AVAHO

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.

The fastest way to a new anticoagulation therapy that prevents blood clots without prolonging bleeding or healing time may be a land snail.

A recent preclinical study in ACS Central Science investigating bioactive molecules derived from the land snail Camaena cicatricosa identified a compound that significantly reduced clot formation without prolonging bleeding time and wound healing in rodent models, directly challenging the assumption that effective anticoagulant therapy must inherently disrupt physiologic repair processes.

“I was quite excited,” said Lisha Lin, PhD, lead author on the study and research assistant at the State Key Laboratory of Phytochemistry and Natural Medicines at the Kunming Institute of Botany, Chinese Academy of Sciences, in Kunming, China. “A novel polysaccharide was identified, and more importantly, it showed anticoagulant activity by inhibiting a novel target, with different action mechanism from heparins.”

What Led to the Land Snail?

The choice of C cicatricosa reflects a shift in thinking. The team screened a range of mollusk-derived biomolecules in search of safer anticoagulation strategies, ultimately isolating a novel galactosylated glycosaminoglycan (CCG) from this terrestrial species.

“We compared the anticoagulant activity of glycosaminoglycans from three snail species,” said Lin. They initially studied polysaccharides from C cicatricosa, Achatina fulica, and Helix lucorum — all sulfated glycosaminoglycans with similar structures. “However, we only found CCG from [C cicatricosa] showed anticoagulant activity but not other snail polysaccharides.”

This unexpected selectivity proved crucial. “The result indicated that the galactose branches and special sulfate substitution were important,” she explained, helping to explain why this particular species stood out among structurally similar compounds.

While CCG shares some similarities with heparin-like molecules, it notably lacks the specific pentasaccharide sequence required for antithrombin binding. Researchers hypothesized that this absence could reduce bleeding risk while maintaining antithrombotic activity.

Rather than broadly inhibiting coagulation, the compound selectively disrupts the intrinsic tenase complex, a pathway more closely associated with pathologic thrombosis than with physiologic hemostasis. This mechanism’s selectivity is central to the study’s findings and helps explain why normal wound healing remained intact in preclinical models.

The isolated compound demonstrated a rare combination in anticoagulant research: potent inhibition of pathologic thrombosis with no significant increase in bleeding time and intact wound healing across multiple experimental models. The compound did not act as a broad-spectrum anticoagulant, instead selectively targeting pathways more relevant to disease-associated clot formation.

The Hope of Lowering Bleeding Risk

For decades, anticoagulation therapy has been built on the assumption that inhibiting clot formation inevitably increases bleeding risk. For physicians treating patients with deep vein thrombosis or atrial fibrillation or those requiring postsurgical attention, the balancing act is constant. Prevent clot formation aggressively enough and the bleeding risk rises. Reduce intensity and thrombosis risk returns.

Current therapies, including heparin and direct oral anticoagulants (DOACs), function by broadly targeting the coagulation cascade. This lack of specialty is precisely what limits them. Even when carefully dosed, the treatments interfere with both pathologic clot formation and physiologic hemostasis.

Physicians managing patients on heparin and DOACs frequently encounter recurrent epistaxis, gastrointestinal bleeding ranging from occult to clinically significant, and urogenital bleeding. A degree of mild bleeding after surgery is often expected and usually resolves on its own. However, it’s crucial to evaluate in the context of ongoing anticoagulation to rule out early signs of clinically significant complications.

“There is definitely a lot of interest in the concept of ‘uncoupling’ thrombosis from hemostasis,” said Yazan Abou-Ismail, MD, hematologist and associate professor of medicine at the University of Utah Health in Salt Lake City, who was not involved in the research. “This concept highlights the differences in pathways essential for normal hemostasis at sites of vessel injury, in contrast with those needed for clot propagation and blood vessel lumen occlusion.”

Abou-Ismail noted that this approach has been explored with Factor XI (FXI) inhibitors currently in clinical trials. However, he raised an important mechanistic concern.

“This mechanism may not necessarily accomplish that goal of uncoupling thrombosis from hemostasis, although it might at narrow therapeutic windows,” Abou-Ismail said. “The tenase complex is a central component of coagulation whose deficiency underlies hemophilia A and B, diseases that cause significant bleeding in humans, and it is more essential to hemostasis than [FXI inhibitors]. Tenase inhibition seems like it may pose a higher bleeding risk in humans.”

He explained that FXI inhibitors have a strong mechanistic rationale because they target the feedback loop that amplifies clot propagation, which is less essential for hemostasis. “FXI inhibitors have clinical trial data demonstrating that FXI inhibition is in fact associated with less bleeding compared to current established anticoagulants,” he said. “However, CCG disrupts the FIXa/FVIIIa intrinsic tenase complex itself, which is considered essential for hemostasis.”

Surprises and Confirmations

The researchers were not anticipating such a clear separation between antithrombotic activity and bleeding risk. The preservation of normal wound healing was equally surprising, directly challenging the belief that interfering with clot formation inevitably disrupts tissue repair.

However, the path to these conclusions was not straightforward. “The structural definition of complex macromolecules like sulfated polysaccharides is a common challenge in the research field,” Lin said. “We spent a lot of time to analyze the structure of CCG.”

Even after identifying the candidate compound, the team had to rigorously confirm that its effects were truly anticoagulant in nature, rather than secondary to anti-inflammatory or vascular remodeling properties. Mechanistic studies were essential in demonstrating its targeted disruption of the intrinsic tenase complex, helping to explain how thrombosis could be reduced without broadly impairing coagulation.

Lin is excited but knows patience and skepticism are needed. “Our research is still at the basic stage, but based on the available data, we may provide a potential anticoagulant option with low bleeding risk,” she said. “In the discussion section of our paper, we also stated that ‘the data suggest a wide therapeutic window of CCG, which may offer therapeutic advantages for patients with bleeding contraindication, such as elderly patients and those with renal failure, as well as for safer long-term anticoagulation.’”

A New Direction for Heparin Alternatives?

Despite these concerns, Abou-Ismail acknowledged that the research has genuinely noteworthy aspects. “A future anticoagulant with a novel mechanism of action may be useful in patients who have experienced anticoagulant failure or breakthrough thrombosis from currently established anticoagulants,” he said. “Having another option might be useful when all other options have failed or are not feasible.”

However, he added a note of caution: “If a therapeutic window exists where partial tenase disruption has antithrombotic effect that does not impair hemostasis, then that would definitely be a promising future finding, but it is too early to arrive at that conclusion with this study.”

The search for safer heparin alternatives has been ongoing for decades, but most candidates still operate within the same fundamental paradigm of broad coagulation inhibition. This snail can’t move fast enough.

Abou-Ismail reported having no relevant conflicts. Disclosure information for study authors is available in the original study publication.

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

The fastest way to a new anticoagulation therapy that prevents blood clots without prolonging bleeding or healing time may be a land snail.

A recent preclinical study in ACS Central Science investigating bioactive molecules derived from the land snail Camaena cicatricosa identified a compound that significantly reduced clot formation without prolonging bleeding time and wound healing in rodent models, directly challenging the assumption that effective anticoagulant therapy must inherently disrupt physiologic repair processes.

“I was quite excited,” said Lisha Lin, PhD, lead author on the study and research assistant at the State Key Laboratory of Phytochemistry and Natural Medicines at the Kunming Institute of Botany, Chinese Academy of Sciences, in Kunming, China. “A novel polysaccharide was identified, and more importantly, it showed anticoagulant activity by inhibiting a novel target, with different action mechanism from heparins.”

What Led to the Land Snail?

The choice of C cicatricosa reflects a shift in thinking. The team screened a range of mollusk-derived biomolecules in search of safer anticoagulation strategies, ultimately isolating a novel galactosylated glycosaminoglycan (CCG) from this terrestrial species.

“We compared the anticoagulant activity of glycosaminoglycans from three snail species,” said Lin. They initially studied polysaccharides from C cicatricosa, Achatina fulica, and Helix lucorum — all sulfated glycosaminoglycans with similar structures. “However, we only found CCG from [C cicatricosa] showed anticoagulant activity but not other snail polysaccharides.”

This unexpected selectivity proved crucial. “The result indicated that the galactose branches and special sulfate substitution were important,” she explained, helping to explain why this particular species stood out among structurally similar compounds.

While CCG shares some similarities with heparin-like molecules, it notably lacks the specific pentasaccharide sequence required for antithrombin binding. Researchers hypothesized that this absence could reduce bleeding risk while maintaining antithrombotic activity.

Rather than broadly inhibiting coagulation, the compound selectively disrupts the intrinsic tenase complex, a pathway more closely associated with pathologic thrombosis than with physiologic hemostasis. This mechanism’s selectivity is central to the study’s findings and helps explain why normal wound healing remained intact in preclinical models.

The isolated compound demonstrated a rare combination in anticoagulant research: potent inhibition of pathologic thrombosis with no significant increase in bleeding time and intact wound healing across multiple experimental models. The compound did not act as a broad-spectrum anticoagulant, instead selectively targeting pathways more relevant to disease-associated clot formation.

The Hope of Lowering Bleeding Risk

For decades, anticoagulation therapy has been built on the assumption that inhibiting clot formation inevitably increases bleeding risk. For physicians treating patients with deep vein thrombosis or atrial fibrillation or those requiring postsurgical attention, the balancing act is constant. Prevent clot formation aggressively enough and the bleeding risk rises. Reduce intensity and thrombosis risk returns.

Current therapies, including heparin and direct oral anticoagulants (DOACs), function by broadly targeting the coagulation cascade. This lack of specialty is precisely what limits them. Even when carefully dosed, the treatments interfere with both pathologic clot formation and physiologic hemostasis.

Physicians managing patients on heparin and DOACs frequently encounter recurrent epistaxis, gastrointestinal bleeding ranging from occult to clinically significant, and urogenital bleeding. A degree of mild bleeding after surgery is often expected and usually resolves on its own. However, it’s crucial to evaluate in the context of ongoing anticoagulation to rule out early signs of clinically significant complications.

“There is definitely a lot of interest in the concept of ‘uncoupling’ thrombosis from hemostasis,” said Yazan Abou-Ismail, MD, hematologist and associate professor of medicine at the University of Utah Health in Salt Lake City, who was not involved in the research. “This concept highlights the differences in pathways essential for normal hemostasis at sites of vessel injury, in contrast with those needed for clot propagation and blood vessel lumen occlusion.”

Abou-Ismail noted that this approach has been explored with Factor XI (FXI) inhibitors currently in clinical trials. However, he raised an important mechanistic concern.

“This mechanism may not necessarily accomplish that goal of uncoupling thrombosis from hemostasis, although it might at narrow therapeutic windows,” Abou-Ismail said. “The tenase complex is a central component of coagulation whose deficiency underlies hemophilia A and B, diseases that cause significant bleeding in humans, and it is more essential to hemostasis than [FXI inhibitors]. Tenase inhibition seems like it may pose a higher bleeding risk in humans.”

He explained that FXI inhibitors have a strong mechanistic rationale because they target the feedback loop that amplifies clot propagation, which is less essential for hemostasis. “FXI inhibitors have clinical trial data demonstrating that FXI inhibition is in fact associated with less bleeding compared to current established anticoagulants,” he said. “However, CCG disrupts the FIXa/FVIIIa intrinsic tenase complex itself, which is considered essential for hemostasis.”

Surprises and Confirmations

The researchers were not anticipating such a clear separation between antithrombotic activity and bleeding risk. The preservation of normal wound healing was equally surprising, directly challenging the belief that interfering with clot formation inevitably disrupts tissue repair.

However, the path to these conclusions was not straightforward. “The structural definition of complex macromolecules like sulfated polysaccharides is a common challenge in the research field,” Lin said. “We spent a lot of time to analyze the structure of CCG.”

Even after identifying the candidate compound, the team had to rigorously confirm that its effects were truly anticoagulant in nature, rather than secondary to anti-inflammatory or vascular remodeling properties. Mechanistic studies were essential in demonstrating its targeted disruption of the intrinsic tenase complex, helping to explain how thrombosis could be reduced without broadly impairing coagulation.

Lin is excited but knows patience and skepticism are needed. “Our research is still at the basic stage, but based on the available data, we may provide a potential anticoagulant option with low bleeding risk,” she said. “In the discussion section of our paper, we also stated that ‘the data suggest a wide therapeutic window of CCG, which may offer therapeutic advantages for patients with bleeding contraindication, such as elderly patients and those with renal failure, as well as for safer long-term anticoagulation.’”

A New Direction for Heparin Alternatives?

Despite these concerns, Abou-Ismail acknowledged that the research has genuinely noteworthy aspects. “A future anticoagulant with a novel mechanism of action may be useful in patients who have experienced anticoagulant failure or breakthrough thrombosis from currently established anticoagulants,” he said. “Having another option might be useful when all other options have failed or are not feasible.”

However, he added a note of caution: “If a therapeutic window exists where partial tenase disruption has antithrombotic effect that does not impair hemostasis, then that would definitely be a promising future finding, but it is too early to arrive at that conclusion with this study.”

