. Spiera noted that, although the sample size was small, and only patients known to have COVID-19 were included, it is one of the largest cohorts to date of vaccinated patients with IBD who developed COVID-19. She said that the study supports prior studies showing that combination therapy and tumor necrosis factor antagonists may result in reduced immunity, and that mRNA vaccines may offer better protection against severe illness in this population.
The study was supported by a Digestive Disease Research Foundation Fellowship. Ms. Spiera and Dr. Caldera reported no relevant disclosures.
Vaccination against SARS-CoV-2 appears to protect people with inflammatory bowel disease (IBD) from the more serious consequences of breakthrough COVID-19 infections, but results may vary by which vaccine was received, results of a small study suggest.
In a study of patients with IBD who had completed a primary vaccine series but went on to develop COVID-19, there were trends toward worse outcomes for patients who received a non-mRNA vaccine, older patients, and those who were on combination therapy rather than monotherapy, reported Emily Spiera, a medical student at the Icahn School of Medicine at Mount Sinai, New York.
“Overall, we saw that vaccinated patients who subsequently developed COVID-19 had low rates of hospitalization, severe COVID, and death,” she said in an oral abstract at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
The study was conducted before the highly infectious Omicron variant of SARS-CoV-2 became dominant, however, and the sample size of 88 patients, combined with a low number of study events, was too small for statistical significance to emerge for most measures, Ms. Spiera acknowledged.
Nonetheless, the findings support the protective benefit of vaccines in this population, said Freddy Caldera, DO, associate professor of gastroenterology at the University of Wisconsin–Madison, who was not involved in the study.
“In my mind, when we think about COVID vaccines, the whole goal is to prevent severe disease,” he said.
Dr. Caldera and colleagues conducted an earlier study of humoral immunogenicity of mRNA COVID-19 vaccines in 122 patients with IBD and 60 healthy controls, and found that all controls and 97% of patients with IBD developed antibodies, although antibody concentrations were lower in patients with IBD, compared with controls (P < .001). Those who received the mRNA-1273 (Moderna) COVID-19 had significantly higher antibody concentrations than those who received the Pfizer-BNT vaccine series (P < .001).
They also found that patients on immune-modifying therapy had lower antibody concentrations, compared with those who were not on such therapy, or those who received aminosalicylates or vedolizumab (Entyvio; P = .003).
The protective effect of vaccines in this population became even more apparent after patients received an additional vaccine dose.
“We actually have a study in preprint of what happens after a third dose, where everyone made antibodies,” he said. “What we tell patients is that vaccines work.”
SECURE-IBD data
The investigators at Mount Sinai, the University of North Carolina at Chapel Hill, and Tel Aviv University analyzed data from the Surveillance Epidemiology of Coronavirus Under Research Exclusion in Inflammatory Bowel Disease (SECURE-IBD) database, an international web-based registry that includes reports from 74 countries, with data reported by 48 U.S. states.
The study sample consisted of patients enrolled from Dec. 12, 2020, to Oct. 1, 2021, who had completed a primary vaccination series with either mRNA vaccines (Pfizer or Moderna) adenoviral vector-based vaccines (AstraZeneca, Sputnik, CanSino, or Janssen/Johnson & Johnson), or an inactivated SARS-CoV-2 vaccine (Sinovac).
Of 2,477 patients with COVID-19 infections reported to SECURE-IBD, 160 reported being vaccinated. Of this group, 53 were excluded because they were only partially vaccinated, and 19 were excluded because of missing data on either vaccine type, number of doses, or COVID-19 outcomes, leaving 88 patients with completed primary vaccination series at the time of COVID-19 infection.
The median patient age was 40.1 years. Nearly two-thirds of the patients had a diagnosis of Crohn’s disease, and slightly more than one-third has a diagnosis of ulcerative colitis. The patients came from 18 countries, with 45.3% of the sample in the United States.
A total of 58% of patients were on biologic monotherapy, with either a tumor necrosis factor antagonist, integrin antagonist, or anti–interleukin-12/13. In addition, 3.4% were on immunomodulator monotherapy, 21.6% were on combination therapy, and 5.7% were receiving corticosteroids.
Lower severity
COVID-19 severity was numerically but not significantly lower among the 88 vaccinated patients, with a rate of 5.7%, compared with 9.3% among 2,317 patients with COVID-19 infections in the database who were not vaccinated.
COVID-19 severity defined as a composite of ICU admission, need for mechanical ventilation and/or death was actually slightly higher among the vaccinated patients, with a rate of 3.4% versus 1.9% for nonvaccinated patients, but this difference was not statistically significant.
There was 1 death among vaccinated patients (1.1%) versus 29 among the unvaccinated (1.2%).
There were trends toward fewer hospitalizations and less-frequent severe COVID-19 infection among patients who received a mRNA vaccine, compared with other vaccine types, but again these differences did not reach statistical significance.
As noted before, there was a higher frequency of severe COVID-19 among patients on combination therapy than on monotherapy, but this difference too was not statistically significant.
As seen with COVID-19 in the general population older patients tended to have worse outcomes, with a mean age of 53 for patients requiring hospitalization, compared with 39 years for patients who stayed out of the hospital (P = .04), and a mean age of 59 among patients with severe COVID-19 infections, compared with 39 for patients with moderate or mild infections (P = .03).
Ms. Spiera described the case of the single vaccinated patient who died. The 63-year-old woman had moderately active Crohn’s disease treated with corticosteroids, adalimumab (Humira) and azathioprine at the time of COVID-19 infection. She had received the AstraZeneca adenoviral-based vaccine more than 30 days prior to infection. She was hospitalized and intubated, and died from gastrointestinal bleeding.
Ms. Spiera noted that, although the sample size was small, and only patients known to have COVID-19 were included, it is one of the largest cohorts to date of vaccinated patients with IBD who developed COVID-19. She said that the study supports prior studies showing that combination therapy and tumor necrosis factor antagonists may result in reduced immunity, and that mRNA vaccines may offer better protection against severe illness in this population.
The study was supported by a Digestive Disease Research Foundation Fellowship. Ms. Spiera and Dr. Caldera reported no relevant disclosures.
FROM THE CROHN’S & COLITIS CONGRESS
Cystic fibrosis in retreat, but still unbeaten
In 1938, the year that cystic fibrosis (CF) was first described clinically, four of five children born with the disease did not live past their first birthdays.
In 2019, the median age at death for patients enrolled in the Cystic Fibrosis Foundation (CFF) registry was 32 years, and the predicted life expectancy for patients with CF who were born from 2015 through 2019 was 46 years.
Those numbers reflect the remarkable progress made in the past 4 decades in the care of patients with CF, but also highlight the obstacles ahead, given that the predicted life expectancy for the overall U.S. population in 2019 (pre–COVID-19) was 78.9 years.
Julie Desch, MD, is a CF survivor who has beaten the odds and then some. At age 61, the retired surgical pathologist is a CF patient advocate, speaker, and a board member of the Cystic Fibrosis Research Institute, a not-for-profit organization that funds CF research and offers education, advocacy, and psychosocial support for persons with CF and their families and caregivers.
In an interview, Dr. Desch said that while there has been remarkable progress in her lifetime in the field of CF research and treatment, particularly in the development of drugs that modulate function of the underlying cause of approximately 90% of CF cases, there are still many CF patients who cannot benefit from these therapies.
“There are still 10% of people who don’t make a protein to be modified, so that’s a huge unmet need,” she said.
Genetic disorder
CF is a chronic autosomal recessive disorder with multiorgan and multisystem manifestations. It is caused by mutations in the CFTR gene, which codes for the protein CF transmembrane conductance regulator. CFTR controls transport of chloride ions across cell membranes, specifically the apical membrane of epithelial cells in tissues of the airways, intestinal tract, pancreas, kidneys, sweat glands, and the reproductive system, notably the vas deferens in males.
The F508 deletion (F508del) mutation is the most common, occurring in approximately 70% of persons with CF. It is a class 2-type protein processing mutation, leading to defects in cellular processing, protein stability, and chloride channel gating defects.
The CFTR protein also secretes bicarbonate to regulate the pH of airway surface liquid, and inhibits the epithelial sodium channel, which mediates passive sodium transport across apical membranes of sodium-absorbing epithelial cells in the kidneys, intestine, and airways.
CF typically presents with the buildup in the lungs of abnormally viscous and sticky mucus leading to frequent, severe infections, particularly with Pseudomonas aeruginosa, progressive lung damage and, prior to the development of effective disease management, to premature death. The phenotype often includes malnutrition due to malabsorption, and failure to thrive.
Diagnosis
In all 50 U.S. states and the District of Columbia, newborns are screened for CF with an assay for immunoreactive trypsinogen (IRT) an indirect marker for pancreatic injury that is elevated in serum in most newborns with CF, but also detected in premature infants or those delivered under stressful circumstances. In some states newborns are tested only for IRT, with a diagnosis confirmed with a sweat chloride test and/or a CFTR mutation panel.
Treatment
There is no cure for CF, but the discovery of the gene in 1989 by Canadian and U.S. investigators has led to life-prolonging therapeutic interventions, specifically the development of CFTR modulators.
