Commentary

Editor's Note: We periodically publish patient viewpoints on specific issues of interest to our audience.

I woke up in a strange bedroom with 24 electrodes glued all over my body and a plastic mask attached to a hose covering my face.

The lab technician who watched me all night via video feed told me that I had “wicked sleep apnea” and that it was “central sleep apnea” – a type that originates in the brain and fails to tell the muscles to inhale.

As a journalist– and one terrified by the diagnosis – I set out to do my own research. After a few weeks of sleuthing and interviewing experts, I reached two important conclusions.

First, I had moderate apnea, if that, and it could be treated without the elaborate machines, mouthpieces, or other devices that specialists who had consulted on my care were talking about.

Second, the American health care system has joined with commercial partners to define a medical condition – in this case, sleep apnea – in a way that allows both parties to generate revenue from a multitude of pricey diagnostic studies, equipment sales, and questionable treatments. I was on a conveyor belt.

It all began with a desire for answers: I had been feeling drowsy during the day, and my wife told me I snored. Both can mean obstructive sleep apnea. With obstructive sleep apnea, the mouth and throat relax when a person is unconscious, sometimes blocking or narrowing the airway. That interrupts breathing, as well as sleep. Without treatment, the resulting disruption in oxygen flow might increase the risk of developing certain cardiovascular diseases.

So I contacted a sleep-treatment center, and doctors gave me an at-home test ($365). Two weeks later, they told me I had “high-moderate” sleep apnea and needed to acquire a continuous positive airway pressure (CPAP) machine, at a cost of about $600.

Though I had hoped to get the equipment and adjust the settings to see what worked best, my doctors said I had to come to the sleep lab for an overnight test ($1,900) to have them “titrate” the optimal CPAP air pressure.

“How do you treat central sleep apnea?” I worriedly asked the technician after that first overnight stay. She said something about an adaptive servo-ventilation machine ($4,000). And one pricey lab sleepover wasn’t enough, she said. I needed to come back for another.

(Most procedures and devices mentioned in this article were covered or would have been covered by insurance – in my case, Medicare, plus a supplemental plan. Unnecessary care is a big reason Americans’ insurance costs – premiums, copays, and deductibles – tend to rise year after year.)

As a journalist who spent years covering the business of health care, I found there was more motivating my expensive testing cascade than concerns about my health.

The American Academy of Sleep Medicine, a nonprofit based near Chicago, decides what is sleep apnea and how to treat it. Working with sleep societies around the world, it publishes the International Classification of Sleep Disorders, relied on by doctors everywhere to diagnose and categorize disease.

But behind that effort lie considerable conflicts of interest. Like so much of U.S. health care, sleep medicine turns out to be a thriving industry. AASM finances its operations in part with payments from CPAP machine manufacturers and other companies that stand to profit from expensive treatments and expansive definitions of apnea and other sleep disorders.

Zoll Itamar, which makes the at-home testing device I used, as well as implantable nerve-stimulation hardware for central sleep apnea, is a $60,000, “platinum” partner in AASM’s Industry Engagement Program. So is Avadel Pharmaceuticals, which is testing a drug to treat narcolepsy, characterized by intense daytime sleepiness.

Other sponsors include the maker of an anti-insomnia drug; another company with a narcolepsy drug; Fisher & Paykel Healthcare, which makes CPAP machines and masks; and Inspire Medical Systems, maker of a heavily advertised surgical implant, costing tens of thousands of dollars, to treat apnea.

Corporate sponsors for Sleep 2022, a convention AASM put on in Charlotte, N.C., with other professional societies, included many of those companies, plus Philips Respironics and ResMed, two of the biggest CPAP machine makers.

In a statement, AASM spokesperson Jennifer Gibson said a conflict-of-interest policy and a noninterference pledge from industry funders protect the integrity of the academy’s work. Industry donations account for about $170,000 of AASM’s annual revenue of about $15 million. Other revenue comes from educational materials and membership and accreditation fees.

Here’s what else I found. Almost everybody breathes irregularly sometime at night, especially during REM sleep, characterized by rapid eye movement and dreams. Blood oxygen levels also fluctuate slightly.

But recent European studies have shown that standards under the International Classification of Sleep Disorders would doom huge portions of the general population to a sleep apnea diagnosis – whether or not people had complaints of daytime tiredness or other sleep problems.

A study in Lausanne, Switzerland, showed that 50% of local men and 23% of the women 40 or older were positive for sleep apnea under such criteria.

Such rates of disease are “extraordinarily high,” “astronomical,” and “implausible,” Dirk Pevernagie, PhD, a scientist at Ghent (Belgium) University Hospital, wrote with colleagues 2 years ago in a comprehensive study in the Journal of Sleep Research.

“Right now, there is no real evidence for the criteria that have been put forward to diagnose obstructive sleep apnea and rate its severity,” he said in an interview.

Likewise, 19% of middle-aged subjects in a 2016 Icelandic study appeared to have moderate to severe “apnea” under one definition in the International Classification of Sleep Disorders even though many reported no drowsiness.

“Most of them were really surprised,” said Erna Sif Arnardóttir, who led the study and is running a large European program to refine detection and treatment of apnea.

Nevertheless, the official AASM journal recommends extremely broad screening for sleep apnea, looking for patients who have what it defines as illness. Everybody 18 and older should be screened every year for apnea if they have diabetes, obesity, untreated high blood pressure, or heart disease – even if they have never complained about sleep problems, the group says.

AASM “continually evaluates the definitions, criteria and recommendations used in the identification of sleep apnea and other sleep disorders,” Ms. Gibson said in the statement. Meanwhile, routine screening by primary care doctors “is a simple way” of gauging whether a high-risk patient may have obstructive sleep apnea, the statement said.

The U.S. Preventive Services Task Force, an authoritative body that reviews the effectiveness of preventive care, takes a conservative view, more like that of the European researchers, concluding there is “insufficient” evidence to support widespread screening among patients with no symptoms.

Many insurers refuse to pay for CPAP machines and other treatments prescribed for people at the outer edges of the AASM’s apnea definition. But AASM is pressuring them to come around.

After all my reporting, I concluded that my apnea is real, though moderate. My alarming reading in the overnight lab – diagnosed quickly as central sleep apnea – was a byproduct of the testing machinery itself. That’s a well-described phenomenon that occurs in 5% to 15% of patients.

And when I looked closely at the results of my at-home diagnostic test, I had an epiphany: My overall score was 26 breathing interruptions and blood-oxygen level declines, on average, per hour – enough to put me in the “high-moderate” category for apnea. But when I looked at the data sorted according to sleeping positions, I saw that I scored much better when I slept on my side: only 10 interruptions in an hour.

So I did a little experiment: I bought a $25 pulse oximeter with a smartphone app that records oxygen dips and breathing interruptions. When I slept on my side, there were hardly any.

Now I sleep on my side. I snore less. I wake up refreshed. I’m not daytime drowsy.

None of my specialists mentioned turning on to my side – known in medical parlance as “positional therapy” – though the intervention is recognized as effective by many researchers. Sleeping on one’s back contributes to snoring and blockages, especially as people age and the muscles in the throat become looser.

“Positional patients ... can sleep in the lateral position and sleep quite well,” said Arie Oksenberg, PhD, a sleep researcher formerly at Loewenstein Hospital in Ra’anana, Israel.

But it’s not easy to find this in the official AASM treatment guidelines, which instead go right to the money-making options like CPAP machines, surgery, central apnea, and mouth appliances.

Dealing with apnea by shifting slightly in bed gets little more than a couple of paragraphs in AASM’s guideline on “other” treatments and a little box on a long and complex decision chart.

A third or more of patients wear CPAPs only a few hours a night or stop using them. It turns out people don’t like machines in their beds.

“Positional therapy is an effective treatment option for some patients,” said Ms. Gibson. But she said there are concerns about whether patients will sleep on their sides long term and whether trying to stay in one position might cause sleep interruptions itself.

It’s true that side-sleeping doesn’t help everybody. And it often takes practice. (Some people tape a tennis ball to their pajamas to keep them off their backs.) Even conservative sleep doctors say CPAP machines are the best solution for many patients.

But there is a largely overlooked alternative.

“Are we missing a simple treatment for most adult sleep apnea patients?” was the name of a 2013 paper that Dr. Oksenberg and a colleague wrote about positional therapy.

In my case, the answer was “yes.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Editor's Note: We periodically publish patient viewpoints on specific issues of interest to our audience.

I woke up in a strange bedroom with 24 electrodes glued all over my body and a plastic mask attached to a hose covering my face.

The lab technician who watched me all night via video feed told me that I had “wicked sleep apnea” and that it was “central sleep apnea” – a type that originates in the brain and fails to tell the muscles to inhale.

As a journalist– and one terrified by the diagnosis – I set out to do my own research. After a few weeks of sleuthing and interviewing experts, I reached two important conclusions.

First, I had moderate apnea, if that, and it could be treated without the elaborate machines, mouthpieces, or other devices that specialists who had consulted on my care were talking about.

Second, the American health care system has joined with commercial partners to define a medical condition – in this case, sleep apnea – in a way that allows both parties to generate revenue from a multitude of pricey diagnostic studies, equipment sales, and questionable treatments. I was on a conveyor belt.

It all began with a desire for answers: I had been feeling drowsy during the day, and my wife told me I snored. Both can mean obstructive sleep apnea. With obstructive sleep apnea, the mouth and throat relax when a person is unconscious, sometimes blocking or narrowing the airway. That interrupts breathing, as well as sleep. Without treatment, the resulting disruption in oxygen flow might increase the risk of developing certain cardiovascular diseases.

So I contacted a sleep-treatment center, and doctors gave me an at-home test ($365). Two weeks later, they told me I had “high-moderate” sleep apnea and needed to acquire a continuous positive airway pressure (CPAP) machine, at a cost of about $600.

Though I had hoped to get the equipment and adjust the settings to see what worked best, my doctors said I had to come to the sleep lab for an overnight test ($1,900) to have them “titrate” the optimal CPAP air pressure.

“How do you treat central sleep apnea?” I worriedly asked the technician after that first overnight stay. She said something about an adaptive servo-ventilation machine ($4,000). And one pricey lab sleepover wasn’t enough, she said. I needed to come back for another.

(Most procedures and devices mentioned in this article were covered or would have been covered by insurance – in my case, Medicare, plus a supplemental plan. Unnecessary care is a big reason Americans’ insurance costs – premiums, copays, and deductibles – tend to rise year after year.)

As a journalist who spent years covering the business of health care, I found there was more motivating my expensive testing cascade than concerns about my health.

The American Academy of Sleep Medicine, a nonprofit based near Chicago, decides what is sleep apnea and how to treat it. Working with sleep societies around the world, it publishes the International Classification of Sleep Disorders, relied on by doctors everywhere to diagnose and categorize disease.

But behind that effort lie considerable conflicts of interest. Like so much of U.S. health care, sleep medicine turns out to be a thriving industry. AASM finances its operations in part with payments from CPAP machine manufacturers and other companies that stand to profit from expensive treatments and expansive definitions of apnea and other sleep disorders.

Zoll Itamar, which makes the at-home testing device I used, as well as implantable nerve-stimulation hardware for central sleep apnea, is a $60,000, “platinum” partner in AASM’s Industry Engagement Program. So is Avadel Pharmaceuticals, which is testing a drug to treat narcolepsy, characterized by intense daytime sleepiness.

Other sponsors include the maker of an anti-insomnia drug; another company with a narcolepsy drug; Fisher & Paykel Healthcare, which makes CPAP machines and masks; and Inspire Medical Systems, maker of a heavily advertised surgical implant, costing tens of thousands of dollars, to treat apnea.

Corporate sponsors for Sleep 2022, a convention AASM put on in Charlotte, N.C., with other professional societies, included many of those companies, plus Philips Respironics and ResMed, two of the biggest CPAP machine makers.

In a statement, AASM spokesperson Jennifer Gibson said a conflict-of-interest policy and a noninterference pledge from industry funders protect the integrity of the academy’s work. Industry donations account for about $170,000 of AASM’s annual revenue of about $15 million. Other revenue comes from educational materials and membership and accreditation fees.

Here’s what else I found. Almost everybody breathes irregularly sometime at night, especially during REM sleep, characterized by rapid eye movement and dreams. Blood oxygen levels also fluctuate slightly.

But recent European studies have shown that standards under the International Classification of Sleep Disorders would doom huge portions of the general population to a sleep apnea diagnosis – whether or not people had complaints of daytime tiredness or other sleep problems.

A study in Lausanne, Switzerland, showed that 50% of local men and 23% of the women 40 or older were positive for sleep apnea under such criteria.

Such rates of disease are “extraordinarily high,” “astronomical,” and “implausible,” Dirk Pevernagie, PhD, a scientist at Ghent (Belgium) University Hospital, wrote with colleagues 2 years ago in a comprehensive study in the Journal of Sleep Research.

“Right now, there is no real evidence for the criteria that have been put forward to diagnose obstructive sleep apnea and rate its severity,” he said in an interview.

Likewise, 19% of middle-aged subjects in a 2016 Icelandic study appeared to have moderate to severe “apnea” under one definition in the International Classification of Sleep Disorders even though many reported no drowsiness.

“Most of them were really surprised,” said Erna Sif Arnardóttir, who led the study and is running a large European program to refine detection and treatment of apnea.

Nevertheless, the official AASM journal recommends extremely broad screening for sleep apnea, looking for patients who have what it defines as illness. Everybody 18 and older should be screened every year for apnea if they have diabetes, obesity, untreated high blood pressure, or heart disease – even if they have never complained about sleep problems, the group says.

AASM “continually evaluates the definitions, criteria and recommendations used in the identification of sleep apnea and other sleep disorders,” Ms. Gibson said in the statement. Meanwhile, routine screening by primary care doctors “is a simple way” of gauging whether a high-risk patient may have obstructive sleep apnea, the statement said.

The U.S. Preventive Services Task Force, an authoritative body that reviews the effectiveness of preventive care, takes a conservative view, more like that of the European researchers, concluding there is “insufficient” evidence to support widespread screening among patients with no symptoms.

Many insurers refuse to pay for CPAP machines and other treatments prescribed for people at the outer edges of the AASM’s apnea definition. But AASM is pressuring them to come around.

After all my reporting, I concluded that my apnea is real, though moderate. My alarming reading in the overnight lab – diagnosed quickly as central sleep apnea – was a byproduct of the testing machinery itself. That’s a well-described phenomenon that occurs in 5% to 15% of patients.

And when I looked closely at the results of my at-home diagnostic test, I had an epiphany: My overall score was 26 breathing interruptions and blood-oxygen level declines, on average, per hour – enough to put me in the “high-moderate” category for apnea. But when I looked at the data sorted according to sleeping positions, I saw that I scored much better when I slept on my side: only 10 interruptions in an hour.

So I did a little experiment: I bought a $25 pulse oximeter with a smartphone app that records oxygen dips and breathing interruptions. When I slept on my side, there were hardly any.

Now I sleep on my side. I snore less. I wake up refreshed. I’m not daytime drowsy.

None of my specialists mentioned turning on to my side – known in medical parlance as “positional therapy” – though the intervention is recognized as effective by many researchers. Sleeping on one’s back contributes to snoring and blockages, especially as people age and the muscles in the throat become looser.