The search for safer heparin alternatives has been ongoing for decades, but most candidates still operate within the same fundamental paradigm of broad coagulation inhibition. This snail can’t move fast enough.

Abou-Ismail reported having no relevant conflicts. Disclosure information for study authors is available in the original study publication.

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

The fastest way to a new anticoagulation therapy that prevents blood clots without prolonging bleeding or healing time may be a land snail.

A recent preclinical study in ACS Central Science investigating bioactive molecules derived from the land snail Camaena cicatricosa identified a compound that significantly reduced clot formation without prolonging bleeding time and wound healing in rodent models, directly challenging the assumption that effective anticoagulant therapy must inherently disrupt physiologic repair processes.

“I was quite excited,” said Lisha Lin, PhD, lead author on the study and research assistant at the State Key Laboratory of Phytochemistry and Natural Medicines at the Kunming Institute of Botany, Chinese Academy of Sciences, in Kunming, China. “A novel polysaccharide was identified, and more importantly, it showed anticoagulant activity by inhibiting a novel target, with different action mechanism from heparins.”

What Led to the Land Snail?

The choice of C cicatricosa reflects a shift in thinking. The team screened a range of mollusk-derived biomolecules in search of safer anticoagulation strategies, ultimately isolating a novel galactosylated glycosaminoglycan (CCG) from this terrestrial species.

“We compared the anticoagulant activity of glycosaminoglycans from three snail species,” said Lin. They initially studied polysaccharides from C cicatricosa, Achatina fulica, and Helix lucorum — all sulfated glycosaminoglycans with similar structures. “However, we only found CCG from [C cicatricosa] showed anticoagulant activity but not other snail polysaccharides.”

This unexpected selectivity proved crucial. “The result indicated that the galactose branches and special sulfate substitution were important,” she explained, helping to explain why this particular species stood out among structurally similar compounds.

While CCG shares some similarities with heparin-like molecules, it notably lacks the specific pentasaccharide sequence required for antithrombin binding. Researchers hypothesized that this absence could reduce bleeding risk while maintaining antithrombotic activity.

Rather than broadly inhibiting coagulation, the compound selectively disrupts the intrinsic tenase complex, a pathway more closely associated with pathologic thrombosis than with physiologic hemostasis. This mechanism’s selectivity is central to the study’s findings and helps explain why normal wound healing remained intact in preclinical models.

The isolated compound demonstrated a rare combination in anticoagulant research: potent inhibition of pathologic thrombosis with no significant increase in bleeding time and intact wound healing across multiple experimental models. The compound did not act as a broad-spectrum anticoagulant, instead selectively targeting pathways more relevant to disease-associated clot formation.

The Hope of Lowering Bleeding Risk

For decades, anticoagulation therapy has been built on the assumption that inhibiting clot formation inevitably increases bleeding risk. For physicians treating patients with deep vein thrombosis or atrial fibrillation or those requiring postsurgical attention, the balancing act is constant. Prevent clot formation aggressively enough and the bleeding risk rises. Reduce intensity and thrombosis risk returns.

Current therapies, including heparin and direct oral anticoagulants (DOACs), function by broadly targeting the coagulation cascade. This lack of specialty is precisely what limits them. Even when carefully dosed, the treatments interfere with both pathologic clot formation and physiologic hemostasis.

Physicians managing patients on heparin and DOACs frequently encounter recurrent epistaxis, gastrointestinal bleeding ranging from occult to clinically significant, and urogenital bleeding. A degree of mild bleeding after surgery is often expected and usually resolves on its own. However, it’s crucial to evaluate in the context of ongoing anticoagulation to rule out early signs of clinically significant complications.

“There is definitely a lot of interest in the concept of ‘uncoupling’ thrombosis from hemostasis,” said Yazan Abou-Ismail, MD, hematologist and associate professor of medicine at the University of Utah Health in Salt Lake City, who was not involved in the research. “This concept highlights the differences in pathways essential for normal hemostasis at sites of vessel injury, in contrast with those needed for clot propagation and blood vessel lumen occlusion.”

Abou-Ismail noted that this approach has been explored with Factor XI (FXI) inhibitors currently in clinical trials. However, he raised an important mechanistic concern.

“This mechanism may not necessarily accomplish that goal of uncoupling thrombosis from hemostasis, although it might at narrow therapeutic windows,” Abou-Ismail said. “The tenase complex is a central component of coagulation whose deficiency underlies hemophilia A and B, diseases that cause significant bleeding in humans, and it is more essential to hemostasis than [FXI inhibitors]. Tenase inhibition seems like it may pose a higher bleeding risk in humans.”

He explained that FXI inhibitors have a strong mechanistic rationale because they target the feedback loop that amplifies clot propagation, which is less essential for hemostasis. “FXI inhibitors have clinical trial data demonstrating that FXI inhibition is in fact associated with less bleeding compared to current established anticoagulants,” he said. “However, CCG disrupts the FIXa/FVIIIa intrinsic tenase complex itself, which is considered essential for hemostasis.”

Surprises and Confirmations

The researchers were not anticipating such a clear separation between antithrombotic activity and bleeding risk. The preservation of normal wound healing was equally surprising, directly challenging the belief that interfering with clot formation inevitably disrupts tissue repair.

However, the path to these conclusions was not straightforward. “The structural definition of complex macromolecules like sulfated polysaccharides is a common challenge in the research field,” Lin said. “We spent a lot of time to analyze the structure of CCG.”

Even after identifying the candidate compound, the team had to rigorously confirm that its effects were truly anticoagulant in nature, rather than secondary to anti-inflammatory or vascular remodeling properties. Mechanistic studies were essential in demonstrating its targeted disruption of the intrinsic tenase complex, helping to explain how thrombosis could be reduced without broadly impairing coagulation.

Lin is excited but knows patience and skepticism are needed. “Our research is still at the basic stage, but based on the available data, we may provide a potential anticoagulant option with low bleeding risk,” she said. “In the discussion section of our paper, we also stated that ‘the data suggest a wide therapeutic window of CCG, which may offer therapeutic advantages for patients with bleeding contraindication, such as elderly patients and those with renal failure, as well as for safer long-term anticoagulation.’”

A New Direction for Heparin Alternatives?

Despite these concerns, Abou-Ismail acknowledged that the research has genuinely noteworthy aspects. “A future anticoagulant with a novel mechanism of action may be useful in patients who have experienced anticoagulant failure or breakthrough thrombosis from currently established anticoagulants,” he said. “Having another option might be useful when all other options have failed or are not feasible.”

However, he added a note of caution: “If a therapeutic window exists where partial tenase disruption has antithrombotic effect that does not impair hemostasis, then that would definitely be a promising future finding, but it is too early to arrive at that conclusion with this study.”

The search for safer heparin alternatives has been ongoing for decades, but most candidates still operate within the same fundamental paradigm of broad coagulation inhibition. This snail can’t move fast enough.

Abou-Ismail reported having no relevant conflicts. Disclosure information for study authors is available in the original study publication.

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

A few days of fasting around chemotherapy sessions may improve treatment response and outcomes for some patients with advanced ovarian cancer, a small phase 2 trial suggests.

The study, of 36 patients with stage III or IV high-grade ovarian cancer, found that those randomly assigned to fast for 36 hours before chemotherapy and 24 hours afterward had stronger pathologic responses to chemotherapy and longer progression-free survival than patients who ate normally during treatment.

The findings, reported at a press briefing ahead the American Society of Clinical Oncology (ASCO) 2026, hint at a straightforward measure to potentially improve patients’ outcomes.

The working theory is that short-term fasting boosts chemotherapy response by lowering insulin and IGF-1 levels, both of which are implicated in tumor growth and chemotherapy resistance, said study presenter Claudia Marchetti, MD, of Agostino Gemelli University in Rome, Italy.

Speaking at the briefing, ASCO President Eric Small, MD, of the University of California San Francisco, called the study “a great example of a very simple intervention that has benefit and can be undertaken and implemented anywhere in the world.”

“It’s not an expensive new drug,” he said, “and yet it has the potential to really have an impact on this cancer.”

Ovarian cancer affects more than 324,000 women worldwide each year and causes more than 206,000 deaths annually. Around 80% of patients are diagnosed at an advanced stage, and up to 60% receive neoadjuvant chemotherapy to reduce tumor size and facilitate surgery.

Despite advances in surgery and chemotherapy, patients with advanced disease still face poor outcomes. There is, Marchetti said, “an urgent need for safe, low-cost, and easily implementable strategies that can enhance treatment efficacy and improve patient prognosis.”

Given evidence on the role of insulin in tumor growth and chemotherapy response, her team hypothesized that short bouts of fasting around the time of treatment might have benefits.

To test that idea, the researchers recruited 36 patients with newly diagnosed stage III or IV high-grade serous ovarian carcinoma who were not candidates for primary cytoreduction. All were in good general health, with a mean age of 62 years.

All patients received 3 rounds of carboplatin and paclitaxel before surgery. Prior to starting chemotherapy, half were randomly assigned to fast for 36 hours before and 24 hours after chemotherapy, whereas the other half ate normally throughout treatment.

Patients in the fasting group consumed no more than 350 calories per day during the fasting window. They were allowed to have unrestricted water, herbal tea, limited vegetable juice, and small amounts of light vegetable broth. (A ketogenic diet group had initially been planned but was closed early because of poor patient compliance.)

The study met its primary endpoint of change in insulin levels during chemotherapy, Marchetti reported. Baseline insulin levels were comparable between the 2 groups, but after 3 rounds of chemotherapy, they’d dipped by an average of 1.12 µIU/mL in the fasting group and increased by 9.76 µIU/mL in the control group (P = .01).

Fasting also improved clinical outcomes. Specifically, Marchetti said, 59% of fasting patients achieved a chemotherapy response score of 3 — indicating complete or near-complete tumor response before surgery — compared with 17% of patients in the control group.

Median progression-free survival was significantly longer in the fasting group, at 38 vs 24 months.

Importantly, Marchetti said, the fasting protocol was feasible, well tolerated, and safe: All patients assigned to the fasting group completed treatment, and rates of chemotherapy-related toxicities were similar between the 2 groups.

Additional analyses shed more light on the possible mechanisms underlying the fasting group’s improved outcomes: The researchers found that those patients tended to have lower levels of circulating suppressor granulocyte and monocyte populations that have been linked to tumor immune escape, which suggests, Marchetti said, fasting may have set the stage for a “more favorable immune environment” during chemotherapy.

However, she cautioned that much more research is needed. Her team is planning a larger multicenter trial to validate the current findings, and longer-term follow-up is necessary to see whether fasting ultimately impacts patients’ survival, Marchetti said.

In a statement, Eleonora Teplinsky, MD, an ASCO expert in gynecologic cancers, said these early findings are “encouraging, support earlier data, and highlight a promising area of cancer research.”

But she, too, emphasized the need for larger clinical trials to build on the results.

The study had no commercial funding. Marchetti disclosed having relationships with Arquer Diagnostics, AstraZeneca, Clovis Oncology, and other companies. Small disclosed having relationships with Janssen, Johnson & Johnson, and others. Teplinsky had no disclosures.

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

A few days of fasting around chemotherapy sessions may improve treatment response and outcomes for some patients with advanced ovarian cancer, a small phase 2 trial suggests.

The study, of 36 patients with stage III or IV high-grade ovarian cancer, found that those randomly assigned to fast for 36 hours before chemotherapy and 24 hours afterward had stronger pathologic responses to chemotherapy and longer progression-free survival than patients who ate normally during treatment.

The findings, reported at a press briefing ahead the American Society of Clinical Oncology (ASCO) 2026, hint at a straightforward measure to potentially improve patients’ outcomes.

The working theory is that short-term fasting boosts chemotherapy response by lowering insulin and IGF-1 levels, both of which are implicated in tumor growth and chemotherapy resistance, said study presenter Claudia Marchetti, MD, of Agostino Gemelli University in Rome, Italy.

Speaking at the briefing, ASCO President Eric Small, MD, of the University of California San Francisco, called the study “a great example of a very simple intervention that has benefit and can be undertaken and implemented anywhere in the world.”

“It’s not an expensive new drug,” he said, “and yet it has the potential to really have an impact on this cancer.”

Ovarian cancer affects more than 324,000 women worldwide each year and causes more than 206,000 deaths annually. Around 80% of patients are diagnosed at an advanced stage, and up to 60% receive neoadjuvant chemotherapy to reduce tumor size and facilitate surgery.

Despite advances in surgery and chemotherapy, patients with advanced disease still face poor outcomes. There is, Marchetti said, “an urgent need for safe, low-cost, and easily implementable strategies that can enhance treatment efficacy and improve patient prognosis.”

Given evidence on the role of insulin in tumor growth and chemotherapy response, her team hypothesized that short bouts of fasting around the time of treatment might have benefits.

