Oncology

The heart is one of the organs least likely to develop cancer, a long-standing biologic puzzle that may now have an explanation. A study published in Science found that the mechanical load generated by the beating heart suppresses tumor cell proliferation through a molecular pathway that alters gene expression, raising the possibility of new therapeutic targets.

Mechanical Protection

Tumors that originate directly in the myocardium are exceptionally rare, occurring in < 1% of autopsies. Even cardiac metastases, which have been reported in up to 18% of autopsies, are often small, asymptomatic, and incidentally discovered. Although this phenomenon has long been recognized, its biologic basis remains unclear.

The heart is notable for its limited capacity for regeneration. After birth, cardiomyocytes stop dividing and subsequently renew at a rate of about 1% per year. However, when the mechanical load is reduced, such as in patients supported by left ventricular assist devices, cardiomyocytes once again show signs of proliferation.

This observation prompted researchers to investigate whether the same mechanical load that restrains normal cardiac cells might also suppress cancer growth.

More Load, Less Growth

To investigate this question, researchers introduced two genetic alterations commonly found in human cancers, activation of the KRAS oncogene and loss of the TP53, into the liver, skeletal muscle, and hearts of mice. Tumors developed in multiple organs, but not in the heart.

The researchers then used a heterotopic heart transplant model in which a donor mouse’s heart is surgically connected to the neck (cervical) or abdominal vessels of a recipient mouse. The transplanted heart remained perfused but lost its normal mechanical loading (constant beating).

When researchers injected lung adenocarcinoma cells into 2 different hearts of the same animal, they observed entirely different outcomes. The cancer cells did not grow in the native mechanically loaded heart. However, the same cells grew rapidly and extensively in the mechanically unloaded transplanted heart.

Tumor cells had replaced nearly all normal tissue in the unloaded heart, whereas they occupied only approximately 20% of the ventricle in the native heart in 14 days. This difference could not be explained by differences in the initial tumor engraftment or cell death. Instead, the findings pointed to substantial differences in tumor cell proliferation.

Similar results were observed in bioengineered cardiac tissues exposed to varying degrees of mechanical stress. Tumor cells proliferated under conditions of low mechanical load but ceased proliferating as the mechanical load increased. Tumor growth was lowest in regions exposed to the greatest mechanical stimulation of cardiomyocytes in vitro.

However, the possibility of metabolic competition between cardiac and tumor cells for nutrition was ruled out.

From Mechanics to Genes

Next, we examined the influence of mechanical forces on tumor cell behavior.

Gene expression analyses of both human cardiac metastases and mouse tumor cells showed that mechanical stimulation altered chromatin accessibility through the activation of genes involved in chromatin remodeling. These changes promoted the expression of genes that suppress cell division.

The study also identified Nesprin-2, a part of the linker of the nucleoskeleton and cytoskeleton complex, which acts as a physical bridge. It is a multitasking protein that connects the cell’s outer structural network (cytoskeleton) to its inner genetic storage (nucleus) and appears to play a significant role in converting mechanical signals into changes in gene expression.

When Nesprin-2 was inactivated, cancer cells resumed proliferation despite exposure to a mechanical load, both in engineered tissues and animal models.

“Collectively, these results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to cancer therapies based on mechanical stimulation,” concluded the authors.

An Actively Protected Organ

Speaking with Univadis Italy, part of the Medscape Professional Network, Giorgio Scita, PhD, director of the Mechanisms of Tumor Cell Migration research unit at AIRC Institute of Molecular Oncology and professor of general pathology at the University of Milan in Milan, Italy, said, “The study addressed a simple but fundamental question: Why is the heart largely resistant to cancer despite being highly vascularized and continuously exposed to circulating tumor cells?

These findings suggest that the heartbeat itself creates a mechanical environment that is hostile to tumor growth. The compressive forces generated by rhythmic myocardial contraction are sensed by cancer cells and translated into biochemical signals that limit their proliferation.

In this view, the heart is not simply an organ that is unfavorable for cancer growth but a tissue actively protected by its own mechanical forces.”

Speaking with Univadis Italy, Serena Zacchigna, PhD, study coauthor and head of the Cardiovascular Biology Laboratory at the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy, said, “Until now, however, attention had focused primarily on signals from the extracellular matrix, such as tissue stiffness. Our study adds a new element: even forces generated directly by the movement of an organ — in this case, cardiac contraction — can influence the growth of cancer cells.”

Beyond the Heart

Scita said the findings have implications that extend well beyond the heart.

“The most significant aspect is that this work identifies tissue mechanics as an active regulator of tumor behavior,” he said. Stiffness, compression, tension, and confinement are not merely consequences of tumor growth, but factors capable of influencing proliferation, invasion, and dormancy.

The concept may apply to many solid tumors. Scita noted that cancer cells growing in confined environments, such as ductal carcinoma in situ of the breast, are exposed to substantial mechanical constraints. Understanding why some tumor cells remain susceptible to these forces whereas others evade them and become invasive remains a major unanswered question in cancer biology.

Research on these mechanisms is expanding internationally and in Italy as well. One example is the AIRC “5 per mille” (5 per thousand) research programs on metastatic disease, which includes projects designed to clarify how the mechanical properties of tumor tissue influence cancer initiation, metastatic spread, and disease progression.

Therapeutic Potential

According to Zacchigna, these findings open 2 principal avenues for future research.

“The first focuses on mechanical stimulation itself. In collaboration with engineers at the University of Siena, including a group led by Domenico Prattichizzo, researchers are developing wearable robotic devices designed to mimic the heartbeat and deliver mechanical stimulation to superficial solid tumors such as certain skin cancers.

The second approach is pharmacology. Researchers are investigating whether epigenetic therapies capable of modifying chromatin remodeling can reproduce the effects of cardiac contraction and suppress tumor cell proliferation.

However, Zacchigna cautioned that this work remains at an early experimental phase.”

However, before therapeutic applications can be pursued, important mechanistic questions remain unanswered.

Zacchigna noted that although the linker of nucleoskeleton and cytoskeleton (LINC) complex and Nesprin-2 are involved in signal transduction leading to chromatin reorganization and activation of cell cycle inhibitory loci, the molecular intermediates involved have yet to be fully defined.

Researchers also need to determine which genes are most critical, whether the mechanism operates across different tumor types, and whether it can be safely manipulated for therapeutic purposes.

In an accompanying commentary published in Science, Wyatt G. Paltzer, PhD, and James F. Martin, MD, from the Department of Integrative Physiology at the Baylor College of Medicine in Houston, noted that the findings suggest enhancing LINC complex activity could potentially suppress tumor growth.

However, because the complex has broad biologic functions, it may prove difficult to target therapeutically. The authors suggested that future studies should focus on identifying proteins that interact with Nesprin-2 or other components of the LINC complex and play a more specific role in inhibiting cancer cell proliferation.

Looking Ahead

Despite these challenges, Scita said that the study’s conceptual significance is already clear.

“Even if therapeutic applications remain years away, the findings suggest that cancer may one day be targeted by altering how tumor cells perceive and interpret physical forces.”

Scita and Zacchigna reported having no relevant conflicts of interest.

This story was translated from Univadis Italy.

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

The heart is one of the organs least likely to develop cancer, a long-standing biologic puzzle that may now have an explanation. A study published in Science found that the mechanical load generated by the beating heart suppresses tumor cell proliferation through a molecular pathway that alters gene expression, raising the possibility of new therapeutic targets.

Mechanical Protection

Tumors that originate directly in the myocardium are exceptionally rare, occurring in < 1% of autopsies. Even cardiac metastases, which have been reported in up to 18% of autopsies, are often small, asymptomatic, and incidentally discovered. Although this phenomenon has long been recognized, its biologic basis remains unclear.

The heart is notable for its limited capacity for regeneration. After birth, cardiomyocytes stop dividing and subsequently renew at a rate of about 1% per year. However, when the mechanical load is reduced, such as in patients supported by left ventricular assist devices, cardiomyocytes once again show signs of proliferation.

This observation prompted researchers to investigate whether the same mechanical load that restrains normal cardiac cells might also suppress cancer growth.

More Load, Less Growth

To investigate this question, researchers introduced two genetic alterations commonly found in human cancers, activation of the KRAS oncogene and loss of the TP53, into the liver, skeletal muscle, and hearts of mice. Tumors developed in multiple organs, but not in the heart.

The researchers then used a heterotopic heart transplant model in which a donor mouse’s heart is surgically connected to the neck (cervical) or abdominal vessels of a recipient mouse. The transplanted heart remained perfused but lost its normal mechanical loading (constant beating).

When researchers injected lung adenocarcinoma cells into 2 different hearts of the same animal, they observed entirely different outcomes. The cancer cells did not grow in the native mechanically loaded heart. However, the same cells grew rapidly and extensively in the mechanically unloaded transplanted heart.

Tumor cells had replaced nearly all normal tissue in the unloaded heart, whereas they occupied only approximately 20% of the ventricle in the native heart in 14 days. This difference could not be explained by differences in the initial tumor engraftment or cell death. Instead, the findings pointed to substantial differences in tumor cell proliferation.

Similar results were observed in bioengineered cardiac tissues exposed to varying degrees of mechanical stress. Tumor cells proliferated under conditions of low mechanical load but ceased proliferating as the mechanical load increased. Tumor growth was lowest in regions exposed to the greatest mechanical stimulation of cardiomyocytes in vitro.

However, the possibility of metabolic competition between cardiac and tumor cells for nutrition was ruled out.

From Mechanics to Genes

Next, we examined the influence of mechanical forces on tumor cell behavior.

Gene expression analyses of both human cardiac metastases and mouse tumor cells showed that mechanical stimulation altered chromatin accessibility through the activation of genes involved in chromatin remodeling. These changes promoted the expression of genes that suppress cell division.

The study also identified Nesprin-2, a part of the linker of the nucleoskeleton and cytoskeleton complex, which acts as a physical bridge. It is a multitasking protein that connects the cell’s outer structural network (cytoskeleton) to its inner genetic storage (nucleus) and appears to play a significant role in converting mechanical signals into changes in gene expression.

When Nesprin-2 was inactivated, cancer cells resumed proliferation despite exposure to a mechanical load, both in engineered tissues and animal models.

“Collectively, these results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to cancer therapies based on mechanical stimulation,” concluded the authors.

An Actively Protected Organ

Speaking with Univadis Italy, part of the Medscape Professional Network, Giorgio Scita, PhD, director of the Mechanisms of Tumor Cell Migration research unit at AIRC Institute of Molecular Oncology and professor of general pathology at the University of Milan in Milan, Italy, said, “The study addressed a simple but fundamental question: Why is the heart largely resistant to cancer despite being highly vascularized and continuously exposed to circulating tumor cells?

These findings suggest that the heartbeat itself creates a mechanical environment that is hostile to tumor growth. The compressive forces generated by rhythmic myocardial contraction are sensed by cancer cells and translated into biochemical signals that limit their proliferation.

In this view, the heart is not simply an organ that is unfavorable for cancer growth but a tissue actively protected by its own mechanical forces.”

Speaking with Univadis Italy, Serena Zacchigna, PhD, study coauthor and head of the Cardiovascular Biology Laboratory at the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy, said, “Until now, however, attention had focused primarily on signals from the extracellular matrix, such as tissue stiffness. Our study adds a new element: even forces generated directly by the movement of an organ — in this case, cardiac contraction — can influence the growth of cancer cells.”

Beyond the Heart

Scita said the findings have implications that extend well beyond the heart.

“The most significant aspect is that this work identifies tissue mechanics as an active regulator of tumor behavior,” he said. Stiffness, compression, tension, and confinement are not merely consequences of tumor growth, but factors capable of influencing proliferation, invasion, and dormancy.

The concept may apply to many solid tumors. Scita noted that cancer cells growing in confined environments, such as ductal carcinoma in situ of the breast, are exposed to substantial mechanical constraints. Understanding why some tumor cells remain susceptible to these forces whereas others evade them and become invasive remains a major unanswered question in cancer biology.

Research on these mechanisms is expanding internationally and in Italy as well. One example is the AIRC “5 per mille” (5 per thousand) research programs on metastatic disease, which includes projects designed to clarify how the mechanical properties of tumor tissue influence cancer initiation, metastatic spread, and disease progression.

Therapeutic Potential

According to Zacchigna, these findings open 2 principal avenues for future research.

“The first focuses on mechanical stimulation itself. In collaboration with engineers at the University of Siena, including a group led by Domenico Prattichizzo, researchers are developing wearable robotic devices designed to mimic the heartbeat and deliver mechanical stimulation to superficial solid tumors such as certain skin cancers.

The second approach is pharmacology. Researchers are investigating whether epigenetic therapies capable of modifying chromatin remodeling can reproduce the effects of cardiac contraction and suppress tumor cell proliferation.

However, Zacchigna cautioned that this work remains at an early experimental phase.”

However, before therapeutic applications can be pursued, important mechanistic questions remain unanswered.

Zacchigna noted that although the linker of nucleoskeleton and cytoskeleton (LINC) complex and Nesprin-2 are involved in signal transduction leading to chromatin reorganization and activation of cell cycle inhibitory loci, the molecular intermediates involved have yet to be fully defined.

Researchers also need to determine which genes are most critical, whether the mechanism operates across different tumor types, and whether it can be safely manipulated for therapeutic purposes.

In an accompanying commentary published in Science, Wyatt G. Paltzer, PhD, and James F. Martin, MD, from the Department of Integrative Physiology at the Baylor College of Medicine in Houston, noted that the findings suggest enhancing LINC complex activity could potentially suppress tumor growth.

However, because the complex has broad biologic functions, it may prove difficult to target therapeutically. The authors suggested that future studies should focus on identifying proteins that interact with Nesprin-2 or other components of the LINC complex and play a more specific role in inhibiting cancer cell proliferation.

Looking Ahead

Despite these challenges, Scita said that the study’s conceptual significance is already clear.

“Even if therapeutic applications remain years away, the findings suggest that cancer may one day be targeted by altering how tumor cells perceive and interpret physical forces.”

Scita and Zacchigna reported having no relevant conflicts of interest.

This story was translated from Univadis Italy.

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

The heart is one of the organs least likely to develop cancer, a long-standing biologic puzzle that may now have an explanation. A study published in Science found that the mechanical load generated by the beating heart suppresses tumor cell proliferation through a molecular pathway that alters gene expression, raising the possibility of new therapeutic targets.

Mechanical Protection

Tumors that originate directly in the myocardium are exceptionally rare, occurring in < 1% of autopsies. Even cardiac metastases, which have been reported in up to 18% of autopsies, are often small, asymptomatic, and incidentally discovered. Although this phenomenon has long been recognized, its biologic basis remains unclear.

The heart is notable for its limited capacity for regeneration. After birth, cardiomyocytes stop dividing and subsequently renew at a rate of about 1% per year. However, when the mechanical load is reduced, such as in patients supported by left ventricular assist devices, cardiomyocytes once again show signs of proliferation.

This observation prompted researchers to investigate whether the same mechanical load that restrains normal cardiac cells might also suppress cancer growth.

More Load, Less Growth

To investigate this question, researchers introduced two genetic alterations commonly found in human cancers, activation of the KRAS oncogene and loss of the TP53, into the liver, skeletal muscle, and hearts of mice. Tumors developed in multiple organs, but not in the heart.

The researchers then used a heterotopic heart transplant model in which a donor mouse’s heart is surgically connected to the neck (cervical) or abdominal vessels of a recipient mouse. The transplanted heart remained perfused but lost its normal mechanical loading (constant beating).