“Positional patients ... can sleep in the lateral position and sleep quite well,” said Arie Oksenberg, PhD, a sleep researcher formerly at Loewenstein Hospital in Ra’anana, Israel.

But it’s not easy to find this in the official AASM treatment guidelines, which instead go right to the money-making options like CPAP machines, surgery, central apnea, and mouth appliances.

Dealing with apnea by shifting slightly in bed gets little more than a couple of paragraphs in AASM’s guideline on “other” treatments and a little box on a long and complex decision chart.

A third or more of patients wear CPAPs only a few hours a night or stop using them. It turns out people don’t like machines in their beds.

“Positional therapy is an effective treatment option for some patients,” said Ms. Gibson. But she said there are concerns about whether patients will sleep on their sides long term and whether trying to stay in one position might cause sleep interruptions itself.

It’s true that side-sleeping doesn’t help everybody. And it often takes practice. (Some people tape a tennis ball to their pajamas to keep them off their backs.) Even conservative sleep doctors say CPAP machines are the best solution for many patients.

But there is a largely overlooked alternative.

“Are we missing a simple treatment for most adult sleep apnea patients?” was the name of a 2013 paper that Dr. Oksenberg and a colleague wrote about positional therapy.

In my case, the answer was “yes.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Editor's Note: We periodically publish patient viewpoints on specific issues of interest to our audience.

I woke up in a strange bedroom with 24 electrodes glued all over my body and a plastic mask attached to a hose covering my face.

The lab technician who watched me all night via video feed told me that I had “wicked sleep apnea” and that it was “central sleep apnea” – a type that originates in the brain and fails to tell the muscles to inhale.

As a journalist– and one terrified by the diagnosis – I set out to do my own research. After a few weeks of sleuthing and interviewing experts, I reached two important conclusions.

First, I had moderate apnea, if that, and it could be treated without the elaborate machines, mouthpieces, or other devices that specialists who had consulted on my care were talking about.

Second, the American health care system has joined with commercial partners to define a medical condition – in this case, sleep apnea – in a way that allows both parties to generate revenue from a multitude of pricey diagnostic studies, equipment sales, and questionable treatments. I was on a conveyor belt.

It all began with a desire for answers: I had been feeling drowsy during the day, and my wife told me I snored. Both can mean obstructive sleep apnea. With obstructive sleep apnea, the mouth and throat relax when a person is unconscious, sometimes blocking or narrowing the airway. That interrupts breathing, as well as sleep. Without treatment, the resulting disruption in oxygen flow might increase the risk of developing certain cardiovascular diseases.

So I contacted a sleep-treatment center, and doctors gave me an at-home test ($365). Two weeks later, they told me I had “high-moderate” sleep apnea and needed to acquire a continuous positive airway pressure (CPAP) machine, at a cost of about $600.

Though I had hoped to get the equipment and adjust the settings to see what worked best, my doctors said I had to come to the sleep lab for an overnight test ($1,900) to have them “titrate” the optimal CPAP air pressure.

“How do you treat central sleep apnea?” I worriedly asked the technician after that first overnight stay. She said something about an adaptive servo-ventilation machine ($4,000). And one pricey lab sleepover wasn’t enough, she said. I needed to come back for another.

(Most procedures and devices mentioned in this article were covered or would have been covered by insurance – in my case, Medicare, plus a supplemental plan. Unnecessary care is a big reason Americans’ insurance costs – premiums, copays, and deductibles – tend to rise year after year.)

As a journalist who spent years covering the business of health care, I found there was more motivating my expensive testing cascade than concerns about my health.

The American Academy of Sleep Medicine, a nonprofit based near Chicago, decides what is sleep apnea and how to treat it. Working with sleep societies around the world, it publishes the International Classification of Sleep Disorders, relied on by doctors everywhere to diagnose and categorize disease.

But behind that effort lie considerable conflicts of interest. Like so much of U.S. health care, sleep medicine turns out to be a thriving industry. AASM finances its operations in part with payments from CPAP machine manufacturers and other companies that stand to profit from expensive treatments and expansive definitions of apnea and other sleep disorders.

Zoll Itamar, which makes the at-home testing device I used, as well as implantable nerve-stimulation hardware for central sleep apnea, is a $60,000, “platinum” partner in AASM’s Industry Engagement Program. So is Avadel Pharmaceuticals, which is testing a drug to treat narcolepsy, characterized by intense daytime sleepiness.

Other sponsors include the maker of an anti-insomnia drug; another company with a narcolepsy drug; Fisher & Paykel Healthcare, which makes CPAP machines and masks; and Inspire Medical Systems, maker of a heavily advertised surgical implant, costing tens of thousands of dollars, to treat apnea.

Corporate sponsors for Sleep 2022, a convention AASM put on in Charlotte, N.C., with other professional societies, included many of those companies, plus Philips Respironics and ResMed, two of the biggest CPAP machine makers.

In a statement, AASM spokesperson Jennifer Gibson said a conflict-of-interest policy and a noninterference pledge from industry funders protect the integrity of the academy’s work. Industry donations account for about $170,000 of AASM’s annual revenue of about $15 million. Other revenue comes from educational materials and membership and accreditation fees.

Here’s what else I found. Almost everybody breathes irregularly sometime at night, especially during REM sleep, characterized by rapid eye movement and dreams. Blood oxygen levels also fluctuate slightly.

But recent European studies have shown that standards under the International Classification of Sleep Disorders would doom huge portions of the general population to a sleep apnea diagnosis – whether or not people had complaints of daytime tiredness or other sleep problems.

A study in Lausanne, Switzerland, showed that 50% of local men and 23% of the women 40 or older were positive for sleep apnea under such criteria.

Such rates of disease are “extraordinarily high,” “astronomical,” and “implausible,” Dirk Pevernagie, PhD, a scientist at Ghent (Belgium) University Hospital, wrote with colleagues 2 years ago in a comprehensive study in the Journal of Sleep Research.

“Right now, there is no real evidence for the criteria that have been put forward to diagnose obstructive sleep apnea and rate its severity,” he said in an interview.

Likewise, 19% of middle-aged subjects in a 2016 Icelandic study appeared to have moderate to severe “apnea” under one definition in the International Classification of Sleep Disorders even though many reported no drowsiness.

“Most of them were really surprised,” said Erna Sif Arnardóttir, who led the study and is running a large European program to refine detection and treatment of apnea.

Nevertheless, the official AASM journal recommends extremely broad screening for sleep apnea, looking for patients who have what it defines as illness. Everybody 18 and older should be screened every year for apnea if they have diabetes, obesity, untreated high blood pressure, or heart disease – even if they have never complained about sleep problems, the group says.

AASM “continually evaluates the definitions, criteria and recommendations used in the identification of sleep apnea and other sleep disorders,” Ms. Gibson said in the statement. Meanwhile, routine screening by primary care doctors “is a simple way” of gauging whether a high-risk patient may have obstructive sleep apnea, the statement said.

The U.S. Preventive Services Task Force, an authoritative body that reviews the effectiveness of preventive care, takes a conservative view, more like that of the European researchers, concluding there is “insufficient” evidence to support widespread screening among patients with no symptoms.

Many insurers refuse to pay for CPAP machines and other treatments prescribed for people at the outer edges of the AASM’s apnea definition. But AASM is pressuring them to come around.

After all my reporting, I concluded that my apnea is real, though moderate. My alarming reading in the overnight lab – diagnosed quickly as central sleep apnea – was a byproduct of the testing machinery itself. That’s a well-described phenomenon that occurs in 5% to 15% of patients.

And when I looked closely at the results of my at-home diagnostic test, I had an epiphany: My overall score was 26 breathing interruptions and blood-oxygen level declines, on average, per hour – enough to put me in the “high-moderate” category for apnea. But when I looked at the data sorted according to sleeping positions, I saw that I scored much better when I slept on my side: only 10 interruptions in an hour.

So I did a little experiment: I bought a $25 pulse oximeter with a smartphone app that records oxygen dips and breathing interruptions. When I slept on my side, there were hardly any.

Now I sleep on my side. I snore less. I wake up refreshed. I’m not daytime drowsy.

None of my specialists mentioned turning on to my side – known in medical parlance as “positional therapy” – though the intervention is recognized as effective by many researchers. Sleeping on one’s back contributes to snoring and blockages, especially as people age and the muscles in the throat become looser.

“Positional patients ... can sleep in the lateral position and sleep quite well,” said Arie Oksenberg, PhD, a sleep researcher formerly at Loewenstein Hospital in Ra’anana, Israel.

But it’s not easy to find this in the official AASM treatment guidelines, which instead go right to the money-making options like CPAP machines, surgery, central apnea, and mouth appliances.

Dealing with apnea by shifting slightly in bed gets little more than a couple of paragraphs in AASM’s guideline on “other” treatments and a little box on a long and complex decision chart.

A third or more of patients wear CPAPs only a few hours a night or stop using them. It turns out people don’t like machines in their beds.

“Positional therapy is an effective treatment option for some patients,” said Ms. Gibson. But she said there are concerns about whether patients will sleep on their sides long term and whether trying to stay in one position might cause sleep interruptions itself.

It’s true that side-sleeping doesn’t help everybody. And it often takes practice. (Some people tape a tennis ball to their pajamas to keep them off their backs.) Even conservative sleep doctors say CPAP machines are the best solution for many patients.

But there is a largely overlooked alternative.

“Are we missing a simple treatment for most adult sleep apnea patients?” was the name of a 2013 paper that Dr. Oksenberg and a colleague wrote about positional therapy.

In my case, the answer was “yes.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Medicine or dietary supplement? N-acetylcysteine (NAC) is marketed as both and in 2021, the supplement abruptly became difficult to find, causing distress to people who had been using it for a variety of conditions. The story behind its disappearance is one of a cat-and-mouse chase between manufacturers, advocacy agencies, and the Food and Drug Administration.

NAC is a medication that was approved by the FDA in 1963. It has two FDA-approved uses: To prevent hepatotoxicity after overdose with acetaminophen, administered intravenously or by mouth, and as a mucolytic agent – previously available as Mucomyst, now available only as a generic – given by inhaler or nebulizer for pulmonary illnesses. Since the 1990s, NAC has been labeled by manufacturers as a dietary supplement. It is a derivative of the amino acid L-cysteine and a precursor to glutathione, an antioxidant.

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. She has disclosed no relevant financial relationships.

Medicine or dietary supplement? N-acetylcysteine (NAC) is marketed as both and in 2021, the supplement abruptly became difficult to find, causing distress to people who had been using it for a variety of conditions. The story behind its disappearance is one of a cat-and-mouse chase between manufacturers, advocacy agencies, and the Food and Drug Administration.

NAC is a medication that was approved by the FDA in 1963. It has two FDA-approved uses: To prevent hepatotoxicity after overdose with acetaminophen, administered intravenously or by mouth, and as a mucolytic agent – previously available as Mucomyst, now available only as a generic – given by inhaler or nebulizer for pulmonary illnesses. Since the 1990s, NAC has been labeled by manufacturers as a dietary supplement. It is a derivative of the amino acid L-cysteine and a precursor to glutathione, an antioxidant.

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. She has disclosed no relevant financial relationships.

Medicine or dietary supplement? N-acetylcysteine (NAC) is marketed as both and in 2021, the supplement abruptly became difficult to find, causing distress to people who had been using it for a variety of conditions. The story behind its disappearance is one of a cat-and-mouse chase between manufacturers, advocacy agencies, and the Food and Drug Administration.

NAC is a medication that was approved by the FDA in 1963. It has two FDA-approved uses: To prevent hepatotoxicity after overdose with acetaminophen, administered intravenously or by mouth, and as a mucolytic agent – previously available as Mucomyst, now available only as a generic – given by inhaler or nebulizer for pulmonary illnesses. Since the 1990s, NAC has been labeled by manufacturers as a dietary supplement. It is a derivative of the amino acid L-cysteine and a precursor to glutathione, an antioxidant.

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. She has disclosed no relevant financial relationships.

Decades ago I saw a patient with non–small cell lung cancer (NSCLC) whose tumor was sent out for next-generation sequencing only to find a HER2 mutation. What to do? Had my patient come in today, we may have had other options.

Multiple studies have shown that trastuzumab (Herceptin, Genentech), as assessed by HER2 overexpression or amplification, has been shown to have essentially no efficacy benefit in NSCLC alone or in combination with chemotherapy. In fact, a randomized, phase 2 study of gemcitabine-cisplatin with or without trastuzumab in HER2 mutation–positive NSCLC essentially showed no difference between gemcitabine-cisplatin or gemcitabine-cisplatin with trastuzumab.

NSCLC has become the poster child for targeted therapies. After all, NSCLC makes up about 85% of all lung cancer cases, some of which are driven by gene mutations or other genetic abnormalities like translocation, fusion, or amplification. Seven of these genetic alterations have Food and Drug Administration–approved targeted drugs: EGFR, ALK, ROS1, BRAF V6006, RET, KRAS, MET, and NTRK fusions. And, now we have a new one: HER2.

In August, the FDA granted accelerated approval of trastuzumab deruxtecan (T-DXd) (Enhertu, Daiichi Sankyo) for the second-line treatment of NSCLC patients with HER alterations. T-DXd is a humanized anti-HER antibody linked to a topoisomerase 1 inhibitor. When given intravenously, the antibody portion of the molecule binds to cells with a mutated HER2 on the surface. The molecule is taken up by the cancer cell and the linker between the antibody and the chemotherapy drug is broken, so the drug will be delivered very specifically only to cancer cells that have a mutated HER2. In theory, they will only target cells with HER alterations and thus should have less toxicity.

Unlike other driver mutations, HER mutations are relatively rare. Roughly 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis. Accelerated approved by the FDA was based on data from the DESTINY-Lung 02 phase 2 trial. An interim efficacy analysis of this trial reported an overall response rate to trastuzumab deruxtecan (at 5.4 mg/kg every 3 weeks) of 57.7% in 52 patients. Median duration of response was 8.7 months. Data are also available from the DESTINY-Lung-01 clinical trial, published in the New England Journal of Medicine, in which 91 patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment were treated with T-DXd (at 6.4 mg/kg every 3 weeks). The investigators reported a 55% objective response rate, a median duration of response of 9.3 months, a median progression-free survival (PFS) of 8.2 months, and a median overall survival of almost 18 months.
 

Companion tests

Biomarker testing is obviously a must in these cases. The FDA-approved companion diagnostic tests to detect HER2 mutations: Life Companion tests, Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue, and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that, if no mutation is detected in a plasma specimen, the tumor tissue should be tested.

Other approvals

T-DXd is also approved for advanced breast and gastric patients who are HER-2 positive. Of note, the majority of HER2-positive NSCLC have HER2 mutations, whereas the majority of HER2-positive breast and gastric cancers have HER2 amplification (increased copy number) or overexpression (increased protein expression).

T-DXd is approved for unresectable or metastatic HER2-positive breast cancer patients who have received a prior anti-HER2–based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. DESTINY-Breast01 enrolled breast cancer patients who had received two or more prior anti-HER2 therapies in the metastatic setting, and reported a response rate of 60.3% with a median duration of response of 14.8 months.

For patients with locally advanced or metastatic HER2-positive gastric cancer who have received two or more prior therapies, including a trastuzumab-based regimen, approval was based on a randomized, phase 3 study comparing 6.4 mg/kg of T-DXd with physician’s choice – either irinotecan or paclitaxel. Overall survival was 12.5 months in the T-DXd arm, compared with 8.4 months in the irinotecan or paclitaxel arm (hazard ratio, 0.59). Response rates were 40.5% and 11.3%, respectively. Median PFS was 5.6 months in the T-DXd arm, compared with a median PFS of 3.5 months in the chemotherapy arm.
 