To test that idea, the researchers recruited 36 patients with newly diagnosed stage III or IV high-grade serous ovarian carcinoma who were not candidates for primary cytoreduction. All were in good general health, with a mean age of 62 years.

All patients received 3 rounds of carboplatin and paclitaxel before surgery. Prior to starting chemotherapy, half were randomly assigned to fast for 36 hours before and 24 hours after chemotherapy, whereas the other half ate normally throughout treatment.

Patients in the fasting group consumed no more than 350 calories per day during the fasting window. They were allowed to have unrestricted water, herbal tea, limited vegetable juice, and small amounts of light vegetable broth. (A ketogenic diet group had initially been planned but was closed early because of poor patient compliance.)

The study met its primary endpoint of change in insulin levels during chemotherapy, Marchetti reported. Baseline insulin levels were comparable between the 2 groups, but after 3 rounds of chemotherapy, they’d dipped by an average of 1.12 µIU/mL in the fasting group and increased by 9.76 µIU/mL in the control group (P = .01).

Fasting also improved clinical outcomes. Specifically, Marchetti said, 59% of fasting patients achieved a chemotherapy response score of 3 — indicating complete or near-complete tumor response before surgery — compared with 17% of patients in the control group.

Median progression-free survival was significantly longer in the fasting group, at 38 vs 24 months.

Importantly, Marchetti said, the fasting protocol was feasible, well tolerated, and safe: All patients assigned to the fasting group completed treatment, and rates of chemotherapy-related toxicities were similar between the 2 groups.

Additional analyses shed more light on the possible mechanisms underlying the fasting group’s improved outcomes: The researchers found that those patients tended to have lower levels of circulating suppressor granulocyte and monocyte populations that have been linked to tumor immune escape, which suggests, Marchetti said, fasting may have set the stage for a “more favorable immune environment” during chemotherapy.

However, she cautioned that much more research is needed. Her team is planning a larger multicenter trial to validate the current findings, and longer-term follow-up is necessary to see whether fasting ultimately impacts patients’ survival, Marchetti said.

In a statement, Eleonora Teplinsky, MD, an ASCO expert in gynecologic cancers, said these early findings are “encouraging, support earlier data, and highlight a promising area of cancer research.”

But she, too, emphasized the need for larger clinical trials to build on the results.

The study had no commercial funding. Marchetti disclosed having relationships with Arquer Diagnostics, AstraZeneca, Clovis Oncology, and other companies. Small disclosed having relationships with Janssen, Johnson & Johnson, and others. Teplinsky had no disclosures.

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

A few days of fasting around chemotherapy sessions may improve treatment response and outcomes for some patients with advanced ovarian cancer, a small phase 2 trial suggests.

The study, of 36 patients with stage III or IV high-grade ovarian cancer, found that those randomly assigned to fast for 36 hours before chemotherapy and 24 hours afterward had stronger pathologic responses to chemotherapy and longer progression-free survival than patients who ate normally during treatment.

The findings, reported at a press briefing ahead the American Society of Clinical Oncology (ASCO) 2026, hint at a straightforward measure to potentially improve patients’ outcomes.

The working theory is that short-term fasting boosts chemotherapy response by lowering insulin and IGF-1 levels, both of which are implicated in tumor growth and chemotherapy resistance, said study presenter Claudia Marchetti, MD, of Agostino Gemelli University in Rome, Italy.

Speaking at the briefing, ASCO President Eric Small, MD, of the University of California San Francisco, called the study “a great example of a very simple intervention that has benefit and can be undertaken and implemented anywhere in the world.”

“It’s not an expensive new drug,” he said, “and yet it has the potential to really have an impact on this cancer.”

Ovarian cancer affects more than 324,000 women worldwide each year and causes more than 206,000 deaths annually. Around 80% of patients are diagnosed at an advanced stage, and up to 60% receive neoadjuvant chemotherapy to reduce tumor size and facilitate surgery.

Despite advances in surgery and chemotherapy, patients with advanced disease still face poor outcomes. There is, Marchetti said, “an urgent need for safe, low-cost, and easily implementable strategies that can enhance treatment efficacy and improve patient prognosis.”

Given evidence on the role of insulin in tumor growth and chemotherapy response, her team hypothesized that short bouts of fasting around the time of treatment might have benefits.

To test that idea, the researchers recruited 36 patients with newly diagnosed stage III or IV high-grade serous ovarian carcinoma who were not candidates for primary cytoreduction. All were in good general health, with a mean age of 62 years.

All patients received 3 rounds of carboplatin and paclitaxel before surgery. Prior to starting chemotherapy, half were randomly assigned to fast for 36 hours before and 24 hours after chemotherapy, whereas the other half ate normally throughout treatment.

Patients in the fasting group consumed no more than 350 calories per day during the fasting window. They were allowed to have unrestricted water, herbal tea, limited vegetable juice, and small amounts of light vegetable broth. (A ketogenic diet group had initially been planned but was closed early because of poor patient compliance.)

The study met its primary endpoint of change in insulin levels during chemotherapy, Marchetti reported. Baseline insulin levels were comparable between the 2 groups, but after 3 rounds of chemotherapy, they’d dipped by an average of 1.12 µIU/mL in the fasting group and increased by 9.76 µIU/mL in the control group (P = .01).

Fasting also improved clinical outcomes. Specifically, Marchetti said, 59% of fasting patients achieved a chemotherapy response score of 3 — indicating complete or near-complete tumor response before surgery — compared with 17% of patients in the control group.

Median progression-free survival was significantly longer in the fasting group, at 38 vs 24 months.

Importantly, Marchetti said, the fasting protocol was feasible, well tolerated, and safe: All patients assigned to the fasting group completed treatment, and rates of chemotherapy-related toxicities were similar between the 2 groups.

Additional analyses shed more light on the possible mechanisms underlying the fasting group’s improved outcomes: The researchers found that those patients tended to have lower levels of circulating suppressor granulocyte and monocyte populations that have been linked to tumor immune escape, which suggests, Marchetti said, fasting may have set the stage for a “more favorable immune environment” during chemotherapy.

However, she cautioned that much more research is needed. Her team is planning a larger multicenter trial to validate the current findings, and longer-term follow-up is necessary to see whether fasting ultimately impacts patients’ survival, Marchetti said.

In a statement, Eleonora Teplinsky, MD, an ASCO expert in gynecologic cancers, said these early findings are “encouraging, support earlier data, and highlight a promising area of cancer research.”

But she, too, emphasized the need for larger clinical trials to build on the results.

The study had no commercial funding. Marchetti disclosed having relationships with Arquer Diagnostics, AstraZeneca, Clovis Oncology, and other companies. Small disclosed having relationships with Janssen, Johnson & Johnson, and others. Teplinsky had no disclosures.

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

TOPLINE:

Telephone outreach by a nurse practitioner (NP) providing counseling and care coordination reduced the gaps in breast and cervical cancer screenings among women veterans in rural areas, according to a retrospective study.

METHODOLOGY:

• Researchers conducted a retrospective chart review of 55 women veterans who received interventions related to breast or cervical cancer screening at a rural Veterans Health Administration health care system.
• A Boost team, including an NP, a medical director, a program coordinator, and a program evaluation team, was established to provide care coordination and counseling for these participants.
• The NP conducted outreach by telephone to these participants receiving care at five community-based outpatient clinics located in rural counties and helped coordinate access to screening appointments through the Office of Community Care.
• Outcomes included the number of veterans due for breast or cervical cancer screening at the time of outreach and the number of mammograms and Pap smears completed in the 12-month period following the intervention.

TAKEAWAY:

• Of the 55 veterans who received Boost interventions related to cancer screening, 35 (64%) were due for breast cancer screening and 27 (49%) were due for cervical cancer screening before the intervention.
• Following the Boost intervention, the number of veterans due for breast cancer and cervical cancer screenings decreased to 18 (32%) and 16 (29%), respectively.
• Among veterans due for breast cancer screening, 29 (83%) received counseling regarding screening and 17 (59%) of counseled participants completed mammography; however, among those due for cervical cancer screening, 22 (81%) received counseling and 11 (50%) completed screening.
• None of the veterans who were due for screening but did not receive counseling completed their screening, demonstrating the critical role of clinician-provided education and counseling.

IN PRACTICE:

“We hope to expand Boost outreach from one NP working part-time across two health systems to a national partnership of licensed independent providers conducting clinician-initiated outreach to a broader and geographically more diverse group of veterans,” the authors wrote.

SOURCE:

This study was led by Lina Vadlamani, MD, MBA, San Francisco Internal Medicine Residency Program, University of California, San Francisco. It was published online on April 24, 2026, in Military Medicine.

LIMITATIONS:

This study was a secondary analysis in which participants were not randomly assigned, limiting causal inferences. Veterans who answered the phone and engaged with the NP were likely easier to reach and potentially more proactive about their health than those who did not engage, and this selection bias may have limited the generalizability of the findings.

DISCLOSURES:

This study was funded by the Department of Veterans Affairs, Veterans Health Administration, and Office of Rural Health. The authors reported having no relevant conflicts of interest.

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

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

TOPLINE:

Telephone outreach by a nurse practitioner (NP) providing counseling and care coordination reduced the gaps in breast and cervical cancer screenings among women veterans in rural areas, according to a retrospective study.

METHODOLOGY:

• Researchers conducted a retrospective chart review of 55 women veterans who received interventions related to breast or cervical cancer screening at a rural Veterans Health Administration health care system.
• A Boost team, including an NP, a medical director, a program coordinator, and a program evaluation team, was established to provide care coordination and counseling for these participants.
• The NP conducted outreach by telephone to these participants receiving care at five community-based outpatient clinics located in rural counties and helped coordinate access to screening appointments through the Office of Community Care.
• Outcomes included the number of veterans due for breast or cervical cancer screening at the time of outreach and the number of mammograms and Pap smears completed in the 12-month period following the intervention.

TAKEAWAY:

• Of the 55 veterans who received Boost interventions related to cancer screening, 35 (64%) were due for breast cancer screening and 27 (49%) were due for cervical cancer screening before the intervention.
• Following the Boost intervention, the number of veterans due for breast cancer and cervical cancer screenings decreased to 18 (32%) and 16 (29%), respectively.
• Among veterans due for breast cancer screening, 29 (83%) received counseling regarding screening and 17 (59%) of counseled participants completed mammography; however, among those due for cervical cancer screening, 22 (81%) received counseling and 11 (50%) completed screening.
• None of the veterans who were due for screening but did not receive counseling completed their screening, demonstrating the critical role of clinician-provided education and counseling.

IN PRACTICE:

“We hope to expand Boost outreach from one NP working part-time across two health systems to a national partnership of licensed independent providers conducting clinician-initiated outreach to a broader and geographically more diverse group of veterans,” the authors wrote.

SOURCE:

This study was led by Lina Vadlamani, MD, MBA, San Francisco Internal Medicine Residency Program, University of California, San Francisco. It was published online on April 24, 2026, in Military Medicine.

LIMITATIONS:

This study was a secondary analysis in which participants were not randomly assigned, limiting causal inferences. Veterans who answered the phone and engaged with the NP were likely easier to reach and potentially more proactive about their health than those who did not engage, and this selection bias may have limited the generalizability of the findings.

DISCLOSURES:

This study was funded by the Department of Veterans Affairs, Veterans Health Administration, and Office of Rural Health. The authors reported having no relevant conflicts of interest.

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

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

TOPLINE:

Telephone outreach by a nurse practitioner (NP) providing counseling and care coordination reduced the gaps in breast and cervical cancer screenings among women veterans in rural areas, according to a retrospective study.

METHODOLOGY:

• Researchers conducted a retrospective chart review of 55 women veterans who received interventions related to breast or cervical cancer screening at a rural Veterans Health Administration health care system.
• A Boost team, including an NP, a medical director, a program coordinator, and a program evaluation team, was established to provide care coordination and counseling for these participants.
• The NP conducted outreach by telephone to these participants receiving care at five community-based outpatient clinics located in rural counties and helped coordinate access to screening appointments through the Office of Community Care.
• Outcomes included the number of veterans due for breast or cervical cancer screening at the time of outreach and the number of mammograms and Pap smears completed in the 12-month period following the intervention.

TAKEAWAY:

• Of the 55 veterans who received Boost interventions related to cancer screening, 35 (64%) were due for breast cancer screening and 27 (49%) were due for cervical cancer screening before the intervention.
• Following the Boost intervention, the number of veterans due for breast cancer and cervical cancer screenings decreased to 18 (32%) and 16 (29%), respectively.
• Among veterans due for breast cancer screening, 29 (83%) received counseling regarding screening and 17 (59%) of counseled participants completed mammography; however, among those due for cervical cancer screening, 22 (81%) received counseling and 11 (50%) completed screening.
• None of the veterans who were due for screening but did not receive counseling completed their screening, demonstrating the critical role of clinician-provided education and counseling.

IN PRACTICE:

“We hope to expand Boost outreach from one NP working part-time across two health systems to a national partnership of licensed independent providers conducting clinician-initiated outreach to a broader and geographically more diverse group of veterans,” the authors wrote.