When researchers injected lung adenocarcinoma cells into 2 different hearts of the same animal, they observed entirely different outcomes. The cancer cells did not grow in the native mechanically loaded heart. However, the same cells grew rapidly and extensively in the mechanically unloaded transplanted heart.

Tumor cells had replaced nearly all normal tissue in the unloaded heart, whereas they occupied only approximately 20% of the ventricle in the native heart in 14 days. This difference could not be explained by differences in the initial tumor engraftment or cell death. Instead, the findings pointed to substantial differences in tumor cell proliferation.

Similar results were observed in bioengineered cardiac tissues exposed to varying degrees of mechanical stress. Tumor cells proliferated under conditions of low mechanical load but ceased proliferating as the mechanical load increased. Tumor growth was lowest in regions exposed to the greatest mechanical stimulation of cardiomyocytes in vitro.

However, the possibility of metabolic competition between cardiac and tumor cells for nutrition was ruled out.

From Mechanics to Genes

Next, we examined the influence of mechanical forces on tumor cell behavior.

Gene expression analyses of both human cardiac metastases and mouse tumor cells showed that mechanical stimulation altered chromatin accessibility through the activation of genes involved in chromatin remodeling. These changes promoted the expression of genes that suppress cell division.

The study also identified Nesprin-2, a part of the linker of the nucleoskeleton and cytoskeleton complex, which acts as a physical bridge. It is a multitasking protein that connects the cell’s outer structural network (cytoskeleton) to its inner genetic storage (nucleus) and appears to play a significant role in converting mechanical signals into changes in gene expression.

When Nesprin-2 was inactivated, cancer cells resumed proliferation despite exposure to a mechanical load, both in engineered tissues and animal models.

“Collectively, these results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to cancer therapies based on mechanical stimulation,” concluded the authors.

An Actively Protected Organ

Speaking with Univadis Italy, part of the Medscape Professional Network, Giorgio Scita, PhD, director of the Mechanisms of Tumor Cell Migration research unit at AIRC Institute of Molecular Oncology and professor of general pathology at the University of Milan in Milan, Italy, said, “The study addressed a simple but fundamental question: Why is the heart largely resistant to cancer despite being highly vascularized and continuously exposed to circulating tumor cells?

These findings suggest that the heartbeat itself creates a mechanical environment that is hostile to tumor growth. The compressive forces generated by rhythmic myocardial contraction are sensed by cancer cells and translated into biochemical signals that limit their proliferation.

In this view, the heart is not simply an organ that is unfavorable for cancer growth but a tissue actively protected by its own mechanical forces.”

Speaking with Univadis Italy, Serena Zacchigna, PhD, study coauthor and head of the Cardiovascular Biology Laboratory at the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy, said, “Until now, however, attention had focused primarily on signals from the extracellular matrix, such as tissue stiffness. Our study adds a new element: even forces generated directly by the movement of an organ — in this case, cardiac contraction — can influence the growth of cancer cells.”

Beyond the Heart

Scita said the findings have implications that extend well beyond the heart.

“The most significant aspect is that this work identifies tissue mechanics as an active regulator of tumor behavior,” he said. Stiffness, compression, tension, and confinement are not merely consequences of tumor growth, but factors capable of influencing proliferation, invasion, and dormancy.

The concept may apply to many solid tumors. Scita noted that cancer cells growing in confined environments, such as ductal carcinoma in situ of the breast, are exposed to substantial mechanical constraints. Understanding why some tumor cells remain susceptible to these forces whereas others evade them and become invasive remains a major unanswered question in cancer biology.

Research on these mechanisms is expanding internationally and in Italy as well. One example is the AIRC “5 per mille” (5 per thousand) research programs on metastatic disease, which includes projects designed to clarify how the mechanical properties of tumor tissue influence cancer initiation, metastatic spread, and disease progression.

Therapeutic Potential

According to Zacchigna, these findings open 2 principal avenues for future research.

“The first focuses on mechanical stimulation itself. In collaboration with engineers at the University of Siena, including a group led by Domenico Prattichizzo, researchers are developing wearable robotic devices designed to mimic the heartbeat and deliver mechanical stimulation to superficial solid tumors such as certain skin cancers.

The second approach is pharmacology. Researchers are investigating whether epigenetic therapies capable of modifying chromatin remodeling can reproduce the effects of cardiac contraction and suppress tumor cell proliferation.

However, Zacchigna cautioned that this work remains at an early experimental phase.”

However, before therapeutic applications can be pursued, important mechanistic questions remain unanswered.

Zacchigna noted that although the linker of nucleoskeleton and cytoskeleton (LINC) complex and Nesprin-2 are involved in signal transduction leading to chromatin reorganization and activation of cell cycle inhibitory loci, the molecular intermediates involved have yet to be fully defined.

Researchers also need to determine which genes are most critical, whether the mechanism operates across different tumor types, and whether it can be safely manipulated for therapeutic purposes.

In an accompanying commentary published in Science, Wyatt G. Paltzer, PhD, and James F. Martin, MD, from the Department of Integrative Physiology at the Baylor College of Medicine in Houston, noted that the findings suggest enhancing LINC complex activity could potentially suppress tumor growth.

However, because the complex has broad biologic functions, it may prove difficult to target therapeutically. The authors suggested that future studies should focus on identifying proteins that interact with Nesprin-2 or other components of the LINC complex and play a more specific role in inhibiting cancer cell proliferation.

Looking Ahead

Despite these challenges, Scita said that the study’s conceptual significance is already clear.

“Even if therapeutic applications remain years away, the findings suggest that cancer may one day be targeted by altering how tumor cells perceive and interpret physical forces.”

Scita and Zacchigna reported having no relevant conflicts of interest.

This story was translated from Univadis Italy.

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

Offering lung cancer screening to everyone with a 20-year smoking history could expand access to screening, identify more cancers, and reduce disparities, new research suggests.

In an analysis of nearly 1 million US veterans, researchers estimated that a simplified approach to lung cancer screening — based on smoking duration rather than pack-years — would expand screening eligibility by nearly 30% and reduce potentially missed lung cancers by over 70%.

Those shifts would be especially pronounced among women and Black individuals — 2 groups that are underserved by current screening criteria.

The results, presented at the American Society of Clinical Oncology (ASCO) 2026, come at a time when some groups are revisiting their lung cancer screening guidelines.

And they support smoking duration as a “simpler, more sensitive, and more equitable metric for screening eligibility,” researcher Brendan T. Heiden, MD, MPHS, Washington University School of Medicine in St. Louis, St. Louis, told meeting attendees.

Toward a Better Metric

Current guidelines from the US Preventive Services Task Force (USPSTF) recommend annual lung cancer screening with low-dose CT for adults aged 50-80 years who have at least a 20 pack-year smoking history and either currently smoke or quit within the past 15 years.

The 20 pack-year metric is equivalent to smoking a pack of cigarettes per day for 20 years. Because it requires patients to remember their smoking intensity over decades, it can be challenging to calculate and translate into care, Heiden said.

As it stands, few Americans who are eligible under current USPSTF guidelines actually undergo lung cancer screening, at about 15%-20%, Heiden noted. Meanwhile, mounting evidence suggests that many lung cancers occur in individuals who never meet those eligibility criteria.

Boosting screening uptake, Heiden said, is not enough: There’s a need to revisit eligibility itself to reach more high-risk individuals.

Some groups are already taking steps in that direction. Recently updated guidelines from the National Comprehensive Cancer Network (NCCN) added a category 2B recommendation supporting screening for individuals with at least a 20-year smoking history, regardless of pack-years. (The guidelines also say former smokers are eligible no matter how long ago they quit.)

For their study, Heiden’s team sought to estimate the performance of that smoking-duration metric against current USPSTF pack-year criteria. They used Veterans Health Administration data on over 980,000 veterans whose smoking histories were prospectively collected; lung cancer diagnoses were identified through the Veterans Affairs Central Cancer Registry.

Most of the included veterans (67%) had a smoking history; their mean age was 64 years, and 21% were Black.

Overall, the researchers found that basing eligibility on 20-year smoking duration would substantially expand access to screening: Among veterans with a smoking history, 68% qualified for screening under current USPSTF criteria compared with 87% using the smoking-duration approach.

The gains were especially pronounced among women and Black individuals (who, based on prior research, typically smoke less intensely than White males). Under USPSTF criteria, only about 55% of female and Black veterans qualified for screening compared with 83% for both groups under the smoking-duration criterion.

Importantly, Heiden said, people meeting the smoking-duration threshold remained at substantially elevated risk for lung cancer, suggesting the broader screening criteria were not merely capturing low-risk smokers.

The 5-year lung cancer incidence among veterans eligible under the smoking-duration approach was 1.59% — 11 times the rate of 0.14% among never smokers.

Perhaps most striking, Heiden said, the proportion of potentially missed cancers dropped from 13% with the pack-year metric to just 4% using the smoking-duration metric — a relative reduction of more than 70%.

Again, women and Black individuals would see the largest gains: Among Black veterans, potentially missed cancers fell from 25% to 6%, whereas among female veterans they declined from 22% to 7%.

Optimal Approach Still Unclear

The analysis had limitations, including a predominantly male veteran population whose smoking exposure was far greater than that of the general US population, indicating high inherent lung cancer risk.

But the results support what the NCCN has already done, according to Mary Reid, PhD, MSPH, BSN, a member of the group’s lung cancer screening guideline panel and chief of cancer screening, survivorship and mentorship at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

“Doing the calculation for pack-years can be difficult,” Reid told Medscape Medical News. “Smoking duration is easier to calculate and really the way to go.”

The USPSTF does not comment on individual studies outside of its recommendation development process.

At the meeting, study discussant Katharine A. Rendle, PhD, called the work “impressive,” citing the size of the cohort and strength of the data.

It’s particularly noteworthy that the simpler screening criteria improved sensitivity for all veterans, while largely eliminating disparities, according to Rendle, of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

Still, she said, further research could better define the optimal screening strategy.

“Smoking duration is a promising approach, but in my opinion, guidelines likely need to account for the underlying risk in the population,” Rendle said, noting that current smoking prevalence in the US population is about 10%.

She suggested future studies consider other smoking-duration thresholds, such as 30 or 40 years, and look at other outcomes, including life-years gained.

“It’s critical that we prioritize strategies that maximize potential benefit from screening — not just identify those at lung cancer risk — given downstream costs and burden on populations and health care systems,” Rendle said.

The study had no commercial funding. Heiden, Rendle, and Reid had no relevant disclosures.

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

Offering lung cancer screening to everyone with a 20-year smoking history could expand access to screening, identify more cancers, and reduce disparities, new research suggests.

In an analysis of nearly 1 million US veterans, researchers estimated that a simplified approach to lung cancer screening — based on smoking duration rather than pack-years — would expand screening eligibility by nearly 30% and reduce potentially missed lung cancers by over 70%.

Those shifts would be especially pronounced among women and Black individuals — 2 groups that are underserved by current screening criteria.

The results, presented at the American Society of Clinical Oncology (ASCO) 2026, come at a time when some groups are revisiting their lung cancer screening guidelines.

And they support smoking duration as a “simpler, more sensitive, and more equitable metric for screening eligibility,” researcher Brendan T. Heiden, MD, MPHS, Washington University School of Medicine in St. Louis, St. Louis, told meeting attendees.

Toward a Better Metric

Current guidelines from the US Preventive Services Task Force (USPSTF) recommend annual lung cancer screening with low-dose CT for adults aged 50-80 years who have at least a 20 pack-year smoking history and either currently smoke or quit within the past 15 years.

The 20 pack-year metric is equivalent to smoking a pack of cigarettes per day for 20 years. Because it requires patients to remember their smoking intensity over decades, it can be challenging to calculate and translate into care, Heiden said.

As it stands, few Americans who are eligible under current USPSTF guidelines actually undergo lung cancer screening, at about 15%-20%, Heiden noted. Meanwhile, mounting evidence suggests that many lung cancers occur in individuals who never meet those eligibility criteria.

Boosting screening uptake, Heiden said, is not enough: There’s a need to revisit eligibility itself to reach more high-risk individuals.

Some groups are already taking steps in that direction. Recently updated guidelines from the National Comprehensive Cancer Network (NCCN) added a category 2B recommendation supporting screening for individuals with at least a 20-year smoking history, regardless of pack-years. (The guidelines also say former smokers are eligible no matter how long ago they quit.)

For their study, Heiden’s team sought to estimate the performance of that smoking-duration metric against current USPSTF pack-year criteria. They used Veterans Health Administration data on over 980,000 veterans whose smoking histories were prospectively collected; lung cancer diagnoses were identified through the Veterans Affairs Central Cancer Registry.

Most of the included veterans (67%) had a smoking history; their mean age was 64 years, and 21% were Black.

Overall, the researchers found that basing eligibility on 20-year smoking duration would substantially expand access to screening: Among veterans with a smoking history, 68% qualified for screening under current USPSTF criteria compared with 87% using the smoking-duration approach.

The gains were especially pronounced among women and Black individuals (who, based on prior research, typically smoke less intensely than White males). Under USPSTF criteria, only about 55% of female and Black veterans qualified for screening compared with 83% for both groups under the smoking-duration criterion.

Importantly, Heiden said, people meeting the smoking-duration threshold remained at substantially elevated risk for lung cancer, suggesting the broader screening criteria were not merely capturing low-risk smokers.

The 5-year lung cancer incidence among veterans eligible under the smoking-duration approach was 1.59% — 11 times the rate of 0.14% among never smokers.

Perhaps most striking, Heiden said, the proportion of potentially missed cancers dropped from 13% with the pack-year metric to just 4% using the smoking-duration metric — a relative reduction of more than 70%.

Again, women and Black individuals would see the largest gains: Among Black veterans, potentially missed cancers fell from 25% to 6%, whereas among female veterans they declined from 22% to 7%.

Optimal Approach Still Unclear

The analysis had limitations, including a predominantly male veteran population whose smoking exposure was far greater than that of the general US population, indicating high inherent lung cancer risk.

But the results support what the NCCN has already done, according to Mary Reid, PhD, MSPH, BSN, a member of the group’s lung cancer screening guideline panel and chief of cancer screening, survivorship and mentorship at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

“Doing the calculation for pack-years can be difficult,” Reid told Medscape Medical News. “Smoking duration is easier to calculate and really the way to go.”

The USPSTF does not comment on individual studies outside of its recommendation development process.

At the meeting, study discussant Katharine A. Rendle, PhD, called the work “impressive,” citing the size of the cohort and strength of the data.

It’s particularly noteworthy that the simpler screening criteria improved sensitivity for all veterans, while largely eliminating disparities, according to Rendle, of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

Still, she said, further research could better define the optimal screening strategy.

“Smoking duration is a promising approach, but in my opinion, guidelines likely need to account for the underlying risk in the population,” Rendle said, noting that current smoking prevalence in the US population is about 10%.

She suggested future studies consider other smoking-duration thresholds, such as 30 or 40 years, and look at other outcomes, including life-years gained.

“It’s critical that we prioritize strategies that maximize potential benefit from screening — not just identify those at lung cancer risk — given downstream costs and burden on populations and health care systems,” Rendle said.

The study had no commercial funding. Heiden, Rendle, and Reid had no relevant disclosures.

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

Offering lung cancer screening to everyone with a 20-year smoking history could expand access to screening, identify more cancers, and reduce disparities, new research suggests.

In an analysis of nearly 1 million US veterans, researchers estimated that a simplified approach to lung cancer screening — based on smoking duration rather than pack-years — would expand screening eligibility by nearly 30% and reduce potentially missed lung cancers by over 70%.

Those shifts would be especially pronounced among women and Black individuals — 2 groups that are underserved by current screening criteria.