CFTR modulators include potentiators such as ivacaftor (Kalydeco), and correctors such as lumacaftor and tezacaftor (available in the combination Orkambi), and most recently in the triple combination of elexacaftor, tezacaftor, and ivacaftor (Trikafta; ETI).
Neil Sweezey, MD, FRCPC, a CF expert at The Hospital for Sick Children (SickKids) in Toronto, told this news organization that the ideal therapy for CF, genetic correction of the underlying mutations, is still not feasible, but that CFTR modulators are a close second.
“For 90% of patients, the three-drug combination Trikafta has been shown to be quite safe, quite tolerable, and quite remarkably beneficial,” he said.
In a study reported at CHEST 2021 by investigators from Nationwide Children’s Hospital in Columbus, Ohio, 32 adults who were started on the triple combination had significantly improved in forced expiratory volume in 1 second (FEV1), gain in body mass index, decreased sweat chloride and decreased colonization by Pseudomonas species. In addition, patients had significant improvements in blood inflammatory markers.
Christopher H. Goss, MD, FCCP, professor of pulmonary critical care and sleep medicine and professor of pediatrics at the University of Washington in Seattle, agreed that with the availability of the triple combination, “these are extraordinary times. An astounding fact is that most patients have complete resolution of cough, and the exacerbation rates have just plummeted,” he said in an interview.
Some of the reductions in exacerbations may be attributable to the COVID-19 pandemic, he noted, because patients in isolation have less exposure to circulating respiratory viruses.
“But it has been miraculous, and the clinical effect is certainly still more astounding than the effects of ivacaftor, which was the first truly breakthrough drug. Weight goes up, well-being increases, and the population lung function has shifted up to better grade lung function, in the entire population,” he said.
In addition, the need for lung and heart transplantation has sharply declined.
“I had a patient who had decided to forgo transplantation, despite absolutely horrible lung function, and he’s now bowling and leading a very productive life, when before he had been preparing for end of life,” Dr. Goss said.
Dr. Sweezey emphasized that as with all medications, patients being started on the triple combination require close monitoring for potential adverse events that might require dose modification or, for a small number of patients, withdrawal.
Burden of care
CFTR modulators have reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease (DNase) that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. This can include both manual percussion and the use of devices for high-frequency chest wall oscillation.
The complex nature of CF often requires a combination of other therapies to address comorbidities. These therapies may include infection prophylaxis and treatment with antibiotics and antifungals, nutrition support, and therapy for CF-related complications, including gastrointestinal issues, liver diseases, diabetes, and osteopenia that may be related to poor nutrient absorption, chronic inflammation, or other sequelae of CF.
In addition, patients often require frequent CF care center visits – ideally a minimum of every 3 months – which can result in significant loss of work or school time.
“Outcomes for patients in the long run have been absolutely proven to be best if they’re followed in big, established, multidisciplinary well-organized CF centers,” Dr. Sweezey said. “In the United States and Canada if you’re looked after on a regular basis, which means quarterly, every 3 months – whether you need it or not, you really do need it – and if the patients are seen and assessed and checked every 3 months all of their lives, they have small changes caught early, whether it’s an infection you can slap down with medication or a nutrition problem that may be affecting a child’s growth and development.”
“We’re really kind of at a pivotal moment in CF, where we realize things are changing,” said A. Whitney Brown, MD, senior director for clinical affairs at the Cystic Fibrosis Foundation, and an adult CF and lung transplant physician in the Inova Advanced Lung Disease Program in Falls Church, Va.
“Patient needs and interest have evolved, because of the pandemic and because of the highly effective modulator therapy, but we want to take great effort to study it in a rigorous way, to make sure that as we are agile and adapt the care model, that we can maintain the same quality outcomes that we have traditionally done,” she said in an interview.
The Lancet Respiratory Medicine Commission on the future of CF care states that models of care “need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation, while minimizing the burden of care for patients and their families.”
‘A great problem to have’
One of the most significant changes in CF care has been the growing population of CF patients like Dr. Desch who are living well into adulthood, with some approaching Medicare eligibility.
With the advent of triple therapy and CFTR modulators being started earlier in life, lung function can be preserved, damage to other organs can be minimized, and life expectancy for patients with CF will continue to improve.
“We’re anticipating that there may be some needs in the aging CF population that are different than what we have historically had,” Dr. Brown said. “Will there be geriatric providers that need to become experts in CF care? That’s a great problem to have,” she said.
Dr. Goss agreed, noting that CF is steadily shifting from a near uniformly fatal disease to a chronic disorder that in many cases can be managed “with a complex regimen of novel drugs, much like HIV.”
He noted that there are multiple drug interactions with the triple combination, “so it’s really important that people don’t start a CF patient on a drug without consulting a pharmacist, because you can totally inactivate ETI, or augment it dramatically, and we’ve seen both happen.”
Cost and access
All experts interviewed for this article agreed that while the care of patients with CF has improved exponentially over the last few decades, there are still troubling inequities in care.
One of the largest impediments is the cost of care, with the triple combination costing more than $300,000 per year.
“Clearly patients aren’t paying that, but insurance companies are, and that’s causing all kinds of trickle-down effects that definitely affect patients. The patients like myself who are able to have insurance that covers it benefit, but there are so many people that don’t,” Dr. Desch said.
Dr. Sweezey noted that prior to the advent of ETI, patients with CF in Canada had better outcomes and longer life expectancy than did similar patients in the United States because of universal access to care and coordinated services under Canada’s health care system, compared with the highly fragmented and inefficient U.S. system. He added that the wider availability of ETI in the United States vs. Canada may begin to narrow that gap, however.
As noted before, there is a substantial proportion of patients – an estimated 10% – who have CFTR mutations that are not correctable by currently available CFTR modulators, and these patients are at significant risk for irreversible airway complications and lung damage.
In addition, although CF occurs most frequently among people of White ancestry, the disease does not respect distinctions of race or ethnicity.
“It’s not just [Whites] – a lot of people from different racial backgrounds, ethnic backgrounds, are not being diagnosed or are not being diagnosed soon enough to have effective care early enough,” Dr. Desch said.
That statement is supported by the Lancet Respiratory Medicine Commission on the future of cystic fibrosis care, whose members noted in 2019 that “epidemiological studies in the past 2 decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognized in many regions of the world.”
The commission members noted that the costs of adequate CF care may be beyond the reach of many patients in developing nations.
Still, if the substantial barriers of cost and access can be overcome, the future will continue to look brighter for patients with CF. As Dr. Sweezey put it: “There are studies that are pushing lower age limits for using these modulators, and as the evidence builds for the efficacy and safety at younger ages, I think all of us are hoping that we’ll end up being able to use either the current or future modulators to actually prevent trouble in CF, rather than trying to come along and fix it after it’s been there.”
Dr. Brown disclosed advisory board activity for Vertex that ended prior to her joining the CF Foundation. Dr. Desch, Dr. Goss, and Dr. Sweezey reported no relevant conflicts of interest.
In 1938, the year that cystic fibrosis (CF) was first described clinically, four of five children born with the disease did not live past their first birthdays.
In 2019, the median age at death for patients enrolled in the Cystic Fibrosis Foundation (CFF) registry was 32 years, and the predicted life expectancy for patients with CF who were born from 2015 through 2019 was 46 years.
Those numbers reflect the remarkable progress made in the past 4 decades in the care of patients with CF, but also highlight the obstacles ahead, given that the predicted life expectancy for the overall U.S. population in 2019 (pre–COVID-19) was 78.9 years.
Julie Desch, MD, is a CF survivor who has beaten the odds and then some. At age 61, the retired surgical pathologist is a CF patient advocate, speaker, and a board member of the Cystic Fibrosis Research Institute, a not-for-profit organization that funds CF research and offers education, advocacy, and psychosocial support for persons with CF and their families and caregivers.
In an interview, Dr. Desch said that while there has been remarkable progress in her lifetime in the field of CF research and treatment, particularly in the development of drugs that modulate function of the underlying cause of approximately 90% of CF cases, there are still many CF patients who cannot benefit from these therapies.
“There are still 10% of people who don’t make a protein to be modified, so that’s a huge unmet need,” she said.
Genetic disorder
CF is a chronic autosomal recessive disorder with multiorgan and multisystem manifestations. It is caused by mutations in the CFTR gene, which codes for the protein CF transmembrane conductance regulator. CFTR controls transport of chloride ions across cell membranes, specifically the apical membrane of epithelial cells in tissues of the airways, intestinal tract, pancreas, kidneys, sweat glands, and the reproductive system, notably the vas deferens in males.
The F508 deletion (F508del) mutation is the most common, occurring in approximately 70% of persons with CF. It is a class 2-type protein processing mutation, leading to defects in cellular processing, protein stability, and chloride channel gating defects.
The CFTR protein also secretes bicarbonate to regulate the pH of airway surface liquid, and inhibits the epithelial sodium channel, which mediates passive sodium transport across apical membranes of sodium-absorbing epithelial cells in the kidneys, intestine, and airways.
CF typically presents with the buildup in the lungs of abnormally viscous and sticky mucus leading to frequent, severe infections, particularly with Pseudomonas aeruginosa, progressive lung damage and, prior to the development of effective disease management, to premature death. The phenotype often includes malnutrition due to malabsorption, and failure to thrive.