SOURCE:

This study was led by Lina Vadlamani, MD, MBA, San Francisco Internal Medicine Residency Program, University of California, San Francisco. It was published online on April 24, 2026, in Military Medicine.

LIMITATIONS:

This study was a secondary analysis in which participants were not randomly assigned, limiting causal inferences. Veterans who answered the phone and engaged with the NP were likely easier to reach and potentially more proactive about their health than those who did not engage, and this selection bias may have limited the generalizability of the findings.

DISCLOSURES:

This study was funded by the Department of Veterans Affairs, Veterans Health Administration, and Office of Rural Health. The authors reported having no relevant conflicts of interest.

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

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.

Precision oncology (PO) is cancer treatment individualized to the special characteristics of a patient’s tumor. It has become standard care for most patients with advanced cancer. Advances in molecular cell biology and immunology have identified numerous targets and many therapies have been developed as a result. Molecular testing and targeted therapy are typically covered by insurance, even when inflation-adjusted price growth is considered.¹ Barriers remain, however, and pathologists are uniquely qualified to address some of the challenges.²

Most US laboratories do not perform molecular diagnostic tests for PO, particularly comprehensive evaluation of multiple targets by next-generation sequencing, or other techniques. Instead, these tests are sent to reference laboratories. The workload associated with referral testing is an obstacle to increased use of such tests. Despite guideline recommendations, a minority of indicated tests are performed.³ This is true even when testing costs are covered by clinical trials or grants, such as those in the Veterans Health Administration (VHA).

The main characteristic of successful PO programs is a multidisciplinary commitment, including pathology involvement in molecular tumor boards and assistance with test selection, tissue collection, and result interpretation.² This, however, adds to the workload for the pathology department, an underappreciated phenomenon in the context of pathology workforce shortages.⁴

Workforce shortages impact all occupations in the laboratory setting. Though the shortage of medical technologists in clinical pathology laboratories has repeatedly been identified as critical at the VHA as well as in the private sector, the same cannot be said for staff shortages in anatomic pathology laboratories. Thus, the hospital laboratory divisions are concerned with biopsy or resection tissue specimens as opposed to the bodily fluid specimens that predominate in clinical laboratories.⁵ The lack of accurate data on histopathology technicians and technologists has precluded the degree of recognition seen for medical technologists. In labor statistics, these occupations are often obscured by inclusion with other jobs in broad categories such as medical and clinical laboratory technologists and technicians.⁶ Vacancy—the principal metric used to assess medical laboratory workforce shortage—fails to account for positions that are eventually eliminated after remaining vacant for prolonged periods, positions not replaced as a result of ambitious efficiency measures, or positions that were never created due to insufficient funding, reasons for administrative disapproval, or coverage by laboratory professionals working extra shifts or second jobs.⁷

Increased demand for pathologists is suggested by a 42% increase in workload per pathologist over the last decade, while a shortage is suggested by decreases in absolute and population-adjusted numbers of pathologists.^8,9 An influx of pathologists is not an expected remedy due to the global decline in medical graduates pursuing careers in the field.⁸

Approximations for required labor and potential revenue generation are necessary to justify creation of pathology positions. This work mostly has gone uncaptured due to the limitations of Current Procedural Terminology (CPT) codes. Few laboratories have consistently used the 88363, 88325, and G0452 CPT codes. The pathology clinical consultation CPT codes (80503-80506) released in 2022 enhance acquisition of this work. The new codes replace 80500 and 80502 and allow for more precise identification of any work requiring medical judgment that a pathologist does at the request of another qualified health care professional (HCP) or as required by federal or state regulation.

The codes can be used to bill for associated time spent reviewing health records, communicating with other HCPs, placing orders, and documentation. An HCP can bill according to level of medical decision-making (MDM) or time spent by the consulting pathologist. Code 80503 can be billed for 5 to 20 minutes of a pathologist's time, 80504 for 21 to 40 minutes, 80505 for 41 to 60 minutes, and 80506 for each additional 30 minutes after the first hour. Levels of MDM (low, moderate, and high) are defined as for other evaluation and management services. A consultation report must be generated and contain documentation of the consultation request, pathologist interpretation, and justification for the level of service associated with the chosen code. Relative value units (RVUs) and reimbursement associated with each as well as other consultation-related codes are available in Table 1.

This article outlines how the pathology time investment associated with anatomic pathology molecular testing at the Kansas City Veterans Affairs Medical Center (KCVAMC) can be captured using the consultation process and new CPT codes. Staff included 4 pathologists, 3 histotechnologists, 1 histology supervisor, 1 grossing room technician, and 1 cytotechnologist, 1 cytology technician.

METHODS

The AP molecular testing consultation process at the KCVAMC was mapped, with the average time measured for each step (Figure). AP records for 2021 were reviewed to determine the number of AP molecular send out tests. Cumulative time investment was calculated in hours and a theoretical number of RVUs was calculated using the new pathology clinical consultation CPT codes (80503-80506). This theoretical number of RVUs was compared with the total AP RVUs generated in 2021 to determine a potential increase in RVUs with use of the new CPT codes to capture pathology work associated with AP molecular testing consultations.

RESULTS

From 2021 to 2023, there were 21,021 AP cases at the KCVAMC. Basal cell carcinomas and squamous cell carcinomas of the skin were excluded because they comprise most cancer cases but almost never necessitate AP molecular test consultations. A total of 2118 cancer cases were included, representing 10.1% of all cases. Ancillary AP molecular send-out tests were performed on 1338 (6.4%) cases. Since ancillary tissue tests are requested by consultation at the KCVAMC, this resulted in 1338 consultations (Table 2).

The time to complete a consultation was measured by calculating the mean time required to complete each step (Table 3). With in-house specimen consultations requiring 90 minutes each and outside specimen consultations requiring 100 minutes each, a total of 2040 hours of pathology staff time was necessary to complete associated consultations. Billing for this time with the new pathology clinical consultation CPT codes would generate 3847 RVUs, which would have equated to 14.8% (3847/25,920) of the anatomic pathology RVUs.

DISCUSSION

When considering the lengths of time for tasks associated with each consultation, it is important to remember that the volume (2-3 daily), was insufficient to meaningfully benefit from batching. Thus, waiting to perform a particular task until it was needed for multiple cases reduced the inefficiency associated with starting and switching between tasks. Both the Computerized Patient Record System and VistA had to be reopened, reauthenticated, and reloaded for each step that required use of the health record, printer, or fax machine. Faxes also required waiting for transmission and printed confirmation of successful transmission. As a result, the time values denoted for each step are likely underestimated, as the effect of interruptions is significant and not reflected in the estimates recorded.¹⁰

This analysis has demonstrated that PO entails a significant amount of work for pathology departments. To determine and maintain appropriate staffing models, this work must be captured and reimbursed. Unlike other pathology work, which is performed in-house and reimbursed for the associated test, a significant proportion of PO testing is sent out. Even if more reliable assays are developed, the physical processes of sending out samples and reporting test results cannot be outsourced. Independent and commensurate reimbursement methods are necessary to allow for this work and PO.

CMS included new pathology clinical consultation codes that may be used to bill for some of this work according to the 2022 physician fee schedule due to advocacy work by the College of American Pathologists and the American Medical Association CPT editorial panel.¹¹

CONCLUSIONS

This analysis found that adoption of PO may present a significant amount of additional work for pathology departments. To determine and maintain appropriate staffing models, work completed by pathologists in this manner must be recorded and reimbursed. Pathologists need to be trained and encouraged to use these CPT codes and bill for the work described in this article. The increased revenue will allow for additional positions to alleviate the burdens imposed by understaffing so that pathology can function as a facilitator of PO rather than as a barrier to it.

Precision oncology (PO) is cancer treatment individualized to the special characteristics of a patient’s tumor. It has become standard care for most patients with advanced cancer. Advances in molecular cell biology and immunology have identified numerous targets and many therapies have been developed as a result. Molecular testing and targeted therapy are typically covered by insurance, even when inflation-adjusted price growth is considered.¹ Barriers remain, however, and pathologists are uniquely qualified to address some of the challenges.²

Most US laboratories do not perform molecular diagnostic tests for PO, particularly comprehensive evaluation of multiple targets by next-generation sequencing, or other techniques. Instead, these tests are sent to reference laboratories. The workload associated with referral testing is an obstacle to increased use of such tests. Despite guideline recommendations, a minority of indicated tests are performed.³ This is true even when testing costs are covered by clinical trials or grants, such as those in the Veterans Health Administration (VHA).

The main characteristic of successful PO programs is a multidisciplinary commitment, including pathology involvement in molecular tumor boards and assistance with test selection, tissue collection, and result interpretation.² This, however, adds to the workload for the pathology department, an underappreciated phenomenon in the context of pathology workforce shortages.⁴

Workforce shortages impact all occupations in the laboratory setting. Though the shortage of medical technologists in clinical pathology laboratories has repeatedly been identified as critical at the VHA as well as in the private sector, the same cannot be said for staff shortages in anatomic pathology laboratories. Thus, the hospital laboratory divisions are concerned with biopsy or resection tissue specimens as opposed to the bodily fluid specimens that predominate in clinical laboratories.⁵ The lack of accurate data on histopathology technicians and technologists has precluded the degree of recognition seen for medical technologists. In labor statistics, these occupations are often obscured by inclusion with other jobs in broad categories such as medical and clinical laboratory technologists and technicians.⁶ Vacancy—the principal metric used to assess medical laboratory workforce shortage—fails to account for positions that are eventually eliminated after remaining vacant for prolonged periods, positions not replaced as a result of ambitious efficiency measures, or positions that were never created due to insufficient funding, reasons for administrative disapproval, or coverage by laboratory professionals working extra shifts or second jobs.⁷

Increased demand for pathologists is suggested by a 42% increase in workload per pathologist over the last decade, while a shortage is suggested by decreases in absolute and population-adjusted numbers of pathologists.^8,9 An influx of pathologists is not an expected remedy due to the global decline in medical graduates pursuing careers in the field.⁸

Approximations for required labor and potential revenue generation are necessary to justify creation of pathology positions. This work mostly has gone uncaptured due to the limitations of Current Procedural Terminology (CPT) codes. Few laboratories have consistently used the 88363, 88325, and G0452 CPT codes. The pathology clinical consultation CPT codes (80503-80506) released in 2022 enhance acquisition of this work. The new codes replace 80500 and 80502 and allow for more precise identification of any work requiring medical judgment that a pathologist does at the request of another qualified health care professional (HCP) or as required by federal or state regulation.

The codes can be used to bill for associated time spent reviewing health records, communicating with other HCPs, placing orders, and documentation. An HCP can bill according to level of medical decision-making (MDM) or time spent by the consulting pathologist. Code 80503 can be billed for 5 to 20 minutes of a pathologist's time, 80504 for 21 to 40 minutes, 80505 for 41 to 60 minutes, and 80506 for each additional 30 minutes after the first hour. Levels of MDM (low, moderate, and high) are defined as for other evaluation and management services. A consultation report must be generated and contain documentation of the consultation request, pathologist interpretation, and justification for the level of service associated with the chosen code. Relative value units (RVUs) and reimbursement associated with each as well as other consultation-related codes are available in Table 1.

This article outlines how the pathology time investment associated with anatomic pathology molecular testing at the Kansas City Veterans Affairs Medical Center (KCVAMC) can be captured using the consultation process and new CPT codes. Staff included 4 pathologists, 3 histotechnologists, 1 histology supervisor, 1 grossing room technician, and 1 cytotechnologist, 1 cytology technician.

METHODS

The AP molecular testing consultation process at the KCVAMC was mapped, with the average time measured for each step (Figure). AP records for 2021 were reviewed to determine the number of AP molecular send out tests. Cumulative time investment was calculated in hours and a theoretical number of RVUs was calculated using the new pathology clinical consultation CPT codes (80503-80506). This theoretical number of RVUs was compared with the total AP RVUs generated in 2021 to determine a potential increase in RVUs with use of the new CPT codes to capture pathology work associated with AP molecular testing consultations.

RESULTS

From 2021 to 2023, there were 21,021 AP cases at the KCVAMC. Basal cell carcinomas and squamous cell carcinomas of the skin were excluded because they comprise most cancer cases but almost never necessitate AP molecular test consultations. A total of 2118 cancer cases were included, representing 10.1% of all cases. Ancillary AP molecular send-out tests were performed on 1338 (6.4%) cases. Since ancillary tissue tests are requested by consultation at the KCVAMC, this resulted in 1338 consultations (Table 2).

The time to complete a consultation was measured by calculating the mean time required to complete each step (Table 3). With in-house specimen consultations requiring 90 minutes each and outside specimen consultations requiring 100 minutes each, a total of 2040 hours of pathology staff time was necessary to complete associated consultations. Billing for this time with the new pathology clinical consultation CPT codes would generate 3847 RVUs, which would have equated to 14.8% (3847/25,920) of the anatomic pathology RVUs.