The results, presented at the American Society of Clinical Oncology (ASCO) 2026, come at a time when some groups are revisiting their lung cancer screening guidelines.

And they support smoking duration as a “simpler, more sensitive, and more equitable metric for screening eligibility,” researcher Brendan T. Heiden, MD, MPHS, Washington University School of Medicine in St. Louis, St. Louis, told meeting attendees.

Toward a Better Metric

Current guidelines from the US Preventive Services Task Force (USPSTF) recommend annual lung cancer screening with low-dose CT for adults aged 50-80 years who have at least a 20 pack-year smoking history and either currently smoke or quit within the past 15 years.

The 20 pack-year metric is equivalent to smoking a pack of cigarettes per day for 20 years. Because it requires patients to remember their smoking intensity over decades, it can be challenging to calculate and translate into care, Heiden said.

As it stands, few Americans who are eligible under current USPSTF guidelines actually undergo lung cancer screening, at about 15%-20%, Heiden noted. Meanwhile, mounting evidence suggests that many lung cancers occur in individuals who never meet those eligibility criteria.

Boosting screening uptake, Heiden said, is not enough: There’s a need to revisit eligibility itself to reach more high-risk individuals.

Some groups are already taking steps in that direction. Recently updated guidelines from the National Comprehensive Cancer Network (NCCN) added a category 2B recommendation supporting screening for individuals with at least a 20-year smoking history, regardless of pack-years. (The guidelines also say former smokers are eligible no matter how long ago they quit.)

For their study, Heiden’s team sought to estimate the performance of that smoking-duration metric against current USPSTF pack-year criteria. They used Veterans Health Administration data on over 980,000 veterans whose smoking histories were prospectively collected; lung cancer diagnoses were identified through the Veterans Affairs Central Cancer Registry.

Most of the included veterans (67%) had a smoking history; their mean age was 64 years, and 21% were Black.

Overall, the researchers found that basing eligibility on 20-year smoking duration would substantially expand access to screening: Among veterans with a smoking history, 68% qualified for screening under current USPSTF criteria compared with 87% using the smoking-duration approach.

The gains were especially pronounced among women and Black individuals (who, based on prior research, typically smoke less intensely than White males). Under USPSTF criteria, only about 55% of female and Black veterans qualified for screening compared with 83% for both groups under the smoking-duration criterion.

Importantly, Heiden said, people meeting the smoking-duration threshold remained at substantially elevated risk for lung cancer, suggesting the broader screening criteria were not merely capturing low-risk smokers.

The 5-year lung cancer incidence among veterans eligible under the smoking-duration approach was 1.59% — 11 times the rate of 0.14% among never smokers.

Perhaps most striking, Heiden said, the proportion of potentially missed cancers dropped from 13% with the pack-year metric to just 4% using the smoking-duration metric — a relative reduction of more than 70%.

Again, women and Black individuals would see the largest gains: Among Black veterans, potentially missed cancers fell from 25% to 6%, whereas among female veterans they declined from 22% to 7%.

Optimal Approach Still Unclear

The analysis had limitations, including a predominantly male veteran population whose smoking exposure was far greater than that of the general US population, indicating high inherent lung cancer risk.

But the results support what the NCCN has already done, according to Mary Reid, PhD, MSPH, BSN, a member of the group’s lung cancer screening guideline panel and chief of cancer screening, survivorship and mentorship at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

“Doing the calculation for pack-years can be difficult,” Reid told Medscape Medical News. “Smoking duration is easier to calculate and really the way to go.”

The USPSTF does not comment on individual studies outside of its recommendation development process.

At the meeting, study discussant Katharine A. Rendle, PhD, called the work “impressive,” citing the size of the cohort and strength of the data.

It’s particularly noteworthy that the simpler screening criteria improved sensitivity for all veterans, while largely eliminating disparities, according to Rendle, of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

Still, she said, further research could better define the optimal screening strategy.

“Smoking duration is a promising approach, but in my opinion, guidelines likely need to account for the underlying risk in the population,” Rendle said, noting that current smoking prevalence in the US population is about 10%.

She suggested future studies consider other smoking-duration thresholds, such as 30 or 40 years, and look at other outcomes, including life-years gained.

“It’s critical that we prioritize strategies that maximize potential benefit from screening — not just identify those at lung cancer risk — given downstream costs and burden on populations and health care systems,” Rendle said.

The study had no commercial funding. Heiden, Rendle, and Reid had no relevant disclosures.

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

TOPLINE: Serum P21 Activated Kinase 6 (PAK6) demonstrated diagnostic accuracy comparable to pro-gastrin-releasing peptide (ProGRP) for small cell lung cancer (SCLC), with area under the curve (AUC) values of 0.892 and 0.935, respectively, in a study of 109 patients with SCLC. Combining PAK6, ProGRP, and neuron-specific enolase (NSE) achieved diagnostic efficiency of 0.98. Elevated baseline PAK6 levels correlated with shorter progression-free survival and increased risk for disease progression.

METHODOLOGY:

• Participants included 380 people in China: 109 with SCLC, 92 with non–small cell lung cancer (NSCLC), 85 with benign pulmonary nodules, and 94 healthy controls who received routine physical examinations. 

• Laboratory testing measured serum PAK6 by ELISA, while NSE, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and ProGRP were quantified by chemiluminescence. 

• Pretreatment and posttreatment serum samples from 56 patients with SCLC were analyzed to evaluate changes in biomarker levels following 3 months of treatment. 

• Progression-free survival data were collected through case review and follow-up, defined as time from treatment initiation to radiographic disease progression per RECIST 1.1 criteria or death from any cause.

TAKEAWAY:

• Median serum PAK6 is reported as 56.44 ng/L in SCLC vs 41.06 ng/L in NSCLC, 37.82 ng/L in pulmonary nodules, and 34.75 ng/L in healthy controls (P < .01). 

• PAK6 demonstrated diagnostic efficacy with and AUC of 0.892 (95% CI, 0.857-0.927), sensitivity of 0.82, and specificity of 0.86 at optimal cut-off value of 47.30 ng/L, comparable to ProGRP (AUC, 0.935) and superior to CEA (AUC, 0.676) and CA19-9 (AUC, 0.611). 

• In 56 paired SCLC samples, PAK6, NSE, and ProGRP decrease after 3 months of treatment (P < .001), while CEA and CA19-9 display no meaningful change. 

• Elevated baseline PAK6 expression correlated with shorter progression-free survival, with high-expression patients demonstrating median survival of 92 days vs 194 days in low-expression patients (HR, 2.02; 95% CI, 1.33-3.07; P = .001).

IN PRACTICE: “We identify PAK6 as a multi-faceted biomarker for SCLC with diagnostic, prognostic, and therapeutic monitoring value. Its cost-effective ELISA quantification facilitates clinical translation,” wrote the authors of the study. “Integrating PAK6 with emerging technologies could further refine SCLC management paradigms.”

SOURCE:The study was led by Simei Chen, Department of Blood Transfusion, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University in Nanchang, China. It was published online in PeerJ.

LIMITATIONS: A single-center design and modest sample size may limit generalizability of the diagnostic and prognostic estimates. The authors also note the absence of immunohistochemical validation, leaving tissue-level correlation of PAK6 unaddressed. Finally, insufficient overall survival data were reported, which constrains interpretation beyond PFS and supports the need for prospective follow-up and larger multi-center validation.

DISCLOSURES: Grant support came from the Science and Technology Program Project of Jiangxi Provincial Administration of Traditional Chinese Medicine (Grant 2024B1433). The authors stated the funders had no role in study design, data collection and analysis, the decision to publish, or manuscript preparation. No competing interests were disclosed.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: Serum P21 Activated Kinase 6 (PAK6) demonstrated diagnostic accuracy comparable to pro-gastrin-releasing peptide (ProGRP) for small cell lung cancer (SCLC), with area under the curve (AUC) values of 0.892 and 0.935, respectively, in a study of 109 patients with SCLC. Combining PAK6, ProGRP, and neuron-specific enolase (NSE) achieved diagnostic efficiency of 0.98. Elevated baseline PAK6 levels correlated with shorter progression-free survival and increased risk for disease progression.

METHODOLOGY:

• Participants included 380 people in China: 109 with SCLC, 92 with non–small cell lung cancer (NSCLC), 85 with benign pulmonary nodules, and 94 healthy controls who received routine physical examinations. 

• Laboratory testing measured serum PAK6 by ELISA, while NSE, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and ProGRP were quantified by chemiluminescence. 

• Pretreatment and posttreatment serum samples from 56 patients with SCLC were analyzed to evaluate changes in biomarker levels following 3 months of treatment. 

• Progression-free survival data were collected through case review and follow-up, defined as time from treatment initiation to radiographic disease progression per RECIST 1.1 criteria or death from any cause.

TAKEAWAY:

• Median serum PAK6 is reported as 56.44 ng/L in SCLC vs 41.06 ng/L in NSCLC, 37.82 ng/L in pulmonary nodules, and 34.75 ng/L in healthy controls (P < .01). 

• PAK6 demonstrated diagnostic efficacy with and AUC of 0.892 (95% CI, 0.857-0.927), sensitivity of 0.82, and specificity of 0.86 at optimal cut-off value of 47.30 ng/L, comparable to ProGRP (AUC, 0.935) and superior to CEA (AUC, 0.676) and CA19-9 (AUC, 0.611). 

• In 56 paired SCLC samples, PAK6, NSE, and ProGRP decrease after 3 months of treatment (P < .001), while CEA and CA19-9 display no meaningful change. 

• Elevated baseline PAK6 expression correlated with shorter progression-free survival, with high-expression patients demonstrating median survival of 92 days vs 194 days in low-expression patients (HR, 2.02; 95% CI, 1.33-3.07; P = .001).

IN PRACTICE: “We identify PAK6 as a multi-faceted biomarker for SCLC with diagnostic, prognostic, and therapeutic monitoring value. Its cost-effective ELISA quantification facilitates clinical translation,” wrote the authors of the study. “Integrating PAK6 with emerging technologies could further refine SCLC management paradigms.”

SOURCE:The study was led by Simei Chen, Department of Blood Transfusion, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University in Nanchang, China. It was published online in PeerJ.

LIMITATIONS: A single-center design and modest sample size may limit generalizability of the diagnostic and prognostic estimates. The authors also note the absence of immunohistochemical validation, leaving tissue-level correlation of PAK6 unaddressed. Finally, insufficient overall survival data were reported, which constrains interpretation beyond PFS and supports the need for prospective follow-up and larger multi-center validation.

DISCLOSURES: Grant support came from the Science and Technology Program Project of Jiangxi Provincial Administration of Traditional Chinese Medicine (Grant 2024B1433). The authors stated the funders had no role in study design, data collection and analysis, the decision to publish, or manuscript preparation. No competing interests were disclosed.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: Serum P21 Activated Kinase 6 (PAK6) demonstrated diagnostic accuracy comparable to pro-gastrin-releasing peptide (ProGRP) for small cell lung cancer (SCLC), with area under the curve (AUC) values of 0.892 and 0.935, respectively, in a study of 109 patients with SCLC. Combining PAK6, ProGRP, and neuron-specific enolase (NSE) achieved diagnostic efficiency of 0.98. Elevated baseline PAK6 levels correlated with shorter progression-free survival and increased risk for disease progression.

METHODOLOGY:

• Participants included 380 people in China: 109 with SCLC, 92 with non–small cell lung cancer (NSCLC), 85 with benign pulmonary nodules, and 94 healthy controls who received routine physical examinations. 

• Laboratory testing measured serum PAK6 by ELISA, while NSE, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and ProGRP were quantified by chemiluminescence. 

• Pretreatment and posttreatment serum samples from 56 patients with SCLC were analyzed to evaluate changes in biomarker levels following 3 months of treatment. 

• Progression-free survival data were collected through case review and follow-up, defined as time from treatment initiation to radiographic disease progression per RECIST 1.1 criteria or death from any cause.

TAKEAWAY:

• Median serum PAK6 is reported as 56.44 ng/L in SCLC vs 41.06 ng/L in NSCLC, 37.82 ng/L in pulmonary nodules, and 34.75 ng/L in healthy controls (P < .01). 

• PAK6 demonstrated diagnostic efficacy with and AUC of 0.892 (95% CI, 0.857-0.927), sensitivity of 0.82, and specificity of 0.86 at optimal cut-off value of 47.30 ng/L, comparable to ProGRP (AUC, 0.935) and superior to CEA (AUC, 0.676) and CA19-9 (AUC, 0.611). 

• In 56 paired SCLC samples, PAK6, NSE, and ProGRP decrease after 3 months of treatment (P < .001), while CEA and CA19-9 display no meaningful change. 

• Elevated baseline PAK6 expression correlated with shorter progression-free survival, with high-expression patients demonstrating median survival of 92 days vs 194 days in low-expression patients (HR, 2.02; 95% CI, 1.33-3.07; P = .001).

IN PRACTICE: “We identify PAK6 as a multi-faceted biomarker for SCLC with diagnostic, prognostic, and therapeutic monitoring value. Its cost-effective ELISA quantification facilitates clinical translation,” wrote the authors of the study. “Integrating PAK6 with emerging technologies could further refine SCLC management paradigms.”

SOURCE:The study was led by Simei Chen, Department of Blood Transfusion, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University in Nanchang, China. It was published online in PeerJ.

LIMITATIONS: A single-center design and modest sample size may limit generalizability of the diagnostic and prognostic estimates. The authors also note the absence of immunohistochemical validation, leaving tissue-level correlation of PAK6 unaddressed. Finally, insufficient overall survival data were reported, which constrains interpretation beyond PFS and supports the need for prospective follow-up and larger multi-center validation.

DISCLOSURES: Grant support came from the Science and Technology Program Project of Jiangxi Provincial Administration of Traditional Chinese Medicine (Grant 2024B1433). The authors stated the funders had no role in study design, data collection and analysis, the decision to publish, or manuscript preparation. No competing interests were disclosed.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

This transcript has been edited for clarity.

Hello, everyone. This is Dr Bishal Gyawali, from Queens University, Kingston, Canada. Today, I’m back with you to talk about some of the fallacies that I have seen in medicine, oncology, and the drug regulatory space. I wanted to clarify some of these fallacies.

In my last video, I talked about the FDA denying the approval of a new cancer drug. Let me start with one of the fallacies that is pertinent to that, which is that some people make an argument that patients are dying from a certain condition, such as cancer, or even any other disease besides cancer. That is an absolutely true statement, but that does not necessarily mean there should be a lower bar for drug approvals or we should be approving any drug that has a hint of benefit.

In fact, if we have increased mortality rates and our patients are dying from a certain condition, that means we actually need to have good drugs. We need to have drugs that prevent mortality. We need to have drugs that improve outcomes. Just having any drug out there, if we lower our threshold and are letting any drug be used in these patients because the argument is that people are dying, then in fact, it can have negative consequences.

First, there will be opportunity costs. If you can get any lousy drug into the market and make billions of dollars out of it, then there is no strong motivation to produce drugs that actually remarkably improve outcomes.

Second, patients will also be misled. It’s the patient’s opportunity cost in that they will use whatever time they have remaining to pursue these treatments that were not going to improve their outcomes anyway. This is time they could have better spent either in pursuing better treatments, if those treatments are out there, or to prioritize their time accordingly. This rather gives them a false hope, which can be harmful in the long term.

The first fallacy is that just because people are dying does not necessarily mean we should have more new drugs with a lower bar for approval.

The second fallacy I want to talk about, which is also related to this, is that if a certain cancer is rare, the bar for new drug approval should be quite low.