Diagnosis
In all 50 U.S. states and the District of Columbia, newborns are screened for CF with an assay for immunoreactive trypsinogen (IRT) an indirect marker for pancreatic injury that is elevated in serum in most newborns with CF, but also detected in premature infants or those delivered under stressful circumstances. In some states newborns are tested only for IRT, with a diagnosis confirmed with a sweat chloride test and/or a CFTR mutation panel.
Treatment
There is no cure for CF, but the discovery of the gene in 1989 by Canadian and U.S. investigators has led to life-prolonging therapeutic interventions, specifically the development of CFTR modulators.
CFTR modulators include potentiators such as ivacaftor (Kalydeco), and correctors such as lumacaftor and tezacaftor (available in the combination Orkambi), and most recently in the triple combination of elexacaftor, tezacaftor, and ivacaftor (Trikafta; ETI).
Neil Sweezey, MD, FRCPC, a CF expert at The Hospital for Sick Children (SickKids) in Toronto, told this news organization that the ideal therapy for CF, genetic correction of the underlying mutations, is still not feasible, but that CFTR modulators are a close second.
“For 90% of patients, the three-drug combination Trikafta has been shown to be quite safe, quite tolerable, and quite remarkably beneficial,” he said.
In a study reported at CHEST 2021 by investigators from Nationwide Children’s Hospital in Columbus, Ohio, 32 adults who were started on the triple combination had significantly improved in forced expiratory volume in 1 second (FEV1), gain in body mass index, decreased sweat chloride and decreased colonization by Pseudomonas species. In addition, patients had significant improvements in blood inflammatory markers.
Christopher H. Goss, MD, FCCP, professor of pulmonary critical care and sleep medicine and professor of pediatrics at the University of Washington in Seattle, agreed that with the availability of the triple combination, “these are extraordinary times. An astounding fact is that most patients have complete resolution of cough, and the exacerbation rates have just plummeted,” he said in an interview.
Some of the reductions in exacerbations may be attributable to the COVID-19 pandemic, he noted, because patients in isolation have less exposure to circulating respiratory viruses.
“But it has been miraculous, and the clinical effect is certainly still more astounding than the effects of ivacaftor, which was the first truly breakthrough drug. Weight goes up, well-being increases, and the population lung function has shifted up to better grade lung function, in the entire population,” he said.
In addition, the need for lung and heart transplantation has sharply declined.
“I had a patient who had decided to forgo transplantation, despite absolutely horrible lung function, and he’s now bowling and leading a very productive life, when before he had been preparing for end of life,” Dr. Goss said.
Dr. Sweezey emphasized that as with all medications, patients being started on the triple combination require close monitoring for potential adverse events that might require dose modification or, for a small number of patients, withdrawal.
Burden of care
CFTR modulators have reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease (DNase) that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. This can include both manual percussion and the use of devices for high-frequency chest wall oscillation.
The complex nature of CF often requires a combination of other therapies to address comorbidities. These therapies may include infection prophylaxis and treatment with antibiotics and antifungals, nutrition support, and therapy for CF-related complications, including gastrointestinal issues, liver diseases, diabetes, and osteopenia that may be related to poor nutrient absorption, chronic inflammation, or other sequelae of CF.
In addition, patients often require frequent CF care center visits – ideally a minimum of every 3 months – which can result in significant loss of work or school time.
“Outcomes for patients in the long run have been absolutely proven to be best if they’re followed in big, established, multidisciplinary well-organized CF centers,” Dr. Sweezey said. “In the United States and Canada if you’re looked after on a regular basis, which means quarterly, every 3 months – whether you need it or not, you really do need it – and if the patients are seen and assessed and checked every 3 months all of their lives, they have small changes caught early, whether it’s an infection you can slap down with medication or a nutrition problem that may be affecting a child’s growth and development.”
“We’re really kind of at a pivotal moment in CF, where we realize things are changing,” said A. Whitney Brown, MD, senior director for clinical affairs at the Cystic Fibrosis Foundation, and an adult CF and lung transplant physician in the Inova Advanced Lung Disease Program in Falls Church, Va.
“Patient needs and interest have evolved, because of the pandemic and because of the highly effective modulator therapy, but we want to take great effort to study it in a rigorous way, to make sure that as we are agile and adapt the care model, that we can maintain the same quality outcomes that we have traditionally done,” she said in an interview.
The Lancet Respiratory Medicine Commission on the future of CF care states that models of care “need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation, while minimizing the burden of care for patients and their families.”
‘A great problem to have’
One of the most significant changes in CF care has been the growing population of CF patients like Dr. Desch who are living well into adulthood, with some approaching Medicare eligibility.
With the advent of triple therapy and CFTR modulators being started earlier in life, lung function can be preserved, damage to other organs can be minimized, and life expectancy for patients with CF will continue to improve.
“We’re anticipating that there may be some needs in the aging CF population that are different than what we have historically had,” Dr. Brown said. “Will there be geriatric providers that need to become experts in CF care? That’s a great problem to have,” she said.
Dr. Goss agreed, noting that CF is steadily shifting from a near uniformly fatal disease to a chronic disorder that in many cases can be managed “with a complex regimen of novel drugs, much like HIV.”
He noted that there are multiple drug interactions with the triple combination, “so it’s really important that people don’t start a CF patient on a drug without consulting a pharmacist, because you can totally inactivate ETI, or augment it dramatically, and we’ve seen both happen.”
Cost and access
All experts interviewed for this article agreed that while the care of patients with CF has improved exponentially over the last few decades, there are still troubling inequities in care.
One of the largest impediments is the cost of care, with the triple combination costing more than $300,000 per year.
“Clearly patients aren’t paying that, but insurance companies are, and that’s causing all kinds of trickle-down effects that definitely affect patients. The patients like myself who are able to have insurance that covers it benefit, but there are so many people that don’t,” Dr. Desch said.
Dr. Sweezey noted that prior to the advent of ETI, patients with CF in Canada had better outcomes and longer life expectancy than did similar patients in the United States because of universal access to care and coordinated services under Canada’s health care system, compared with the highly fragmented and inefficient U.S. system. He added that the wider availability of ETI in the United States vs. Canada may begin to narrow that gap, however.
As noted before, there is a substantial proportion of patients – an estimated 10% – who have CFTR mutations that are not correctable by currently available CFTR modulators, and these patients are at significant risk for irreversible airway complications and lung damage.
In addition, although CF occurs most frequently among people of White ancestry, the disease does not respect distinctions of race or ethnicity.
“It’s not just [Whites] – a lot of people from different racial backgrounds, ethnic backgrounds, are not being diagnosed or are not being diagnosed soon enough to have effective care early enough,” Dr. Desch said.
That statement is supported by the Lancet Respiratory Medicine Commission on the future of cystic fibrosis care, whose members noted in 2019 that “epidemiological studies in the past 2 decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognized in many regions of the world.”
The commission members noted that the costs of adequate CF care may be beyond the reach of many patients in developing nations.
Still, if the substantial barriers of cost and access can be overcome, the future will continue to look brighter for patients with CF. As Dr. Sweezey put it: “There are studies that are pushing lower age limits for using these modulators, and as the evidence builds for the efficacy and safety at younger ages, I think all of us are hoping that we’ll end up being able to use either the current or future modulators to actually prevent trouble in CF, rather than trying to come along and fix it after it’s been there.”
Dr. Brown disclosed advisory board activity for Vertex that ended prior to her joining the CF Foundation. Dr. Desch, Dr. Goss, and Dr. Sweezey reported no relevant conflicts of interest.
In 1938, the year that cystic fibrosis (CF) was first described clinically, four of five children born with the disease did not live past their first birthdays.
In 2019, the median age at death for patients enrolled in the Cystic Fibrosis Foundation (CFF) registry was 32 years, and the predicted life expectancy for patients with CF who were born from 2015 through 2019 was 46 years.
Those numbers reflect the remarkable progress made in the past 4 decades in the care of patients with CF, but also highlight the obstacles ahead, given that the predicted life expectancy for the overall U.S. population in 2019 (pre–COVID-19) was 78.9 years.
Julie Desch, MD, is a CF survivor who has beaten the odds and then some. At age 61, the retired surgical pathologist is a CF patient advocate, speaker, and a board member of the Cystic Fibrosis Research Institute, a not-for-profit organization that funds CF research and offers education, advocacy, and psychosocial support for persons with CF and their families and caregivers.
In an interview, Dr. Desch said that while there has been remarkable progress in her lifetime in the field of CF research and treatment, particularly in the development of drugs that modulate function of the underlying cause of approximately 90% of CF cases, there are still many CF patients who cannot benefit from these therapies.
“There are still 10% of people who don’t make a protein to be modified, so that’s a huge unmet need,” she said.
Genetic disorder
CF is a chronic autosomal recessive disorder with multiorgan and multisystem manifestations. It is caused by mutations in the CFTR gene, which codes for the protein CF transmembrane conductance regulator. CFTR controls transport of chloride ions across cell membranes, specifically the apical membrane of epithelial cells in tissues of the airways, intestinal tract, pancreas, kidneys, sweat glands, and the reproductive system, notably the vas deferens in males.