Trastuzumab emtansine vs. trastuzumab deruxtecan

Trastuzumab emtansine (T-DM1, ado-trastuzumab emtansine, Kadcyla) is another antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the antimicrotubule agent DM1. It is also approved for advanced breast cancer patients with HER2-positive disease. Although no studies comparing T-DXd with trastuzumab emtansine have been conducted in lung cancer patients, a randomized, phase 3 trial in patients with HER2-positive advanced breast cancer comparing the two reported an overall response rate of 79.7% of the patients who received trastuzumab deruxtecan and 34.2% of those who received trastuzumab emtansine. Drug-related interstitial lung disease (ILD) occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; at 12 months, 75.8% of the patients in the trastuzumab deruxtecan were alive without progression, compared with 34.1% of those receiving trastuzumab emtansine.

ILDs

In DESTINY-Lung01, ILD occurred in 26% of patients and resulted in death in two patients. Increased rates of ILD were more commonly observed at higher dose levels. Of 491 patients with unresectable or metastatic HER2-positive breast cancer treated with 5.4 mg/kg of T-TDx, ILD occurred in 13% of patients. Fatal outcomes caused by ILD and/or pneumonitis occurred in 1.4% of patients. Median time to first onset was 5.5 months (range, 1.1-20.8 months). In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with 6.4 mg/kg, T-DXd ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range, 1.2-21.0 months).

Chemotherapy-like adverse effects

Other adverse events are more typically seen with cytotoxic agents and are presumably related to the release of the topoisomerase inhibitor into the blood stream. Although common (occurring in 97% of patients), these adverse events are generally mild (grade 1 or 2). Nausea was reported in about two-thirds of patients. Other side effects occurring in 20% or more of patients included vomiting, decreased appetite, alopecia, and constipation and diarrhea, musculoskeletal pain, and respiratory infections. Laboratory abnormalities occurred in 20% or more of patients included myelosuppression, increased AST, ALT, alkaline phosphatase, and hypokalemia (28%). Grade 3 or higher drug-related adverse events were observed in 46% of patients, with the most common being neutropenia and anemia which was observed in 19% and 10% of patients in the DESTINY-LUNG-01 trial.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Decades ago I saw a patient with non–small cell lung cancer (NSCLC) whose tumor was sent out for next-generation sequencing only to find a HER2 mutation. What to do? Had my patient come in today, we may have had other options.

Multiple studies have shown that trastuzumab (Herceptin, Genentech), as assessed by HER2 overexpression or amplification, has been shown to have essentially no efficacy benefit in NSCLC alone or in combination with chemotherapy. In fact, a randomized, phase 2 study of gemcitabine-cisplatin with or without trastuzumab in HER2 mutation–positive NSCLC essentially showed no difference between gemcitabine-cisplatin or gemcitabine-cisplatin with trastuzumab.

NSCLC has become the poster child for targeted therapies. After all, NSCLC makes up about 85% of all lung cancer cases, some of which are driven by gene mutations or other genetic abnormalities like translocation, fusion, or amplification. Seven of these genetic alterations have Food and Drug Administration–approved targeted drugs: EGFR, ALK, ROS1, BRAF V6006, RET, KRAS, MET, and NTRK fusions. And, now we have a new one: HER2.

In August, the FDA granted accelerated approval of trastuzumab deruxtecan (T-DXd) (Enhertu, Daiichi Sankyo) for the second-line treatment of NSCLC patients with HER alterations. T-DXd is a humanized anti-HER antibody linked to a topoisomerase 1 inhibitor. When given intravenously, the antibody portion of the molecule binds to cells with a mutated HER2 on the surface. The molecule is taken up by the cancer cell and the linker between the antibody and the chemotherapy drug is broken, so the drug will be delivered very specifically only to cancer cells that have a mutated HER2. In theory, they will only target cells with HER alterations and thus should have less toxicity.

Unlike other driver mutations, HER mutations are relatively rare. Roughly 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis. Accelerated approved by the FDA was based on data from the DESTINY-Lung 02 phase 2 trial. An interim efficacy analysis of this trial reported an overall response rate to trastuzumab deruxtecan (at 5.4 mg/kg every 3 weeks) of 57.7% in 52 patients. Median duration of response was 8.7 months. Data are also available from the DESTINY-Lung-01 clinical trial, published in the New England Journal of Medicine, in which 91 patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment were treated with T-DXd (at 6.4 mg/kg every 3 weeks). The investigators reported a 55% objective response rate, a median duration of response of 9.3 months, a median progression-free survival (PFS) of 8.2 months, and a median overall survival of almost 18 months.
 

Companion tests

Biomarker testing is obviously a must in these cases. The FDA-approved companion diagnostic tests to detect HER2 mutations: Life Companion tests, Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue, and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that, if no mutation is detected in a plasma specimen, the tumor tissue should be tested.

Other approvals

T-DXd is also approved for advanced breast and gastric patients who are HER-2 positive. Of note, the majority of HER2-positive NSCLC have HER2 mutations, whereas the majority of HER2-positive breast and gastric cancers have HER2 amplification (increased copy number) or overexpression (increased protein expression).

T-DXd is approved for unresectable or metastatic HER2-positive breast cancer patients who have received a prior anti-HER2–based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. DESTINY-Breast01 enrolled breast cancer patients who had received two or more prior anti-HER2 therapies in the metastatic setting, and reported a response rate of 60.3% with a median duration of response of 14.8 months.

For patients with locally advanced or metastatic HER2-positive gastric cancer who have received two or more prior therapies, including a trastuzumab-based regimen, approval was based on a randomized, phase 3 study comparing 6.4 mg/kg of T-DXd with physician’s choice – either irinotecan or paclitaxel. Overall survival was 12.5 months in the T-DXd arm, compared with 8.4 months in the irinotecan or paclitaxel arm (hazard ratio, 0.59). Response rates were 40.5% and 11.3%, respectively. Median PFS was 5.6 months in the T-DXd arm, compared with a median PFS of 3.5 months in the chemotherapy arm.
 

Trastuzumab emtansine vs. trastuzumab deruxtecan

Trastuzumab emtansine (T-DM1, ado-trastuzumab emtansine, Kadcyla) is another antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the antimicrotubule agent DM1. It is also approved for advanced breast cancer patients with HER2-positive disease. Although no studies comparing T-DXd with trastuzumab emtansine have been conducted in lung cancer patients, a randomized, phase 3 trial in patients with HER2-positive advanced breast cancer comparing the two reported an overall response rate of 79.7% of the patients who received trastuzumab deruxtecan and 34.2% of those who received trastuzumab emtansine. Drug-related interstitial lung disease (ILD) occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; at 12 months, 75.8% of the patients in the trastuzumab deruxtecan were alive without progression, compared with 34.1% of those receiving trastuzumab emtansine.

ILDs

In DESTINY-Lung01, ILD occurred in 26% of patients and resulted in death in two patients. Increased rates of ILD were more commonly observed at higher dose levels. Of 491 patients with unresectable or metastatic HER2-positive breast cancer treated with 5.4 mg/kg of T-TDx, ILD occurred in 13% of patients. Fatal outcomes caused by ILD and/or pneumonitis occurred in 1.4% of patients. Median time to first onset was 5.5 months (range, 1.1-20.8 months). In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with 6.4 mg/kg, T-DXd ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range, 1.2-21.0 months).

Chemotherapy-like adverse effects

Other adverse events are more typically seen with cytotoxic agents and are presumably related to the release of the topoisomerase inhibitor into the blood stream. Although common (occurring in 97% of patients), these adverse events are generally mild (grade 1 or 2). Nausea was reported in about two-thirds of patients. Other side effects occurring in 20% or more of patients included vomiting, decreased appetite, alopecia, and constipation and diarrhea, musculoskeletal pain, and respiratory infections. Laboratory abnormalities occurred in 20% or more of patients included myelosuppression, increased AST, ALT, alkaline phosphatase, and hypokalemia (28%). Grade 3 or higher drug-related adverse events were observed in 46% of patients, with the most common being neutropenia and anemia which was observed in 19% and 10% of patients in the DESTINY-LUNG-01 trial.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Decades ago I saw a patient with non–small cell lung cancer (NSCLC) whose tumor was sent out for next-generation sequencing only to find a HER2 mutation. What to do? Had my patient come in today, we may have had other options.

Multiple studies have shown that trastuzumab (Herceptin, Genentech), as assessed by HER2 overexpression or amplification, has been shown to have essentially no efficacy benefit in NSCLC alone or in combination with chemotherapy. In fact, a randomized, phase 2 study of gemcitabine-cisplatin with or without trastuzumab in HER2 mutation–positive NSCLC essentially showed no difference between gemcitabine-cisplatin or gemcitabine-cisplatin with trastuzumab.

NSCLC has become the poster child for targeted therapies. After all, NSCLC makes up about 85% of all lung cancer cases, some of which are driven by gene mutations or other genetic abnormalities like translocation, fusion, or amplification. Seven of these genetic alterations have Food and Drug Administration–approved targeted drugs: EGFR, ALK, ROS1, BRAF V6006, RET, KRAS, MET, and NTRK fusions. And, now we have a new one: HER2.

In August, the FDA granted accelerated approval of trastuzumab deruxtecan (T-DXd) (Enhertu, Daiichi Sankyo) for the second-line treatment of NSCLC patients with HER alterations. T-DXd is a humanized anti-HER antibody linked to a topoisomerase 1 inhibitor. When given intravenously, the antibody portion of the molecule binds to cells with a mutated HER2 on the surface. The molecule is taken up by the cancer cell and the linker between the antibody and the chemotherapy drug is broken, so the drug will be delivered very specifically only to cancer cells that have a mutated HER2. In theory, they will only target cells with HER alterations and thus should have less toxicity.

Unlike other driver mutations, HER mutations are relatively rare. Roughly 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis. Accelerated approved by the FDA was based on data from the DESTINY-Lung 02 phase 2 trial. An interim efficacy analysis of this trial reported an overall response rate to trastuzumab deruxtecan (at 5.4 mg/kg every 3 weeks) of 57.7% in 52 patients. Median duration of response was 8.7 months. Data are also available from the DESTINY-Lung-01 clinical trial, published in the New England Journal of Medicine, in which 91 patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment were treated with T-DXd (at 6.4 mg/kg every 3 weeks). The investigators reported a 55% objective response rate, a median duration of response of 9.3 months, a median progression-free survival (PFS) of 8.2 months, and a median overall survival of almost 18 months.
 

Companion tests

Biomarker testing is obviously a must in these cases. The FDA-approved companion diagnostic tests to detect HER2 mutations: Life Companion tests, Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue, and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that, if no mutation is detected in a plasma specimen, the tumor tissue should be tested.

Other approvals

T-DXd is also approved for advanced breast and gastric patients who are HER-2 positive. Of note, the majority of HER2-positive NSCLC have HER2 mutations, whereas the majority of HER2-positive breast and gastric cancers have HER2 amplification (increased copy number) or overexpression (increased protein expression).

T-DXd is approved for unresectable or metastatic HER2-positive breast cancer patients who have received a prior anti-HER2–based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. DESTINY-Breast01 enrolled breast cancer patients who had received two or more prior anti-HER2 therapies in the metastatic setting, and reported a response rate of 60.3% with a median duration of response of 14.8 months.

For patients with locally advanced or metastatic HER2-positive gastric cancer who have received two or more prior therapies, including a trastuzumab-based regimen, approval was based on a randomized, phase 3 study comparing 6.4 mg/kg of T-DXd with physician’s choice – either irinotecan or paclitaxel. Overall survival was 12.5 months in the T-DXd arm, compared with 8.4 months in the irinotecan or paclitaxel arm (hazard ratio, 0.59). Response rates were 40.5% and 11.3%, respectively. Median PFS was 5.6 months in the T-DXd arm, compared with a median PFS of 3.5 months in the chemotherapy arm.
 

Trastuzumab emtansine vs. trastuzumab deruxtecan

Trastuzumab emtansine (T-DM1, ado-trastuzumab emtansine, Kadcyla) is another antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the antimicrotubule agent DM1. It is also approved for advanced breast cancer patients with HER2-positive disease. Although no studies comparing T-DXd with trastuzumab emtansine have been conducted in lung cancer patients, a randomized, phase 3 trial in patients with HER2-positive advanced breast cancer comparing the two reported an overall response rate of 79.7% of the patients who received trastuzumab deruxtecan and 34.2% of those who received trastuzumab emtansine. Drug-related interstitial lung disease (ILD) occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; at 12 months, 75.8% of the patients in the trastuzumab deruxtecan were alive without progression, compared with 34.1% of those receiving trastuzumab emtansine.

ILDs

In DESTINY-Lung01, ILD occurred in 26% of patients and resulted in death in two patients. Increased rates of ILD were more commonly observed at higher dose levels. Of 491 patients with unresectable or metastatic HER2-positive breast cancer treated with 5.4 mg/kg of T-TDx, ILD occurred in 13% of patients. Fatal outcomes caused by ILD and/or pneumonitis occurred in 1.4% of patients. Median time to first onset was 5.5 months (range, 1.1-20.8 months). In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with 6.4 mg/kg, T-DXd ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range, 1.2-21.0 months).

Chemotherapy-like adverse effects

Other adverse events are more typically seen with cytotoxic agents and are presumably related to the release of the topoisomerase inhibitor into the blood stream. Although common (occurring in 97% of patients), these adverse events are generally mild (grade 1 or 2). Nausea was reported in about two-thirds of patients. Other side effects occurring in 20% or more of patients included vomiting, decreased appetite, alopecia, and constipation and diarrhea, musculoskeletal pain, and respiratory infections. Laboratory abnormalities occurred in 20% or more of patients included myelosuppression, increased AST, ALT, alkaline phosphatase, and hypokalemia (28%). Grade 3 or higher drug-related adverse events were observed in 46% of patients, with the most common being neutropenia and anemia which was observed in 19% and 10% of patients in the DESTINY-LUNG-01 trial.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

John worked as a handyman and lived on a small sailboat in a marina. When he was diagnosed with metastatic kidney cancer at age 48, he quickly fell through the cracks. He failed to show to appointments and took oral anticancer treatments, but just sporadically. He had Medicaid, so insurance wasn’t the issue. It was everything else.

John was behind on his slip fees; he hadn’t been able to work for some time because of his progressive weakness and pain. He was chronically in danger of getting kicked out of his makeshift home aboard the boat. He had no reliable transportation to the clinic and so he didn’t come to appointments regularly. The specialty pharmacy refused to deliver his expensive oral chemotherapy to his address at the marina. He went days without eating full meals because he was too weak to cook for himself. Plus, he was estranged from his family who were unaware of his illness. His oncologist was overwhelmed trying to take care of him. He had a reasonable chance of achieving disease control on first-line oral therapy, but his problems seemed to hinder these chances at every turn. She was distraught – what could she do?