Of course, rare cancers are a special category, and rare cancers should be treated differently from a regulatory perspective. Absolutely. If the cancer is rare, we cannot have trials with large sample sizes to generate evidence. That problem is there, but that does not necessarily translate to the decision that we should approve anything, even something with a small hint of benefit.

There are other methods to make sure that, even in rare cancers, we can generate good-quality evidence. In fact, from an equity perspective, why should patients with rare cancer not deserve drugs that have good-quality evidence?

We can’t tell someone that, “Your cancer is rare, so you should get drugs that only have a benefit in terms of response rate whereas other cancers that are not rare will have drugs based on survival.”

Going back to the point about the difficulty in doing big trials in patients with rare cancers, that is absolutely true and there should be regulatory flexibility in this. I think accelerated approval is a pathway that allows for this regulatory flexibility, which allows access to these drugs early on based on earlier signals of benefit. You can continue to generate evidence in the future and confirm the clinical benefit.

There are also other nuances to this. One is that we should also make sure that this regulatory flexibility with rare cancers should not be misused. What do I mean by that? First, all rare cancers are not the same. There are some cancers that are ultra rare, and then there are some cancers that technically might fit the definition of rare, but trials are possible. Case in point: adrenocortical cancer. It is considered to be a very rare cancer, but there have been randomized trials in adrenocortical cancer.

Our efforts should be to maximize our collaboration globally so that a cancer that is rare locally will still not be so rare globally when we collect all these patients.

In certain situations, like let’s say, based on the molecular subtypes, any common cancer can be sliced and diced into a rare subtype: MSI-high, BRAF-negative, HER2-positive, right-sided colon cancer. If you start to slice cancers into these smaller and smaller molecular subtypes, you can consider anything as a rare cancer. That should not be misused as an excuse to get away from doing proper trials and generating adequate evidence for our patients.

The third fallacy I want to talk about is that increasing cancer incidence in a certain subgroup of population does not automatically translate into, “We should start screening this subgroup of population.”

A certain cancer — let’s say cancer X or cancer Y — is increasing in a young population, so therefore, we should lower the age of the screening of young populations. This cancer is increasing in this ethnic population, so therefore we should start screening this ethnic population more frequently. This cancer is increasing in this type of minority, so therefore, we should start screening this minority more.

No, it does not work like that. Increasing incidence will make us concerned, of course, but that does not necessarily translate into, “We should start screening them.” In order for a screening test to be useful, it has to fulfill a number of criteria.

The goal is not to detect cancers. The goal is to detect cancers that are not indolent enough that they would have never caused problems, nor speed up the diagnosis of aggressive cancers that are going to be lethal pretty soon anyway. The goal is to detect those cancers in the middle, so that by detecting early, we can intervene and improve the outcomes and improve the mortality from that cancer.

This type of intervention requires a thoughtful consideration of the increasing incidence of the cancer, of course, but also the utility of the screening test in that subgroup of population; the life expectancy of this subgroup of patients with and without cancer; the interventions available to address that increasing burden of cancer; and whether by intervening we are going to reduce the mortality rates.

Just because we can detect cancers does not mean we should detect cancers. That’s the third fallacy I wanted to talk about.

The fourth fallacy is related to when someone is asking for more evidence for anything. There is a new drug for this cancer,so what is the evidence? Or there is this new intervention that will detect ctDNA or whatever before the cancer relapses, or before the cancer even shows up as a screening test.

Whenever there is any treatment that is being promoted and someone asks for evidence, people sometimes try to make personal attacks by saying, “Oh, so, you’re okay with patients dying. You don’t want to save lives.”

Absolutely we want to save lives. That’s why we’re in this field, and that’s why we’re asking for more evidence. You should not consider someone who is asking for evidence as evil or that this person does not want this new drug, or this person does not want this innovation. No, that person actually wants to make sure that that innovation actually helps people. That’s why that person is asking for more evidence.

If we stop asking for evidence, then our whole practice becomes based on emotions, faith, and trust rather than science. You could extrapolate it to the other extreme, like if you are not asking for evidence. If it is interpreted as someone who is asking for evidence is evil, or someone who does not want patients to get new drugs, then you could extrapolate these to people also making claims about alternative medicines or ivermectin nowadays, and claiming that this cures cancer.

Science is science. You need to be the same no matter the circumstances. If you are asking for data for ivermectin, you should also be asking data for your cancer drug that you think is going to work. We should always ask for evidence.

Asking for evidence is not a sign that whoever is asking for evidence does not want the patient to have access to the drug. It is showing that the person who is asking for evidence actually wants to make sure that the patients who get this drug are actually being helped by the drug rather than being harmed.

I’m talking about 5 fallacies today. The final, fifth fallacy is that clinical expertise does not equal expertise in making public health decisions or even expertise in critical appraisal. Someone can be a fantastic breast cancer doctor, the best oncologist for breast cancer. That does not automatically make that person the best person to evaluate clinical trials of breast cancer drugs.

Someone can be a fantastic colon cancer doctor. That does not make that person automatically the best person to evaluate whether or not colonoscopy or colon cancer screening is indicated in a certain patient population.

These population-level decisions — including should this drug be approved, should this drug be funded, and should this screening test be made a public health measure, all of these public health decisions that are done at a population level — require different expertise in critical appraisal, clinical epidemiology, and public health.

Just because someone is a fantastic clinician does not make that person a fantastic public health expert. I see on social media often that a famous doctor with expertise in their domain, let’s say a famous neurosurgeon, might say, “I think brain tumors are increasing in incidence in young persons, so we should be targeting an MRI screening for everyone over the age of 30.”

I’m just making this up, but we see examples of things not dissimilar to this. Just because someone is a neurosurgeon does not make them an expert on brain tumor epidemiology, surveillance, or screening. We should separate clinical expertise from public health expertise.

Thank you.

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

This transcript has been edited for clarity.

Hello, everyone. This is Dr Bishal Gyawali, from Queens University, Kingston, Canada. Today, I’m back with you to talk about some of the fallacies that I have seen in medicine, oncology, and the drug regulatory space. I wanted to clarify some of these fallacies.

In my last video, I talked about the FDA denying the approval of a new cancer drug. Let me start with one of the fallacies that is pertinent to that, which is that some people make an argument that patients are dying from a certain condition, such as cancer, or even any other disease besides cancer. That is an absolutely true statement, but that does not necessarily mean there should be a lower bar for drug approvals or we should be approving any drug that has a hint of benefit.

In fact, if we have increased mortality rates and our patients are dying from a certain condition, that means we actually need to have good drugs. We need to have drugs that prevent mortality. We need to have drugs that improve outcomes. Just having any drug out there, if we lower our threshold and are letting any drug be used in these patients because the argument is that people are dying, then in fact, it can have negative consequences.

First, there will be opportunity costs. If you can get any lousy drug into the market and make billions of dollars out of it, then there is no strong motivation to produce drugs that actually remarkably improve outcomes.

Second, patients will also be misled. It’s the patient’s opportunity cost in that they will use whatever time they have remaining to pursue these treatments that were not going to improve their outcomes anyway. This is time they could have better spent either in pursuing better treatments, if those treatments are out there, or to prioritize their time accordingly. This rather gives them a false hope, which can be harmful in the long term.

The first fallacy is that just because people are dying does not necessarily mean we should have more new drugs with a lower bar for approval.

The second fallacy I want to talk about, which is also related to this, is that if a certain cancer is rare, the bar for new drug approval should be quite low.

Of course, rare cancers are a special category, and rare cancers should be treated differently from a regulatory perspective. Absolutely. If the cancer is rare, we cannot have trials with large sample sizes to generate evidence. That problem is there, but that does not necessarily translate to the decision that we should approve anything, even something with a small hint of benefit.

There are other methods to make sure that, even in rare cancers, we can generate good-quality evidence. In fact, from an equity perspective, why should patients with rare cancer not deserve drugs that have good-quality evidence?

We can’t tell someone that, “Your cancer is rare, so you should get drugs that only have a benefit in terms of response rate whereas other cancers that are not rare will have drugs based on survival.”

Going back to the point about the difficulty in doing big trials in patients with rare cancers, that is absolutely true and there should be regulatory flexibility in this. I think accelerated approval is a pathway that allows for this regulatory flexibility, which allows access to these drugs early on based on earlier signals of benefit. You can continue to generate evidence in the future and confirm the clinical benefit.

There are also other nuances to this. One is that we should also make sure that this regulatory flexibility with rare cancers should not be misused. What do I mean by that? First, all rare cancers are not the same. There are some cancers that are ultra rare, and then there are some cancers that technically might fit the definition of rare, but trials are possible. Case in point: adrenocortical cancer. It is considered to be a very rare cancer, but there have been randomized trials in adrenocortical cancer.

Our efforts should be to maximize our collaboration globally so that a cancer that is rare locally will still not be so rare globally when we collect all these patients.

In certain situations, like let’s say, based on the molecular subtypes, any common cancer can be sliced and diced into a rare subtype: MSI-high, BRAF-negative, HER2-positive, right-sided colon cancer. If you start to slice cancers into these smaller and smaller molecular subtypes, you can consider anything as a rare cancer. That should not be misused as an excuse to get away from doing proper trials and generating adequate evidence for our patients.

The third fallacy I want to talk about is that increasing cancer incidence in a certain subgroup of population does not automatically translate into, “We should start screening this subgroup of population.”

A certain cancer — let’s say cancer X or cancer Y — is increasing in a young population, so therefore, we should lower the age of the screening of young populations. This cancer is increasing in this ethnic population, so therefore we should start screening this ethnic population more frequently. This cancer is increasing in this type of minority, so therefore, we should start screening this minority more.

No, it does not work like that. Increasing incidence will make us concerned, of course, but that does not necessarily translate into, “We should start screening them.” In order for a screening test to be useful, it has to fulfill a number of criteria.

The goal is not to detect cancers. The goal is to detect cancers that are not indolent enough that they would have never caused problems, nor speed up the diagnosis of aggressive cancers that are going to be lethal pretty soon anyway. The goal is to detect those cancers in the middle, so that by detecting early, we can intervene and improve the outcomes and improve the mortality from that cancer.

This type of intervention requires a thoughtful consideration of the increasing incidence of the cancer, of course, but also the utility of the screening test in that subgroup of population; the life expectancy of this subgroup of patients with and without cancer; the interventions available to address that increasing burden of cancer; and whether by intervening we are going to reduce the mortality rates.

Just because we can detect cancers does not mean we should detect cancers. That’s the third fallacy I wanted to talk about.

The fourth fallacy is related to when someone is asking for more evidence for anything. There is a new drug for this cancer,so what is the evidence? Or there is this new intervention that will detect ctDNA or whatever before the cancer relapses, or before the cancer even shows up as a screening test.

Whenever there is any treatment that is being promoted and someone asks for evidence, people sometimes try to make personal attacks by saying, “Oh, so, you’re okay with patients dying. You don’t want to save lives.”

Absolutely we want to save lives. That’s why we’re in this field, and that’s why we’re asking for more evidence. You should not consider someone who is asking for evidence as evil or that this person does not want this new drug, or this person does not want this innovation. No, that person actually wants to make sure that that innovation actually helps people. That’s why that person is asking for more evidence.

If we stop asking for evidence, then our whole practice becomes based on emotions, faith, and trust rather than science. You could extrapolate it to the other extreme, like if you are not asking for evidence. If it is interpreted as someone who is asking for evidence is evil, or someone who does not want patients to get new drugs, then you could extrapolate these to people also making claims about alternative medicines or ivermectin nowadays, and claiming that this cures cancer.

Science is science. You need to be the same no matter the circumstances. If you are asking for data for ivermectin, you should also be asking data for your cancer drug that you think is going to work. We should always ask for evidence.

Asking for evidence is not a sign that whoever is asking for evidence does not want the patient to have access to the drug. It is showing that the person who is asking for evidence actually wants to make sure that the patients who get this drug are actually being helped by the drug rather than being harmed.

I’m talking about 5 fallacies today. The final, fifth fallacy is that clinical expertise does not equal expertise in making public health decisions or even expertise in critical appraisal. Someone can be a fantastic breast cancer doctor, the best oncologist for breast cancer. That does not automatically make that person the best person to evaluate clinical trials of breast cancer drugs.

Someone can be a fantastic colon cancer doctor. That does not make that person automatically the best person to evaluate whether or not colonoscopy or colon cancer screening is indicated in a certain patient population.

These population-level decisions — including should this drug be approved, should this drug be funded, and should this screening test be made a public health measure, all of these public health decisions that are done at a population level — require different expertise in critical appraisal, clinical epidemiology, and public health.

Just because someone is a fantastic clinician does not make that person a fantastic public health expert. I see on social media often that a famous doctor with expertise in their domain, let’s say a famous neurosurgeon, might say, “I think brain tumors are increasing in incidence in young persons, so we should be targeting an MRI screening for everyone over the age of 30.”

I’m just making this up, but we see examples of things not dissimilar to this. Just because someone is a neurosurgeon does not make them an expert on brain tumor epidemiology, surveillance, or screening. We should separate clinical expertise from public health expertise.

Thank you.

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

This transcript has been edited for clarity.

Hello, everyone. This is Dr Bishal Gyawali, from Queens University, Kingston, Canada. Today, I’m back with you to talk about some of the fallacies that I have seen in medicine, oncology, and the drug regulatory space. I wanted to clarify some of these fallacies.

In my last video, I talked about the FDA denying the approval of a new cancer drug. Let me start with one of the fallacies that is pertinent to that, which is that some people make an argument that patients are dying from a certain condition, such as cancer, or even any other disease besides cancer. That is an absolutely true statement, but that does not necessarily mean there should be a lower bar for drug approvals or we should be approving any drug that has a hint of benefit.

In fact, if we have increased mortality rates and our patients are dying from a certain condition, that means we actually need to have good drugs. We need to have drugs that prevent mortality. We need to have drugs that improve outcomes. Just having any drug out there, if we lower our threshold and are letting any drug be used in these patients because the argument is that people are dying, then in fact, it can have negative consequences.

First, there will be opportunity costs. If you can get any lousy drug into the market and make billions of dollars out of it, then there is no strong motivation to produce drugs that actually remarkably improve outcomes.

Second, patients will also be misled. It’s the patient’s opportunity cost in that they will use whatever time they have remaining to pursue these treatments that were not going to improve their outcomes anyway. This is time they could have better spent either in pursuing better treatments, if those treatments are out there, or to prioritize their time accordingly. This rather gives them a false hope, which can be harmful in the long term.

The first fallacy is that just because people are dying does not necessarily mean we should have more new drugs with a lower bar for approval.

The second fallacy I want to talk about, which is also related to this, is that if a certain cancer is rare, the bar for new drug approval should be quite low.

Of course, rare cancers are a special category, and rare cancers should be treated differently from a regulatory perspective. Absolutely. If the cancer is rare, we cannot have trials with large sample sizes to generate evidence. That problem is there, but that does not necessarily translate to the decision that we should approve anything, even something with a small hint of benefit.

There are other methods to make sure that, even in rare cancers, we can generate good-quality evidence. In fact, from an equity perspective, why should patients with rare cancer not deserve drugs that have good-quality evidence?

We can’t tell someone that, “Your cancer is rare, so you should get drugs that only have a benefit in terms of response rate whereas other cancers that are not rare will have drugs based on survival.”

Going back to the point about the difficulty in doing big trials in patients with rare cancers, that is absolutely true and there should be regulatory flexibility in this. I think accelerated approval is a pathway that allows for this regulatory flexibility, which allows access to these drugs early on based on earlier signals of benefit. You can continue to generate evidence in the future and confirm the clinical benefit.