The F508 deletion (F508del) mutation is the most common, occurring in approximately 70% of persons with CF. It is a class 2-type protein processing mutation, leading to defects in cellular processing, protein stability, and chloride channel gating defects.
The CFTR protein also secretes bicarbonate to regulate the pH of airway surface liquid, and inhibits the epithelial sodium channel, which mediates passive sodium transport across apical membranes of sodium-absorbing epithelial cells in the kidneys, intestine, and airways.
CF typically presents with the buildup in the lungs of abnormally viscous and sticky mucus leading to frequent, severe infections, particularly with Pseudomonas aeruginosa, progressive lung damage and, prior to the development of effective disease management, to premature death. The phenotype often includes malnutrition due to malabsorption, and failure to thrive.
Diagnosis
In all 50 U.S. states and the District of Columbia, newborns are screened for CF with an assay for immunoreactive trypsinogen (IRT) an indirect marker for pancreatic injury that is elevated in serum in most newborns with CF, but also detected in premature infants or those delivered under stressful circumstances. In some states newborns are tested only for IRT, with a diagnosis confirmed with a sweat chloride test and/or a CFTR mutation panel.
Treatment
There is no cure for CF, but the discovery of the gene in 1989 by Canadian and U.S. investigators has led to life-prolonging therapeutic interventions, specifically the development of CFTR modulators.
CFTR modulators include potentiators such as ivacaftor (Kalydeco), and correctors such as lumacaftor and tezacaftor (available in the combination Orkambi), and most recently in the triple combination of elexacaftor, tezacaftor, and ivacaftor (Trikafta; ETI).
Neil Sweezey, MD, FRCPC, a CF expert at The Hospital for Sick Children (SickKids) in Toronto, told this news organization that the ideal therapy for CF, genetic correction of the underlying mutations, is still not feasible, but that CFTR modulators are a close second.
“For 90% of patients, the three-drug combination Trikafta has been shown to be quite safe, quite tolerable, and quite remarkably beneficial,” he said.
In a study reported at CHEST 2021 by investigators from Nationwide Children’s Hospital in Columbus, Ohio, 32 adults who were started on the triple combination had significantly improved in forced expiratory volume in 1 second (FEV1), gain in body mass index, decreased sweat chloride and decreased colonization by Pseudomonas species. In addition, patients had significant improvements in blood inflammatory markers.
Christopher H. Goss, MD, FCCP, professor of pulmonary critical care and sleep medicine and professor of pediatrics at the University of Washington in Seattle, agreed that with the availability of the triple combination, “these are extraordinary times. An astounding fact is that most patients have complete resolution of cough, and the exacerbation rates have just plummeted,” he said in an interview.
Some of the reductions in exacerbations may be attributable to the COVID-19 pandemic, he noted, because patients in isolation have less exposure to circulating respiratory viruses.
“But it has been miraculous, and the clinical effect is certainly still more astounding than the effects of ivacaftor, which was the first truly breakthrough drug. Weight goes up, well-being increases, and the population lung function has shifted up to better grade lung function, in the entire population,” he said.
In addition, the need for lung and heart transplantation has sharply declined.
“I had a patient who had decided to forgo transplantation, despite absolutely horrible lung function, and he’s now bowling and leading a very productive life, when before he had been preparing for end of life,” Dr. Goss said.
Dr. Sweezey emphasized that as with all medications, patients being started on the triple combination require close monitoring for potential adverse events that might require dose modification or, for a small number of patients, withdrawal.
Burden of care
CFTR modulators have reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease (DNase) that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. This can include both manual percussion and the use of devices for high-frequency chest wall oscillation.
The complex nature of CF often requires a combination of other therapies to address comorbidities. These therapies may include infection prophylaxis and treatment with antibiotics and antifungals, nutrition support, and therapy for CF-related complications, including gastrointestinal issues, liver diseases, diabetes, and osteopenia that may be related to poor nutrient absorption, chronic inflammation, or other sequelae of CF.
In addition, patients often require frequent CF care center visits – ideally a minimum of every 3 months – which can result in significant loss of work or school time.
“Outcomes for patients in the long run have been absolutely proven to be best if they’re followed in big, established, multidisciplinary well-organized CF centers,” Dr. Sweezey said. “In the United States and Canada if you’re looked after on a regular basis, which means quarterly, every 3 months – whether you need it or not, you really do need it – and if the patients are seen and assessed and checked every 3 months all of their lives, they have small changes caught early, whether it’s an infection you can slap down with medication or a nutrition problem that may be affecting a child’s growth and development.”
“We’re really kind of at a pivotal moment in CF, where we realize things are changing,” said A. Whitney Brown, MD, senior director for clinical affairs at the Cystic Fibrosis Foundation, and an adult CF and lung transplant physician in the Inova Advanced Lung Disease Program in Falls Church, Va.
“Patient needs and interest have evolved, because of the pandemic and because of the highly effective modulator therapy, but we want to take great effort to study it in a rigorous way, to make sure that as we are agile and adapt the care model, that we can maintain the same quality outcomes that we have traditionally done,” she said in an interview.
The Lancet Respiratory Medicine Commission on the future of CF care states that models of care “need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation, while minimizing the burden of care for patients and their families.”
‘A great problem to have’
One of the most significant changes in CF care has been the growing population of CF patients like Dr. Desch who are living well into adulthood, with some approaching Medicare eligibility.
With the advent of triple therapy and CFTR modulators being started earlier in life, lung function can be preserved, damage to other organs can be minimized, and life expectancy for patients with CF will continue to improve.
“We’re anticipating that there may be some needs in the aging CF population that are different than what we have historically had,” Dr. Brown said. “Will there be geriatric providers that need to become experts in CF care? That’s a great problem to have,” she said.
Dr. Goss agreed, noting that CF is steadily shifting from a near uniformly fatal disease to a chronic disorder that in many cases can be managed “with a complex regimen of novel drugs, much like HIV.”
He noted that there are multiple drug interactions with the triple combination, “so it’s really important that people don’t start a CF patient on a drug without consulting a pharmacist, because you can totally inactivate ETI, or augment it dramatically, and we’ve seen both happen.”
Cost and access
All experts interviewed for this article agreed that while the care of patients with CF has improved exponentially over the last few decades, there are still troubling inequities in care.
One of the largest impediments is the cost of care, with the triple combination costing more than $300,000 per year.
“Clearly patients aren’t paying that, but insurance companies are, and that’s causing all kinds of trickle-down effects that definitely affect patients. The patients like myself who are able to have insurance that covers it benefit, but there are so many people that don’t,” Dr. Desch said.
Dr. Sweezey noted that prior to the advent of ETI, patients with CF in Canada had better outcomes and longer life expectancy than did similar patients in the United States because of universal access to care and coordinated services under Canada’s health care system, compared with the highly fragmented and inefficient U.S. system. He added that the wider availability of ETI in the United States vs. Canada may begin to narrow that gap, however.
As noted before, there is a substantial proportion of patients – an estimated 10% – who have CFTR mutations that are not correctable by currently available CFTR modulators, and these patients are at significant risk for irreversible airway complications and lung damage.
In addition, although CF occurs most frequently among people of White ancestry, the disease does not respect distinctions of race or ethnicity.
“It’s not just [Whites] – a lot of people from different racial backgrounds, ethnic backgrounds, are not being diagnosed or are not being diagnosed soon enough to have effective care early enough,” Dr. Desch said.
That statement is supported by the Lancet Respiratory Medicine Commission on the future of cystic fibrosis care, whose members noted in 2019 that “epidemiological studies in the past 2 decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognized in many regions of the world.”
The commission members noted that the costs of adequate CF care may be beyond the reach of many patients in developing nations.
Still, if the substantial barriers of cost and access can be overcome, the future will continue to look brighter for patients with CF. As Dr. Sweezey put it: “There are studies that are pushing lower age limits for using these modulators, and as the evidence builds for the efficacy and safety at younger ages, I think all of us are hoping that we’ll end up being able to use either the current or future modulators to actually prevent trouble in CF, rather than trying to come along and fix it after it’s been there.”
Dr. Brown disclosed advisory board activity for Vertex that ended prior to her joining the CF Foundation. Dr. Desch, Dr. Goss, and Dr. Sweezey reported no relevant conflicts of interest.
ARFID or reasonable food restriction? The jury is out
Problems with eating and nutrition are common among patients with inflammatory bowel disease (IBD) and other gastrointestinal disorders, but clinicians who treat them should be careful not to automatically assume that patients have eating disorders, according to a psychologist who specializes in the psychological and social aspects of chronic digestive diseases.
On the other hand, clinicians must also be aware of the possibility that patients could have a recently identified syndrome cluster called avoidant restrictive food intake disorder (ARFID), said Tiffany Taft, PsyD, a research associate professor of medicine (gastroenterology and hepatology), medical social sciences, and psychiatry and behavioral sciences at Northwestern University, Chicago. In a recent study, she and her colleagues defined ARFID as “failure to meet one’s nutritional needs owing to sensory hypersensitivity, lack of interest in eating, or fear of aversive consequences from eating, and is associated with negative medical and psychosocial outcomes.”