Enter the team approach. John’s oncologist reached out to our palliative care program for help. We recognized that this was a job too big for us alone so we connected John with the Extensivist Medicine program at UCLA Health, a high-intensity primary care program led by a physician specializing in primary care for high-risk individuals. The program provides wraparound outpatient services for chronically and seriously ill patients, like John, who are at risk for falling through the cracks. John went from receiving very little support to now having an entire team of caring professionals focused on helping him achieve his best possible outcome despite the seriousness of his disease.

He now had the support of a high-functioning team with clearly defined roles. Social work connected him with housing, food, and transportation resources. A nurse called him every day to check in and make sure he was taking medications and reminded him about his upcoming appointments. Case management helped him get needed equipment, such as grab bars and a walker. As his palliative care nurse practitioner, I counseled him on understanding his prognosis and planning ahead for medical emergencies. Our psycho-oncology clinicians helped John reconcile with his family, who were more than willing to take him in once they realized how ill he was. Once these social factors were addressed, John could more easily stay current with his oral chemotherapy, giving him the best chance possible to achieve a robust treatment response that could buy him more time.

And, John did get that time – he got 6 months of improved quality of life, during which he reconnected with his family, including his children, and rebuilt these important relationships. Eventually treatment failed him. His disease, already widely metastatic, became more active and painful. He accepted hospice care at his sister’s house and we transitioned him from our team to the hospice team. He died peacefully surrounded by family.
 

Interprofessional teamwork is fundamental to treat ‘total pain’

None of this would have been possible without the work of high-functioning teams. It is a commonly held belief that interprofessional teamwork is fundamental to the care of patients and families living with serious illness. But why? How did this idea come about? And what evidence is there to support teamwork?

Dame Cicely Saunders, who founded the modern hospice movement in mid-20th century England, embodied the interdisciplinary team by working first as a nurse, then a social worker, and finally as a physician. She wrote about patients’ “total pain,” the crisis of physical, spiritual, social, and emotional distress that many people have at the end of life. She understood that no single health care discipline was adequate to the task of addressing each of these domains equally well. Thus, hospice became synonymous with care provided by a quartet of specialists – physicians, nurses, social workers, and chaplains. Nowadays, there are other specialists that are added to the mix – home health aides, pharmacists, physical and occupational therapists, music and pet therapists, and so on.

But in medicine, like all areas of science, convention and tradition only go so far. What evidence is there to support the work of an interdisciplinary team in managing the distress of patients and families living with advanced illnesses? It turns out that there is good evidence to support the use of high-functioning interdisciplinary teams in the care of the seriously ill. Palliative care is associated with improved patient outcomes, including improvements in symptom control, quality of life, and end of life care, when it is delivered by an interdisciplinary team rather than by a solo practitioner.

You may think that teamwork is most useful for patients like John who have seemingly intractable social barriers. But it is also true that for even patients with many more social advantages teamwork improves quality of life. I got to see this up close recently in my own life.
 

Teamwork improves quality of life

My father recently passed away after a 9-month battle with advanced cancer. He had every advantage possible – financial stability, high health literacy, an incredibly devoted spouse who happens to be an RN, good insurance, and access to top-notch medical care. Yet, even he benefited from a team approach. It started small, with the oncologist and oncology NP providing excellent, patient-centered care. Then it grew to include myself as the daughter/palliative care nurse practitioner who made recommendations for treating his nausea and ensured that his advance directive was completed and uploaded to his chart. When my dad needed physical therapy, the home health agency sent a wonderful physical therapist, who brought all sorts of equipment that kept him more functional than he would have been otherwise. Other family members helped out – my sisters helped connect my dad with a priest who came to the home to provide spiritual care, which was crucial to ensuring that he was at peace. And, in his final days, my dad had the hospice team to help manage his symptoms and his family members to provide hands-on care.

Cancer, as one of my patients once remarked to me, is a “full-contact sport.” Living with advanced cancer touches nearly every aspect of a person’s life. The complexity of cancer care has long necessitated a team approach to planning cancer treatment – known as a tumor board – with medical oncology, radiation oncology, surgery, and pathology all weighing in. It makes sense that patients and their families would also need a team of clinicians representing different specialty areas to assist with the wide array of physical, psychosocial, practical, and spiritual concerns that arise throughout the cancer disease trajectory.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

John worked as a handyman and lived on a small sailboat in a marina. When he was diagnosed with metastatic kidney cancer at age 48, he quickly fell through the cracks. He failed to show to appointments and took oral anticancer treatments, but just sporadically. He had Medicaid, so insurance wasn’t the issue. It was everything else.

John was behind on his slip fees; he hadn’t been able to work for some time because of his progressive weakness and pain. He was chronically in danger of getting kicked out of his makeshift home aboard the boat. He had no reliable transportation to the clinic and so he didn’t come to appointments regularly. The specialty pharmacy refused to deliver his expensive oral chemotherapy to his address at the marina. He went days without eating full meals because he was too weak to cook for himself. Plus, he was estranged from his family who were unaware of his illness. His oncologist was overwhelmed trying to take care of him. He had a reasonable chance of achieving disease control on first-line oral therapy, but his problems seemed to hinder these chances at every turn. She was distraught – what could she do?

Enter the team approach. John’s oncologist reached out to our palliative care program for help. We recognized that this was a job too big for us alone so we connected John with the Extensivist Medicine program at UCLA Health, a high-intensity primary care program led by a physician specializing in primary care for high-risk individuals. The program provides wraparound outpatient services for chronically and seriously ill patients, like John, who are at risk for falling through the cracks. John went from receiving very little support to now having an entire team of caring professionals focused on helping him achieve his best possible outcome despite the seriousness of his disease.

He now had the support of a high-functioning team with clearly defined roles. Social work connected him with housing, food, and transportation resources. A nurse called him every day to check in and make sure he was taking medications and reminded him about his upcoming appointments. Case management helped him get needed equipment, such as grab bars and a walker. As his palliative care nurse practitioner, I counseled him on understanding his prognosis and planning ahead for medical emergencies. Our psycho-oncology clinicians helped John reconcile with his family, who were more than willing to take him in once they realized how ill he was. Once these social factors were addressed, John could more easily stay current with his oral chemotherapy, giving him the best chance possible to achieve a robust treatment response that could buy him more time.

And, John did get that time – he got 6 months of improved quality of life, during which he reconnected with his family, including his children, and rebuilt these important relationships. Eventually treatment failed him. His disease, already widely metastatic, became more active and painful. He accepted hospice care at his sister’s house and we transitioned him from our team to the hospice team. He died peacefully surrounded by family.
 

Interprofessional teamwork is fundamental to treat ‘total pain’

None of this would have been possible without the work of high-functioning teams. It is a commonly held belief that interprofessional teamwork is fundamental to the care of patients and families living with serious illness. But why? How did this idea come about? And what evidence is there to support teamwork?

Dame Cicely Saunders, who founded the modern hospice movement in mid-20th century England, embodied the interdisciplinary team by working first as a nurse, then a social worker, and finally as a physician. She wrote about patients’ “total pain,” the crisis of physical, spiritual, social, and emotional distress that many people have at the end of life. She understood that no single health care discipline was adequate to the task of addressing each of these domains equally well. Thus, hospice became synonymous with care provided by a quartet of specialists – physicians, nurses, social workers, and chaplains. Nowadays, there are other specialists that are added to the mix – home health aides, pharmacists, physical and occupational therapists, music and pet therapists, and so on.

But in medicine, like all areas of science, convention and tradition only go so far. What evidence is there to support the work of an interdisciplinary team in managing the distress of patients and families living with advanced illnesses? It turns out that there is good evidence to support the use of high-functioning interdisciplinary teams in the care of the seriously ill. Palliative care is associated with improved patient outcomes, including improvements in symptom control, quality of life, and end of life care, when it is delivered by an interdisciplinary team rather than by a solo practitioner.

You may think that teamwork is most useful for patients like John who have seemingly intractable social barriers. But it is also true that for even patients with many more social advantages teamwork improves quality of life. I got to see this up close recently in my own life.
 

Teamwork improves quality of life

My father recently passed away after a 9-month battle with advanced cancer. He had every advantage possible – financial stability, high health literacy, an incredibly devoted spouse who happens to be an RN, good insurance, and access to top-notch medical care. Yet, even he benefited from a team approach. It started small, with the oncologist and oncology NP providing excellent, patient-centered care. Then it grew to include myself as the daughter/palliative care nurse practitioner who made recommendations for treating his nausea and ensured that his advance directive was completed and uploaded to his chart. When my dad needed physical therapy, the home health agency sent a wonderful physical therapist, who brought all sorts of equipment that kept him more functional than he would have been otherwise. Other family members helped out – my sisters helped connect my dad with a priest who came to the home to provide spiritual care, which was crucial to ensuring that he was at peace. And, in his final days, my dad had the hospice team to help manage his symptoms and his family members to provide hands-on care.

Cancer, as one of my patients once remarked to me, is a “full-contact sport.” Living with advanced cancer touches nearly every aspect of a person’s life. The complexity of cancer care has long necessitated a team approach to planning cancer treatment – known as a tumor board – with medical oncology, radiation oncology, surgery, and pathology all weighing in. It makes sense that patients and their families would also need a team of clinicians representing different specialty areas to assist with the wide array of physical, psychosocial, practical, and spiritual concerns that arise throughout the cancer disease trajectory.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

John worked as a handyman and lived on a small sailboat in a marina. When he was diagnosed with metastatic kidney cancer at age 48, he quickly fell through the cracks. He failed to show to appointments and took oral anticancer treatments, but just sporadically. He had Medicaid, so insurance wasn’t the issue. It was everything else.

John was behind on his slip fees; he hadn’t been able to work for some time because of his progressive weakness and pain. He was chronically in danger of getting kicked out of his makeshift home aboard the boat. He had no reliable transportation to the clinic and so he didn’t come to appointments regularly. The specialty pharmacy refused to deliver his expensive oral chemotherapy to his address at the marina. He went days without eating full meals because he was too weak to cook for himself. Plus, he was estranged from his family who were unaware of his illness. His oncologist was overwhelmed trying to take care of him. He had a reasonable chance of achieving disease control on first-line oral therapy, but his problems seemed to hinder these chances at every turn. She was distraught – what could she do?

Enter the team approach. John’s oncologist reached out to our palliative care program for help. We recognized that this was a job too big for us alone so we connected John with the Extensivist Medicine program at UCLA Health, a high-intensity primary care program led by a physician specializing in primary care for high-risk individuals. The program provides wraparound outpatient services for chronically and seriously ill patients, like John, who are at risk for falling through the cracks. John went from receiving very little support to now having an entire team of caring professionals focused on helping him achieve his best possible outcome despite the seriousness of his disease.

He now had the support of a high-functioning team with clearly defined roles. Social work connected him with housing, food, and transportation resources. A nurse called him every day to check in and make sure he was taking medications and reminded him about his upcoming appointments. Case management helped him get needed equipment, such as grab bars and a walker. As his palliative care nurse practitioner, I counseled him on understanding his prognosis and planning ahead for medical emergencies. Our psycho-oncology clinicians helped John reconcile with his family, who were more than willing to take him in once they realized how ill he was. Once these social factors were addressed, John could more easily stay current with his oral chemotherapy, giving him the best chance possible to achieve a robust treatment response that could buy him more time.

And, John did get that time – he got 6 months of improved quality of life, during which he reconnected with his family, including his children, and rebuilt these important relationships. Eventually treatment failed him. His disease, already widely metastatic, became more active and painful. He accepted hospice care at his sister’s house and we transitioned him from our team to the hospice team. He died peacefully surrounded by family.
 

Interprofessional teamwork is fundamental to treat ‘total pain’

None of this would have been possible without the work of high-functioning teams. It is a commonly held belief that interprofessional teamwork is fundamental to the care of patients and families living with serious illness. But why? How did this idea come about? And what evidence is there to support teamwork?

Dame Cicely Saunders, who founded the modern hospice movement in mid-20th century England, embodied the interdisciplinary team by working first as a nurse, then a social worker, and finally as a physician. She wrote about patients’ “total pain,” the crisis of physical, spiritual, social, and emotional distress that many people have at the end of life. She understood that no single health care discipline was adequate to the task of addressing each of these domains equally well. Thus, hospice became synonymous with care provided by a quartet of specialists – physicians, nurses, social workers, and chaplains. Nowadays, there are other specialists that are added to the mix – home health aides, pharmacists, physical and occupational therapists, music and pet therapists, and so on.

But in medicine, like all areas of science, convention and tradition only go so far. What evidence is there to support the work of an interdisciplinary team in managing the distress of patients and families living with advanced illnesses? It turns out that there is good evidence to support the use of high-functioning interdisciplinary teams in the care of the seriously ill. Palliative care is associated with improved patient outcomes, including improvements in symptom control, quality of life, and end of life care, when it is delivered by an interdisciplinary team rather than by a solo practitioner.

You may think that teamwork is most useful for patients like John who have seemingly intractable social barriers. But it is also true that for even patients with many more social advantages teamwork improves quality of life. I got to see this up close recently in my own life.
 

Teamwork improves quality of life

My father recently passed away after a 9-month battle with advanced cancer. He had every advantage possible – financial stability, high health literacy, an incredibly devoted spouse who happens to be an RN, good insurance, and access to top-notch medical care. Yet, even he benefited from a team approach. It started small, with the oncologist and oncology NP providing excellent, patient-centered care. Then it grew to include myself as the daughter/palliative care nurse practitioner who made recommendations for treating his nausea and ensured that his advance directive was completed and uploaded to his chart. When my dad needed physical therapy, the home health agency sent a wonderful physical therapist, who brought all sorts of equipment that kept him more functional than he would have been otherwise. Other family members helped out – my sisters helped connect my dad with a priest who came to the home to provide spiritual care, which was crucial to ensuring that he was at peace. And, in his final days, my dad had the hospice team to help manage his symptoms and his family members to provide hands-on care.

Cancer, as one of my patients once remarked to me, is a “full-contact sport.” Living with advanced cancer touches nearly every aspect of a person’s life. The complexity of cancer care has long necessitated a team approach to planning cancer treatment – known as a tumor board – with medical oncology, radiation oncology, surgery, and pathology all weighing in. It makes sense that patients and their families would also need a team of clinicians representing different specialty areas to assist with the wide array of physical, psychosocial, practical, and spiritual concerns that arise throughout the cancer disease trajectory.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

According to the second law of thermo­dynamics, it is inevitable that entropy will continue to increase over time.¹ Entropy is a measure of disorder, which can eventuate in chaos and lead to profound uncertainty, with serious psychological consequences.

The increase in entropy is usually gradual. It took hundreds of years for powerful empires and civilizations to collapse and disappear. Inanimate objects such as a house, a piece of furniture, or a piece of equipment eventually deteriorate and break down over time. Tidy offices will become messy, cluttered, and dirty unless attended to regularly. Living organisms, including humans, inevitably undergo an aging process with cell­ular senescence, atrophy, and loss of cerebral, muscle, and bone tissue, ending in death. Even human relationships will eventually fracture, wither, and end. The passage of time ruthlessly increases the entropy of everything in life. Even the 13-billion-year-old universe, which currently looks formidable and permanent to us, is inexorably expanding and hurtling towards a calamitous end a few billion years from now.

To slow down, halt, or reverse entropy, work and energy must be invested. A house requires regular maintenance for all its components to avoid deteriorating and becoming uninhabitable (very high entropy). Humans require massive amounts of work during fetal life, infancy, childhood, adolescence, adulthood, and throughout old age. This includes work by parents, teachers, friends, physicians, farmers, and manufacturers of food, clothing, and sundry supplies, all targeted to maintain an individual and slow the rate of entropy. But death is inevitable as the final stage of human entropy.