There are also other nuances to this. One is that we should also make sure that this regulatory flexibility with rare cancers should not be misused. What do I mean by that? First, all rare cancers are not the same. There are some cancers that are ultra rare, and then there are some cancers that technically might fit the definition of rare, but trials are possible. Case in point: adrenocortical cancer. It is considered to be a very rare cancer, but there have been randomized trials in adrenocortical cancer.

Our efforts should be to maximize our collaboration globally so that a cancer that is rare locally will still not be so rare globally when we collect all these patients.

In certain situations, like let’s say, based on the molecular subtypes, any common cancer can be sliced and diced into a rare subtype: MSI-high, BRAF-negative, HER2-positive, right-sided colon cancer. If you start to slice cancers into these smaller and smaller molecular subtypes, you can consider anything as a rare cancer. That should not be misused as an excuse to get away from doing proper trials and generating adequate evidence for our patients.

The third fallacy I want to talk about is that increasing cancer incidence in a certain subgroup of population does not automatically translate into, “We should start screening this subgroup of population.”

A certain cancer — let’s say cancer X or cancer Y — is increasing in a young population, so therefore, we should lower the age of the screening of young populations. This cancer is increasing in this ethnic population, so therefore we should start screening this ethnic population more frequently. This cancer is increasing in this type of minority, so therefore, we should start screening this minority more.

No, it does not work like that. Increasing incidence will make us concerned, of course, but that does not necessarily translate into, “We should start screening them.” In order for a screening test to be useful, it has to fulfill a number of criteria.

The goal is not to detect cancers. The goal is to detect cancers that are not indolent enough that they would have never caused problems, nor speed up the diagnosis of aggressive cancers that are going to be lethal pretty soon anyway. The goal is to detect those cancers in the middle, so that by detecting early, we can intervene and improve the outcomes and improve the mortality from that cancer.

This type of intervention requires a thoughtful consideration of the increasing incidence of the cancer, of course, but also the utility of the screening test in that subgroup of population; the life expectancy of this subgroup of patients with and without cancer; the interventions available to address that increasing burden of cancer; and whether by intervening we are going to reduce the mortality rates.

Just because we can detect cancers does not mean we should detect cancers. That’s the third fallacy I wanted to talk about.

The fourth fallacy is related to when someone is asking for more evidence for anything. There is a new drug for this cancer,so what is the evidence? Or there is this new intervention that will detect ctDNA or whatever before the cancer relapses, or before the cancer even shows up as a screening test.

Whenever there is any treatment that is being promoted and someone asks for evidence, people sometimes try to make personal attacks by saying, “Oh, so, you’re okay with patients dying. You don’t want to save lives.”

Absolutely we want to save lives. That’s why we’re in this field, and that’s why we’re asking for more evidence. You should not consider someone who is asking for evidence as evil or that this person does not want this new drug, or this person does not want this innovation. No, that person actually wants to make sure that that innovation actually helps people. That’s why that person is asking for more evidence.

If we stop asking for evidence, then our whole practice becomes based on emotions, faith, and trust rather than science. You could extrapolate it to the other extreme, like if you are not asking for evidence. If it is interpreted as someone who is asking for evidence is evil, or someone who does not want patients to get new drugs, then you could extrapolate these to people also making claims about alternative medicines or ivermectin nowadays, and claiming that this cures cancer.

Science is science. You need to be the same no matter the circumstances. If you are asking for data for ivermectin, you should also be asking data for your cancer drug that you think is going to work. We should always ask for evidence.

Asking for evidence is not a sign that whoever is asking for evidence does not want the patient to have access to the drug. It is showing that the person who is asking for evidence actually wants to make sure that the patients who get this drug are actually being helped by the drug rather than being harmed.

I’m talking about 5 fallacies today. The final, fifth fallacy is that clinical expertise does not equal expertise in making public health decisions or even expertise in critical appraisal. Someone can be a fantastic breast cancer doctor, the best oncologist for breast cancer. That does not automatically make that person the best person to evaluate clinical trials of breast cancer drugs.

Someone can be a fantastic colon cancer doctor. That does not make that person automatically the best person to evaluate whether or not colonoscopy or colon cancer screening is indicated in a certain patient population.

These population-level decisions — including should this drug be approved, should this drug be funded, and should this screening test be made a public health measure, all of these public health decisions that are done at a population level — require different expertise in critical appraisal, clinical epidemiology, and public health.

Just because someone is a fantastic clinician does not make that person a fantastic public health expert. I see on social media often that a famous doctor with expertise in their domain, let’s say a famous neurosurgeon, might say, “I think brain tumors are increasing in incidence in young persons, so we should be targeting an MRI screening for everyone over the age of 30.”

I’m just making this up, but we see examples of things not dissimilar to this. Just because someone is a neurosurgeon does not make them an expert on brain tumor epidemiology, surveillance, or screening. We should separate clinical expertise from public health expertise.

Thank you.

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

Approximately about 1 in 4 eligible Americans are up to date on their lung cancer screening, according to a recent study in JAMA Internal Medicine, prompting a need for clinicians to simplify referrals and scheduling of annual appointments.

Despite a 32% increase in lung cancer screening between 2022 and 2024, rates overall remain low at nearly 25%, and especially among patients between ages 50 and 54 years (11.32%; P < .05).

Determining eligibility entails calculating the total years a patient smoked cigarettes, whereas other screenings are based solely on age, such as breast cancer and colon cancer.

Some clinicians “will get into trying to do an actual pack year calculation, or where they smoked half a pack for this many years, and then they quit for this many years, and then, you know, they’re trying to do this massive calculation. And the reality is, we’re just trying to get a patient who’s at high risk for lung cancer” in for screening, said Timothy Mullett, MD, a thoracic surgeon and medical director of the Markey Cancer Center Network Development, University of Kentucky in Lexington, Kentucky, who helped the study authors.

As the second most common form of the disease, lung cancer is the leading cause of such mortality in the US. But low rates of screening mean opportunities for early detection are missed.

In an analysis of national survey data including 26,104 patients (45.6% women and 54.4% men) eligible for lung cancer screening between ages 50 and 79 years, rates increased from 18.49% to 24.49% (P < .05) over a 2-year period starting in 2022. 

Approximately one quarter of men and women were up to date on their screening (P < .05). Nearly one third of patients aged 65 years or older were up to date, whereas those between ages 50 and 54 years (11.32%), 55 and 59 years (19.45%), and 60 and 64 years (23.99%) showed lower rates.

Patients were most likely to be up to date on their screenings in the Northeast region of the country, with Massachusetts showing the highest prevalence rate (38.36%). The rate was lowest in South Dakota (13.43%).

No significant changes in rates were observed for Asian, Black, or Hispanic adults. Adults who were American Indian or Alaska native showed the largest improvement, from 18.74% in 2022 to 30.8% in 2024 (P < .05).

The US Preventive Services Task Force recommends annual screening starting at age 50 for individuals who are current smokers or previous smokers who have a history of consuming at least a pack a day for two decades. Previous smokers must have quit within the previous 15 years to qualify.

Making these calculations can be tricky, Mullett said. Patients’ tobacco use can change over time and a screening tool may not account for those changes. He encourages clinicians to take time to ask patients for more detail about their history. For instance, someone who smokes a half a pack a day now may not immediately qualify for screening, but deeper probing might reveal that they previously smoked two packs a day.

Tamatha Hughes, RN, a nurse navigator for the Missouri Baptist Lung Cancer Screening Program, Missouri Baptist Medical Center in St. Louis, said she often calms fears and corrects misinformation when scheduling patients for their first screening. Some patients think the screening involves an MRI or that radiation from the CT scan is dangerous.

“We go through explaining it as simple as possible,” she said.

If she has a referral for a patient who does not move forward with scheduling, she said she will try them again a few weeks later. Annual screenings are scheduled at a patient’s first appointment, and she said her clinic has an 80% rate for returning patients.

Getting the first scan is the biggest hurdle. Many patients feel stigma or associate lung cancer with a hopeless diagnosis, which can reduce rates, Mullet said.

“There’s a sense of fatalism, because all they’ve ever experienced with lung cancer has been someone who’s died from lung cancer, their grandmother, their grandfather, died of lung cancer. And historically, lung cancer has been found in late stages over 80% of the time,” he said. But screening has drastically improved rates of survival.

“We keep trying to tell patients that this is not your grandfather’s lung cancer,” Mullett said. “This is not what you saw in your family growing up, and we can find it early and we can treat it, and we even if we find it late, we have better treatments now.”

The study was funded by grants from the National Cancer Institute, the William Stamps Farish Endowed Chair in Cancer Research, and the CDC. Mullett and Hughes reported having no relevant financial disclosures.

Kelsey Mesmer, PhD, is a freelance journalist and journalism professor at Saint Louis University in St. Louis.

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

Approximately about 1 in 4 eligible Americans are up to date on their lung cancer screening, according to a recent study in JAMA Internal Medicine, prompting a need for clinicians to simplify referrals and scheduling of annual appointments.

Despite a 32% increase in lung cancer screening between 2022 and 2024, rates overall remain low at nearly 25%, and especially among patients between ages 50 and 54 years (11.32%; P < .05).

Determining eligibility entails calculating the total years a patient smoked cigarettes, whereas other screenings are based solely on age, such as breast cancer and colon cancer.

Some clinicians “will get into trying to do an actual pack year calculation, or where they smoked half a pack for this many years, and then they quit for this many years, and then, you know, they’re trying to do this massive calculation. And the reality is, we’re just trying to get a patient who’s at high risk for lung cancer” in for screening, said Timothy Mullett, MD, a thoracic surgeon and medical director of the Markey Cancer Center Network Development, University of Kentucky in Lexington, Kentucky, who helped the study authors.

As the second most common form of the disease, lung cancer is the leading cause of such mortality in the US. But low rates of screening mean opportunities for early detection are missed.

In an analysis of national survey data including 26,104 patients (45.6% women and 54.4% men) eligible for lung cancer screening between ages 50 and 79 years, rates increased from 18.49% to 24.49% (P < .05) over a 2-year period starting in 2022. 

Approximately one quarter of men and women were up to date on their screening (P < .05). Nearly one third of patients aged 65 years or older were up to date, whereas those between ages 50 and 54 years (11.32%), 55 and 59 years (19.45%), and 60 and 64 years (23.99%) showed lower rates.

Patients were most likely to be up to date on their screenings in the Northeast region of the country, with Massachusetts showing the highest prevalence rate (38.36%). The rate was lowest in South Dakota (13.43%).

No significant changes in rates were observed for Asian, Black, or Hispanic adults. Adults who were American Indian or Alaska native showed the largest improvement, from 18.74% in 2022 to 30.8% in 2024 (P < .05).

The US Preventive Services Task Force recommends annual screening starting at age 50 for individuals who are current smokers or previous smokers who have a history of consuming at least a pack a day for two decades. Previous smokers must have quit within the previous 15 years to qualify.

Making these calculations can be tricky, Mullett said. Patients’ tobacco use can change over time and a screening tool may not account for those changes. He encourages clinicians to take time to ask patients for more detail about their history. For instance, someone who smokes a half a pack a day now may not immediately qualify for screening, but deeper probing might reveal that they previously smoked two packs a day.

Tamatha Hughes, RN, a nurse navigator for the Missouri Baptist Lung Cancer Screening Program, Missouri Baptist Medical Center in St. Louis, said she often calms fears and corrects misinformation when scheduling patients for their first screening. Some patients think the screening involves an MRI or that radiation from the CT scan is dangerous.

“We go through explaining it as simple as possible,” she said.

If she has a referral for a patient who does not move forward with scheduling, she said she will try them again a few weeks later. Annual screenings are scheduled at a patient’s first appointment, and she said her clinic has an 80% rate for returning patients.

Getting the first scan is the biggest hurdle. Many patients feel stigma or associate lung cancer with a hopeless diagnosis, which can reduce rates, Mullet said.

“There’s a sense of fatalism, because all they’ve ever experienced with lung cancer has been someone who’s died from lung cancer, their grandmother, their grandfather, died of lung cancer. And historically, lung cancer has been found in late stages over 80% of the time,” he said. But screening has drastically improved rates of survival.

“We keep trying to tell patients that this is not your grandfather’s lung cancer,” Mullett said. “This is not what you saw in your family growing up, and we can find it early and we can treat it, and we even if we find it late, we have better treatments now.”

The study was funded by grants from the National Cancer Institute, the William Stamps Farish Endowed Chair in Cancer Research, and the CDC. Mullett and Hughes reported having no relevant financial disclosures.

Kelsey Mesmer, PhD, is a freelance journalist and journalism professor at Saint Louis University in St. Louis.

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

Approximately about 1 in 4 eligible Americans are up to date on their lung cancer screening, according to a recent study in JAMA Internal Medicine, prompting a need for clinicians to simplify referrals and scheduling of annual appointments.

Despite a 32% increase in lung cancer screening between 2022 and 2024, rates overall remain low at nearly 25%, and especially among patients between ages 50 and 54 years (11.32%; P < .05).

Determining eligibility entails calculating the total years a patient smoked cigarettes, whereas other screenings are based solely on age, such as breast cancer and colon cancer.

Some clinicians “will get into trying to do an actual pack year calculation, or where they smoked half a pack for this many years, and then they quit for this many years, and then, you know, they’re trying to do this massive calculation. And the reality is, we’re just trying to get a patient who’s at high risk for lung cancer” in for screening, said Timothy Mullett, MD, a thoracic surgeon and medical director of the Markey Cancer Center Network Development, University of Kentucky in Lexington, Kentucky, who helped the study authors.

As the second most common form of the disease, lung cancer is the leading cause of such mortality in the US. But low rates of screening mean opportunities for early detection are missed.

In an analysis of national survey data including 26,104 patients (45.6% women and 54.4% men) eligible for lung cancer screening between ages 50 and 79 years, rates increased from 18.49% to 24.49% (P < .05) over a 2-year period starting in 2022. 

Approximately one quarter of men and women were up to date on their screening (P < .05). Nearly one third of patients aged 65 years or older were up to date, whereas those between ages 50 and 54 years (11.32%), 55 and 59 years (19.45%), and 60 and 64 years (23.99%) showed lower rates.

Patients were most likely to be up to date on their screenings in the Northeast region of the country, with Massachusetts showing the highest prevalence rate (38.36%). The rate was lowest in South Dakota (13.43%).

No significant changes in rates were observed for Asian, Black, or Hispanic adults. Adults who were American Indian or Alaska native showed the largest improvement, from 18.74% in 2022 to 30.8% in 2024 (P < .05).

The US Preventive Services Task Force recommends annual screening starting at age 50 for individuals who are current smokers or previous smokers who have a history of consuming at least a pack a day for two decades. Previous smokers must have quit within the previous 15 years to qualify.

Making these calculations can be tricky, Mullett said. Patients’ tobacco use can change over time and a screening tool may not account for those changes. He encourages clinicians to take time to ask patients for more detail about their history. For instance, someone who smokes a half a pack a day now may not immediately qualify for screening, but deeper probing might reveal that they previously smoked two packs a day.

Tamatha Hughes, RN, a nurse navigator for the Missouri Baptist Lung Cancer Screening Program, Missouri Baptist Medical Center in St. Louis, said she often calms fears and corrects misinformation when scheduling patients for their first screening. Some patients think the screening involves an MRI or that radiation from the CT scan is dangerous.

“We go through explaining it as simple as possible,” she said.

If she has a referral for a patient who does not move forward with scheduling, she said she will try them again a few weeks later. Annual screenings are scheduled at a patient’s first appointment, and she said her clinic has an 80% rate for returning patients.

Getting the first scan is the biggest hurdle. Many patients feel stigma or associate lung cancer with a hopeless diagnosis, which can reduce rates, Mullet said.