DISCUSSION

When considering the lengths of time for tasks associated with each consultation, it is important to remember that the volume (2-3 daily), was insufficient to meaningfully benefit from batching. Thus, waiting to perform a particular task until it was needed for multiple cases reduced the inefficiency associated with starting and switching between tasks. Both the Computerized Patient Record System and VistA had to be reopened, reauthenticated, and reloaded for each step that required use of the health record, printer, or fax machine. Faxes also required waiting for transmission and printed confirmation of successful transmission. As a result, the time values denoted for each step are likely underestimated, as the effect of interruptions is significant and not reflected in the estimates recorded.¹⁰

This analysis has demonstrated that PO entails a significant amount of work for pathology departments. To determine and maintain appropriate staffing models, this work must be captured and reimbursed. Unlike other pathology work, which is performed in-house and reimbursed for the associated test, a significant proportion of PO testing is sent out. Even if more reliable assays are developed, the physical processes of sending out samples and reporting test results cannot be outsourced. Independent and commensurate reimbursement methods are necessary to allow for this work and PO.

CMS included new pathology clinical consultation codes that may be used to bill for some of this work according to the 2022 physician fee schedule due to advocacy work by the College of American Pathologists and the American Medical Association CPT editorial panel.¹¹

CONCLUSIONS

This analysis found that adoption of PO may present a significant amount of additional work for pathology departments. To determine and maintain appropriate staffing models, work completed by pathologists in this manner must be recorded and reimbursed. Pathologists need to be trained and encouraged to use these CPT codes and bill for the work described in this article. The increased revenue will allow for additional positions to alleviate the burdens imposed by understaffing so that pathology can function as a facilitator of PO rather than as a barrier to it.

Precision oncology (PO) is cancer treatment individualized to the special characteristics of a patient’s tumor. It has become standard care for most patients with advanced cancer. Advances in molecular cell biology and immunology have identified numerous targets and many therapies have been developed as a result. Molecular testing and targeted therapy are typically covered by insurance, even when inflation-adjusted price growth is considered.¹ Barriers remain, however, and pathologists are uniquely qualified to address some of the challenges.²

Most US laboratories do not perform molecular diagnostic tests for PO, particularly comprehensive evaluation of multiple targets by next-generation sequencing, or other techniques. Instead, these tests are sent to reference laboratories. The workload associated with referral testing is an obstacle to increased use of such tests. Despite guideline recommendations, a minority of indicated tests are performed.³ This is true even when testing costs are covered by clinical trials or grants, such as those in the Veterans Health Administration (VHA).

The main characteristic of successful PO programs is a multidisciplinary commitment, including pathology involvement in molecular tumor boards and assistance with test selection, tissue collection, and result interpretation.² This, however, adds to the workload for the pathology department, an underappreciated phenomenon in the context of pathology workforce shortages.⁴

Workforce shortages impact all occupations in the laboratory setting. Though the shortage of medical technologists in clinical pathology laboratories has repeatedly been identified as critical at the VHA as well as in the private sector, the same cannot be said for staff shortages in anatomic pathology laboratories. Thus, the hospital laboratory divisions are concerned with biopsy or resection tissue specimens as opposed to the bodily fluid specimens that predominate in clinical laboratories.⁵ The lack of accurate data on histopathology technicians and technologists has precluded the degree of recognition seen for medical technologists. In labor statistics, these occupations are often obscured by inclusion with other jobs in broad categories such as medical and clinical laboratory technologists and technicians.⁶ Vacancy—the principal metric used to assess medical laboratory workforce shortage—fails to account for positions that are eventually eliminated after remaining vacant for prolonged periods, positions not replaced as a result of ambitious efficiency measures, or positions that were never created due to insufficient funding, reasons for administrative disapproval, or coverage by laboratory professionals working extra shifts or second jobs.⁷

Increased demand for pathologists is suggested by a 42% increase in workload per pathologist over the last decade, while a shortage is suggested by decreases in absolute and population-adjusted numbers of pathologists.^8,9 An influx of pathologists is not an expected remedy due to the global decline in medical graduates pursuing careers in the field.⁸

Approximations for required labor and potential revenue generation are necessary to justify creation of pathology positions. This work mostly has gone uncaptured due to the limitations of Current Procedural Terminology (CPT) codes. Few laboratories have consistently used the 88363, 88325, and G0452 CPT codes. The pathology clinical consultation CPT codes (80503-80506) released in 2022 enhance acquisition of this work. The new codes replace 80500 and 80502 and allow for more precise identification of any work requiring medical judgment that a pathologist does at the request of another qualified health care professional (HCP) or as required by federal or state regulation.

The codes can be used to bill for associated time spent reviewing health records, communicating with other HCPs, placing orders, and documentation. An HCP can bill according to level of medical decision-making (MDM) or time spent by the consulting pathologist. Code 80503 can be billed for 5 to 20 minutes of a pathologist's time, 80504 for 21 to 40 minutes, 80505 for 41 to 60 minutes, and 80506 for each additional 30 minutes after the first hour. Levels of MDM (low, moderate, and high) are defined as for other evaluation and management services. A consultation report must be generated and contain documentation of the consultation request, pathologist interpretation, and justification for the level of service associated with the chosen code. Relative value units (RVUs) and reimbursement associated with each as well as other consultation-related codes are available in Table 1.

This article outlines how the pathology time investment associated with anatomic pathology molecular testing at the Kansas City Veterans Affairs Medical Center (KCVAMC) can be captured using the consultation process and new CPT codes. Staff included 4 pathologists, 3 histotechnologists, 1 histology supervisor, 1 grossing room technician, and 1 cytotechnologist, 1 cytology technician.

METHODS

The AP molecular testing consultation process at the KCVAMC was mapped, with the average time measured for each step (Figure). AP records for 2021 were reviewed to determine the number of AP molecular send out tests. Cumulative time investment was calculated in hours and a theoretical number of RVUs was calculated using the new pathology clinical consultation CPT codes (80503-80506). This theoretical number of RVUs was compared with the total AP RVUs generated in 2021 to determine a potential increase in RVUs with use of the new CPT codes to capture pathology work associated with AP molecular testing consultations.

RESULTS

From 2021 to 2023, there were 21,021 AP cases at the KCVAMC. Basal cell carcinomas and squamous cell carcinomas of the skin were excluded because they comprise most cancer cases but almost never necessitate AP molecular test consultations. A total of 2118 cancer cases were included, representing 10.1% of all cases. Ancillary AP molecular send-out tests were performed on 1338 (6.4%) cases. Since ancillary tissue tests are requested by consultation at the KCVAMC, this resulted in 1338 consultations (Table 2).

The time to complete a consultation was measured by calculating the mean time required to complete each step (Table 3). With in-house specimen consultations requiring 90 minutes each and outside specimen consultations requiring 100 minutes each, a total of 2040 hours of pathology staff time was necessary to complete associated consultations. Billing for this time with the new pathology clinical consultation CPT codes would generate 3847 RVUs, which would have equated to 14.8% (3847/25,920) of the anatomic pathology RVUs.

DISCUSSION

When considering the lengths of time for tasks associated with each consultation, it is important to remember that the volume (2-3 daily), was insufficient to meaningfully benefit from batching. Thus, waiting to perform a particular task until it was needed for multiple cases reduced the inefficiency associated with starting and switching between tasks. Both the Computerized Patient Record System and VistA had to be reopened, reauthenticated, and reloaded for each step that required use of the health record, printer, or fax machine. Faxes also required waiting for transmission and printed confirmation of successful transmission. As a result, the time values denoted for each step are likely underestimated, as the effect of interruptions is significant and not reflected in the estimates recorded.¹⁰

This analysis has demonstrated that PO entails a significant amount of work for pathology departments. To determine and maintain appropriate staffing models, this work must be captured and reimbursed. Unlike other pathology work, which is performed in-house and reimbursed for the associated test, a significant proportion of PO testing is sent out. Even if more reliable assays are developed, the physical processes of sending out samples and reporting test results cannot be outsourced. Independent and commensurate reimbursement methods are necessary to allow for this work and PO.

CMS included new pathology clinical consultation codes that may be used to bill for some of this work according to the 2022 physician fee schedule due to advocacy work by the College of American Pathologists and the American Medical Association CPT editorial panel.¹¹

CONCLUSIONS

This analysis found that adoption of PO may present a significant amount of additional work for pathology departments. To determine and maintain appropriate staffing models, work completed by pathologists in this manner must be recorded and reimbursed. Pathologists need to be trained and encouraged to use these CPT codes and bill for the work described in this article. The increased revenue will allow for additional positions to alleviate the burdens imposed by understaffing so that pathology can function as a facilitator of PO rather than as a barrier to it.

The US Department of Veterans Affairs (VA) annually treats around 450,000 veterans with cancer and diagnoses an additional 56,000.^1,2 Oral multikinase inhibitors (MKIs) are widely used as targeted therapies for many different malignancies. Despite the ease of oral administration, these agents are often accompanied by significant adverse effects (AEs) and drug-drug interactions.^3,4 Common AEs include hypertension, cutaneous reactions, gastrointestinal disturbances, proteinuria, and fatigue. Some serious outcomes that may occur are myocardial infarction, thrombosis, nephrotic syndrome, hemorrhage, hepatotoxicity, and gastrointestinal events.^5,6 Due to poor tolerability of these AEs, dose reductions, frequent therapy holds, and discontinuation of therapy may occur.

The US Food and Drug Administration recognizes dosing challenges with novel therapies and has created the Oncology Center of Excellence (OCE) Project Optimus initiative to reform dose optimization in oncology drug development. The initiative aims to shift the focus from establishing dose regimens based on the maximum tolerated doses of cytotoxic chemotherapeutics to an emphasis on maximum efficacy, safety, and tolerability, which better reflect real-world dosing.^7,8

MKIs can be challenging to manage because of the frequent toxicity-related dose reductions, interruptions, and discontinuations. In a multicenter retrospective study, Schnadig et al investigated dosing characteristics of first-line sunitinib for advanced renal cell carcinoma (RCC) and found that, among 114 patients who experienced AEs while taking sunitinib, 39.5% had dose reductions, 5.3% delayed therapy, 18.4% required additional supportive medications, and 22.8% discontinued sunitinib.⁹ Overall survival and median progression-free survival of these patients were lower than reported by Motzer et al in a phase 3 clinical trial.¹⁰ Schnadig et al concluded that patients treated with sunitinib for RCC in the community setting required more frequent dose reductions and had less time on therapy compared with patients in clinical trials, which ultimately impacted clinical outcomes.⁹

At the VA North Texas Health Care System (VANTHCS), patients with cancer have difficulty tolerating MKIs and often require dose alterations and/or discontinuation because of drug intolerance rather than discontinuation due to progression. Frequent dose adjustments for toxicity management can place more strain on patients and health care resources because of additional appointments, clinician time, and emergency department visits. Escalating drug costs can also cause concern when prescription doses are unused or changed frequently.

To capture and quantify prescribing practices and dose adjustments, this study evaluated the tolerability of MKIs at VANTHCS. This analysis may also guide clinicians in the selection of starting doses as well as dose titration expectations to optimize MKI therapy.

METHODS

This single-center, retrospective chart review analyzed patients receiving oral oncology MKIs for various malignancies at VANTHCS between January 1, 2014, and October 31, 2024. Participants included adults aged ≥ 18 years with a prescription for axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, or sunitinib initiated by the hematology/oncology service at VANTHCS. Patients were included if they had follow-up documentation with the hematology/oncology service and/or other VANTHCS clinicians outlining their course of therapy after MKI initiation. Patients were excluded if they did not have sufficient follow-up documentation (eg, transferred care to a non-VA health care practitioner [HCP], moved to another VA health care system), were enrolled in clinical trials, or were prescribed an MKI from a Care in the Community (CITC) prescriber. Electronic health record review and data collection were performed using the VA Computerized Patient Record System and Research Electronic Data Capture. Data were collected from the time of initiation to cessation of therapy and included information regarding therapy changes, progressive disease, and date of death, when available. Data collected included age, sex, race, comorbidities, date of death, type of malignancy and subtypes, cancer stage, MKI used (ie, drug, dose, frequency, schedule, and indication), dates of medication changes (ie, start, adjustment, hold, discontinuation), concurrent antineoplastic treatments, and AEs documented at times of dose change or interruption.

The primary outcome was MKI tolerance determined using relative dose intensity (RDI) and mean and median time on therapy. Two methods are used to calculate RDI that vary in how they approach time on therapy as outlined in Hawn et al.¹¹ This study used method 2, which accounts for holds in therapy by comparing the actual duration of treatment with the duration expected according to treatment protocol. Method 1 compares the prescribed dose with the administered dose and does not adjust for holds.¹¹ Using method 2, the RDI in this study was calculated by dividing the total actual dose given by the total indicated dose for the malignancy being treated, which accounts for duration of treatment.