The brain is an entropic organ.² Psychiatric disorders can be conceptualized as a neurobiologic consequence of a major rise in brain entropy. The chaos created by high brain entropy will lead to a disruption of basic mental functions such as thought, mood, affect, impulses, behavior, and cognition. Brain entropy increases can be due to genetics or the environment, but most often are due an interaction of both (G x E).

Societal entropy and our patients

Psychiatric patients are deeply influenced by the context in which they live (society). The entropy of contemporary society is rising at an alarming rate, which means that order is rapidly degenerating into disorder at an unprecedented pace. When the COVID-19 pandemic abruptly emerged in early 2020, it was a major public health shock that drastically changed the lives of all citizens and dramatically increased societal entropy. The pandemic led to lockdowns, fear of death, gut-wrenching uncertainty (especially for a whole year before vaccines were developed, but even after), loss of socialization and sexual intimacy, loss of employment, financial straits, and an inability to access routine medical or surgical procedures. Everyone in society developed anxiety and acute stress reaction, but those with pre-existing psychiatric disorders suffered the most with an intensification of their symptoms.

The unforeseen, sudden, and traumatically life-altering pandemic triggered various degrees of posttraumatic stress disorder across all age groups, and painful death in medically compromised individuals and older adults. Both physical and psychological entropy skyrocketed and the “order” of life as we knew it rapidly disintegrated into shambles and disorder. The abrupt traumatic jolt triggered various degrees of deleterious impacts on the brains of all who experienced it in real time. The rise in the psychobiological entropy was unprecedented across the structures of society, especially the population, its vulnerable human component.

But even as the worst of the pandemic is in our rearview mirror and life again has a semblance of normality, the rise of entropy continues to accelerate because we continue to be surrounded and engulfed by countless stressful events in contemporary society. Those nagging stresses continue to transmute order to chaos and metamorphose comforting predictability to entrenched uncertainty:

• Toxic political hyperpartisanship, with intense animus and visceral bi­directional hatred
• Racial tensions, with overt bias across groups
• Economic turmoil, with inflation and threats of recession
• Actual wars and threats of war
• Social media that spreads bad news and distorts facts
• An opioid crisis, with hundreds of thousands of deaths
• Skyrocketing crime, with a decline in policing and quick release of criminals without bail
• A ruthless and arbitrary “cancel culture” that doesn’t even spare the previously revered founders of the republic
• Cognitive dissonance of disparaging Abraham Lincoln despite his major achievement of eliminating slavery by waging a civil war
• The social and medical strife regarding access to abortion.

Continue to: I also would include...

(I also would include some “entropy pet peeves” of mine: Torn clothes as a fashion statement, transforming tattoos from an oddity to a fad, nose rings that disfigure pretty faces, and banishing neckties for men.)

Our role in this scenario

As psychiatrists, we must step up to intensify the work needed to slow down and even reverse the dangerously rising brain entropy in our patients. But that is not an easy task given the implosion of societal norms and traditional values, along with the radicalization of beliefs, with utter intolerance of others’ beliefs. We also face the challenge of maintaining a modicum of resilience and wellness in ourselves, which can be antidotes to entropy.

It’s impossible to stop the inevitability of rising entropy, both physical and psychological, but psychiatrists and other mental health professionals must invest their skills and talents now more than ever to at least slow down the pace of entropy among our patients. Otherwise, psychological chaos and disorder will be quite damaging to their lives, and worsen their outcomes.

According to the second law of thermo­dynamics, it is inevitable that entropy will continue to increase over time.¹ Entropy is a measure of disorder, which can eventuate in chaos and lead to profound uncertainty, with serious psychological consequences.

The increase in entropy is usually gradual. It took hundreds of years for powerful empires and civilizations to collapse and disappear. Inanimate objects such as a house, a piece of furniture, or a piece of equipment eventually deteriorate and break down over time. Tidy offices will become messy, cluttered, and dirty unless attended to regularly. Living organisms, including humans, inevitably undergo an aging process with cell­ular senescence, atrophy, and loss of cerebral, muscle, and bone tissue, ending in death. Even human relationships will eventually fracture, wither, and end. The passage of time ruthlessly increases the entropy of everything in life. Even the 13-billion-year-old universe, which currently looks formidable and permanent to us, is inexorably expanding and hurtling towards a calamitous end a few billion years from now.

To slow down, halt, or reverse entropy, work and energy must be invested. A house requires regular maintenance for all its components to avoid deteriorating and becoming uninhabitable (very high entropy). Humans require massive amounts of work during fetal life, infancy, childhood, adolescence, adulthood, and throughout old age. This includes work by parents, teachers, friends, physicians, farmers, and manufacturers of food, clothing, and sundry supplies, all targeted to maintain an individual and slow the rate of entropy. But death is inevitable as the final stage of human entropy.

The brain is an entropic organ.² Psychiatric disorders can be conceptualized as a neurobiologic consequence of a major rise in brain entropy. The chaos created by high brain entropy will lead to a disruption of basic mental functions such as thought, mood, affect, impulses, behavior, and cognition. Brain entropy increases can be due to genetics or the environment, but most often are due an interaction of both (G x E).

Societal entropy and our patients

Psychiatric patients are deeply influenced by the context in which they live (society). The entropy of contemporary society is rising at an alarming rate, which means that order is rapidly degenerating into disorder at an unprecedented pace. When the COVID-19 pandemic abruptly emerged in early 2020, it was a major public health shock that drastically changed the lives of all citizens and dramatically increased societal entropy. The pandemic led to lockdowns, fear of death, gut-wrenching uncertainty (especially for a whole year before vaccines were developed, but even after), loss of socialization and sexual intimacy, loss of employment, financial straits, and an inability to access routine medical or surgical procedures. Everyone in society developed anxiety and acute stress reaction, but those with pre-existing psychiatric disorders suffered the most with an intensification of their symptoms.

The unforeseen, sudden, and traumatically life-altering pandemic triggered various degrees of posttraumatic stress disorder across all age groups, and painful death in medically compromised individuals and older adults. Both physical and psychological entropy skyrocketed and the “order” of life as we knew it rapidly disintegrated into shambles and disorder. The abrupt traumatic jolt triggered various degrees of deleterious impacts on the brains of all who experienced it in real time. The rise in the psychobiological entropy was unprecedented across the structures of society, especially the population, its vulnerable human component.

But even as the worst of the pandemic is in our rearview mirror and life again has a semblance of normality, the rise of entropy continues to accelerate because we continue to be surrounded and engulfed by countless stressful events in contemporary society. Those nagging stresses continue to transmute order to chaos and metamorphose comforting predictability to entrenched uncertainty:

• Toxic political hyperpartisanship, with intense animus and visceral bi­directional hatred
• Racial tensions, with overt bias across groups
• Economic turmoil, with inflation and threats of recession
• Actual wars and threats of war
• Social media that spreads bad news and distorts facts
• An opioid crisis, with hundreds of thousands of deaths
• Skyrocketing crime, with a decline in policing and quick release of criminals without bail
• A ruthless and arbitrary “cancel culture” that doesn’t even spare the previously revered founders of the republic
• Cognitive dissonance of disparaging Abraham Lincoln despite his major achievement of eliminating slavery by waging a civil war
• The social and medical strife regarding access to abortion.

Continue to: I also would include...

(I also would include some “entropy pet peeves” of mine: Torn clothes as a fashion statement, transforming tattoos from an oddity to a fad, nose rings that disfigure pretty faces, and banishing neckties for men.)

Our role in this scenario

As psychiatrists, we must step up to intensify the work needed to slow down and even reverse the dangerously rising brain entropy in our patients. But that is not an easy task given the implosion of societal norms and traditional values, along with the radicalization of beliefs, with utter intolerance of others’ beliefs. We also face the challenge of maintaining a modicum of resilience and wellness in ourselves, which can be antidotes to entropy.

It’s impossible to stop the inevitability of rising entropy, both physical and psychological, but psychiatrists and other mental health professionals must invest their skills and talents now more than ever to at least slow down the pace of entropy among our patients. Otherwise, psychological chaos and disorder will be quite damaging to their lives, and worsen their outcomes.

According to the second law of thermo­dynamics, it is inevitable that entropy will continue to increase over time.¹ Entropy is a measure of disorder, which can eventuate in chaos and lead to profound uncertainty, with serious psychological consequences.

The increase in entropy is usually gradual. It took hundreds of years for powerful empires and civilizations to collapse and disappear. Inanimate objects such as a house, a piece of furniture, or a piece of equipment eventually deteriorate and break down over time. Tidy offices will become messy, cluttered, and dirty unless attended to regularly. Living organisms, including humans, inevitably undergo an aging process with cell­ular senescence, atrophy, and loss of cerebral, muscle, and bone tissue, ending in death. Even human relationships will eventually fracture, wither, and end. The passage of time ruthlessly increases the entropy of everything in life. Even the 13-billion-year-old universe, which currently looks formidable and permanent to us, is inexorably expanding and hurtling towards a calamitous end a few billion years from now.

To slow down, halt, or reverse entropy, work and energy must be invested. A house requires regular maintenance for all its components to avoid deteriorating and becoming uninhabitable (very high entropy). Humans require massive amounts of work during fetal life, infancy, childhood, adolescence, adulthood, and throughout old age. This includes work by parents, teachers, friends, physicians, farmers, and manufacturers of food, clothing, and sundry supplies, all targeted to maintain an individual and slow the rate of entropy. But death is inevitable as the final stage of human entropy.

The brain is an entropic organ.² Psychiatric disorders can be conceptualized as a neurobiologic consequence of a major rise in brain entropy. The chaos created by high brain entropy will lead to a disruption of basic mental functions such as thought, mood, affect, impulses, behavior, and cognition. Brain entropy increases can be due to genetics or the environment, but most often are due an interaction of both (G x E).

Societal entropy and our patients

Psychiatric patients are deeply influenced by the context in which they live (society). The entropy of contemporary society is rising at an alarming rate, which means that order is rapidly degenerating into disorder at an unprecedented pace. When the COVID-19 pandemic abruptly emerged in early 2020, it was a major public health shock that drastically changed the lives of all citizens and dramatically increased societal entropy. The pandemic led to lockdowns, fear of death, gut-wrenching uncertainty (especially for a whole year before vaccines were developed, but even after), loss of socialization and sexual intimacy, loss of employment, financial straits, and an inability to access routine medical or surgical procedures. Everyone in society developed anxiety and acute stress reaction, but those with pre-existing psychiatric disorders suffered the most with an intensification of their symptoms.

The unforeseen, sudden, and traumatically life-altering pandemic triggered various degrees of posttraumatic stress disorder across all age groups, and painful death in medically compromised individuals and older adults. Both physical and psychological entropy skyrocketed and the “order” of life as we knew it rapidly disintegrated into shambles and disorder. The abrupt traumatic jolt triggered various degrees of deleterious impacts on the brains of all who experienced it in real time. The rise in the psychobiological entropy was unprecedented across the structures of society, especially the population, its vulnerable human component.

But even as the worst of the pandemic is in our rearview mirror and life again has a semblance of normality, the rise of entropy continues to accelerate because we continue to be surrounded and engulfed by countless stressful events in contemporary society. Those nagging stresses continue to transmute order to chaos and metamorphose comforting predictability to entrenched uncertainty:

• Toxic political hyperpartisanship, with intense animus and visceral bi­directional hatred
• Racial tensions, with overt bias across groups
• Economic turmoil, with inflation and threats of recession
• Actual wars and threats of war
• Social media that spreads bad news and distorts facts
• An opioid crisis, with hundreds of thousands of deaths
• Skyrocketing crime, with a decline in policing and quick release of criminals without bail
• A ruthless and arbitrary “cancel culture” that doesn’t even spare the previously revered founders of the republic
• Cognitive dissonance of disparaging Abraham Lincoln despite his major achievement of eliminating slavery by waging a civil war
• The social and medical strife regarding access to abortion.

Continue to: I also would include...

(I also would include some “entropy pet peeves” of mine: Torn clothes as a fashion statement, transforming tattoos from an oddity to a fad, nose rings that disfigure pretty faces, and banishing neckties for men.)

Our role in this scenario

As psychiatrists, we must step up to intensify the work needed to slow down and even reverse the dangerously rising brain entropy in our patients. But that is not an easy task given the implosion of societal norms and traditional values, along with the radicalization of beliefs, with utter intolerance of others’ beliefs. We also face the challenge of maintaining a modicum of resilience and wellness in ourselves, which can be antidotes to entropy.

It’s impossible to stop the inevitability of rising entropy, both physical and psychological, but psychiatrists and other mental health professionals must invest their skills and talents now more than ever to at least slow down the pace of entropy among our patients. Otherwise, psychological chaos and disorder will be quite damaging to their lives, and worsen their outcomes.

Murray et al have written a timely, thoughtful, and useful article (“Smoking cessation: Varenicline and the risk of neuropsychiatric adverse events,” Current Psychiatry, July 2022, p. 41-45) about the role of the nicotinic acetylcholine receptor partial agonist varenicline for helping patients stop smoking, which is still the main preventable cause of morbidity and premature death. Smoking remains a major problem among patients who are chronically mentally ill and those with substance use disorders, as well as “recovering” populations such as Alcoholic Anonymous participants.¹ Reviews of the EAGLES trial and other research analyses have gone a long way to allaying anxiety about interventions for smoking cessation.²

Just a few caveats regarding Murray et al’s excellent summary:

• The article did not address that nicotine is consumed in multiple ways, such as vaping, snuff, chewing tobacco, and hookah

• The safety of varenicline appears fair when psychiatric illness is well controlled but can be problematic (and even severely detrimental) when mental illness is not well controlled. This should not be glossed over, especially since it was the reason for the original black-box warning (for risks including behavioral impulsivity, suicidality, severe insomnia, and nightmares) that was removed in 2016

• Patients with severe mental illness may not fully understand the risks, benefits, and priorities of the treatment intervention. The importance of psychiatric and internal medicine in addition to pharmacy follow-up is critical and needs to be documented.

Varenicline has been contextualized in its current role as a first-line treatment for smoking cessation. By bypassing a sizeable population of patients who have unstable psychiatric illness (especially bipolar I disorder), the path has been opened for risky “off-label” varenicline prescribing to this population by internists, who should be very cautious and prudent about prescribing for such patients. This alone is probably a good reason to reinstate the black-box warning.

Interestingly, one review found that only 1 of 11 patients receiving varenicline stopped smoking.¹ Not dramatically beneficial for a first-line treatment! Decreasing smoking occurs as well and is more robust with combinational use with bupropion, nicotine replacement therapy, and cognitive-behavioral therapy.

If we are focusing on patients with unstable mental illness—who are seen primarily by psychiatrists—adherence, urgency of intervention, and context regarding acute safety for this population must be seen as top priorities.

So-called “second-line” treatment options must also be considered. Sandiego et al³ make excellent points regarding the role of alpha-adrenergic agonists such as guanfacine, which have been shown to be helpful in smoking cessation. They work by decreasing cortical dopamine release and their calming effects on the noradrenergic system, which may decrease smoking precipitated by stress. For the particularly challenging subpopulation of unstable smokers, the combination of varenicline plus guanfacine ER may turn out to be a game-changer.