ARFID “is a hot topic that we really don’t understand,” she said in an online presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Nutritional deficiencies
Nutritional deficiencies are common among patients with IBD, “and nutritional deficiencies themselves can lead to symptoms or side effects that can cause people to eat less,” she said.
“As our vitamin B12 goes down, our cognitive functioning starts to decline, and we might not be making clear decisions in how we’re deciding what to eat, when to eat, if we should be eating at all – just something to think about in your patients who have nutritional deficiencies,” she told the audience.
Other common nutritional deficiencies that can affect eating and food choice among patients with IBD include low folate (B9) levels associated with sore tongue and weight loss, low iron levels leading to nausea and loss of appetite, and zinc deficiency leading to loss of appetite and alterations in taste and/or smell, she said.
Newly recognized in GI
She noted that “ARFID actually originates in the pediatric psychiatric literature, mostly in children with sensory issues [such as] autism spectrum disorder, so this is not a construct that started in digestive disease, but has been adapted and applied to patients with digestive disease, including IBD.”
The DSM-5 lists four criteria for ARFID: significant weight loss, significant nutritional deficiency, dependence on enteral nutrition or oral supplements, and marked interference with psychosocial functions.
Helen Burton Murray, PhD, director of the gastrointestinal behavioral health program in the Center for Neurointestinal Health at Massachusetts General Hospital, Boston, who is familiar with Dr. Taft’s work, said in an interview that inclusion of ARFID in DSM-5 has put a name to a syndrome or symptom cluster that in all likelihood already existed.
However, “the jury is still out about whether, if we do diagnose patients who have digestive diseases with ARFID, that then helps them get to a treatment that improves their relationship with food and improves nutritional issues that may have occurred as a result of a restricted food intake,” she said.
“We don’t know yet if the diagnosis will actually improve things. In our clinical practice, anecdotally, it has, both for patients with IBDs and for patients with other GI conditions, particularly GI functional motility disorders. We’re a little bit more confident about making the diagnosis of ARFID in GI functional motility disorders than we are in IBD of course,” she said.
Screening measures
To get a better sense of the prevalence of ARFID, compared with reasonable responses to digestive diseases, Dr. Taft and colleagues conducted their cross-sectional study in 289 adults with achalasia, celiac, eosinophilic esophagitis, or IBD.
They found that 51.3% of the total sample met the diagnostic criteria for ARFID based on the Nine-Item ARFID Screen (NIAS), including 75.7 % of patients with achalasia. But Dr. Taft had cautions
“I can tell you, working with achalasia patients, 75% do not have ARFID,” Dr. Taft said.
She noted that the 51.3% of patients with IBD identified by NIAS or the 53% identified by the ARFID+ scale as having ARFID was also highly doubtful.
Dr. Taft and colleagues determined that nearly half of the variance in the NIAS could be accounted for by GI symptoms rather than psychosocial factors, making it less than ideal for use in the clinic or by researchers.
She also noted, however, that she received an email from one of the creators of NIAS, Hana F. Zickgraf, PhD, from the University of South Alabama, Mobile. Dr. Zickgraf agreed that the scale had drawbacks when applied to patients with GI disease, and pointed instead to the Fear of Food Questionnaire, a newly developed 18-item GI disease-specific instrument. Dr. Taft recommended the new questionnaire for research purposes, and expressed hope that a shorter version could be made available for screening patients in clinic.
Dr. Burton Murray said that while the Fear of Food Questionnaire, perhaps in combination with NIAS, has the potential to be a useful screening tool, cutoffs for it have yet to be established.
“At the end of the day, the diagnosis would be made by a clinician who is able to determine whether the life impairment or if the nutritional impairment or restricted food intake are reasonable in the realm of their digestive disease, or could a treatment for ARFID be warranted to help them to make changes to improve their quality of life and nutrition,” she said.
Check biases at the door
Before arriving at a diagnosis of ARFID, clinicians should also consider biases, Dr. Taft said.
“Eating disorders are highly stigmatized and stereotyped diagnoses,” more often attributed to young White women than to either men or to people of racial or ethnic minorities, she said.
Cultural background may contribute to food restrictions, and the risk may increase with age, with 68% of patients with later-onset IBD restricting diets to control the disease. It’s also possible that beliefs about food and “clean and healthy” eating may influence food and eating choices after a patient receives an IBD diagnosis.
Dr. Taft also pointed out that clinicians and patients may have different ideas about what constitutes significant food avoidance. Clinicians may expect patients with IBD to eat despite feeling nauseated, having abdominal pains, or diarrhea, for example, when the same food avoidance might be deemed reasonable in patients with short-term GI infections.
“Severe IBD symptoms are a significant predictor of posttraumatic stress disorder symptoms, and PTSD is hallmarked by avoidance behaviors,” she added.
She emphasized the need for clinicians to ask the right questions of patients to get at the roots of their nutritional deficiency or eating behavior, and to refer patients to mental health professionals with expertise in disordered eating or GI psychology.
Dr. Taft and Dr. Burton Murray reported having no conflicts of interest to disclose.
This article was updated on Feb. 4, 2022.
Problems with eating and nutrition are common among patients with inflammatory bowel disease (IBD) and other gastrointestinal disorders, but clinicians who treat them should be careful not to automatically assume that patients have eating disorders, according to a psychologist who specializes in the psychological and social aspects of chronic digestive diseases.
On the other hand, clinicians must also be aware of the possibility that patients could have a recently identified syndrome cluster called avoidant restrictive food intake disorder (ARFID), said Tiffany Taft, PsyD, a research associate professor of medicine (gastroenterology and hepatology), medical social sciences, and psychiatry and behavioral sciences at Northwestern University, Chicago. In a recent study, she and her colleagues defined ARFID as “failure to meet one’s nutritional needs owing to sensory hypersensitivity, lack of interest in eating, or fear of aversive consequences from eating, and is associated with negative medical and psychosocial outcomes.”
ARFID “is a hot topic that we really don’t understand,” she said in an online presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Nutritional deficiencies
Nutritional deficiencies are common among patients with IBD, “and nutritional deficiencies themselves can lead to symptoms or side effects that can cause people to eat less,” she said.
“As our vitamin B12 goes down, our cognitive functioning starts to decline, and we might not be making clear decisions in how we’re deciding what to eat, when to eat, if we should be eating at all – just something to think about in your patients who have nutritional deficiencies,” she told the audience.
Other common nutritional deficiencies that can affect eating and food choice among patients with IBD include low folate (B9) levels associated with sore tongue and weight loss, low iron levels leading to nausea and loss of appetite, and zinc deficiency leading to loss of appetite and alterations in taste and/or smell, she said.
Newly recognized in GI
She noted that “ARFID actually originates in the pediatric psychiatric literature, mostly in children with sensory issues [such as] autism spectrum disorder, so this is not a construct that started in digestive disease, but has been adapted and applied to patients with digestive disease, including IBD.”
The DSM-5 lists four criteria for ARFID: significant weight loss, significant nutritional deficiency, dependence on enteral nutrition or oral supplements, and marked interference with psychosocial functions.
Helen Burton Murray, PhD, director of the gastrointestinal behavioral health program in the Center for Neurointestinal Health at Massachusetts General Hospital, Boston, who is familiar with Dr. Taft’s work, said in an interview that inclusion of ARFID in DSM-5 has put a name to a syndrome or symptom cluster that in all likelihood already existed.
However, “the jury is still out about whether, if we do diagnose patients who have digestive diseases with ARFID, that then helps them get to a treatment that improves their relationship with food and improves nutritional issues that may have occurred as a result of a restricted food intake,” she said.
“We don’t know yet if the diagnosis will actually improve things. In our clinical practice, anecdotally, it has, both for patients with IBDs and for patients with other GI conditions, particularly GI functional motility disorders. We’re a little bit more confident about making the diagnosis of ARFID in GI functional motility disorders than we are in IBD of course,” she said.
Screening measures
To get a better sense of the prevalence of ARFID, compared with reasonable responses to digestive diseases, Dr. Taft and colleagues conducted their cross-sectional study in 289 adults with achalasia, celiac, eosinophilic esophagitis, or IBD.
They found that 51.3% of the total sample met the diagnostic criteria for ARFID based on the Nine-Item ARFID Screen (NIAS), including 75.7 % of patients with achalasia. But Dr. Taft had cautions
“I can tell you, working with achalasia patients, 75% do not have ARFID,” Dr. Taft said.
She noted that the 51.3% of patients with IBD identified by NIAS or the 53% identified by the ARFID+ scale as having ARFID was also highly doubtful.
Dr. Taft and colleagues determined that nearly half of the variance in the NIAS could be accounted for by GI symptoms rather than psychosocial factors, making it less than ideal for use in the clinic or by researchers.
She also noted, however, that she received an email from one of the creators of NIAS, Hana F. Zickgraf, PhD, from the University of South Alabama, Mobile. Dr. Zickgraf agreed that the scale had drawbacks when applied to patients with GI disease, and pointed instead to the Fear of Food Questionnaire, a newly developed 18-item GI disease-specific instrument. Dr. Taft recommended the new questionnaire for research purposes, and expressed hope that a shorter version could be made available for screening patients in clinic.