The total actual dose was the strength, frequency, and days on therapy for each time frame of treatment multiplied together. This method accounted for all dose adjustments and time periods of treatment holds, including patient self-adjustments, prescriber-directed adjustments, and nonadherence determined by HCP documentation and/or prescription data. Similarly, the indicated total dose was calculated by multiplying the indicated strength, frequency, and all days that treatment should have occurred (time from start to finish). Indicated doses were derived from the prescribing information for each malignancy with the exception of sunitinib, for which the off-label dose of 37.5 mg daily was considered a full dose.^12,13 The total indicated dose for axitinib was calculated by considering the dose escalation schedule from the prescribing information.

Patients who required dose reductions due to renal/hepatic impairments or drug-drug interactions had their total indicated dose calculated using dose adjustments listed in the prescribing information. The mean RDI for each MKI agent was calculated by averaging the RDI for each prescription. The overall combined mean RDI included the means of all the MKIs reviewed to avoid skewing the results toward an MKI with more prescriptions. RDIs were also calculated for each cancer type for each agent. Additional descriptive secondary outcomes included rates of AEs and adjustments in doses.

RESULTS

Electronic data extraction identified 278 patients with 366 MKI prescriptions, of which 108 veterans with 158 MKI prescriptions were excluded. The top reason for exclusion was patients managed through CITC. Ultimately, 170 veterans with 208 MKI prescriptions managed by the VANTHCS hematology/oncology clinic were included (Table 1). Among patients receiving MKIs, the mean age was 72.7 years, 98% were male, and 99% had metastatic disease.

The overall combined mean MKI RDI was 67.5% using method 2 and ranged from 85.5% for sunitinib to 49.0% for sorafenib (Figure 1). Additional information regarding mean and median RDIs using method 2 is shown in Figure 1 and further subdivided by cancer type in Table 2. Median RDIs overall were similar to mean RDIs for most agents. Figure 2 indicates the mean and median time on therapy, reflecting time on therapy excluding days therapy was held. The overall combined mean and median days on therapy for all MKIs were 155 days and 95 days, respectively. Mean time on therapy depended on the agent used and ranged from 35 days (regorafenib) to 237 days (cabozantinib).

Of 208 MKI prescriptions, 127 (61.1%) were initiated at a reduced dose due to baseline concerns for tolerance such as performance status, frailty, and prior intolerance of other treatments. Eighty-one prescriptions (38.9%) were initiated at their indicated doses. Ninety prescriptions (43.3%) required dose reductions during treatment. Some MKI prescriptions had multiple dose increases and decreases, which is why RDI more accurately reflects dose adjustments. A total of 376 AEs that contributed to a dose adjustment, hold, or discontinuation occurred across all MKI prescriptions. The most common AEs were 82 failure-to-thrive events (21.8%) (fatigue, malaise, loss of appetite, reduced mobility, global decline), 79 gastrointestinal events (21.0%) (nausea, vomiting, diarrhea, abdominal pain), 62 dermatologic events (16.5%) (rash, hand-foot skin reactions, allergic response), 61 hepatic dysfunction events (16.2%) (liver enzyme elevations, hyperbilirubinemia), 40 cardiovascular events (10.6%) (hypertension, heart failure exacerbations, edema), and 33 renal dysfunction events (8.8%) (acute kidney injury, proteinuria) (Appendix 1).

DISCUSSION

The mean RDI of MKI prescriptions used in the veteran population at VANTHCS was about two-thirds of the indicated dose. These results indicate that most veterans required dose reductions and/or holds due to concerns over initial tolerance/performance status, worsening clinical condition, and/or intolerable AEs attributed to treatment. A retrospective study conducted by Denduluri et al suggested that an RDI of < 85% is a clinically meaningful reduction for traditional chemotherapy based on previous literature.¹⁴ However, it is less clear what RDI should be expected specifically for MKIs in real-world populations. The MKI phase 3 approval trials in RCC for axitinib, lenvatinib, and sunitinib found median RDIs of 89.4%, 69.6% to 70.4%, and 83.9%, respectively. Each trial cited dose reductions most commonly as the result of treatment-related AEs.^15,16

Studies on the impact of RDIs on survival outcomes found that higher RDIs may improve overall and progression-free survival. Retrospective studies inspecting lenvatinib in hepatocellular carcinoma (HCC) indicated that an RDI > 70% in the initial 4 weeks resulted in favorable survival outcomes.¹⁷ Similarly, a retrospective study investigating sunitinib in RCC found that an RDI > 60% conferred favorable survival outcomes.¹⁸ Alghamdi et al noted that patients taking sorafenib for HCC who had RDI > 50% had a favorable trend in survival characteristics. Interestingly, the study found an RDI of 50% to 75% appeared to have better survival than an RDI > 75%.¹⁹ The authors of these studies hypothesized that additional dose reductions allowed for longer total time on therapy due to improved tolerability.^17-19

This analysis found that the RDIs for most MKI agents at VANTHCS were < 85% and lower than the RDIs found in other review articles and phase 3 trials, with the exceptions of pazopanib in thyroid cancer and sunitinib in gastrointestinal stromal tumor (GIST), thyroid cancer, and neuroendocrine cancer. The reasons for the lower RDIs in this study are likely multifactorial, reflecting patient population characteristics, off-label dosing practices, and HCP experiences with these agents. Many veterans have chronic comorbidities that could contribute to reduced performance status and ability to tolerate these therapies. Despite attempts to preemptively reduce doses for patients and account for potential impaired tolerance, there were patients who required further dose reductions in our study.

Failure to thrive was the most common AE leading to dose adjustment or discontinuation, which illustrates the extensive effects these agents have on patient functioning in a real-world population. Notably though, the RDI for sunitinib was higher in this population because about half of patients were dosed using the off-label recommendation, whereas the prescribing information recommends a more intensive 6-week dosing cycle for certain cancer types.^12,13,20 Sorafenib was also often dose-adjusted based on a pharmacokinetic study of sorafenib in renal/hepatic dysfunction, and the RDI likely reflects the off-label prescribing pattern.²¹

Patients with thyroid cancer were found to have higher RDIs compared with those receiving the same agents for other cancer types. Improved tolerability of MKIs in thyroid cancer may be due to a generally more tolerable disease course. Thyroid cancer is the most common cancer in individuals aged < 40 years, a population that is often more robust with fewer comorbidities. Moreover, the 5-year relative survival rate for thyroid cancer remains > 98%.²² This rate is in contrast to those for other cancer types such as HCC, with a 5-year relative survival rate of only 15%.²³

It is challenging to compare the mean and median times on therapy found in this study with those in current literature, as this review included multiple different cancer types for each agent. However, the numbers are generally lower than durations of therapy found across the different disease states and further emphasize the difficulty in tolerating MKIs in the VANTHCS population. Regorafenib had a short duration of time on therapy, which highlights the importance of trials like ReDOS and initiatives such as OCE Project Optimus in helping improve tolerance.^7,8,24

Comparing our results with other studies proved challenging because the RDI calculation methods were not specified. Calculating RDIs in this study using method 1, which does not account for holds, resulted in higher RDIs (Appendix 2). Using method 1, all MKIs had RDIs < 85%, except for pazopanib in thyroid cancer (100%) and RCC (87.9%), and sunitinib in GIST (93.6%), thyroid cancer (100%), and neuroendocrine cancer (93.7%). Notably, using method 1 increased the RDI for pazopanib in neuroendocrine cancer from 5.4% to 50.0%. The low RDI was attributed to a single veteran with a long hold duration, which demonstrates the discrepancy that can occur between the 2 methods.

Limitations

The retrospective design, lack of survival outcomes, and difficulty comparing results with other literature were limitations of this study. Because survival outcomes were not evaluated, future research should seek to investigate how RDIs and dose adjustments made among MKIs can affect survival outcomes in real-world populations. This veteran population with cancer often had multiple chronic comorbidities, which may have contributed to difficulty tolerating MKIs and could have impacted results. Disease-related factors may have influenced the poor tolerance of the MKIs and were not specifically accounted for. Adjustment for comorbidities was not possible because of discrepancies and/or incomplete diagnosis codes and Eastern Cooperative Oncology Group performance status scores documented in patient charts. Therefore, we decided not to report these findings due to potential inaccuracies.

CONCLUSIONS

Results of this study demonstrate that oncology MKI agents used at VANTHCS were difficult for patients to tolerate, leading to suboptimal dosing compared with indicated doses established in clinical trials and prescribing information. Clinicians may use these data to help guide clinical decision-making whenever initiating and managing MKI agents in this population. These findings reinforce that MKI agents are often difficult to tolerate in real-world practice, and indicated doses are often not achieved. Further studies should aim to investigate the effect that various RDIs have on overall survival. Further investigation into different dosing schemes for MKIs to improve tolerability and longer-term use may also prove beneficial.

This analysis may help guide clinicians to carefully approach dosing MKI agents in the veteran population. Given the RDI and AEs, more clinicians may consider starting at lower than indicated doses with the goal to titrate up as tolerated. Additionally, the results highlight the importance of considering palliative care consults and ensuring appropriate supportive care agents are preemptively engaged and adjusted as needed. Approaching dosing and titrations cautiously may help reduce the burden of management on the health care system.

The US Department of Veterans Affairs (VA) annually treats around 450,000 veterans with cancer and diagnoses an additional 56,000.^1,2 Oral multikinase inhibitors (MKIs) are widely used as targeted therapies for many different malignancies. Despite the ease of oral administration, these agents are often accompanied by significant adverse effects (AEs) and drug-drug interactions.^3,4 Common AEs include hypertension, cutaneous reactions, gastrointestinal disturbances, proteinuria, and fatigue. Some serious outcomes that may occur are myocardial infarction, thrombosis, nephrotic syndrome, hemorrhage, hepatotoxicity, and gastrointestinal events.^5,6 Due to poor tolerability of these AEs, dose reductions, frequent therapy holds, and discontinuation of therapy may occur.

The US Food and Drug Administration recognizes dosing challenges with novel therapies and has created the Oncology Center of Excellence (OCE) Project Optimus initiative to reform dose optimization in oncology drug development. The initiative aims to shift the focus from establishing dose regimens based on the maximum tolerated doses of cytotoxic chemotherapeutics to an emphasis on maximum efficacy, safety, and tolerability, which better reflect real-world dosing.^7,8

MKIs can be challenging to manage because of the frequent toxicity-related dose reductions, interruptions, and discontinuations. In a multicenter retrospective study, Schnadig et al investigated dosing characteristics of first-line sunitinib for advanced renal cell carcinoma (RCC) and found that, among 114 patients who experienced AEs while taking sunitinib, 39.5% had dose reductions, 5.3% delayed therapy, 18.4% required additional supportive medications, and 22.8% discontinued sunitinib.⁹ Overall survival and median progression-free survival of these patients were lower than reported by Motzer et al in a phase 3 clinical trial.¹⁰ Schnadig et al concluded that patients treated with sunitinib for RCC in the community setting required more frequent dose reductions and had less time on therapy compared with patients in clinical trials, which ultimately impacted clinical outcomes.⁹

At the VA North Texas Health Care System (VANTHCS), patients with cancer have difficulty tolerating MKIs and often require dose alterations and/or discontinuation because of drug intolerance rather than discontinuation due to progression. Frequent dose adjustments for toxicity management can place more strain on patients and health care resources because of additional appointments, clinician time, and emergency department visits. Escalating drug costs can also cause concern when prescription doses are unused or changed frequently.

To capture and quantify prescribing practices and dose adjustments, this study evaluated the tolerability of MKIs at VANTHCS. This analysis may also guide clinicians in the selection of starting doses as well as dose titration expectations to optimize MKI therapy.

METHODS

This single-center, retrospective chart review analyzed patients receiving oral oncology MKIs for various malignancies at VANTHCS between January 1, 2014, and October 31, 2024. Participants included adults aged ≥ 18 years with a prescription for axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, or sunitinib initiated by the hematology/oncology service at VANTHCS. Patients were included if they had follow-up documentation with the hematology/oncology service and/or other VANTHCS clinicians outlining their course of therapy after MKI initiation. Patients were excluded if they did not have sufficient follow-up documentation (eg, transferred care to a non-VA health care practitioner [HCP], moved to another VA health care system), were enrolled in clinical trials, or were prescribed an MKI from a Care in the Community (CITC) prescriber. Electronic health record review and data collection were performed using the VA Computerized Patient Record System and Research Electronic Data Capture. Data were collected from the time of initiation to cessation of therapy and included information regarding therapy changes, progressive disease, and date of death, when available. Data collected included age, sex, race, comorbidities, date of death, type of malignancy and subtypes, cancer stage, MKI used (ie, drug, dose, frequency, schedule, and indication), dates of medication changes (ie, start, adjustment, hold, discontinuation), concurrent antineoplastic treatments, and AEs documented at times of dose change or interruption.