Varenicline has not proven itself to be useful in patients who are severely mentally ill, and due to its low success rate, expectations should remain tempered, pragmatically realistic, and safety-based.^4,5 The bottom line is that in an unstable psychiatrically ill patient, interventions other than varenicline should be first-line.

Murray et al have written a timely, thoughtful, and useful article (“Smoking cessation: Varenicline and the risk of neuropsychiatric adverse events,” Current Psychiatry, July 2022, p. 41-45) about the role of the nicotinic acetylcholine receptor partial agonist varenicline for helping patients stop smoking, which is still the main preventable cause of morbidity and premature death. Smoking remains a major problem among patients who are chronically mentally ill and those with substance use disorders, as well as “recovering” populations such as Alcoholic Anonymous participants.¹ Reviews of the EAGLES trial and other research analyses have gone a long way to allaying anxiety about interventions for smoking cessation.²

Just a few caveats regarding Murray et al’s excellent summary:

• The article did not address that nicotine is consumed in multiple ways, such as vaping, snuff, chewing tobacco, and hookah

• The safety of varenicline appears fair when psychiatric illness is well controlled but can be problematic (and even severely detrimental) when mental illness is not well controlled. This should not be glossed over, especially since it was the reason for the original black-box warning (for risks including behavioral impulsivity, suicidality, severe insomnia, and nightmares) that was removed in 2016

• Patients with severe mental illness may not fully understand the risks, benefits, and priorities of the treatment intervention. The importance of psychiatric and internal medicine in addition to pharmacy follow-up is critical and needs to be documented.

Varenicline has been contextualized in its current role as a first-line treatment for smoking cessation. By bypassing a sizeable population of patients who have unstable psychiatric illness (especially bipolar I disorder), the path has been opened for risky “off-label” varenicline prescribing to this population by internists, who should be very cautious and prudent about prescribing for such patients. This alone is probably a good reason to reinstate the black-box warning.

Interestingly, one review found that only 1 of 11 patients receiving varenicline stopped smoking.¹ Not dramatically beneficial for a first-line treatment! Decreasing smoking occurs as well and is more robust with combinational use with bupropion, nicotine replacement therapy, and cognitive-behavioral therapy.

If we are focusing on patients with unstable mental illness—who are seen primarily by psychiatrists—adherence, urgency of intervention, and context regarding acute safety for this population must be seen as top priorities.

So-called “second-line” treatment options must also be considered. Sandiego et al³ make excellent points regarding the role of alpha-adrenergic agonists such as guanfacine, which have been shown to be helpful in smoking cessation. They work by decreasing cortical dopamine release and their calming effects on the noradrenergic system, which may decrease smoking precipitated by stress. For the particularly challenging subpopulation of unstable smokers, the combination of varenicline plus guanfacine ER may turn out to be a game-changer.

Varenicline has not proven itself to be useful in patients who are severely mentally ill, and due to its low success rate, expectations should remain tempered, pragmatically realistic, and safety-based.^4,5 The bottom line is that in an unstable psychiatrically ill patient, interventions other than varenicline should be first-line.

Murray et al have written a timely, thoughtful, and useful article (“Smoking cessation: Varenicline and the risk of neuropsychiatric adverse events,” Current Psychiatry, July 2022, p. 41-45) about the role of the nicotinic acetylcholine receptor partial agonist varenicline for helping patients stop smoking, which is still the main preventable cause of morbidity and premature death. Smoking remains a major problem among patients who are chronically mentally ill and those with substance use disorders, as well as “recovering” populations such as Alcoholic Anonymous participants.¹ Reviews of the EAGLES trial and other research analyses have gone a long way to allaying anxiety about interventions for smoking cessation.²

Just a few caveats regarding Murray et al’s excellent summary:

• The article did not address that nicotine is consumed in multiple ways, such as vaping, snuff, chewing tobacco, and hookah

• The safety of varenicline appears fair when psychiatric illness is well controlled but can be problematic (and even severely detrimental) when mental illness is not well controlled. This should not be glossed over, especially since it was the reason for the original black-box warning (for risks including behavioral impulsivity, suicidality, severe insomnia, and nightmares) that was removed in 2016

• Patients with severe mental illness may not fully understand the risks, benefits, and priorities of the treatment intervention. The importance of psychiatric and internal medicine in addition to pharmacy follow-up is critical and needs to be documented.

Varenicline has been contextualized in its current role as a first-line treatment for smoking cessation. By bypassing a sizeable population of patients who have unstable psychiatric illness (especially bipolar I disorder), the path has been opened for risky “off-label” varenicline prescribing to this population by internists, who should be very cautious and prudent about prescribing for such patients. This alone is probably a good reason to reinstate the black-box warning.

Interestingly, one review found that only 1 of 11 patients receiving varenicline stopped smoking.¹ Not dramatically beneficial for a first-line treatment! Decreasing smoking occurs as well and is more robust with combinational use with bupropion, nicotine replacement therapy, and cognitive-behavioral therapy.

If we are focusing on patients with unstable mental illness—who are seen primarily by psychiatrists—adherence, urgency of intervention, and context regarding acute safety for this population must be seen as top priorities.

So-called “second-line” treatment options must also be considered. Sandiego et al³ make excellent points regarding the role of alpha-adrenergic agonists such as guanfacine, which have been shown to be helpful in smoking cessation. They work by decreasing cortical dopamine release and their calming effects on the noradrenergic system, which may decrease smoking precipitated by stress. For the particularly challenging subpopulation of unstable smokers, the combination of varenicline plus guanfacine ER may turn out to be a game-changer.

Varenicline has not proven itself to be useful in patients who are severely mentally ill, and due to its low success rate, expectations should remain tempered, pragmatically realistic, and safety-based.^4,5 The bottom line is that in an unstable psychiatrically ill patient, interventions other than varenicline should be first-line.

I had the opportunity to experience first-hand acute postoperative pain management in both the United States and Saudi Arabia. In this article, I discuss some of the differences in how postop pain is managed in each location, potential reasons for these differences, how they may impact patients over time, and the psychiatrist’s role in raising awareness about the hazards of overprescribing analgesic medications.

Vast differences in postop opioid prescribing

From personal observation and literature review, I was appalled by the amount of oxycodone tablets patients are typically discharged home with after a surgical procedure in the United States. Depending on the extent of the surgical procedure, opioid-naïve patients were routinely discharged with 40 to 120 tablets of oxycodone 5 mg. A ventral hernia repair or laparotomy was on the high end of how much oxycodone was provided, and a laparoscopic cholecystectomy or inguinal hernia repair was on the low end. At least one study has supported this observation, finding a wide variation and excessive doses of opioids prescribed postop.¹ Notably, among opioids obtained by postsurgical patients, 42% to 71% of all tablets went unused.² Nevertheless, prescribing in this manner became the standard for postop pain management—possibly in an effort to maximize patient satisfaction on surveys. Additionally, marketing and promotion by the pharmaceutical industry appears to have considerably amplified the prescription, sales, and availability of opioids.³

Signing those prescriptions always left a bad taste in my mouth out of concern for the potential for initiating chronic opioid use.⁴ Personally, I would prescribe the lowest reasonable number of narcotic tablets for my patients, along with acetaminophen and ibuprofen, knowing that nonsteroidal anti-inflammatory drugs are sufficient for treating postop pain and will decrease opioid requirements, therefore minimizing opiate-induced adverse events.⁵ Overtreatment of pain with narcotics as first-line therapy is particularly problematic when treating postop pain in children after minor procedures, such as an umbilical hernia repair.Allowing children to resort to a narcotic analgesic agent as a first-line therapy had the potential to develop into an opioid use disorder (OUD) later in life if environmental factors tipped the scales.⁶

In the hospital in Saudi Arabia where I initially trained, surgery residents were not permitted to prescribe narcotics. The standard of care was to discharge patients with acetaminophen and ibuprofen. In cases where there was an indication for pain treatment with narcotics, stringent regulations were in place. For example, in my experience, which is corroborated by one study,⁶ special “narcotic forms” are required in the Middle East. In most of these countries, access to these forms is restricted.⁷ Moreover, pharmacists would only accept this special form when attested to by the surgery consultant (the equivalent of an attending physician in the United States). These consultants would typically write a prescription for 9 to 15 oxycodone 5 mg tablets. Patients receiving such medications were closely watched and followed up in the surgery clinic 3 to 5 days after discharge. Patients were also required to fill out a form detailing their contact information, including their home address and national ID number, to be able to pick up their prescription. Furthermore, apart from 2 Middle East countries, opioids were only available from hospital pharmacies, which were independent of the general hospital pharmacy in location and staff training.⁸

The psychiatrist’s role

Adapting similar stringent practices for prescribing narcotics in the United States might reduce 1 risk factor for OUD in postop patients. Surgeons attempt to provide the best care by maximizing analgesia, but psychiatrists see firsthand the consequences of overprescribing, and play a direct role in managing patients’ OUDs. As psychiatrists, we have a duty to continue to raise awareness and alert other clinicians about the hazards of overprescribing narcotic analgesic agents.

I had the opportunity to experience first-hand acute postoperative pain management in both the United States and Saudi Arabia. In this article, I discuss some of the differences in how postop pain is managed in each location, potential reasons for these differences, how they may impact patients over time, and the psychiatrist’s role in raising awareness about the hazards of overprescribing analgesic medications.

Vast differences in postop opioid prescribing

From personal observation and literature review, I was appalled by the amount of oxycodone tablets patients are typically discharged home with after a surgical procedure in the United States. Depending on the extent of the surgical procedure, opioid-naïve patients were routinely discharged with 40 to 120 tablets of oxycodone 5 mg. A ventral hernia repair or laparotomy was on the high end of how much oxycodone was provided, and a laparoscopic cholecystectomy or inguinal hernia repair was on the low end. At least one study has supported this observation, finding a wide variation and excessive doses of opioids prescribed postop.¹ Notably, among opioids obtained by postsurgical patients, 42% to 71% of all tablets went unused.² Nevertheless, prescribing in this manner became the standard for postop pain management—possibly in an effort to maximize patient satisfaction on surveys. Additionally, marketing and promotion by the pharmaceutical industry appears to have considerably amplified the prescription, sales, and availability of opioids.³

Signing those prescriptions always left a bad taste in my mouth out of concern for the potential for initiating chronic opioid use.⁴ Personally, I would prescribe the lowest reasonable number of narcotic tablets for my patients, along with acetaminophen and ibuprofen, knowing that nonsteroidal anti-inflammatory drugs are sufficient for treating postop pain and will decrease opioid requirements, therefore minimizing opiate-induced adverse events.⁵ Overtreatment of pain with narcotics as first-line therapy is particularly problematic when treating postop pain in children after minor procedures, such as an umbilical hernia repair.Allowing children to resort to a narcotic analgesic agent as a first-line therapy had the potential to develop into an opioid use disorder (OUD) later in life if environmental factors tipped the scales.⁶

In the hospital in Saudi Arabia where I initially trained, surgery residents were not permitted to prescribe narcotics. The standard of care was to discharge patients with acetaminophen and ibuprofen. In cases where there was an indication for pain treatment with narcotics, stringent regulations were in place. For example, in my experience, which is corroborated by one study,⁶ special “narcotic forms” are required in the Middle East. In most of these countries, access to these forms is restricted.⁷ Moreover, pharmacists would only accept this special form when attested to by the surgery consultant (the equivalent of an attending physician in the United States). These consultants would typically write a prescription for 9 to 15 oxycodone 5 mg tablets. Patients receiving such medications were closely watched and followed up in the surgery clinic 3 to 5 days after discharge. Patients were also required to fill out a form detailing their contact information, including their home address and national ID number, to be able to pick up their prescription. Furthermore, apart from 2 Middle East countries, opioids were only available from hospital pharmacies, which were independent of the general hospital pharmacy in location and staff training.⁸

The psychiatrist’s role

Adapting similar stringent practices for prescribing narcotics in the United States might reduce 1 risk factor for OUD in postop patients. Surgeons attempt to provide the best care by maximizing analgesia, but psychiatrists see firsthand the consequences of overprescribing, and play a direct role in managing patients’ OUDs. As psychiatrists, we have a duty to continue to raise awareness and alert other clinicians about the hazards of overprescribing narcotic analgesic agents.

I had the opportunity to experience first-hand acute postoperative pain management in both the United States and Saudi Arabia. In this article, I discuss some of the differences in how postop pain is managed in each location, potential reasons for these differences, how they may impact patients over time, and the psychiatrist’s role in raising awareness about the hazards of overprescribing analgesic medications.

Vast differences in postop opioid prescribing

From personal observation and literature review, I was appalled by the amount of oxycodone tablets patients are typically discharged home with after a surgical procedure in the United States. Depending on the extent of the surgical procedure, opioid-naïve patients were routinely discharged with 40 to 120 tablets of oxycodone 5 mg. A ventral hernia repair or laparotomy was on the high end of how much oxycodone was provided, and a laparoscopic cholecystectomy or inguinal hernia repair was on the low end. At least one study has supported this observation, finding a wide variation and excessive doses of opioids prescribed postop.¹ Notably, among opioids obtained by postsurgical patients, 42% to 71% of all tablets went unused.² Nevertheless, prescribing in this manner became the standard for postop pain management—possibly in an effort to maximize patient satisfaction on surveys. Additionally, marketing and promotion by the pharmaceutical industry appears to have considerably amplified the prescription, sales, and availability of opioids.³

Signing those prescriptions always left a bad taste in my mouth out of concern for the potential for initiating chronic opioid use.⁴ Personally, I would prescribe the lowest reasonable number of narcotic tablets for my patients, along with acetaminophen and ibuprofen, knowing that nonsteroidal anti-inflammatory drugs are sufficient for treating postop pain and will decrease opioid requirements, therefore minimizing opiate-induced adverse events.⁵ Overtreatment of pain with narcotics as first-line therapy is particularly problematic when treating postop pain in children after minor procedures, such as an umbilical hernia repair.Allowing children to resort to a narcotic analgesic agent as a first-line therapy had the potential to develop into an opioid use disorder (OUD) later in life if environmental factors tipped the scales.⁶

In the hospital in Saudi Arabia where I initially trained, surgery residents were not permitted to prescribe narcotics. The standard of care was to discharge patients with acetaminophen and ibuprofen. In cases where there was an indication for pain treatment with narcotics, stringent regulations were in place. For example, in my experience, which is corroborated by one study,⁶ special “narcotic forms” are required in the Middle East. In most of these countries, access to these forms is restricted.⁷ Moreover, pharmacists would only accept this special form when attested to by the surgery consultant (the equivalent of an attending physician in the United States). These consultants would typically write a prescription for 9 to 15 oxycodone 5 mg tablets. Patients receiving such medications were closely watched and followed up in the surgery clinic 3 to 5 days after discharge. Patients were also required to fill out a form detailing their contact information, including their home address and national ID number, to be able to pick up their prescription. Furthermore, apart from 2 Middle East countries, opioids were only available from hospital pharmacies, which were independent of the general hospital pharmacy in location and staff training.⁸

The psychiatrist’s role

Adapting similar stringent practices for prescribing narcotics in the United States might reduce 1 risk factor for OUD in postop patients. Surgeons attempt to provide the best care by maximizing analgesia, but psychiatrists see firsthand the consequences of overprescribing, and play a direct role in managing patients’ OUDs. As psychiatrists, we have a duty to continue to raise awareness and alert other clinicians about the hazards of overprescribing narcotic analgesic agents.