Dr. Burton Murray said that while the Fear of Food Questionnaire, perhaps in combination with NIAS, has the potential to be a useful screening tool, cutoffs for it have yet to be established.
“At the end of the day, the diagnosis would be made by a clinician who is able to determine whether the life impairment or if the nutritional impairment or restricted food intake are reasonable in the realm of their digestive disease, or could a treatment for ARFID be warranted to help them to make changes to improve their quality of life and nutrition,” she said.
Check biases at the door
Before arriving at a diagnosis of ARFID, clinicians should also consider biases, Dr. Taft said.
“Eating disorders are highly stigmatized and stereotyped diagnoses,” more often attributed to young White women than to either men or to people of racial or ethnic minorities, she said.
Cultural background may contribute to food restrictions, and the risk may increase with age, with 68% of patients with later-onset IBD restricting diets to control the disease. It’s also possible that beliefs about food and “clean and healthy” eating may influence food and eating choices after a patient receives an IBD diagnosis.
Dr. Taft also pointed out that clinicians and patients may have different ideas about what constitutes significant food avoidance. Clinicians may expect patients with IBD to eat despite feeling nauseated, having abdominal pains, or diarrhea, for example, when the same food avoidance might be deemed reasonable in patients with short-term GI infections.
“Severe IBD symptoms are a significant predictor of posttraumatic stress disorder symptoms, and PTSD is hallmarked by avoidance behaviors,” she added.
She emphasized the need for clinicians to ask the right questions of patients to get at the roots of their nutritional deficiency or eating behavior, and to refer patients to mental health professionals with expertise in disordered eating or GI psychology.
Dr. Taft and Dr. Burton Murray reported having no conflicts of interest to disclose.
This article was updated on Feb. 4, 2022.
Problems with eating and nutrition are common among patients with inflammatory bowel disease (IBD) and other gastrointestinal disorders, but clinicians who treat them should be careful not to automatically assume that patients have eating disorders, according to a psychologist who specializes in the psychological and social aspects of chronic digestive diseases.
On the other hand, clinicians must also be aware of the possibility that patients could have a recently identified syndrome cluster called avoidant restrictive food intake disorder (ARFID), said Tiffany Taft, PsyD, a research associate professor of medicine (gastroenterology and hepatology), medical social sciences, and psychiatry and behavioral sciences at Northwestern University, Chicago. In a recent study, she and her colleagues defined ARFID as “failure to meet one’s nutritional needs owing to sensory hypersensitivity, lack of interest in eating, or fear of aversive consequences from eating, and is associated with negative medical and psychosocial outcomes.”
ARFID “is a hot topic that we really don’t understand,” she said in an online presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Nutritional deficiencies
Nutritional deficiencies are common among patients with IBD, “and nutritional deficiencies themselves can lead to symptoms or side effects that can cause people to eat less,” she said.
“As our vitamin B12 goes down, our cognitive functioning starts to decline, and we might not be making clear decisions in how we’re deciding what to eat, when to eat, if we should be eating at all – just something to think about in your patients who have nutritional deficiencies,” she told the audience.
Other common nutritional deficiencies that can affect eating and food choice among patients with IBD include low folate (B9) levels associated with sore tongue and weight loss, low iron levels leading to nausea and loss of appetite, and zinc deficiency leading to loss of appetite and alterations in taste and/or smell, she said.
Newly recognized in GI
She noted that “ARFID actually originates in the pediatric psychiatric literature, mostly in children with sensory issues [such as] autism spectrum disorder, so this is not a construct that started in digestive disease, but has been adapted and applied to patients with digestive disease, including IBD.”
The DSM-5 lists four criteria for ARFID: significant weight loss, significant nutritional deficiency, dependence on enteral nutrition or oral supplements, and marked interference with psychosocial functions.
Helen Burton Murray, PhD, director of the gastrointestinal behavioral health program in the Center for Neurointestinal Health at Massachusetts General Hospital, Boston, who is familiar with Dr. Taft’s work, said in an interview that inclusion of ARFID in DSM-5 has put a name to a syndrome or symptom cluster that in all likelihood already existed.
However, “the jury is still out about whether, if we do diagnose patients who have digestive diseases with ARFID, that then helps them get to a treatment that improves their relationship with food and improves nutritional issues that may have occurred as a result of a restricted food intake,” she said.
“We don’t know yet if the diagnosis will actually improve things. In our clinical practice, anecdotally, it has, both for patients with IBDs and for patients with other GI conditions, particularly GI functional motility disorders. We’re a little bit more confident about making the diagnosis of ARFID in GI functional motility disorders than we are in IBD of course,” she said.
Screening measures
To get a better sense of the prevalence of ARFID, compared with reasonable responses to digestive diseases, Dr. Taft and colleagues conducted their cross-sectional study in 289 adults with achalasia, celiac, eosinophilic esophagitis, or IBD.
They found that 51.3% of the total sample met the diagnostic criteria for ARFID based on the Nine-Item ARFID Screen (NIAS), including 75.7 % of patients with achalasia. But Dr. Taft had cautions
“I can tell you, working with achalasia patients, 75% do not have ARFID,” Dr. Taft said.
She noted that the 51.3% of patients with IBD identified by NIAS or the 53% identified by the ARFID+ scale as having ARFID was also highly doubtful.
Dr. Taft and colleagues determined that nearly half of the variance in the NIAS could be accounted for by GI symptoms rather than psychosocial factors, making it less than ideal for use in the clinic or by researchers.
She also noted, however, that she received an email from one of the creators of NIAS, Hana F. Zickgraf, PhD, from the University of South Alabama, Mobile. Dr. Zickgraf agreed that the scale had drawbacks when applied to patients with GI disease, and pointed instead to the Fear of Food Questionnaire, a newly developed 18-item GI disease-specific instrument. Dr. Taft recommended the new questionnaire for research purposes, and expressed hope that a shorter version could be made available for screening patients in clinic.
Dr. Burton Murray said that while the Fear of Food Questionnaire, perhaps in combination with NIAS, has the potential to be a useful screening tool, cutoffs for it have yet to be established.
“At the end of the day, the diagnosis would be made by a clinician who is able to determine whether the life impairment or if the nutritional impairment or restricted food intake are reasonable in the realm of their digestive disease, or could a treatment for ARFID be warranted to help them to make changes to improve their quality of life and nutrition,” she said.
Check biases at the door
Before arriving at a diagnosis of ARFID, clinicians should also consider biases, Dr. Taft said.
“Eating disorders are highly stigmatized and stereotyped diagnoses,” more often attributed to young White women than to either men or to people of racial or ethnic minorities, she said.
Cultural background may contribute to food restrictions, and the risk may increase with age, with 68% of patients with later-onset IBD restricting diets to control the disease. It’s also possible that beliefs about food and “clean and healthy” eating may influence food and eating choices after a patient receives an IBD diagnosis.
Dr. Taft also pointed out that clinicians and patients may have different ideas about what constitutes significant food avoidance. Clinicians may expect patients with IBD to eat despite feeling nauseated, having abdominal pains, or diarrhea, for example, when the same food avoidance might be deemed reasonable in patients with short-term GI infections.
“Severe IBD symptoms are a significant predictor of posttraumatic stress disorder symptoms, and PTSD is hallmarked by avoidance behaviors,” she added.
She emphasized the need for clinicians to ask the right questions of patients to get at the roots of their nutritional deficiency or eating behavior, and to refer patients to mental health professionals with expertise in disordered eating or GI psychology.
Dr. Taft and Dr. Burton Murray reported having no conflicts of interest to disclose.
This article was updated on Feb. 4, 2022.
FROM CROHN’S & COLITIS CONGRESS
Monotherapy or one-two punch against EGFR-mutant NSCLC?
It is indisputable that patients with newly diagnosed advanced non–small cell lung cancer (NSCLC) bearing mutations in the epidermal growth factor receptor (EGFR) pathway may benefit from targeted therapy with a tyrosine kinase inhibitor (TKI) directed against EGFR.
What’s less clear is whether monotherapy with an EGFR TKI or combination therapy with a TKI and chemotherapy, immunotherapy, monoclonal antibodies or other targeted agents is the preferred frontline strategy.
NSCLC guidelines from the National Comprehensive Cancer Network, for example, recommend that patients with EFGR mutations such as exon 19 deletion, discovered prior to first-line systemic therapy, should preferably received osimertinib (Tagrisso) or another TKI, such as erlotinib (Tarceva), afatinib (Gilotrif), gefitinib (Iressa) or dacomitinib (Vizimpro), or erlotinib with a VEGF inhibitor. For patients with EGFR mutations identified during first-line systemic therapy, NCCN recommends complete systemic therapy or interrupting it, followed by osimertinib as the preferred agent, or another TKI with or without a VEGF inhibitors.
Similarly, guidelines from the American Society of Clinical Oncology and Ontario Health recommend osimertinib monotherapy as a preferred first-line option for patients with L858R/exon 19 deletion EGFR mutations. Alternatives for patients for whom osimertinib is not available include gefitinib plus platinum/pemetrexed chemotherapy with maintenance pemetrexed, monotherapy with dacomitinib, or other targeted agents with or without VEGF inhibitors.