“There’s a sense of fatalism, because all they’ve ever experienced with lung cancer has been someone who’s died from lung cancer, their grandmother, their grandfather, died of lung cancer. And historically, lung cancer has been found in late stages over 80% of the time,” he said. But screening has drastically improved rates of survival.

“We keep trying to tell patients that this is not your grandfather’s lung cancer,” Mullett said. “This is not what you saw in your family growing up, and we can find it early and we can treat it, and we even if we find it late, we have better treatments now.”

The study was funded by grants from the National Cancer Institute, the William Stamps Farish Endowed Chair in Cancer Research, and the CDC. Mullett and Hughes reported having no relevant financial disclosures.

Kelsey Mesmer, PhD, is a freelance journalist and journalism professor at Saint Louis University in St. Louis.

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

Chest CT is being ordered too often for incidental pulmonary nodules found on neck imaging, according to a study at one US health system.

It’s not uncommon for neck CT or MRI to show nodules in the lung apices, but there’s been no data on how often those incidental findings turn out to be lung cancer.

For the new study, researchers analyzed data of 22,173 patients who underwent neck, brachial plexus, or parathyroid imaging at the Massachusetts General Brigham in Boston.

Of those patients, 273 (1.2%) had requests for supplemental chest CTs due to incidental lung findings. Ultimately, only one new lung cancer was detected — an indolent adenocarcinoma — yielding a 2-year incidence rate of 0.40%.

The results suggest that recommendations for chest CT “should likely be substantially decreased,” the researchers conclude in the Journal of the American College of Radiology — though they also acknowledge a need for studies of larger datasets.

As for what drives such CT requests, study co-author Mark Hammer, MD, a thoracic radiologist at Brigham and Women’s Hospital, Harvard Medical School in Boston, offered one possibility: Neuroradiologists, who typically interpret neck imaging, might be less familiar with lung nodule follow-up guidelines.

At his institution, Hammer told Medscape Medical News, thoracic radiologists generally follow the Fleischner Society guidelines on management of incidentally detected pulmonary nodules.

“The reality is that neuroradiologists are often unfamiliar with those guidelines and may recommend follow-up for nodules that do not require it,” he said.

The Fleischner guidelines don’t recommend imaging nodules smaller than 6 mm given the very low cancer risk. For nodules of 6-8 mm, they recommend follow-up chest CTs at 3-12 months to see if the nodule has grown or changed. For larger or otherwise suspicious lesions, they advise prompt evaluation.

But while guidelines exist, follow-up decisions after neck imaging are largely at the discretion of the provider, said Dave Yousem, MD, MBA, a neuroradiologist at Johns Hopkins University in Baltimore.

According to Yousem, some physicians might be comfortable with the possibility of missing a low-risk indolent cancer to spare many patients from unnecessary CTs. But there’s also concern that overlooking even one tumor could trigger litigation, he said.

Hammer’s team found that of all patients with chest CT recommendations, only 171 (62.6%) underwent scanning — a rate consistent with previous reports of incidentaloma follow-up.

Hammer said, thoracic radiologists might have been applying the Fleischner guidelines, but some patients might simply have been lost to follow-up, among other possibilities.

He and his colleagues said recommendations for additional imaging should be evidence-based and judicious to ensure “appropriate follow-up and early detection of lung cancer.”

Potential solutions, they added, include incidentaloma tracking systems, improved communication between providers, and AI-assisted image interpretation.

The study was funded by the Association of University Radiologists and the Agency for Healthcare Research and Quality. Hammer and Yousem had no relevant disclosures.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. He is also an MIT Knight Science Journalism fellow. Email: aotto@medscape.net.

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

Chest CT is being ordered too often for incidental pulmonary nodules found on neck imaging, according to a study at one US health system.

It’s not uncommon for neck CT or MRI to show nodules in the lung apices, but there’s been no data on how often those incidental findings turn out to be lung cancer.

For the new study, researchers analyzed data of 22,173 patients who underwent neck, brachial plexus, or parathyroid imaging at the Massachusetts General Brigham in Boston.

Of those patients, 273 (1.2%) had requests for supplemental chest CTs due to incidental lung findings. Ultimately, only one new lung cancer was detected — an indolent adenocarcinoma — yielding a 2-year incidence rate of 0.40%.

The results suggest that recommendations for chest CT “should likely be substantially decreased,” the researchers conclude in the Journal of the American College of Radiology — though they also acknowledge a need for studies of larger datasets.

As for what drives such CT requests, study co-author Mark Hammer, MD, a thoracic radiologist at Brigham and Women’s Hospital, Harvard Medical School in Boston, offered one possibility: Neuroradiologists, who typically interpret neck imaging, might be less familiar with lung nodule follow-up guidelines.

At his institution, Hammer told Medscape Medical News, thoracic radiologists generally follow the Fleischner Society guidelines on management of incidentally detected pulmonary nodules.

“The reality is that neuroradiologists are often unfamiliar with those guidelines and may recommend follow-up for nodules that do not require it,” he said.

The Fleischner guidelines don’t recommend imaging nodules smaller than 6 mm given the very low cancer risk. For nodules of 6-8 mm, they recommend follow-up chest CTs at 3-12 months to see if the nodule has grown or changed. For larger or otherwise suspicious lesions, they advise prompt evaluation.

But while guidelines exist, follow-up decisions after neck imaging are largely at the discretion of the provider, said Dave Yousem, MD, MBA, a neuroradiologist at Johns Hopkins University in Baltimore.

According to Yousem, some physicians might be comfortable with the possibility of missing a low-risk indolent cancer to spare many patients from unnecessary CTs. But there’s also concern that overlooking even one tumor could trigger litigation, he said.

Hammer’s team found that of all patients with chest CT recommendations, only 171 (62.6%) underwent scanning — a rate consistent with previous reports of incidentaloma follow-up.

Hammer said, thoracic radiologists might have been applying the Fleischner guidelines, but some patients might simply have been lost to follow-up, among other possibilities.

He and his colleagues said recommendations for additional imaging should be evidence-based and judicious to ensure “appropriate follow-up and early detection of lung cancer.”

Potential solutions, they added, include incidentaloma tracking systems, improved communication between providers, and AI-assisted image interpretation.

The study was funded by the Association of University Radiologists and the Agency for Healthcare Research and Quality. Hammer and Yousem had no relevant disclosures.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. He is also an MIT Knight Science Journalism fellow. Email: aotto@medscape.net.

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

Chest CT is being ordered too often for incidental pulmonary nodules found on neck imaging, according to a study at one US health system.

It’s not uncommon for neck CT or MRI to show nodules in the lung apices, but there’s been no data on how often those incidental findings turn out to be lung cancer.

For the new study, researchers analyzed data of 22,173 patients who underwent neck, brachial plexus, or parathyroid imaging at the Massachusetts General Brigham in Boston.

Of those patients, 273 (1.2%) had requests for supplemental chest CTs due to incidental lung findings. Ultimately, only one new lung cancer was detected — an indolent adenocarcinoma — yielding a 2-year incidence rate of 0.40%.

The results suggest that recommendations for chest CT “should likely be substantially decreased,” the researchers conclude in the Journal of the American College of Radiology — though they also acknowledge a need for studies of larger datasets.

As for what drives such CT requests, study co-author Mark Hammer, MD, a thoracic radiologist at Brigham and Women’s Hospital, Harvard Medical School in Boston, offered one possibility: Neuroradiologists, who typically interpret neck imaging, might be less familiar with lung nodule follow-up guidelines.

At his institution, Hammer told Medscape Medical News, thoracic radiologists generally follow the Fleischner Society guidelines on management of incidentally detected pulmonary nodules.

“The reality is that neuroradiologists are often unfamiliar with those guidelines and may recommend follow-up for nodules that do not require it,” he said.

The Fleischner guidelines don’t recommend imaging nodules smaller than 6 mm given the very low cancer risk. For nodules of 6-8 mm, they recommend follow-up chest CTs at 3-12 months to see if the nodule has grown or changed. For larger or otherwise suspicious lesions, they advise prompt evaluation.

But while guidelines exist, follow-up decisions after neck imaging are largely at the discretion of the provider, said Dave Yousem, MD, MBA, a neuroradiologist at Johns Hopkins University in Baltimore.

According to Yousem, some physicians might be comfortable with the possibility of missing a low-risk indolent cancer to spare many patients from unnecessary CTs. But there’s also concern that overlooking even one tumor could trigger litigation, he said.

Hammer’s team found that of all patients with chest CT recommendations, only 171 (62.6%) underwent scanning — a rate consistent with previous reports of incidentaloma follow-up.

Hammer said, thoracic radiologists might have been applying the Fleischner guidelines, but some patients might simply have been lost to follow-up, among other possibilities.

He and his colleagues said recommendations for additional imaging should be evidence-based and judicious to ensure “appropriate follow-up and early detection of lung cancer.”

Potential solutions, they added, include incidentaloma tracking systems, improved communication between providers, and AI-assisted image interpretation.

The study was funded by the Association of University Radiologists and the Agency for Healthcare Research and Quality. Hammer and Yousem had no relevant disclosures.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. He is also an MIT Knight Science Journalism fellow. Email: aotto@medscape.net.

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

Immune checkpoint inhibitors (ICIs) have become important in oncology and represent an evolving area of therapeutics. Since their approval by the US Food and Drug Administration (FDA) in 2011, ICIs have been increasingly used as modalities in neoadjuvant and adjuvant treatment for resectable solid malignancies and in unresectable disease, such as advanced melanoma, and are associated with improved survival.¹

Immune checkpoints are present on the cell surface of activated T cells as well as other immune cells like B cells and natural killer cells. By regulating the length and amplitude of the body’s innate immune response, they maintain immune homeostasis and prevent its overactivation. Immune checkpoints are often thought of as the brakes on the immune system.²

Two glycoproteins that act as immune checkpoints and are targeted by ICIs are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is upregulated on activated T cells. PD-1 is also expressed on activated T cells, as well as macrophages, B cells, and dendritic cells. Cancer cells can evade immune surveillance by exploiting immune checkpoint pathways. Inhibition of these checkpoints with ICIs reactivates T cells and enables the immune system to recognize and attack cancer cells more effectively. Ipilimumab blocks the activity of CTLA-4 on T cells. Nivolumab and pembrolizumab block the interaction between PD-1 on T cells and its ligand PD-L1 on cancer cells.^3,4

Inhibition of these checkpoints is often effective in cancer treatment but can result in the loss of immunologic tolerance with resultant immune-related adverse events (irAEs) and potentially permanent autoimmune disorders. Autoreactive T cells can damage host cell tissues including the colon, lungs, liver, pituitary gland, thyroid, and skin. Severe irAEs include type 1 diabetes mellitus, myositis, nephritis, colitis, pneumonitis, hepatitis, uveitis, hypophysitis, and adrenalitis.⁴

Hypophysitis is inflammation of the pituitary gland, often with thickening of the pituitary stalk, resulting in dysfunction and hormone deficiencies. While primary hypophysitis is idiopathic, secondary hypophysitis is the result of an underlying condition such as exposure to an ICI. Immune-mediated inflammation of the pituitary gland in hypophysitis may disrupt corticotroph function, leading to adrenocorticotropic hormone (ACTH) deficiency. Early warning features are often vague and nonspecific, such as headache, fatigue, and weakness, which makes diagnosis challenging.^3,5

CASE PRESENTATION

A 73-year-old male veteran with a history of metastatic melanoma on ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (a standard combination regimen for advanced melanoma) presented to the emergency department (ED) with 2 weeks of cough, nausea, and severe headache 3 weeks after cycle 2 of combination ICI therapy. The patient had undergone excision of multiple sites of melanoma in situ with recurrence and disease progression after 5 cycles of pembrolizumab. He was subsequently started on combination ICI therapy.

On ED arrival, the patient was afebrile and saturating well on room air. He was normotensive but found to have orthostatic blood pressure. Physical examination was remarkable for dry oral mucosa and decreased skin turgor. Initial laboratory results were significant for hyponatremia of 123 mmol/L (reference range, 136-145 mmol/L), low-normal free thyroxine (T4) level of 0.5 ng/dL (reference range, 0.6-1.2 ng/dL), a low total triiodothyronine level of 32.14 ng/dL (reference range, 85-178 ng/dL), and a low thyrotropin level of 0.19 mIU/L (reference range, 0.35-5.50 mIU/L). Serum osmolarity was low at 259 mOsm/kg (reference range, 285-315 mOsm/kg), urine sodium was high at 168 mEq/L (reference, 20 mEq/L), and urine osmolarity was inappropriately concentrated at 726 mOsm/kg (reference range, 250-1000 mOsm/kg). The patient was admitted for additional testing. His morning cortisol level was within normal limits at 15 mcg/dL (reference range, 6.7-22.5 mcg/dL).

Computed tomography (CT) of the patient’s head revealed no acute findings. Chest CT revealed posterior right lower lobe mild ground-glass opacities, with possible ICI-induced pneumonitis. The patient received fluid resuscitation. Given concern for syndrome of inappropriate antidiuretic hormone secretion, the patient was started on 3 g salt tablets 3 times a day and urea 30 g powder daily. The etiology of the abnormal thyroid levels was unclear to endocrinology at that time. The differential diagnosis included a nonthyroidal illness or central hypothyroidism.

The patient started levothyroxine 75 mcg due to abnormal thyroid levels and persistent fatigue and fludrocortisone 0.1 mg daily to manage orthostatic hypotension. His sodium levels improved to 132 mmol/L over 6 days and he was discharged with levothyroxine 75 mcg daily, fludrocortisone 0.1 mg daily, 3 g salt tabs 3 times a day, urea 30 g powder daily, as well as oral cefpodoxime 500 mg twice daily for 3 days and azithromycin 500 mg once daily for 2 days (for a total of 10 days of antibiotic therapy) to treat potential occult pneumonia.

The patient returned to the ED 3 days after discharge following an outpatient oncology appointment with ongoing severe headaches and persistent nausea. There was concern for recurrent hyponatremia. His sodium level was within normal limits at 133 mmol/L. Repeat morning cortisol was low-normal at 9 mcg/dL. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease, but showed a slight interval increase in size of the pituitary gland compared with an MRI from 6 months prior, with mild fullness and a slightly convex superior margin near homogeneous enhancement, raising concern for infection or hypophysitis (Figure 1).

The patient was readmitted to the general medicine service and was given intravenous hydrocortisone 100 mg every 8 hours because of concern for central adrenal insufficiency due to grade 3 hypophysitis in the setting of MRI imaging and severe headaches (Table 1). He was not hypotensive at the time of hydrocortisone initiation and other vital signs were stable. A cosyntropin stimulation test—a standard diagnostic test for central adrenal insufficiency—was not performed because the patient had already started high-dose hydrocortisone. The patient’s free T4 on this admission remained low at 0.6 ng/dL.

No adjustments were made to his levothyroxine dose given that he recently began the medication and levels may lag after initiation. After a 4-day hospitalization, the decision was made to continue with the steroid taper and follow up with outpatient endocrinology to obtain a cosyntropin stimulation test to complete a full assessment of his pituitary axis (Figure 2). Repeat thyroid function testing for levothyroxine titration was arranged. The levothyroxine dosage was later increased to 88 mcg daily, but the patient discontinued the medication and remained euthyroid. Endocrinology attributed a nonthyroidal illness as the etiology of his hypothyroidism, likely euthyroid sick syndrome in the setting of illness. His hydrocortisone was tapered during outpatient care and fludrocortisone was discontinued due to hypertension.