In the second issue of GI & Hepatology News in February 2007, an article reviewed the disruptive forces to colonoscopy including CT colonography and the colon capsule. The article stated that “colonoscopy is still the preferred method, but the emerging technology could catch up in 3-5 years.”

While this prediction did not come to pass, the field of endoscopy has evolved in remarkable ways over the last 15 years. From the development of high-definition endoscopes to the transformation of interventional endoscopy to include “third space” procedures, previously unimaginable techniques have now become commonplace. This transformation has changed the nature and training of our field and, even more importantly, dramatically improved the care of our patients.

Just as notably, the regulatory and practice environment for endoscopy has also changed in the last 15 years, albeit at a slower pace. In January of 2007, as the first issue of GI & Hepatology News came out, Medicare announced that it would cover all screening procedures without a copay but left a loophole that charged patients if their screening colonoscopy became therapeutic. That loophole was finally fixed this year as GI & Hepatology News celebrates its 15-year anniversary.

If the past 15 years are any indication, endoscopy practice will continue to change at a humbling pace over the next 15 years. I look forward to seeing those changes unfold through the pages of GI & Hepatology News.
 

Dr. Gellad is associate professor of medicine and associate vice chair of ambulatory services at Duke University Medical Center, Durham, N.C. He is also a staff physician with the Durham VA Health Care system. He disclosed ties with Merck, Novo Nordisk, and Higgs Boson Health.

In the second issue of GI & Hepatology News in February 2007, an article reviewed the disruptive forces to colonoscopy including CT colonography and the colon capsule. The article stated that “colonoscopy is still the preferred method, but the emerging technology could catch up in 3-5 years.”

While this prediction did not come to pass, the field of endoscopy has evolved in remarkable ways over the last 15 years. From the development of high-definition endoscopes to the transformation of interventional endoscopy to include “third space” procedures, previously unimaginable techniques have now become commonplace. This transformation has changed the nature and training of our field and, even more importantly, dramatically improved the care of our patients.

Just as notably, the regulatory and practice environment for endoscopy has also changed in the last 15 years, albeit at a slower pace. In January of 2007, as the first issue of GI & Hepatology News came out, Medicare announced that it would cover all screening procedures without a copay but left a loophole that charged patients if their screening colonoscopy became therapeutic. That loophole was finally fixed this year as GI & Hepatology News celebrates its 15-year anniversary.

If the past 15 years are any indication, endoscopy practice will continue to change at a humbling pace over the next 15 years. I look forward to seeing those changes unfold through the pages of GI & Hepatology News.
 

Dr. Gellad is associate professor of medicine and associate vice chair of ambulatory services at Duke University Medical Center, Durham, N.C. He is also a staff physician with the Durham VA Health Care system. He disclosed ties with Merck, Novo Nordisk, and Higgs Boson Health.

In the second issue of GI & Hepatology News in February 2007, an article reviewed the disruptive forces to colonoscopy including CT colonography and the colon capsule. The article stated that “colonoscopy is still the preferred method, but the emerging technology could catch up in 3-5 years.”

While this prediction did not come to pass, the field of endoscopy has evolved in remarkable ways over the last 15 years. From the development of high-definition endoscopes to the transformation of interventional endoscopy to include “third space” procedures, previously unimaginable techniques have now become commonplace. This transformation has changed the nature and training of our field and, even more importantly, dramatically improved the care of our patients.

Just as notably, the regulatory and practice environment for endoscopy has also changed in the last 15 years, albeit at a slower pace. In January of 2007, as the first issue of GI & Hepatology News came out, Medicare announced that it would cover all screening procedures without a copay but left a loophole that charged patients if their screening colonoscopy became therapeutic. That loophole was finally fixed this year as GI & Hepatology News celebrates its 15-year anniversary.

If the past 15 years are any indication, endoscopy practice will continue to change at a humbling pace over the next 15 years. I look forward to seeing those changes unfold through the pages of GI & Hepatology News.
 

Dr. Gellad is associate professor of medicine and associate vice chair of ambulatory services at Duke University Medical Center, Durham, N.C. He is also a staff physician with the Durham VA Health Care system. He disclosed ties with Merck, Novo Nordisk, and Higgs Boson Health.

In 2002, two landmark trials found that targeted temperature management (TTM) after out-of-hospital cardiac arrest led to improvements in neurologic outcomes. The larger of the two trials found a reduction in mortality. Such treatment benefits are hard to come by in critical care in general and in out-of-hospital cardiac arrest in particular. With the therapeutic overconfidence typical of our profession, my institution embraced TTM quickly and completely soon after these trials were published. Remember, this was “back in the day” when sepsis management included drotrecogin alfa, Cortrosyn stim tests, tight glucose control (90-120 mg/dL), and horrible over-resuscitation via the early goal-directed therapy paradigm.

If you’ve been practicing critical care medicine for more than a few years, you already know where I’m going. Most of the interventions in the preceding paragraph were adopted but discarded before 2010. Though TTM has managed to stand the test of time, our confidence in its benefit has waned since 2002. Hypothermia – temperature management with a goal of 32-36° C – has been struggling to stay relevant ever since the publication of the TTM randomized controlled trial (RCT) in 2013. Then came the HYPERION trial, which brought the 32-36° C target back from the dead (pun definitely intended) in 2019. This is critical care medicine: Today’s life-saving intervention proves harmful tomorrow, but withholding it may constitute malpractice a few months down the road.

So where are we now? Good question. I’ve had seasoned neurointensivists insist that 33° C remains the standard of care and others who’ve endorsed normothermia. So much for finding an answer via my more specialized colleagues.

Let’s go to the guidelines then. Prompted largely by HYPERION, a temperature target of 32-36° C was endorsed in 2020 and 2021. Then came publication of the TTM2 trial, the largest temperature management RCT to date, which found no benefit to targeting 33° C. A network meta-analysis published in 2021 reached a similar conclusion. A recently released update by the same international guideline group now recommends targeting normothermia (< 37.7° C) and avoiding fever, and it specifically says that there is insufficient evidence to support a 32-36° C target. Okay, everyone tracking all that?

Lest I sound overly catty and nihilistic, I see all this in a positive light. Huge credit goes to the critical care medicine academic community for putting together so many RCTs. The scientific reality is that it takes “a lotta” sample size to clarify the effects of an intervention. Throw in the inevitable bevy of confounders (in- vs. out-of-hospital cardiac arrest, resuscitation time, initial rhythm, and so on), and you get a feel for the work required to understand a treatment’s true effects.

Advances in guideline science and the hard, often unpaid work of panels are also important. The guideline panel I’ve been citing came out for aggressive temperature control (32-36° C) a few months before the TTM2 RCT was published. In the past, they updated their recommendations every 5 years, but this time, they were out with a new manuscript that incorporated TTM2 in less than a year. If you’ve been involved at any level with producing guidelines, you can appreciate this achievement. Assuming that aggressive hypothermia is truly harmful, waiting 5 years to incorporate TTM2 could have led to significant morbidity.

I do take issue with you early adopters, though. Given the litany of failed therapies that have shown initial promise, and the well-documented human tendency to underestimate the impact of sample size, your rapid implementation of major interventions is puzzling. One might think you’d learned your lessons after seeing drotrecogin alfa, Cortrosyn stim tests, tight glucose control, early goal-directed therapy, and aggressive TTM come and go. Your recent enthusiasm for vitamin C after publication of a single before-after study suggests that you haven’t.

Aaron B. Holley, MD, is an associate professor of medicine at Uniformed Services University and program director of pulmonary and critical care medicine at Walter Reed National Military Medical Center, Bethesda, Md. He has received a research grant from Fisher-Paykel.

A version of this article first appeared on Medscape.com.

In 2002, two landmark trials found that targeted temperature management (TTM) after out-of-hospital cardiac arrest led to improvements in neurologic outcomes. The larger of the two trials found a reduction in mortality. Such treatment benefits are hard to come by in critical care in general and in out-of-hospital cardiac arrest in particular. With the therapeutic overconfidence typical of our profession, my institution embraced TTM quickly and completely soon after these trials were published. Remember, this was “back in the day” when sepsis management included drotrecogin alfa, Cortrosyn stim tests, tight glucose control (90-120 mg/dL), and horrible over-resuscitation via the early goal-directed therapy paradigm.

If you’ve been practicing critical care medicine for more than a few years, you already know where I’m going. Most of the interventions in the preceding paragraph were adopted but discarded before 2010. Though TTM has managed to stand the test of time, our confidence in its benefit has waned since 2002. Hypothermia – temperature management with a goal of 32-36° C – has been struggling to stay relevant ever since the publication of the TTM randomized controlled trial (RCT) in 2013. Then came the HYPERION trial, which brought the 32-36° C target back from the dead (pun definitely intended) in 2019. This is critical care medicine: Today’s life-saving intervention proves harmful tomorrow, but withholding it may constitute malpractice a few months down the road.

So where are we now? Good question. I’ve had seasoned neurointensivists insist that 33° C remains the standard of care and others who’ve endorsed normothermia. So much for finding an answer via my more specialized colleagues.

Let’s go to the guidelines then. Prompted largely by HYPERION, a temperature target of 32-36° C was endorsed in 2020 and 2021. Then came publication of the TTM2 trial, the largest temperature management RCT to date, which found no benefit to targeting 33° C. A network meta-analysis published in 2021 reached a similar conclusion. A recently released update by the same international guideline group now recommends targeting normothermia (< 37.7° C) and avoiding fever, and it specifically says that there is insufficient evidence to support a 32-36° C target. Okay, everyone tracking all that?

Lest I sound overly catty and nihilistic, I see all this in a positive light. Huge credit goes to the critical care medicine academic community for putting together so many RCTs. The scientific reality is that it takes “a lotta” sample size to clarify the effects of an intervention. Throw in the inevitable bevy of confounders (in- vs. out-of-hospital cardiac arrest, resuscitation time, initial rhythm, and so on), and you get a feel for the work required to understand a treatment’s true effects.

Advances in guideline science and the hard, often unpaid work of panels are also important. The guideline panel I’ve been citing came out for aggressive temperature control (32-36° C) a few months before the TTM2 RCT was published. In the past, they updated their recommendations every 5 years, but this time, they were out with a new manuscript that incorporated TTM2 in less than a year. If you’ve been involved at any level with producing guidelines, you can appreciate this achievement. Assuming that aggressive hypothermia is truly harmful, waiting 5 years to incorporate TTM2 could have led to significant morbidity.

I do take issue with you early adopters, though. Given the litany of failed therapies that have shown initial promise, and the well-documented human tendency to underestimate the impact of sample size, your rapid implementation of major interventions is puzzling. One might think you’d learned your lessons after seeing drotrecogin alfa, Cortrosyn stim tests, tight glucose control, early goal-directed therapy, and aggressive TTM come and go. Your recent enthusiasm for vitamin C after publication of a single before-after study suggests that you haven’t.

Aaron B. Holley, MD, is an associate professor of medicine at Uniformed Services University and program director of pulmonary and critical care medicine at Walter Reed National Military Medical Center, Bethesda, Md. He has received a research grant from Fisher-Paykel.

A version of this article first appeared on Medscape.com.

In 2002, two landmark trials found that targeted temperature management (TTM) after out-of-hospital cardiac arrest led to improvements in neurologic outcomes. The larger of the two trials found a reduction in mortality. Such treatment benefits are hard to come by in critical care in general and in out-of-hospital cardiac arrest in particular. With the therapeutic overconfidence typical of our profession, my institution embraced TTM quickly and completely soon after these trials were published. Remember, this was “back in the day” when sepsis management included drotrecogin alfa, Cortrosyn stim tests, tight glucose control (90-120 mg/dL), and horrible over-resuscitation via the early goal-directed therapy paradigm.

If you’ve been practicing critical care medicine for more than a few years, you already know where I’m going. Most of the interventions in the preceding paragraph were adopted but discarded before 2010. Though TTM has managed to stand the test of time, our confidence in its benefit has waned since 2002. Hypothermia – temperature management with a goal of 32-36° C – has been struggling to stay relevant ever since the publication of the TTM randomized controlled trial (RCT) in 2013. Then came the HYPERION trial, which brought the 32-36° C target back from the dead (pun definitely intended) in 2019. This is critical care medicine: Today’s life-saving intervention proves harmful tomorrow, but withholding it may constitute malpractice a few months down the road.

So where are we now? Good question. I’ve had seasoned neurointensivists insist that 33° C remains the standard of care and others who’ve endorsed normothermia. So much for finding an answer via my more specialized colleagues.

Let’s go to the guidelines then. Prompted largely by HYPERION, a temperature target of 32-36° C was endorsed in 2020 and 2021. Then came publication of the TTM2 trial, the largest temperature management RCT to date, which found no benefit to targeting 33° C. A network meta-analysis published in 2021 reached a similar conclusion. A recently released update by the same international guideline group now recommends targeting normothermia (< 37.7° C) and avoiding fever, and it specifically says that there is insufficient evidence to support a 32-36° C target. Okay, everyone tracking all that?

Lest I sound overly catty and nihilistic, I see all this in a positive light. Huge credit goes to the critical care medicine academic community for putting together so many RCTs. The scientific reality is that it takes “a lotta” sample size to clarify the effects of an intervention. Throw in the inevitable bevy of confounders (in- vs. out-of-hospital cardiac arrest, resuscitation time, initial rhythm, and so on), and you get a feel for the work required to understand a treatment’s true effects.

Advances in guideline science and the hard, often unpaid work of panels are also important. The guideline panel I’ve been citing came out for aggressive temperature control (32-36° C) a few months before the TTM2 RCT was published. In the past, they updated their recommendations every 5 years, but this time, they were out with a new manuscript that incorporated TTM2 in less than a year. If you’ve been involved at any level with producing guidelines, you can appreciate this achievement. Assuming that aggressive hypothermia is truly harmful, waiting 5 years to incorporate TTM2 could have led to significant morbidity.

I do take issue with you early adopters, though. Given the litany of failed therapies that have shown initial promise, and the well-documented human tendency to underestimate the impact of sample size, your rapid implementation of major interventions is puzzling. One might think you’d learned your lessons after seeing drotrecogin alfa, Cortrosyn stim tests, tight glucose control, early goal-directed therapy, and aggressive TTM come and go. Your recent enthusiasm for vitamin C after publication of a single before-after study suggests that you haven’t.

Aaron B. Holley, MD, is an associate professor of medicine at Uniformed Services University and program director of pulmonary and critical care medicine at Walter Reed National Military Medical Center, Bethesda, Md. He has received a research grant from Fisher-Paykel.

A version of this article first appeared on Medscape.com.

Shortly after osimertinib was approved for patients with non–small cell lung cancer in 2020 by the Food and Drug Administration, a patient came to me with increasing shortness of breath. He had been on erlotinib (Tarceva) for about 2 years and had done well. Nearly all of his pulmonary lesions had resolved and he was feeling well. He enjoyed boating in the summer and visiting grandkids in California in the winter. However, on this day, it was different. He was losing weight; he was tired and didn’t feel strong enough to put his boat in the water that spring. Long story short: We ordered a CT scan and all of his lesions were progressing. Since osimertinib had just been approved, we got a second biopsy, hoping that his insurance would pay for it. It did and sure enough, a new T790M mutation was present. He was on osimertinib for another 2 years before progressing and starting chemotherapy.