Combination or go it alone?
The guidelines are largely mute on the question of chemotherapy in this population, primarily because they have not caught up to clinical trial evidence, said Paul Wheatley-Price, MBChB, FRCP, MD, from the University of Ottawa Hospital Research Institute.
“There is recent data that looks quite promising on combining EGFR inhibitors with either chemotherapy or antiangiogenic drugs, but it’s too soon, I think, and while the trials are promising, there are still too many question marks over it to make it into the guidelines,” he said in an interview.
The question of frontline combinations vs. monotherapy in patients with advanced EGFR-mutated NSCLC was the subject of a recent “controversies in thoracic oncology” feature in the Journal of Thoracic Oncology, with Dr. Wheatley-Price and University of Ottawa colleague Sara Moore, MD, FRCPC, arguing that combining EGFR TKIs with either cytotoxic chemotherapy or antiangiogenic monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) receptor has been shown consistently to improve progression-free survival (PFS) and in some cases overall survival (OS).
“There is a consistent drop-off in patients who receive second-line therapy, highlighting the importance of using combination therapy in the first-line setting to ensure patients will be exposed to multiple available therapies that may prolong survival. Chemotherapy-based combinations lead to improved response rates which may be especially helpful in patients with a significant burden of disease,” they wrote.
The authors noted that, compared with patients with wild-type EGFR, patients with EGFR-mutated NSCLC had a doubling of response rates to chemotherapy with a platinum-based doublet in the IPASS trial, suggesting that EGFR-mutated tumors may be more chemosensitive.
Promising trials, old drug
“Chemotherapy and EGFR TKIs may have a synergistic effect through combined reduction in vascular endothelial growth factor (VEGF)–mediated angiogenesis, and with EGFR TKIs counteracting chemotherapy-induced up-regulation of downstream EGFR signaling,” they wrote.
The authors cited two studies, one from Japan, and one from India, both of which showed significant improvements in response rates, PFS, and OS with the combination of gefitinib plus carboplatin and pemetrexed chemotherapy with pemetrexed maintenance vs. carboplatin alone,
“Now of course we don’t use gefitinib as our first-line treatment. In Canada and the United States, we use osimertinib, so certainly the chemotherapy/TKI combination, while it looks quite promising, was compared to an old control arm,” Dr. Wheatley-Price said.
He noted that the phase 3 FLAURA2 trial, currently underway, will address the question of whether adding osimertinib to a chemotherapy doublet with pemetrexed plus either carboplatin or cisplatin can improve PFS in patients with EGFR-positive locally advanced or metastatic NSCLC, compared with osimertinib alone.
The authors acknowledged that chemotherapy adds toxicities, compared with the use of TKI monotherapy, but added that, “even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”
VEGF plus EGFR
Adding a VEGF-targeted monoclonal antibody or TKI to and EGFR TKI has shown consistent PFS benefits in the NEJ026, ARTEMIS, RELAY, and ACTIVE trials, Dr. Moore and Dr. Wheatley-Price noted.
“In all four trials, resistance testing at the time of progression revealed similar rates of T790M mutation in both arms, highlighting the potential role of optimizing the sequence of therapy with use of second-line osimertinib among those with a T790M resistance mutation,” they wrote.
All four trials also showed higher rates of adverse events in the combination arms, but most, except for hypertension, were low grade, and in the RELAY trial the added toxicities did not significantly affect patient quality of life, they said.
Monotherapy advocated
Although in agreement that the combination of gefitinib and chemotherapy has both PFS and OS benefits compared with monotherapy alone, “these combinations are not applicable to real-life practice given their use of first-generation EGFR TKIs rather than third-generation EGFR TKI osimertinib,” wrote Sophie Stock-Martineau, MD, FRCPC from Hôpital Maisonneuve-Rosemont and the University of Montreal, and Frances A. Shepherd, MD, FRCPC from the Princess Margaret Cancer Centre in Toronto, in an article touting EGFR monotherapy.
They stated that until the results of FLAURA2 are available “osimertinib alone remains the current standard first-line therapy in metastatic EGFRm+ NSCLC.”
“The addition of an antiangiogenic agent to an EGFR TKI mildly prolongs PFS; however, it does not yet translate into survival benefit. Not only does it add more toxicity to patients, but it also adds cost, which is far from negligible,” they wrote.
Dr. Stock-Martineau and Dr. Shepherd also noted that two phase 2 trials comparing afatinib with the EGFR monoclonal antibody cetuximab (Erbitux) showed no PFS or OS benefits in patients with untreated EGFR-mutated NSCLC and were terminated for lack of efficacy.
In addition, clinical trials of combinations of EGFR TKIs with immune checkpoint inhibitors or MET inhibitors have failed to date to demonstrate survival benefits, the authors said.
“No trials have yet revealed PFS or OS benefit with osimertinib combinations. Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system. Combinations could potentially also worsen quality of life given their heightened toxicity profiles. Therefore, single-agent EGFR TKI, such as osimertinib, remains for now the standard of care in the first-line setting for advanced EGFRm+ NSCLC,” they concluded.
No funding sources for the articles were reported. All authors declared no conflicts of interest to disclose.
It is indisputable that patients with newly diagnosed advanced non–small cell lung cancer (NSCLC) bearing mutations in the epidermal growth factor receptor (EGFR) pathway may benefit from targeted therapy with a tyrosine kinase inhibitor (TKI) directed against EGFR.
What’s less clear is whether monotherapy with an EGFR TKI or combination therapy with a TKI and chemotherapy, immunotherapy, monoclonal antibodies or other targeted agents is the preferred frontline strategy.
NSCLC guidelines from the National Comprehensive Cancer Network, for example, recommend that patients with EFGR mutations such as exon 19 deletion, discovered prior to first-line systemic therapy, should preferably received osimertinib (Tagrisso) or another TKI, such as erlotinib (Tarceva), afatinib (Gilotrif), gefitinib (Iressa) or dacomitinib (Vizimpro), or erlotinib with a VEGF inhibitor. For patients with EGFR mutations identified during first-line systemic therapy, NCCN recommends complete systemic therapy or interrupting it, followed by osimertinib as the preferred agent, or another TKI with or without a VEGF inhibitors.
Similarly, guidelines from the American Society of Clinical Oncology and Ontario Health recommend osimertinib monotherapy as a preferred first-line option for patients with L858R/exon 19 deletion EGFR mutations. Alternatives for patients for whom osimertinib is not available include gefitinib plus platinum/pemetrexed chemotherapy with maintenance pemetrexed, monotherapy with dacomitinib, or other targeted agents with or without VEGF inhibitors.
Combination or go it alone?
The guidelines are largely mute on the question of chemotherapy in this population, primarily because they have not caught up to clinical trial evidence, said Paul Wheatley-Price, MBChB, FRCP, MD, from the University of Ottawa Hospital Research Institute.
“There is recent data that looks quite promising on combining EGFR inhibitors with either chemotherapy or antiangiogenic drugs, but it’s too soon, I think, and while the trials are promising, there are still too many question marks over it to make it into the guidelines,” he said in an interview.
The question of frontline combinations vs. monotherapy in patients with advanced EGFR-mutated NSCLC was the subject of a recent “controversies in thoracic oncology” feature in the Journal of Thoracic Oncology, with Dr. Wheatley-Price and University of Ottawa colleague Sara Moore, MD, FRCPC, arguing that combining EGFR TKIs with either cytotoxic chemotherapy or antiangiogenic monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) receptor has been shown consistently to improve progression-free survival (PFS) and in some cases overall survival (OS).
“There is a consistent drop-off in patients who receive second-line therapy, highlighting the importance of using combination therapy in the first-line setting to ensure patients will be exposed to multiple available therapies that may prolong survival. Chemotherapy-based combinations lead to improved response rates which may be especially helpful in patients with a significant burden of disease,” they wrote.
The authors noted that, compared with patients with wild-type EGFR, patients with EGFR-mutated NSCLC had a doubling of response rates to chemotherapy with a platinum-based doublet in the IPASS trial, suggesting that EGFR-mutated tumors may be more chemosensitive.
Promising trials, old drug
“Chemotherapy and EGFR TKIs may have a synergistic effect through combined reduction in vascular endothelial growth factor (VEGF)–mediated angiogenesis, and with EGFR TKIs counteracting chemotherapy-induced up-regulation of downstream EGFR signaling,” they wrote.
The authors cited two studies, one from Japan, and one from India, both of which showed significant improvements in response rates, PFS, and OS with the combination of gefitinib plus carboplatin and pemetrexed chemotherapy with pemetrexed maintenance vs. carboplatin alone,
“Now of course we don’t use gefitinib as our first-line treatment. In Canada and the United States, we use osimertinib, so certainly the chemotherapy/TKI combination, while it looks quite promising, was compared to an old control arm,” Dr. Wheatley-Price said.
He noted that the phase 3 FLAURA2 trial, currently underway, will address the question of whether adding osimertinib to a chemotherapy doublet with pemetrexed plus either carboplatin or cisplatin can improve PFS in patients with EGFR-positive locally advanced or metastatic NSCLC, compared with osimertinib alone.