The primary outcome was MKI tolerance determined using relative dose intensity (RDI) and mean and median time on therapy. Two methods are used to calculate RDI that vary in how they approach time on therapy as outlined in Hawn et al.¹¹ This study used method 2, which accounts for holds in therapy by comparing the actual duration of treatment with the duration expected according to treatment protocol. Method 1 compares the prescribed dose with the administered dose and does not adjust for holds.¹¹ Using method 2, the RDI in this study was calculated by dividing the total actual dose given by the total indicated dose for the malignancy being treated, which accounts for duration of treatment.

The total actual dose was the strength, frequency, and days on therapy for each time frame of treatment multiplied together. This method accounted for all dose adjustments and time periods of treatment holds, including patient self-adjustments, prescriber-directed adjustments, and nonadherence determined by HCP documentation and/or prescription data. Similarly, the indicated total dose was calculated by multiplying the indicated strength, frequency, and all days that treatment should have occurred (time from start to finish). Indicated doses were derived from the prescribing information for each malignancy with the exception of sunitinib, for which the off-label dose of 37.5 mg daily was considered a full dose.^12,13 The total indicated dose for axitinib was calculated by considering the dose escalation schedule from the prescribing information.

Patients who required dose reductions due to renal/hepatic impairments or drug-drug interactions had their total indicated dose calculated using dose adjustments listed in the prescribing information. The mean RDI for each MKI agent was calculated by averaging the RDI for each prescription. The overall combined mean RDI included the means of all the MKIs reviewed to avoid skewing the results toward an MKI with more prescriptions. RDIs were also calculated for each cancer type for each agent. Additional descriptive secondary outcomes included rates of AEs and adjustments in doses.

RESULTS

Electronic data extraction identified 278 patients with 366 MKI prescriptions, of which 108 veterans with 158 MKI prescriptions were excluded. The top reason for exclusion was patients managed through CITC. Ultimately, 170 veterans with 208 MKI prescriptions managed by the VANTHCS hematology/oncology clinic were included (Table 1). Among patients receiving MKIs, the mean age was 72.7 years, 98% were male, and 99% had metastatic disease.

The overall combined mean MKI RDI was 67.5% using method 2 and ranged from 85.5% for sunitinib to 49.0% for sorafenib (Figure 1). Additional information regarding mean and median RDIs using method 2 is shown in Figure 1 and further subdivided by cancer type in Table 2. Median RDIs overall were similar to mean RDIs for most agents. Figure 2 indicates the mean and median time on therapy, reflecting time on therapy excluding days therapy was held. The overall combined mean and median days on therapy for all MKIs were 155 days and 95 days, respectively. Mean time on therapy depended on the agent used and ranged from 35 days (regorafenib) to 237 days (cabozantinib).

Of 208 MKI prescriptions, 127 (61.1%) were initiated at a reduced dose due to baseline concerns for tolerance such as performance status, frailty, and prior intolerance of other treatments. Eighty-one prescriptions (38.9%) were initiated at their indicated doses. Ninety prescriptions (43.3%) required dose reductions during treatment. Some MKI prescriptions had multiple dose increases and decreases, which is why RDI more accurately reflects dose adjustments. A total of 376 AEs that contributed to a dose adjustment, hold, or discontinuation occurred across all MKI prescriptions. The most common AEs were 82 failure-to-thrive events (21.8%) (fatigue, malaise, loss of appetite, reduced mobility, global decline), 79 gastrointestinal events (21.0%) (nausea, vomiting, diarrhea, abdominal pain), 62 dermatologic events (16.5%) (rash, hand-foot skin reactions, allergic response), 61 hepatic dysfunction events (16.2%) (liver enzyme elevations, hyperbilirubinemia), 40 cardiovascular events (10.6%) (hypertension, heart failure exacerbations, edema), and 33 renal dysfunction events (8.8%) (acute kidney injury, proteinuria) (Appendix 1).

DISCUSSION

The mean RDI of MKI prescriptions used in the veteran population at VANTHCS was about two-thirds of the indicated dose. These results indicate that most veterans required dose reductions and/or holds due to concerns over initial tolerance/performance status, worsening clinical condition, and/or intolerable AEs attributed to treatment. A retrospective study conducted by Denduluri et al suggested that an RDI of < 85% is a clinically meaningful reduction for traditional chemotherapy based on previous literature.¹⁴ However, it is less clear what RDI should be expected specifically for MKIs in real-world populations. The MKI phase 3 approval trials in RCC for axitinib, lenvatinib, and sunitinib found median RDIs of 89.4%, 69.6% to 70.4%, and 83.9%, respectively. Each trial cited dose reductions most commonly as the result of treatment-related AEs.^15,16

Studies on the impact of RDIs on survival outcomes found that higher RDIs may improve overall and progression-free survival. Retrospective studies inspecting lenvatinib in hepatocellular carcinoma (HCC) indicated that an RDI > 70% in the initial 4 weeks resulted in favorable survival outcomes.¹⁷ Similarly, a retrospective study investigating sunitinib in RCC found that an RDI > 60% conferred favorable survival outcomes.¹⁸ Alghamdi et al noted that patients taking sorafenib for HCC who had RDI > 50% had a favorable trend in survival characteristics. Interestingly, the study found an RDI of 50% to 75% appeared to have better survival than an RDI > 75%.¹⁹ The authors of these studies hypothesized that additional dose reductions allowed for longer total time on therapy due to improved tolerability.^17-19

This analysis found that the RDIs for most MKI agents at VANTHCS were < 85% and lower than the RDIs found in other review articles and phase 3 trials, with the exceptions of pazopanib in thyroid cancer and sunitinib in gastrointestinal stromal tumor (GIST), thyroid cancer, and neuroendocrine cancer. The reasons for the lower RDIs in this study are likely multifactorial, reflecting patient population characteristics, off-label dosing practices, and HCP experiences with these agents. Many veterans have chronic comorbidities that could contribute to reduced performance status and ability to tolerate these therapies. Despite attempts to preemptively reduce doses for patients and account for potential impaired tolerance, there were patients who required further dose reductions in our study.

Failure to thrive was the most common AE leading to dose adjustment or discontinuation, which illustrates the extensive effects these agents have on patient functioning in a real-world population. Notably though, the RDI for sunitinib was higher in this population because about half of patients were dosed using the off-label recommendation, whereas the prescribing information recommends a more intensive 6-week dosing cycle for certain cancer types.^12,13,20 Sorafenib was also often dose-adjusted based on a pharmacokinetic study of sorafenib in renal/hepatic dysfunction, and the RDI likely reflects the off-label prescribing pattern.²¹

Patients with thyroid cancer were found to have higher RDIs compared with those receiving the same agents for other cancer types. Improved tolerability of MKIs in thyroid cancer may be due to a generally more tolerable disease course. Thyroid cancer is the most common cancer in individuals aged < 40 years, a population that is often more robust with fewer comorbidities. Moreover, the 5-year relative survival rate for thyroid cancer remains > 98%.²² This rate is in contrast to those for other cancer types such as HCC, with a 5-year relative survival rate of only 15%.²³

It is challenging to compare the mean and median times on therapy found in this study with those in current literature, as this review included multiple different cancer types for each agent. However, the numbers are generally lower than durations of therapy found across the different disease states and further emphasize the difficulty in tolerating MKIs in the VANTHCS population. Regorafenib had a short duration of time on therapy, which highlights the importance of trials like ReDOS and initiatives such as OCE Project Optimus in helping improve tolerance.^7,8,24

Comparing our results with other studies proved challenging because the RDI calculation methods were not specified. Calculating RDIs in this study using method 1, which does not account for holds, resulted in higher RDIs (Appendix 2). Using method 1, all MKIs had RDIs < 85%, except for pazopanib in thyroid cancer (100%) and RCC (87.9%), and sunitinib in GIST (93.6%), thyroid cancer (100%), and neuroendocrine cancer (93.7%). Notably, using method 1 increased the RDI for pazopanib in neuroendocrine cancer from 5.4% to 50.0%. The low RDI was attributed to a single veteran with a long hold duration, which demonstrates the discrepancy that can occur between the 2 methods.

Limitations

The retrospective design, lack of survival outcomes, and difficulty comparing results with other literature were limitations of this study. Because survival outcomes were not evaluated, future research should seek to investigate how RDIs and dose adjustments made among MKIs can affect survival outcomes in real-world populations. This veteran population with cancer often had multiple chronic comorbidities, which may have contributed to difficulty tolerating MKIs and could have impacted results. Disease-related factors may have influenced the poor tolerance of the MKIs and were not specifically accounted for. Adjustment for comorbidities was not possible because of discrepancies and/or incomplete diagnosis codes and Eastern Cooperative Oncology Group performance status scores documented in patient charts. Therefore, we decided not to report these findings due to potential inaccuracies.

CONCLUSIONS

Results of this study demonstrate that oncology MKI agents used at VANTHCS were difficult for patients to tolerate, leading to suboptimal dosing compared with indicated doses established in clinical trials and prescribing information. Clinicians may use these data to help guide clinical decision-making whenever initiating and managing MKI agents in this population. These findings reinforce that MKI agents are often difficult to tolerate in real-world practice, and indicated doses are often not achieved. Further studies should aim to investigate the effect that various RDIs have on overall survival. Further investigation into different dosing schemes for MKIs to improve tolerability and longer-term use may also prove beneficial.

This analysis may help guide clinicians to carefully approach dosing MKI agents in the veteran population. Given the RDI and AEs, more clinicians may consider starting at lower than indicated doses with the goal to titrate up as tolerated. Additionally, the results highlight the importance of considering palliative care consults and ensuring appropriate supportive care agents are preemptively engaged and adjusted as needed. Approaching dosing and titrations cautiously may help reduce the burden of management on the health care system.

The US Department of Veterans Affairs (VA) annually treats around 450,000 veterans with cancer and diagnoses an additional 56,000.^1,2 Oral multikinase inhibitors (MKIs) are widely used as targeted therapies for many different malignancies. Despite the ease of oral administration, these agents are often accompanied by significant adverse effects (AEs) and drug-drug interactions.^3,4 Common AEs include hypertension, cutaneous reactions, gastrointestinal disturbances, proteinuria, and fatigue. Some serious outcomes that may occur are myocardial infarction, thrombosis, nephrotic syndrome, hemorrhage, hepatotoxicity, and gastrointestinal events.^5,6 Due to poor tolerability of these AEs, dose reductions, frequent therapy holds, and discontinuation of therapy may occur.

The US Food and Drug Administration recognizes dosing challenges with novel therapies and has created the Oncology Center of Excellence (OCE) Project Optimus initiative to reform dose optimization in oncology drug development. The initiative aims to shift the focus from establishing dose regimens based on the maximum tolerated doses of cytotoxic chemotherapeutics to an emphasis on maximum efficacy, safety, and tolerability, which better reflect real-world dosing.^7,8

MKIs can be challenging to manage because of the frequent toxicity-related dose reductions, interruptions, and discontinuations. In a multicenter retrospective study, Schnadig et al investigated dosing characteristics of first-line sunitinib for advanced renal cell carcinoma (RCC) and found that, among 114 patients who experienced AEs while taking sunitinib, 39.5% had dose reductions, 5.3% delayed therapy, 18.4% required additional supportive medications, and 22.8% discontinued sunitinib.⁹ Overall survival and median progression-free survival of these patients were lower than reported by Motzer et al in a phase 3 clinical trial.¹⁰ Schnadig et al concluded that patients treated with sunitinib for RCC in the community setting required more frequent dose reductions and had less time on therapy compared with patients in clinical trials, which ultimately impacted clinical outcomes.⁹

At the VA North Texas Health Care System (VANTHCS), patients with cancer have difficulty tolerating MKIs and often require dose alterations and/or discontinuation because of drug intolerance rather than discontinuation due to progression. Frequent dose adjustments for toxicity management can place more strain on patients and health care resources because of additional appointments, clinician time, and emergency department visits. Escalating drug costs can also cause concern when prescription doses are unused or changed frequently.

To capture and quantify prescribing practices and dose adjustments, this study evaluated the tolerability of MKIs at VANTHCS. This analysis may also guide clinicians in the selection of starting doses as well as dose titration expectations to optimize MKI therapy.

METHODS

This single-center, retrospective chart review analyzed patients receiving oral oncology MKIs for various malignancies at VANTHCS between January 1, 2014, and October 31, 2024. Participants included adults aged ≥ 18 years with a prescription for axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, or sunitinib initiated by the hematology/oncology service at VANTHCS. Patients were included if they had follow-up documentation with the hematology/oncology service and/or other VANTHCS clinicians outlining their course of therapy after MKI initiation. Patients were excluded if they did not have sufficient follow-up documentation (eg, transferred care to a non-VA health care practitioner [HCP], moved to another VA health care system), were enrolled in clinical trials, or were prescribed an MKI from a Care in the Community (CITC) prescriber. Electronic health record review and data collection were performed using the VA Computerized Patient Record System and Research Electronic Data Capture. Data were collected from the time of initiation to cessation of therapy and included information regarding therapy changes, progressive disease, and date of death, when available. Data collected included age, sex, race, comorbidities, date of death, type of malignancy and subtypes, cancer stage, MKI used (ie, drug, dose, frequency, schedule, and indication), dates of medication changes (ie, start, adjustment, hold, discontinuation), concurrent antineoplastic treatments, and AEs documented at times of dose change or interruption.