Second biopsies increasingly routine

The practice of ordering a second biopsy for patients with non–small cell lung carcinoma (NSCLC) was not common practice until after 2015 when the Food and Drug Administration approved gefitinib, a tyrosine kinase inhibitor (TKI) for patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

Up until then, second biopsies were not routinely done for lung cancers. But with the advent of targeted therapy and new drugs designed specifically to tackle first- and second-line treatment resistance mutations, rebiopsies have become a necessity for patients with progressive disease.

Epidermal growth factors, including HER2, ErbB2, and MET, are receptors of tyrosine kinases that control cell growth, but when in overdrive, they can lead to the development of cancers, including lung adenocarcinoma, conventional glioblastoma multiforme, glioblastoma, colon adenocarcinoma, and NSCLC.

EGFRs date back to 1962 with their discovery by Stanley Cohen. The discovery was so important that in 1986, Mr. Cohen was awarded the Nobel Prize in physiology or medicine for the discovery along with Rita Levi-Montalcini.

Now, many years later, we finally have a string of new approvals for mutations in the EGF family of receptors and several under study.

Sensitizing mutations

The more commonly used strategy for blocking EGFR signaling in lung cancer is the use of tyrosine kinase inhibitors, which compete with adenosine triphosphate (ATP) for binding to the tyrosine kinase portion of the receptor. They are located at chromosome 7p11.2. The most frequent mutations that sensitize patients to EGFR inhibitors include exon 19 deletions and L858R point mutation in exon 21, although multiple other driver mutations also exist.

The first-generation of EGFR TKIs include gefitinib and erlotinib, which bind reversibly to the EGF receptor. Second-generation inhibitors afatinib and dacomitinib bind irreversibly. Osimertinib, a third-generation EGFR TKI, which also binds irreversibly, was approved in 2020 for adjuvant therapy, and first- and second-line treatment in patients with NSCLC who have EGFR mutation–positive disease.
 

First-generation EGFR tyrosine kinase inhibitors

Four randomized, first-line, placebo-controlled phase 3 trials conducted with EGFR TKIs in combination with platinum-based doublet chemotherapy in an EGFR nonselected patient population failed to show a survival benefit with erlotinib or gefitinib (TRIBUTE, Tarceva Lung Cancer Investigation Trial, INTACT 1, INTACT 2).

However, a first-line study randomized patients to gefitinib or chemotherapy with carboplatin-paclitaxel, and included patients with or without an EGFR mutations. In the subgroup of patients with an EGFR mutation, progression-free survival (PFS) was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48), whereas in the subgroup of patients who were negative for the mutation, PFS was significantly longer among those who received chemotherapy (HR for progression or death with gefitinib, 2.85).

Numerous studies have shown that EGFR TKIs used in the first-line setting improved progression free survival, response rates, and quality of life while reducing toxicity. A recent meta-analysis of randomized clinical trials involving EGFR TKIs showed that EGFR TKI improved PFS with a HR of 0.40, compared with standard chemotherapy with fewer serious adverse events, although no benefit on overall survival was observed (HR, 0.96; 95% confidence interval, 0.83-1.10; P = .556).
 

T790M: The most common resistance mutation

T790M is the most common resistance mechanism to develop in patients with EGFR mutations being treated with EGFR TKIs. A randomized phase 3 trial of osimertinib vs. chemotherapy in patients with T790M-positive advanced NSCLC who had disease progression after first-line EGFR-TKI therapy, reported a median duration of progression-free survival that was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; HR, 0.30). In addition, among 144 patients with metastases to the central nervous system, the median duration of PFS was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; HR, 0.32). However, now that osimertinib has moved into the front-line setting, it has left a void for the treatment of patients with advanced disease who have failed osimertinib.

New resistance mechanisms continue to be identified

One of the most common sets of resistance mutations are insertions in exon 20 of the EGF receptor gene. These are a heterogenous group of mutations, many of which do not respond to first-, second-, or third-generation TKIs. Some, such as EGFR-A763_Y764insFQEA, may be sensitive to first- and third-generation EGFR TKIs. Other drugs targeting exon 20 insertion mutations are under development.

Newly approved by the FDA within the last year are mobocertinib and CLN-081 for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.

Savolitinib is a receptor tyrosine kinase (MET) inhibitor currently under development for NSCLC and other cancers. Amivantamab-vmjw was approved by the FDA last year for metastatic NSCLC. It targets EGF and MET receptors in patients with EGFR exon 20 insertion mutations.

We finally have approved drugs for exon 20 insertions and c-Met amplification, even though their approvals are based on small, single arm studies with no definitive claims of improved efficacy over older therapies. Taking a second biopsy will help determine which resistance mechanisms are active to better identify subsequent treatment as in my patient described in this article.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Shortly after osimertinib was approved for patients with non–small cell lung cancer in 2020 by the Food and Drug Administration, a patient came to me with increasing shortness of breath. He had been on erlotinib (Tarceva) for about 2 years and had done well. Nearly all of his pulmonary lesions had resolved and he was feeling well. He enjoyed boating in the summer and visiting grandkids in California in the winter. However, on this day, it was different. He was losing weight; he was tired and didn’t feel strong enough to put his boat in the water that spring. Long story short: We ordered a CT scan and all of his lesions were progressing. Since osimertinib had just been approved, we got a second biopsy, hoping that his insurance would pay for it. It did and sure enough, a new T790M mutation was present. He was on osimertinib for another 2 years before progressing and starting chemotherapy.

Second biopsies increasingly routine

The practice of ordering a second biopsy for patients with non–small cell lung carcinoma (NSCLC) was not common practice until after 2015 when the Food and Drug Administration approved gefitinib, a tyrosine kinase inhibitor (TKI) for patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

Up until then, second biopsies were not routinely done for lung cancers. But with the advent of targeted therapy and new drugs designed specifically to tackle first- and second-line treatment resistance mutations, rebiopsies have become a necessity for patients with progressive disease.

Epidermal growth factors, including HER2, ErbB2, and MET, are receptors of tyrosine kinases that control cell growth, but when in overdrive, they can lead to the development of cancers, including lung adenocarcinoma, conventional glioblastoma multiforme, glioblastoma, colon adenocarcinoma, and NSCLC.

EGFRs date back to 1962 with their discovery by Stanley Cohen. The discovery was so important that in 1986, Mr. Cohen was awarded the Nobel Prize in physiology or medicine for the discovery along with Rita Levi-Montalcini.

Now, many years later, we finally have a string of new approvals for mutations in the EGF family of receptors and several under study.

Sensitizing mutations

The more commonly used strategy for blocking EGFR signaling in lung cancer is the use of tyrosine kinase inhibitors, which compete with adenosine triphosphate (ATP) for binding to the tyrosine kinase portion of the receptor. They are located at chromosome 7p11.2. The most frequent mutations that sensitize patients to EGFR inhibitors include exon 19 deletions and L858R point mutation in exon 21, although multiple other driver mutations also exist.

The first-generation of EGFR TKIs include gefitinib and erlotinib, which bind reversibly to the EGF receptor. Second-generation inhibitors afatinib and dacomitinib bind irreversibly. Osimertinib, a third-generation EGFR TKI, which also binds irreversibly, was approved in 2020 for adjuvant therapy, and first- and second-line treatment in patients with NSCLC who have EGFR mutation–positive disease.
 

First-generation EGFR tyrosine kinase inhibitors

Four randomized, first-line, placebo-controlled phase 3 trials conducted with EGFR TKIs in combination with platinum-based doublet chemotherapy in an EGFR nonselected patient population failed to show a survival benefit with erlotinib or gefitinib (TRIBUTE, Tarceva Lung Cancer Investigation Trial, INTACT 1, INTACT 2).

However, a first-line study randomized patients to gefitinib or chemotherapy with carboplatin-paclitaxel, and included patients with or without an EGFR mutations. In the subgroup of patients with an EGFR mutation, progression-free survival (PFS) was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48), whereas in the subgroup of patients who were negative for the mutation, PFS was significantly longer among those who received chemotherapy (HR for progression or death with gefitinib, 2.85).

Numerous studies have shown that EGFR TKIs used in the first-line setting improved progression free survival, response rates, and quality of life while reducing toxicity. A recent meta-analysis of randomized clinical trials involving EGFR TKIs showed that EGFR TKI improved PFS with a HR of 0.40, compared with standard chemotherapy with fewer serious adverse events, although no benefit on overall survival was observed (HR, 0.96; 95% confidence interval, 0.83-1.10; P = .556).
 

T790M: The most common resistance mutation

T790M is the most common resistance mechanism to develop in patients with EGFR mutations being treated with EGFR TKIs. A randomized phase 3 trial of osimertinib vs. chemotherapy in patients with T790M-positive advanced NSCLC who had disease progression after first-line EGFR-TKI therapy, reported a median duration of progression-free survival that was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; HR, 0.30). In addition, among 144 patients with metastases to the central nervous system, the median duration of PFS was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; HR, 0.32). However, now that osimertinib has moved into the front-line setting, it has left a void for the treatment of patients with advanced disease who have failed osimertinib.

New resistance mechanisms continue to be identified

One of the most common sets of resistance mutations are insertions in exon 20 of the EGF receptor gene. These are a heterogenous group of mutations, many of which do not respond to first-, second-, or third-generation TKIs. Some, such as EGFR-A763_Y764insFQEA, may be sensitive to first- and third-generation EGFR TKIs. Other drugs targeting exon 20 insertion mutations are under development.

Newly approved by the FDA within the last year are mobocertinib and CLN-081 for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.

Savolitinib is a receptor tyrosine kinase (MET) inhibitor currently under development for NSCLC and other cancers. Amivantamab-vmjw was approved by the FDA last year for metastatic NSCLC. It targets EGF and MET receptors in patients with EGFR exon 20 insertion mutations.

We finally have approved drugs for exon 20 insertions and c-Met amplification, even though their approvals are based on small, single arm studies with no definitive claims of improved efficacy over older therapies. Taking a second biopsy will help determine which resistance mechanisms are active to better identify subsequent treatment as in my patient described in this article.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Shortly after osimertinib was approved for patients with non–small cell lung cancer in 2020 by the Food and Drug Administration, a patient came to me with increasing shortness of breath. He had been on erlotinib (Tarceva) for about 2 years and had done well. Nearly all of his pulmonary lesions had resolved and he was feeling well. He enjoyed boating in the summer and visiting grandkids in California in the winter. However, on this day, it was different. He was losing weight; he was tired and didn’t feel strong enough to put his boat in the water that spring. Long story short: We ordered a CT scan and all of his lesions were progressing. Since osimertinib had just been approved, we got a second biopsy, hoping that his insurance would pay for it. It did and sure enough, a new T790M mutation was present. He was on osimertinib for another 2 years before progressing and starting chemotherapy.

Second biopsies increasingly routine

The practice of ordering a second biopsy for patients with non–small cell lung carcinoma (NSCLC) was not common practice until after 2015 when the Food and Drug Administration approved gefitinib, a tyrosine kinase inhibitor (TKI) for patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

Up until then, second biopsies were not routinely done for lung cancers. But with the advent of targeted therapy and new drugs designed specifically to tackle first- and second-line treatment resistance mutations, rebiopsies have become a necessity for patients with progressive disease.

Epidermal growth factors, including HER2, ErbB2, and MET, are receptors of tyrosine kinases that control cell growth, but when in overdrive, they can lead to the development of cancers, including lung adenocarcinoma, conventional glioblastoma multiforme, glioblastoma, colon adenocarcinoma, and NSCLC.

EGFRs date back to 1962 with their discovery by Stanley Cohen. The discovery was so important that in 1986, Mr. Cohen was awarded the Nobel Prize in physiology or medicine for the discovery along with Rita Levi-Montalcini.

Now, many years later, we finally have a string of new approvals for mutations in the EGF family of receptors and several under study.

Sensitizing mutations

The more commonly used strategy for blocking EGFR signaling in lung cancer is the use of tyrosine kinase inhibitors, which compete with adenosine triphosphate (ATP) for binding to the tyrosine kinase portion of the receptor. They are located at chromosome 7p11.2. The most frequent mutations that sensitize patients to EGFR inhibitors include exon 19 deletions and L858R point mutation in exon 21, although multiple other driver mutations also exist.

The first-generation of EGFR TKIs include gefitinib and erlotinib, which bind reversibly to the EGF receptor. Second-generation inhibitors afatinib and dacomitinib bind irreversibly. Osimertinib, a third-generation EGFR TKI, which also binds irreversibly, was approved in 2020 for adjuvant therapy, and first- and second-line treatment in patients with NSCLC who have EGFR mutation–positive disease.
 

First-generation EGFR tyrosine kinase inhibitors

Four randomized, first-line, placebo-controlled phase 3 trials conducted with EGFR TKIs in combination with platinum-based doublet chemotherapy in an EGFR nonselected patient population failed to show a survival benefit with erlotinib or gefitinib (TRIBUTE, Tarceva Lung Cancer Investigation Trial, INTACT 1, INTACT 2).

However, a first-line study randomized patients to gefitinib or chemotherapy with carboplatin-paclitaxel, and included patients with or without an EGFR mutations. In the subgroup of patients with an EGFR mutation, progression-free survival (PFS) was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48), whereas in the subgroup of patients who were negative for the mutation, PFS was significantly longer among those who received chemotherapy (HR for progression or death with gefitinib, 2.85).

Numerous studies have shown that EGFR TKIs used in the first-line setting improved progression free survival, response rates, and quality of life while reducing toxicity. A recent meta-analysis of randomized clinical trials involving EGFR TKIs showed that EGFR TKI improved PFS with a HR of 0.40, compared with standard chemotherapy with fewer serious adverse events, although no benefit on overall survival was observed (HR, 0.96; 95% confidence interval, 0.83-1.10; P = .556).
 

T790M: The most common resistance mutation

T790M is the most common resistance mechanism to develop in patients with EGFR mutations being treated with EGFR TKIs. A randomized phase 3 trial of osimertinib vs. chemotherapy in patients with T790M-positive advanced NSCLC who had disease progression after first-line EGFR-TKI therapy, reported a median duration of progression-free survival that was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; HR, 0.30). In addition, among 144 patients with metastases to the central nervous system, the median duration of PFS was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; HR, 0.32). However, now that osimertinib has moved into the front-line setting, it has left a void for the treatment of patients with advanced disease who have failed osimertinib.

New resistance mechanisms continue to be identified

One of the most common sets of resistance mutations are insertions in exon 20 of the EGF receptor gene. These are a heterogenous group of mutations, many of which do not respond to first-, second-, or third-generation TKIs. Some, such as EGFR-A763_Y764insFQEA, may be sensitive to first- and third-generation EGFR TKIs. Other drugs targeting exon 20 insertion mutations are under development.

Newly approved by the FDA within the last year are mobocertinib and CLN-081 for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.

Savolitinib is a receptor tyrosine kinase (MET) inhibitor currently under development for NSCLC and other cancers. Amivantamab-vmjw was approved by the FDA last year for metastatic NSCLC. It targets EGF and MET receptors in patients with EGFR exon 20 insertion mutations.

We finally have approved drugs for exon 20 insertions and c-Met amplification, even though their approvals are based on small, single arm studies with no definitive claims of improved efficacy over older therapies. Taking a second biopsy will help determine which resistance mechanisms are active to better identify subsequent treatment as in my patient described in this article.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.