The authors acknowledged that chemotherapy adds toxicities, compared with the use of TKI monotherapy, but added that, “even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”
VEGF plus EGFR
Adding a VEGF-targeted monoclonal antibody or TKI to and EGFR TKI has shown consistent PFS benefits in the NEJ026, ARTEMIS, RELAY, and ACTIVE trials, Dr. Moore and Dr. Wheatley-Price noted.
“In all four trials, resistance testing at the time of progression revealed similar rates of T790M mutation in both arms, highlighting the potential role of optimizing the sequence of therapy with use of second-line osimertinib among those with a T790M resistance mutation,” they wrote.
All four trials also showed higher rates of adverse events in the combination arms, but most, except for hypertension, were low grade, and in the RELAY trial the added toxicities did not significantly affect patient quality of life, they said.
Monotherapy advocated
Although in agreement that the combination of gefitinib and chemotherapy has both PFS and OS benefits compared with monotherapy alone, “these combinations are not applicable to real-life practice given their use of first-generation EGFR TKIs rather than third-generation EGFR TKI osimertinib,” wrote Sophie Stock-Martineau, MD, FRCPC from Hôpital Maisonneuve-Rosemont and the University of Montreal, and Frances A. Shepherd, MD, FRCPC from the Princess Margaret Cancer Centre in Toronto, in an article touting EGFR monotherapy.
They stated that until the results of FLAURA2 are available “osimertinib alone remains the current standard first-line therapy in metastatic EGFRm+ NSCLC.”
“The addition of an antiangiogenic agent to an EGFR TKI mildly prolongs PFS; however, it does not yet translate into survival benefit. Not only does it add more toxicity to patients, but it also adds cost, which is far from negligible,” they wrote.
Dr. Stock-Martineau and Dr. Shepherd also noted that two phase 2 trials comparing afatinib with the EGFR monoclonal antibody cetuximab (Erbitux) showed no PFS or OS benefits in patients with untreated EGFR-mutated NSCLC and were terminated for lack of efficacy.
In addition, clinical trials of combinations of EGFR TKIs with immune checkpoint inhibitors or MET inhibitors have failed to date to demonstrate survival benefits, the authors said.
“No trials have yet revealed PFS or OS benefit with osimertinib combinations. Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system. Combinations could potentially also worsen quality of life given their heightened toxicity profiles. Therefore, single-agent EGFR TKI, such as osimertinib, remains for now the standard of care in the first-line setting for advanced EGFRm+ NSCLC,” they concluded.
No funding sources for the articles were reported. All authors declared no conflicts of interest to disclose.
It is indisputable that patients with newly diagnosed advanced non–small cell lung cancer (NSCLC) bearing mutations in the epidermal growth factor receptor (EGFR) pathway may benefit from targeted therapy with a tyrosine kinase inhibitor (TKI) directed against EGFR.
What’s less clear is whether monotherapy with an EGFR TKI or combination therapy with a TKI and chemotherapy, immunotherapy, monoclonal antibodies or other targeted agents is the preferred frontline strategy.
NSCLC guidelines from the National Comprehensive Cancer Network, for example, recommend that patients with EFGR mutations such as exon 19 deletion, discovered prior to first-line systemic therapy, should preferably received osimertinib (Tagrisso) or another TKI, such as erlotinib (Tarceva), afatinib (Gilotrif), gefitinib (Iressa) or dacomitinib (Vizimpro), or erlotinib with a VEGF inhibitor. For patients with EGFR mutations identified during first-line systemic therapy, NCCN recommends complete systemic therapy or interrupting it, followed by osimertinib as the preferred agent, or another TKI with or without a VEGF inhibitors.
Similarly, guidelines from the American Society of Clinical Oncology and Ontario Health recommend osimertinib monotherapy as a preferred first-line option for patients with L858R/exon 19 deletion EGFR mutations. Alternatives for patients for whom osimertinib is not available include gefitinib plus platinum/pemetrexed chemotherapy with maintenance pemetrexed, monotherapy with dacomitinib, or other targeted agents with or without VEGF inhibitors.
Combination or go it alone?
The guidelines are largely mute on the question of chemotherapy in this population, primarily because they have not caught up to clinical trial evidence, said Paul Wheatley-Price, MBChB, FRCP, MD, from the University of Ottawa Hospital Research Institute.
“There is recent data that looks quite promising on combining EGFR inhibitors with either chemotherapy or antiangiogenic drugs, but it’s too soon, I think, and while the trials are promising, there are still too many question marks over it to make it into the guidelines,” he said in an interview.
The question of frontline combinations vs. monotherapy in patients with advanced EGFR-mutated NSCLC was the subject of a recent “controversies in thoracic oncology” feature in the Journal of Thoracic Oncology, with Dr. Wheatley-Price and University of Ottawa colleague Sara Moore, MD, FRCPC, arguing that combining EGFR TKIs with either cytotoxic chemotherapy or antiangiogenic monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) receptor has been shown consistently to improve progression-free survival (PFS) and in some cases overall survival (OS).
“There is a consistent drop-off in patients who receive second-line therapy, highlighting the importance of using combination therapy in the first-line setting to ensure patients will be exposed to multiple available therapies that may prolong survival. Chemotherapy-based combinations lead to improved response rates which may be especially helpful in patients with a significant burden of disease,” they wrote.
The authors noted that, compared with patients with wild-type EGFR, patients with EGFR-mutated NSCLC had a doubling of response rates to chemotherapy with a platinum-based doublet in the IPASS trial, suggesting that EGFR-mutated tumors may be more chemosensitive.
Promising trials, old drug
“Chemotherapy and EGFR TKIs may have a synergistic effect through combined reduction in vascular endothelial growth factor (VEGF)–mediated angiogenesis, and with EGFR TKIs counteracting chemotherapy-induced up-regulation of downstream EGFR signaling,” they wrote.
The authors cited two studies, one from Japan, and one from India, both of which showed significant improvements in response rates, PFS, and OS with the combination of gefitinib plus carboplatin and pemetrexed chemotherapy with pemetrexed maintenance vs. carboplatin alone,
“Now of course we don’t use gefitinib as our first-line treatment. In Canada and the United States, we use osimertinib, so certainly the chemotherapy/TKI combination, while it looks quite promising, was compared to an old control arm,” Dr. Wheatley-Price said.
He noted that the phase 3 FLAURA2 trial, currently underway, will address the question of whether adding osimertinib to a chemotherapy doublet with pemetrexed plus either carboplatin or cisplatin can improve PFS in patients with EGFR-positive locally advanced or metastatic NSCLC, compared with osimertinib alone.
The authors acknowledged that chemotherapy adds toxicities, compared with the use of TKI monotherapy, but added that, “even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”
VEGF plus EGFR
Adding a VEGF-targeted monoclonal antibody or TKI to and EGFR TKI has shown consistent PFS benefits in the NEJ026, ARTEMIS, RELAY, and ACTIVE trials, Dr. Moore and Dr. Wheatley-Price noted.
“In all four trials, resistance testing at the time of progression revealed similar rates of T790M mutation in both arms, highlighting the potential role of optimizing the sequence of therapy with use of second-line osimertinib among those with a T790M resistance mutation,” they wrote.
All four trials also showed higher rates of adverse events in the combination arms, but most, except for hypertension, were low grade, and in the RELAY trial the added toxicities did not significantly affect patient quality of life, they said.
Monotherapy advocated
Although in agreement that the combination of gefitinib and chemotherapy has both PFS and OS benefits compared with monotherapy alone, “these combinations are not applicable to real-life practice given their use of first-generation EGFR TKIs rather than third-generation EGFR TKI osimertinib,” wrote Sophie Stock-Martineau, MD, FRCPC from Hôpital Maisonneuve-Rosemont and the University of Montreal, and Frances A. Shepherd, MD, FRCPC from the Princess Margaret Cancer Centre in Toronto, in an article touting EGFR monotherapy.
They stated that until the results of FLAURA2 are available “osimertinib alone remains the current standard first-line therapy in metastatic EGFRm+ NSCLC.”
“The addition of an antiangiogenic agent to an EGFR TKI mildly prolongs PFS; however, it does not yet translate into survival benefit. Not only does it add more toxicity to patients, but it also adds cost, which is far from negligible,” they wrote.
Dr. Stock-Martineau and Dr. Shepherd also noted that two phase 2 trials comparing afatinib with the EGFR monoclonal antibody cetuximab (Erbitux) showed no PFS or OS benefits in patients with untreated EGFR-mutated NSCLC and were terminated for lack of efficacy.
In addition, clinical trials of combinations of EGFR TKIs with immune checkpoint inhibitors or MET inhibitors have failed to date to demonstrate survival benefits, the authors said.
“No trials have yet revealed PFS or OS benefit with osimertinib combinations. Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system. Combinations could potentially also worsen quality of life given their heightened toxicity profiles. Therefore, single-agent EGFR TKI, such as osimertinib, remains for now the standard of care in the first-line setting for advanced EGFRm+ NSCLC,” they concluded.
No funding sources for the articles were reported. All authors declared no conflicts of interest to disclose.
FROM JOURNAL OF THORACIC ONCOLOGY