One month after his second discharge, the patient presented to the ED with 2 weeks of dizziness, associated lightheadedness, and blurred vision when standing from a sitting position. Upon assessment, symptoms were attributed to poor oral intake. The patient’s vital signs were again positive for orthostatic hypotension, though refractory to adequate fluid replacement. Laboratory testing was significant for a low ACTH level of 3.0 pg/mL (reference range, 7.2-63.3 pg/mL). Given that the patient had not received steroids for 1 week, he underwent a cosyntropin stimulation test, which revealed a blunted response supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis (Table 2).

The patient was again readmitted to the general medicine service. A brain MRI showed interval shrinkage of the pituitary gland compared to imaging one month prior, which was attributed to hydrocortisone treatment during this month. CT of the patient’s abdomen demonstrated normal-sized adrenal glands. Positron emission tomography (PET)/CT showed no evidence of pituitary or adrenal metastases. Endocrinology recommended reinitiating oral hydrocortisone 50 mg in the morning and 50 mg around 3 pm daily with fludrocortisone 0.2 mg once daily, which resulted in near resolution of the patient’s symptoms. He was discharged after a 14-day hospitalization with home physical therapy services and endocrinology, nephrology, and oncology follow-up appointments.

The patient was readmitted twice to the general medicine service over the next 6 months for complications from hydrocortisone and fludrocortisone treatment including hypokalemia. He followed up with outpatient clinicians until his death 14 months later. He did not restart ICI therapy, and eventually joined a clinical trial for other advanced melanoma treatments at another institution. The patient’s family consented to the publication of this case report with the accompanying images.

DISCUSSION

The combination of ipilimumab (anti-CTLA-4 monoclonal antibody) and nivolumab (anti-PD-1 monoclonal antibody) is FDA-approved for treatment of advanced melanoma with the goal of harnessing complementary and synergistic mechanisms of dual therapy.^6-8 Combination therapy, however, can increase the incidence of irAEs, which are often endocrine-related and more common in patients treated with dual immunotherapy than with monotherapy.⁹ Hypophysitis has the lowest reported fatality rate among ICI-related irAEs (< 1%), compared with higher mortality rates seen in myocarditis (25%-50%) and pneumonitis (10%-20%).^4,10

The patient initially presented with ICI-related hypothyroidism, later identified as secondary (central) hypothyroidism. He was treated with levothyroxine until central hypothyroidism was confirmed. Subsequently, the patient developed headache, poor appetite, and lightheadedness, with MRI findings suggestive of hypophysitis, for which he was started on hydrocortisone. A component of primary adrenal insufficiency was initially considered, given the low ACTH level and blunted response to cosyntropin stimulation following prior high-dose steroid therapy. However, CT imaging demonstrated normal adrenal morphology without atrophy, supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis.

The estimated incidence of ICI-induced hypophysitis is 1.5% to 13.3% with anti-CTLA-4 agents, 0.3% to 3.0% with anti-PD-1 agents, and can be as high as 12.8% with combination therapy.¹ ICI-induced hypophysitis is believed to arise from the direct binding of ICI antibodies to their targets on anterior pituitary cells, such as corticotrophs, thyrotrophs, and gonadotrophs, triggering an immune response. One theory for targeting these cells is high CTLA-4 expression in the anterior pituitary gland.¹¹ PD-1 therapies tend to manifest as either hypothyroidism, hyperthyroidism, Graves’ disease, diabetes, or adrenal insufficiency.¹⁰

A concern in patients with advanced melanoma is metastasis. Melanoma has a high propensity for brain metastasis.¹² There was moderate suspicion for pituitary gland metastasis in this case, though pituitary metastasis more often manifests with symptoms of posterior pituitary gland deficiency, such as polyuria and polydipsia.¹³ The adrenal gland is the fourth-most common site for melanoma metastases, after the lung, liver, and bone.¹⁴ This patient had no evidence of pituitary or adrenal metastases on PET/CT. Therefore, his symptoms were most likely due to ICI therapy. Cases of ≥ 1 endocrine dysfunction have been reported as an ICI therapy irAE.¹⁵ In these situations, diagnosing primary and central adrenal insufficiency in the same patient is complex because hormone profiles are intertwined.

Many patients who develop hypophysitis from ICI therapy will require permanent replacement therapy. It is unclear whether low-dose replacement steroids have a significant effect on the efficacy of ICIs. Given that ICI treatment works by enhancing the immune system, medications that suppress the body’s immune system, such as steroids, could interfere with treatment efficacy. However, there are speculations that the development of irAEs is an indicator of effective treatment. In a phase 1 trial of a CTLA-4 blocker in patients with metastatic melanoma, there was a correlation between reduced CTLA-4 expression as well as low rates of melanoma recurrence and a higher incidence of irAEs.¹⁶

When assessing patients on ICI treatment, clinicians must remain vigilant for all potential irAEs, especially in patients receiving combination therapy. ICI-induced irAEs can present with vague and nonspecific symptoms. Concurrent endocrine irAEs, such as hypophysitis with thyroiditis or adrenalitis, are not uncommon in combination therapy and can complicate interpretation of hormone profiles. It is prudent for clinicians to review known risk factors. Hypophysitis is typically associated with older adult male patients.^17,18

The irAEs of ICI therapy deeply affected the quality of life of the patient in this case, as he was often experiencing many of the clinical symptoms of his hormone insufficiencies as well as the treatment modalities, thus requiring repeated hospital admissions. The risks and benefits of continuing ICI therapy should be an ongoing discussion between the physician and patient and should take into account the acuity and severity of irAEs and oncological disease burden, among other variables. Given the severity of his AEs, the patient stopped ICI therapy and instead opted to enroll in a clinical trial at another institution for continued alternative treatments.

CONCLUSIONS

This case offers a lesson in the diagnostic challenges of vague symptoms in patients with cancer who are receiving ICI therapy. ICI therapy is widely used in the treatment of solid malignancies, and as its use increases, it is expected that clinicians will likely see more cases of irAEs in hospitalized patients. The vague presentation of irAEs can often lead to treatment delays, especially when > 1 irAE presents concurrently. There are ongoing studies researching potential ways to predict the likelihood of developing these irAEs. It is imperative that clinicians are aware of these ICI-related complications and that more research be conducted to understand patient quality of life and treatment guidance based on irAE severity and disease burden.

Immune checkpoint inhibitors (ICIs) have become important in oncology and represent an evolving area of therapeutics. Since their approval by the US Food and Drug Administration (FDA) in 2011, ICIs have been increasingly used as modalities in neoadjuvant and adjuvant treatment for resectable solid malignancies and in unresectable disease, such as advanced melanoma, and are associated with improved survival.¹

Immune checkpoints are present on the cell surface of activated T cells as well as other immune cells like B cells and natural killer cells. By regulating the length and amplitude of the body’s innate immune response, they maintain immune homeostasis and prevent its overactivation. Immune checkpoints are often thought of as the brakes on the immune system.²

Two glycoproteins that act as immune checkpoints and are targeted by ICIs are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is upregulated on activated T cells. PD-1 is also expressed on activated T cells, as well as macrophages, B cells, and dendritic cells. Cancer cells can evade immune surveillance by exploiting immune checkpoint pathways. Inhibition of these checkpoints with ICIs reactivates T cells and enables the immune system to recognize and attack cancer cells more effectively. Ipilimumab blocks the activity of CTLA-4 on T cells. Nivolumab and pembrolizumab block the interaction between PD-1 on T cells and its ligand PD-L1 on cancer cells.^3,4

Inhibition of these checkpoints is often effective in cancer treatment but can result in the loss of immunologic tolerance with resultant immune-related adverse events (irAEs) and potentially permanent autoimmune disorders. Autoreactive T cells can damage host cell tissues including the colon, lungs, liver, pituitary gland, thyroid, and skin. Severe irAEs include type 1 diabetes mellitus, myositis, nephritis, colitis, pneumonitis, hepatitis, uveitis, hypophysitis, and adrenalitis.⁴

Hypophysitis is inflammation of the pituitary gland, often with thickening of the pituitary stalk, resulting in dysfunction and hormone deficiencies. While primary hypophysitis is idiopathic, secondary hypophysitis is the result of an underlying condition such as exposure to an ICI. Immune-mediated inflammation of the pituitary gland in hypophysitis may disrupt corticotroph function, leading to adrenocorticotropic hormone (ACTH) deficiency. Early warning features are often vague and nonspecific, such as headache, fatigue, and weakness, which makes diagnosis challenging.^3,5

CASE PRESENTATION

A 73-year-old male veteran with a history of metastatic melanoma on ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (a standard combination regimen for advanced melanoma) presented to the emergency department (ED) with 2 weeks of cough, nausea, and severe headache 3 weeks after cycle 2 of combination ICI therapy. The patient had undergone excision of multiple sites of melanoma in situ with recurrence and disease progression after 5 cycles of pembrolizumab. He was subsequently started on combination ICI therapy.

On ED arrival, the patient was afebrile and saturating well on room air. He was normotensive but found to have orthostatic blood pressure. Physical examination was remarkable for dry oral mucosa and decreased skin turgor. Initial laboratory results were significant for hyponatremia of 123 mmol/L (reference range, 136-145 mmol/L), low-normal free thyroxine (T4) level of 0.5 ng/dL (reference range, 0.6-1.2 ng/dL), a low total triiodothyronine level of 32.14 ng/dL (reference range, 85-178 ng/dL), and a low thyrotropin level of 0.19 mIU/L (reference range, 0.35-5.50 mIU/L). Serum osmolarity was low at 259 mOsm/kg (reference range, 285-315 mOsm/kg), urine sodium was high at 168 mEq/L (reference, 20 mEq/L), and urine osmolarity was inappropriately concentrated at 726 mOsm/kg (reference range, 250-1000 mOsm/kg). The patient was admitted for additional testing. His morning cortisol level was within normal limits at 15 mcg/dL (reference range, 6.7-22.5 mcg/dL).

Computed tomography (CT) of the patient’s head revealed no acute findings. Chest CT revealed posterior right lower lobe mild ground-glass opacities, with possible ICI-induced pneumonitis. The patient received fluid resuscitation. Given concern for syndrome of inappropriate antidiuretic hormone secretion, the patient was started on 3 g salt tablets 3 times a day and urea 30 g powder daily. The etiology of the abnormal thyroid levels was unclear to endocrinology at that time. The differential diagnosis included a nonthyroidal illness or central hypothyroidism.

The patient started levothyroxine 75 mcg due to abnormal thyroid levels and persistent fatigue and fludrocortisone 0.1 mg daily to manage orthostatic hypotension. His sodium levels improved to 132 mmol/L over 6 days and he was discharged with levothyroxine 75 mcg daily, fludrocortisone 0.1 mg daily, 3 g salt tabs 3 times a day, urea 30 g powder daily, as well as oral cefpodoxime 500 mg twice daily for 3 days and azithromycin 500 mg once daily for 2 days (for a total of 10 days of antibiotic therapy) to treat potential occult pneumonia.

The patient returned to the ED 3 days after discharge following an outpatient oncology appointment with ongoing severe headaches and persistent nausea. There was concern for recurrent hyponatremia. His sodium level was within normal limits at 133 mmol/L. Repeat morning cortisol was low-normal at 9 mcg/dL. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease, but showed a slight interval increase in size of the pituitary gland compared with an MRI from 6 months prior, with mild fullness and a slightly convex superior margin near homogeneous enhancement, raising concern for infection or hypophysitis (Figure 1).

The patient was readmitted to the general medicine service and was given intravenous hydrocortisone 100 mg every 8 hours because of concern for central adrenal insufficiency due to grade 3 hypophysitis in the setting of MRI imaging and severe headaches (Table 1). He was not hypotensive at the time of hydrocortisone initiation and other vital signs were stable. A cosyntropin stimulation test—a standard diagnostic test for central adrenal insufficiency—was not performed because the patient had already started high-dose hydrocortisone. The patient’s free T4 on this admission remained low at 0.6 ng/dL.

No adjustments were made to his levothyroxine dose given that he recently began the medication and levels may lag after initiation. After a 4-day hospitalization, the decision was made to continue with the steroid taper and follow up with outpatient endocrinology to obtain a cosyntropin stimulation test to complete a full assessment of his pituitary axis (Figure 2). Repeat thyroid function testing for levothyroxine titration was arranged. The levothyroxine dosage was later increased to 88 mcg daily, but the patient discontinued the medication and remained euthyroid. Endocrinology attributed a nonthyroidal illness as the etiology of his hypothyroidism, likely euthyroid sick syndrome in the setting of illness. His hydrocortisone was tapered during outpatient care and fludrocortisone was discontinued due to hypertension.

One month after his second discharge, the patient presented to the ED with 2 weeks of dizziness, associated lightheadedness, and blurred vision when standing from a sitting position. Upon assessment, symptoms were attributed to poor oral intake. The patient’s vital signs were again positive for orthostatic hypotension, though refractory to adequate fluid replacement. Laboratory testing was significant for a low ACTH level of 3.0 pg/mL (reference range, 7.2-63.3 pg/mL). Given that the patient had not received steroids for 1 week, he underwent a cosyntropin stimulation test, which revealed a blunted response supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis (Table 2).

The patient was again readmitted to the general medicine service. A brain MRI showed interval shrinkage of the pituitary gland compared to imaging one month prior, which was attributed to hydrocortisone treatment during this month. CT of the patient’s abdomen demonstrated normal-sized adrenal glands. Positron emission tomography (PET)/CT showed no evidence of pituitary or adrenal metastases. Endocrinology recommended reinitiating oral hydrocortisone 50 mg in the morning and 50 mg around 3 pm daily with fludrocortisone 0.2 mg once daily, which resulted in near resolution of the patient’s symptoms. He was discharged after a 14-day hospitalization with home physical therapy services and endocrinology, nephrology, and oncology follow-up appointments.

The patient was readmitted twice to the general medicine service over the next 6 months for complications from hydrocortisone and fludrocortisone treatment including hypokalemia. He followed up with outpatient clinicians until his death 14 months later. He did not restart ICI therapy, and eventually joined a clinical trial for other advanced melanoma treatments at another institution. The patient’s family consented to the publication of this case report with the accompanying images.

DISCUSSION

The combination of ipilimumab (anti-CTLA-4 monoclonal antibody) and nivolumab (anti-PD-1 monoclonal antibody) is FDA-approved for treatment of advanced melanoma with the goal of harnessing complementary and synergistic mechanisms of dual therapy.^6-8 Combination therapy, however, can increase the incidence of irAEs, which are often endocrine-related and more common in patients treated with dual immunotherapy than with monotherapy.⁹ Hypophysitis has the lowest reported fatality rate among ICI-related irAEs (< 1%), compared with higher mortality rates seen in myocarditis (25%-50%) and pneumonitis (10%-20%).^4,10

The patient initially presented with ICI-related hypothyroidism, later identified as secondary (central) hypothyroidism. He was treated with levothyroxine until central hypothyroidism was confirmed. Subsequently, the patient developed headache, poor appetite, and lightheadedness, with MRI findings suggestive of hypophysitis, for which he was started on hydrocortisone. A component of primary adrenal insufficiency was initially considered, given the low ACTH level and blunted response to cosyntropin stimulation following prior high-dose steroid therapy. However, CT imaging demonstrated normal adrenal morphology without atrophy, supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis.

The estimated incidence of ICI-induced hypophysitis is 1.5% to 13.3% with anti-CTLA-4 agents, 0.3% to 3.0% with anti-PD-1 agents, and can be as high as 12.8% with combination therapy.¹ ICI-induced hypophysitis is believed to arise from the direct binding of ICI antibodies to their targets on anterior pituitary cells, such as corticotrophs, thyrotrophs, and gonadotrophs, triggering an immune response. One theory for targeting these cells is high CTLA-4 expression in the anterior pituitary gland.¹¹ PD-1 therapies tend to manifest as either hypothyroidism, hyperthyroidism, Graves’ disease, diabetes, or adrenal insufficiency.¹⁰

A concern in patients with advanced melanoma is metastasis. Melanoma has a high propensity for brain metastasis.¹² There was moderate suspicion for pituitary gland metastasis in this case, though pituitary metastasis more often manifests with symptoms of posterior pituitary gland deficiency, such as polyuria and polydipsia.¹³ The adrenal gland is the fourth-most common site for melanoma metastases, after the lung, liver, and bone.¹⁴ This patient had no evidence of pituitary or adrenal metastases on PET/CT. Therefore, his symptoms were most likely due to ICI therapy. Cases of ≥ 1 endocrine dysfunction have been reported as an ICI therapy irAE.¹⁵ In these situations, diagnosing primary and central adrenal insufficiency in the same patient is complex because hormone profiles are intertwined.

Many patients who develop hypophysitis from ICI therapy will require permanent replacement therapy. It is unclear whether low-dose replacement steroids have a significant effect on the efficacy of ICIs. Given that ICI treatment works by enhancing the immune system, medications that suppress the body’s immune system, such as steroids, could interfere with treatment efficacy. However, there are speculations that the development of irAEs is an indicator of effective treatment. In a phase 1 trial of a CTLA-4 blocker in patients with metastatic melanoma, there was a correlation between reduced CTLA-4 expression as well as low rates of melanoma recurrence and a higher incidence of irAEs.¹⁶

When assessing patients on ICI treatment, clinicians must remain vigilant for all potential irAEs, especially in patients receiving combination therapy. ICI-induced irAEs can present with vague and nonspecific symptoms. Concurrent endocrine irAEs, such as hypophysitis with thyroiditis or adrenalitis, are not uncommon in combination therapy and can complicate interpretation of hormone profiles. It is prudent for clinicians to review known risk factors. Hypophysitis is typically associated with older adult male patients.^17,18

The irAEs of ICI therapy deeply affected the quality of life of the patient in this case, as he was often experiencing many of the clinical symptoms of his hormone insufficiencies as well as the treatment modalities, thus requiring repeated hospital admissions. The risks and benefits of continuing ICI therapy should be an ongoing discussion between the physician and patient and should take into account the acuity and severity of irAEs and oncological disease burden, among other variables. Given the severity of his AEs, the patient stopped ICI therapy and instead opted to enroll in a clinical trial at another institution for continued alternative treatments.

CONCLUSIONS

This case offers a lesson in the diagnostic challenges of vague symptoms in patients with cancer who are receiving ICI therapy. ICI therapy is widely used in the treatment of solid malignancies, and as its use increases, it is expected that clinicians will likely see more cases of irAEs in hospitalized patients. The vague presentation of irAEs can often lead to treatment delays, especially when > 1 irAE presents concurrently. There are ongoing studies researching potential ways to predict the likelihood of developing these irAEs. It is imperative that clinicians are aware of these ICI-related complications and that more research be conducted to understand patient quality of life and treatment guidance based on irAE severity and disease burden.

Immune checkpoint inhibitors (ICIs) have become important in oncology and represent an evolving area of therapeutics. Since their approval by the US Food and Drug Administration (FDA) in 2011, ICIs have been increasingly used as modalities in neoadjuvant and adjuvant treatment for resectable solid malignancies and in unresectable disease, such as advanced melanoma, and are associated with improved survival.¹

Immune checkpoints are present on the cell surface of activated T cells as well as other immune cells like B cells and natural killer cells. By regulating the length and amplitude of the body’s innate immune response, they maintain immune homeostasis and prevent its overactivation. Immune checkpoints are often thought of as the brakes on the immune system.²

Two glycoproteins that act as immune checkpoints and are targeted by ICIs are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is upregulated on activated T cells. PD-1 is also expressed on activated T cells, as well as macrophages, B cells, and dendritic cells. Cancer cells can evade immune surveillance by exploiting immune checkpoint pathways. Inhibition of these checkpoints with ICIs reactivates T cells and enables the immune system to recognize and attack cancer cells more effectively. Ipilimumab blocks the activity of CTLA-4 on T cells. Nivolumab and pembrolizumab block the interaction between PD-1 on T cells and its ligand PD-L1 on cancer cells.^3,4

Inhibition of these checkpoints is often effective in cancer treatment but can result in the loss of immunologic tolerance with resultant immune-related adverse events (irAEs) and potentially permanent autoimmune disorders. Autoreactive T cells can damage host cell tissues including the colon, lungs, liver, pituitary gland, thyroid, and skin. Severe irAEs include type 1 diabetes mellitus, myositis, nephritis, colitis, pneumonitis, hepatitis, uveitis, hypophysitis, and adrenalitis.⁴

Hypophysitis is inflammation of the pituitary gland, often with thickening of the pituitary stalk, resulting in dysfunction and hormone deficiencies. While primary hypophysitis is idiopathic, secondary hypophysitis is the result of an underlying condition such as exposure to an ICI. Immune-mediated inflammation of the pituitary gland in hypophysitis may disrupt corticotroph function, leading to adrenocorticotropic hormone (ACTH) deficiency. Early warning features are often vague and nonspecific, such as headache, fatigue, and weakness, which makes diagnosis challenging.^3,5

CASE PRESENTATION

A 73-year-old male veteran with a history of metastatic melanoma on ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (a standard combination regimen for advanced melanoma) presented to the emergency department (ED) with 2 weeks of cough, nausea, and severe headache 3 weeks after cycle 2 of combination ICI therapy. The patient had undergone excision of multiple sites of melanoma in situ with recurrence and disease progression after 5 cycles of pembrolizumab. He was subsequently started on combination ICI therapy.

On ED arrival, the patient was afebrile and saturating well on room air. He was normotensive but found to have orthostatic blood pressure. Physical examination was remarkable for dry oral mucosa and decreased skin turgor. Initial laboratory results were significant for hyponatremia of 123 mmol/L (reference range, 136-145 mmol/L), low-normal free thyroxine (T4) level of 0.5 ng/dL (reference range, 0.6-1.2 ng/dL), a low total triiodothyronine level of 32.14 ng/dL (reference range, 85-178 ng/dL), and a low thyrotropin level of 0.19 mIU/L (reference range, 0.35-5.50 mIU/L). Serum osmolarity was low at 259 mOsm/kg (reference range, 285-315 mOsm/kg), urine sodium was high at 168 mEq/L (reference, 20 mEq/L), and urine osmolarity was inappropriately concentrated at 726 mOsm/kg (reference range, 250-1000 mOsm/kg). The patient was admitted for additional testing. His morning cortisol level was within normal limits at 15 mcg/dL (reference range, 6.7-22.5 mcg/dL).

Computed tomography (CT) of the patient’s head revealed no acute findings. Chest CT revealed posterior right lower lobe mild ground-glass opacities, with possible ICI-induced pneumonitis. The patient received fluid resuscitation. Given concern for syndrome of inappropriate antidiuretic hormone secretion, the patient was started on 3 g salt tablets 3 times a day and urea 30 g powder daily. The etiology of the abnormal thyroid levels was unclear to endocrinology at that time. The differential diagnosis included a nonthyroidal illness or central hypothyroidism.

The patient started levothyroxine 75 mcg due to abnormal thyroid levels and persistent fatigue and fludrocortisone 0.1 mg daily to manage orthostatic hypotension. His sodium levels improved to 132 mmol/L over 6 days and he was discharged with levothyroxine 75 mcg daily, fludrocortisone 0.1 mg daily, 3 g salt tabs 3 times a day, urea 30 g powder daily, as well as oral cefpodoxime 500 mg twice daily for 3 days and azithromycin 500 mg once daily for 2 days (for a total of 10 days of antibiotic therapy) to treat potential occult pneumonia.

The patient returned to the ED 3 days after discharge following an outpatient oncology appointment with ongoing severe headaches and persistent nausea. There was concern for recurrent hyponatremia. His sodium level was within normal limits at 133 mmol/L. Repeat morning cortisol was low-normal at 9 mcg/dL. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease, but showed a slight interval increase in size of the pituitary gland compared with an MRI from 6 months prior, with mild fullness and a slightly convex superior margin near homogeneous enhancement, raising concern for infection or hypophysitis (Figure 1).

The patient was readmitted to the general medicine service and was given intravenous hydrocortisone 100 mg every 8 hours because of concern for central adrenal insufficiency due to grade 3 hypophysitis in the setting of MRI imaging and severe headaches (Table 1). He was not hypotensive at the time of hydrocortisone initiation and other vital signs were stable. A cosyntropin stimulation test—a standard diagnostic test for central adrenal insufficiency—was not performed because the patient had already started high-dose hydrocortisone. The patient’s free T4 on this admission remained low at 0.6 ng/dL.

No adjustments were made to his levothyroxine dose given that he recently began the medication and levels may lag after initiation. After a 4-day hospitalization, the decision was made to continue with the steroid taper and follow up with outpatient endocrinology to obtain a cosyntropin stimulation test to complete a full assessment of his pituitary axis (Figure 2). Repeat thyroid function testing for levothyroxine titration was arranged. The levothyroxine dosage was later increased to 88 mcg daily, but the patient discontinued the medication and remained euthyroid. Endocrinology attributed a nonthyroidal illness as the etiology of his hypothyroidism, likely euthyroid sick syndrome in the setting of illness. His hydrocortisone was tapered during outpatient care and fludrocortisone was discontinued due to hypertension.

One month after his second discharge, the patient presented to the ED with 2 weeks of dizziness, associated lightheadedness, and blurred vision when standing from a sitting position. Upon assessment, symptoms were attributed to poor oral intake. The patient’s vital signs were again positive for orthostatic hypotension, though refractory to adequate fluid replacement. Laboratory testing was significant for a low ACTH level of 3.0 pg/mL (reference range, 7.2-63.3 pg/mL). Given that the patient had not received steroids for 1 week, he underwent a cosyntropin stimulation test, which revealed a blunted response supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis (Table 2).

The patient was again readmitted to the general medicine service. A brain MRI showed interval shrinkage of the pituitary gland compared to imaging one month prior, which was attributed to hydrocortisone treatment during this month. CT of the patient’s abdomen demonstrated normal-sized adrenal glands. Positron emission tomography (PET)/CT showed no evidence of pituitary or adrenal metastases. Endocrinology recommended reinitiating oral hydrocortisone 50 mg in the morning and 50 mg around 3 pm daily with fludrocortisone 0.2 mg once daily, which resulted in near resolution of the patient’s symptoms. He was discharged after a 14-day hospitalization with home physical therapy services and endocrinology, nephrology, and oncology follow-up appointments.

The patient was readmitted twice to the general medicine service over the next 6 months for complications from hydrocortisone and fludrocortisone treatment including hypokalemia. He followed up with outpatient clinicians until his death 14 months later. He did not restart ICI therapy, and eventually joined a clinical trial for other advanced melanoma treatments at another institution. The patient’s family consented to the publication of this case report with the accompanying images.

DISCUSSION

The combination of ipilimumab (anti-CTLA-4 monoclonal antibody) and nivolumab (anti-PD-1 monoclonal antibody) is FDA-approved for treatment of advanced melanoma with the goal of harnessing complementary and synergistic mechanisms of dual therapy.^6-8 Combination therapy, however, can increase the incidence of irAEs, which are often endocrine-related and more common in patients treated with dual immunotherapy than with monotherapy.⁹ Hypophysitis has the lowest reported fatality rate among ICI-related irAEs (< 1%), compared with higher mortality rates seen in myocarditis (25%-50%) and pneumonitis (10%-20%).^4,10

The patient initially presented with ICI-related hypothyroidism, later identified as secondary (central) hypothyroidism. He was treated with levothyroxine until central hypothyroidism was confirmed. Subsequently, the patient developed headache, poor appetite, and lightheadedness, with MRI findings suggestive of hypophysitis, for which he was started on hydrocortisone. A component of primary adrenal insufficiency was initially considered, given the low ACTH level and blunted response to cosyntropin stimulation following prior high-dose steroid therapy. However, CT imaging demonstrated normal adrenal morphology without atrophy, supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis.

The estimated incidence of ICI-induced hypophysitis is 1.5% to 13.3% with anti-CTLA-4 agents, 0.3% to 3.0% with anti-PD-1 agents, and can be as high as 12.8% with combination therapy.¹ ICI-induced hypophysitis is believed to arise from the direct binding of ICI antibodies to their targets on anterior pituitary cells, such as corticotrophs, thyrotrophs, and gonadotrophs, triggering an immune response. One theory for targeting these cells is high CTLA-4 expression in the anterior pituitary gland.¹¹ PD-1 therapies tend to manifest as either hypothyroidism, hyperthyroidism, Graves’ disease, diabetes, or adrenal insufficiency.¹⁰

A concern in patients with advanced melanoma is metastasis. Melanoma has a high propensity for brain metastasis.¹² There was moderate suspicion for pituitary gland metastasis in this case, though pituitary metastasis more often manifests with symptoms of posterior pituitary gland deficiency, such as polyuria and polydipsia.¹³ The adrenal gland is the fourth-most common site for melanoma metastases, after the lung, liver, and bone.¹⁴ This patient had no evidence of pituitary or adrenal metastases on PET/CT. Therefore, his symptoms were most likely due to ICI therapy. Cases of ≥ 1 endocrine dysfunction have been reported as an ICI therapy irAE.¹⁵ In these situations, diagnosing primary and central adrenal insufficiency in the same patient is complex because hormone profiles are intertwined.

Many patients who develop hypophysitis from ICI therapy will require permanent replacement therapy. It is unclear whether low-dose replacement steroids have a significant effect on the efficacy of ICIs. Given that ICI treatment works by enhancing the immune system, medications that suppress the body’s immune system, such as steroids, could interfere with treatment efficacy. However, there are speculations that the development of irAEs is an indicator of effective treatment. In a phase 1 trial of a CTLA-4 blocker in patients with metastatic melanoma, there was a correlation between reduced CTLA-4 expression as well as low rates of melanoma recurrence and a higher incidence of irAEs.¹⁶

When assessing patients on ICI treatment, clinicians must remain vigilant for all potential irAEs, especially in patients receiving combination therapy. ICI-induced irAEs can present with vague and nonspecific symptoms. Concurrent endocrine irAEs, such as hypophysitis with thyroiditis or adrenalitis, are not uncommon in combination therapy and can complicate interpretation of hormone profiles. It is prudent for clinicians to review known risk factors. Hypophysitis is typically associated with older adult male patients.^17,18

The irAEs of ICI therapy deeply affected the quality of life of the patient in this case, as he was often experiencing many of the clinical symptoms of his hormone insufficiencies as well as the treatment modalities, thus requiring repeated hospital admissions. The risks and benefits of continuing ICI therapy should be an ongoing discussion between the physician and patient and should take into account the acuity and severity of irAEs and oncological disease burden, among other variables. Given the severity of his AEs, the patient stopped ICI therapy and instead opted to enroll in a clinical trial at another institution for continued alternative treatments.

CONCLUSIONS

This case offers a lesson in the diagnostic challenges of vague symptoms in patients with cancer who are receiving ICI therapy. ICI therapy is widely used in the treatment of solid malignancies, and as its use increases, it is expected that clinicians will likely see more cases of irAEs in hospitalized patients. The vague presentation of irAEs can often lead to treatment delays, especially when > 1 irAE presents concurrently. There are ongoing studies researching potential ways to predict the likelihood of developing these irAEs. It is imperative that clinicians are aware of these ICI-related complications and that more research be conducted to understand patient quality of life and treatment guidance based on irAE severity and disease burden.