The primary outcome was MKI tolerance determined using relative dose intensity (RDI) and mean and median time on therapy. Two methods are used to calculate RDI that vary in how they approach time on therapy as outlined in Hawn et al.¹¹ This study used method 2, which accounts for holds in therapy by comparing the actual duration of treatment with the duration expected according to treatment protocol. Method 1 compares the prescribed dose with the administered dose and does not adjust for holds.¹¹ Using method 2, the RDI in this study was calculated by dividing the total actual dose given by the total indicated dose for the malignancy being treated, which accounts for duration of treatment.

The total actual dose was the strength, frequency, and days on therapy for each time frame of treatment multiplied together. This method accounted for all dose adjustments and time periods of treatment holds, including patient self-adjustments, prescriber-directed adjustments, and nonadherence determined by HCP documentation and/or prescription data. Similarly, the indicated total dose was calculated by multiplying the indicated strength, frequency, and all days that treatment should have occurred (time from start to finish). Indicated doses were derived from the prescribing information for each malignancy with the exception of sunitinib, for which the off-label dose of 37.5 mg daily was considered a full dose.^12,13 The total indicated dose for axitinib was calculated by considering the dose escalation schedule from the prescribing information.

Patients who required dose reductions due to renal/hepatic impairments or drug-drug interactions had their total indicated dose calculated using dose adjustments listed in the prescribing information. The mean RDI for each MKI agent was calculated by averaging the RDI for each prescription. The overall combined mean RDI included the means of all the MKIs reviewed to avoid skewing the results toward an MKI with more prescriptions. RDIs were also calculated for each cancer type for each agent. Additional descriptive secondary outcomes included rates of AEs and adjustments in doses.

RESULTS

Electronic data extraction identified 278 patients with 366 MKI prescriptions, of which 108 veterans with 158 MKI prescriptions were excluded. The top reason for exclusion was patients managed through CITC. Ultimately, 170 veterans with 208 MKI prescriptions managed by the VANTHCS hematology/oncology clinic were included (Table 1). Among patients receiving MKIs, the mean age was 72.7 years, 98% were male, and 99% had metastatic disease.

The overall combined mean MKI RDI was 67.5% using method 2 and ranged from 85.5% for sunitinib to 49.0% for sorafenib (Figure 1). Additional information regarding mean and median RDIs using method 2 is shown in Figure 1 and further subdivided by cancer type in Table 2. Median RDIs overall were similar to mean RDIs for most agents. Figure 2 indicates the mean and median time on therapy, reflecting time on therapy excluding days therapy was held. The overall combined mean and median days on therapy for all MKIs were 155 days and 95 days, respectively. Mean time on therapy depended on the agent used and ranged from 35 days (regorafenib) to 237 days (cabozantinib).

Of 208 MKI prescriptions, 127 (61.1%) were initiated at a reduced dose due to baseline concerns for tolerance such as performance status, frailty, and prior intolerance of other treatments. Eighty-one prescriptions (38.9%) were initiated at their indicated doses. Ninety prescriptions (43.3%) required dose reductions during treatment. Some MKI prescriptions had multiple dose increases and decreases, which is why RDI more accurately reflects dose adjustments. A total of 376 AEs that contributed to a dose adjustment, hold, or discontinuation occurred across all MKI prescriptions. The most common AEs were 82 failure-to-thrive events (21.8%) (fatigue, malaise, loss of appetite, reduced mobility, global decline), 79 gastrointestinal events (21.0%) (nausea, vomiting, diarrhea, abdominal pain), 62 dermatologic events (16.5%) (rash, hand-foot skin reactions, allergic response), 61 hepatic dysfunction events (16.2%) (liver enzyme elevations, hyperbilirubinemia), 40 cardiovascular events (10.6%) (hypertension, heart failure exacerbations, edema), and 33 renal dysfunction events (8.8%) (acute kidney injury, proteinuria) (Appendix 1).

DISCUSSION

The mean RDI of MKI prescriptions used in the veteran population at VANTHCS was about two-thirds of the indicated dose. These results indicate that most veterans required dose reductions and/or holds due to concerns over initial tolerance/performance status, worsening clinical condition, and/or intolerable AEs attributed to treatment. A retrospective study conducted by Denduluri et al suggested that an RDI of < 85% is a clinically meaningful reduction for traditional chemotherapy based on previous literature.¹⁴ However, it is less clear what RDI should be expected specifically for MKIs in real-world populations. The MKI phase 3 approval trials in RCC for axitinib, lenvatinib, and sunitinib found median RDIs of 89.4%, 69.6% to 70.4%, and 83.9%, respectively. Each trial cited dose reductions most commonly as the result of treatment-related AEs.^15,16

Studies on the impact of RDIs on survival outcomes found that higher RDIs may improve overall and progression-free survival. Retrospective studies inspecting lenvatinib in hepatocellular carcinoma (HCC) indicated that an RDI > 70% in the initial 4 weeks resulted in favorable survival outcomes.¹⁷ Similarly, a retrospective study investigating sunitinib in RCC found that an RDI > 60% conferred favorable survival outcomes.¹⁸ Alghamdi et al noted that patients taking sorafenib for HCC who had RDI > 50% had a favorable trend in survival characteristics. Interestingly, the study found an RDI of 50% to 75% appeared to have better survival than an RDI > 75%.¹⁹ The authors of these studies hypothesized that additional dose reductions allowed for longer total time on therapy due to improved tolerability.^17-19

This analysis found that the RDIs for most MKI agents at VANTHCS were < 85% and lower than the RDIs found in other review articles and phase 3 trials, with the exceptions of pazopanib in thyroid cancer and sunitinib in gastrointestinal stromal tumor (GIST), thyroid cancer, and neuroendocrine cancer. The reasons for the lower RDIs in this study are likely multifactorial, reflecting patient population characteristics, off-label dosing practices, and HCP experiences with these agents. Many veterans have chronic comorbidities that could contribute to reduced performance status and ability to tolerate these therapies. Despite attempts to preemptively reduce doses for patients and account for potential impaired tolerance, there were patients who required further dose reductions in our study.

Failure to thrive was the most common AE leading to dose adjustment or discontinuation, which illustrates the extensive effects these agents have on patient functioning in a real-world population. Notably though, the RDI for sunitinib was higher in this population because about half of patients were dosed using the off-label recommendation, whereas the prescribing information recommends a more intensive 6-week dosing cycle for certain cancer types.^12,13,20 Sorafenib was also often dose-adjusted based on a pharmacokinetic study of sorafenib in renal/hepatic dysfunction, and the RDI likely reflects the off-label prescribing pattern.²¹

Patients with thyroid cancer were found to have higher RDIs compared with those receiving the same agents for other cancer types. Improved tolerability of MKIs in thyroid cancer may be due to a generally more tolerable disease course. Thyroid cancer is the most common cancer in individuals aged < 40 years, a population that is often more robust with fewer comorbidities. Moreover, the 5-year relative survival rate for thyroid cancer remains > 98%.²² This rate is in contrast to those for other cancer types such as HCC, with a 5-year relative survival rate of only 15%.²³

It is challenging to compare the mean and median times on therapy found in this study with those in current literature, as this review included multiple different cancer types for each agent. However, the numbers are generally lower than durations of therapy found across the different disease states and further emphasize the difficulty in tolerating MKIs in the VANTHCS population. Regorafenib had a short duration of time on therapy, which highlights the importance of trials like ReDOS and initiatives such as OCE Project Optimus in helping improve tolerance.^7,8,24

Comparing our results with other studies proved challenging because the RDI calculation methods were not specified. Calculating RDIs in this study using method 1, which does not account for holds, resulted in higher RDIs (Appendix 2). Using method 1, all MKIs had RDIs < 85%, except for pazopanib in thyroid cancer (100%) and RCC (87.9%), and sunitinib in GIST (93.6%), thyroid cancer (100%), and neuroendocrine cancer (93.7%). Notably, using method 1 increased the RDI for pazopanib in neuroendocrine cancer from 5.4% to 50.0%. The low RDI was attributed to a single veteran with a long hold duration, which demonstrates the discrepancy that can occur between the 2 methods.

Limitations

The retrospective design, lack of survival outcomes, and difficulty comparing results with other literature were limitations of this study. Because survival outcomes were not evaluated, future research should seek to investigate how RDIs and dose adjustments made among MKIs can affect survival outcomes in real-world populations. This veteran population with cancer often had multiple chronic comorbidities, which may have contributed to difficulty tolerating MKIs and could have impacted results. Disease-related factors may have influenced the poor tolerance of the MKIs and were not specifically accounted for. Adjustment for comorbidities was not possible because of discrepancies and/or incomplete diagnosis codes and Eastern Cooperative Oncology Group performance status scores documented in patient charts. Therefore, we decided not to report these findings due to potential inaccuracies.

CONCLUSIONS

Results of this study demonstrate that oncology MKI agents used at VANTHCS were difficult for patients to tolerate, leading to suboptimal dosing compared with indicated doses established in clinical trials and prescribing information. Clinicians may use these data to help guide clinical decision-making whenever initiating and managing MKI agents in this population. These findings reinforce that MKI agents are often difficult to tolerate in real-world practice, and indicated doses are often not achieved. Further studies should aim to investigate the effect that various RDIs have on overall survival. Further investigation into different dosing schemes for MKIs to improve tolerability and longer-term use may also prove beneficial.

This analysis may help guide clinicians to carefully approach dosing MKI agents in the veteran population. Given the RDI and AEs, more clinicians may consider starting at lower than indicated doses with the goal to titrate up as tolerated. Additionally, the results highlight the importance of considering palliative care consults and ensuring appropriate supportive care agents are preemptively engaged and adjusted as needed. Approaching dosing and titrations cautiously may help reduce the burden of management on the health care system.

Chronic myeloid leukemia (CML) is a hematologic malignancy resulting from an acquired mutation. The mutation results in a reciprocal translocation between the long arms of chromosomes 9 and 22 and is known as the Philadelphia chromosome (Ph), or Ph-positive (Ph+) when present. The translocation results in the formation of a BCR-ABL fusion oncogene, which leads to continuous cell cycling and proliferation, altered differentiation, and a loss of apoptosis.^1,2

Until the 1980s, CML was considered fatal.³ The mainstay of treatment consisted of 2 oral chemotherapeutic agents, busulfan and hydroxyurea. These medications did not prevent blast crisis, a fatal form of leukemia.^4,5 The introduction of tyrosine kinase inhibitors (TKIs) transformed CML management and improved 10-year overall survival from about 20% to > 80% by delaying the transition to blast crisis. Now, the risk of death from general health conditions or comorbidities is higher than that of CML.⁶

TKIs target the root cause of CML through inhibition of the BCR-ABL oncoprotein.^1,2 For CML, the goals of treatment include maintaining hematologic, cytogenetic, and molecular remission; preventing progression to accelerated phase or blast crisis; minimizing toxicity; and enabling potential cessation of therapy in carefully selected patients.^7,8

Small cohort studies suggest that dose reduction of TKIs in patients who achieve optimal responses may reduce the risk of long-term adverse effects (AEs). However, optimal dose-reduction and minimum effective dose of each agent are unknown.⁷ The ability to maintain undetectable minimal residual disease or disease detectable at a stable low level after TKI discontinuation has been called treatment-free remission. Studies suggest that about 40% to 50% of patients who have achieved a stable deep molecular response remain in treatment-free remission after stopping first-line treatment.^9,10 Of the patients who relapse following TKI discontinuation, 80% relapse within the first 6 months of treatment cessation. Molecular response is regained in almost all patients when treatment is resumed with the same TKI.¹¹

The National Comprehensive Cancer Network (NCCN) recommends considering discontinuation of TKI therapy only outside the setting of a clinical trial and only in patients who consent to discontinuation after a thorough discussion of the potential risks and benefits. The NCCN criteria for patients who may be eligible for discontinuation are listed in Table 1. The Life After Stopping TKIs study reported that 80% of patients with well-controlled chronic phase CML who discontinued TKIs had a clinically meaningful improvement in fatigue. Patients also reported clinically meaningful improvements in depression, diarrhea, sleep disturbance, and pain interference. These symptoms worsened after restarting TKI therapy.¹²

TKI DISCONTINUATION

Electronic health record data were extracted using structured query language from the US Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW). To be eligible for discontinuation, veterans had to be aged > 18 years, receive oncology care within a Veterans Integrated Services Network (VISN) 21 health care system (HCS) (VA Sierra Nevada HCS, VA Southern Nevada HCS, VA Central California HCS, VA Palo Alto HCS, VA Northern California HCS, and VA San Francisco HCS) or be a veteran referred to a community-based oncology practitioner. Patients had to have a documented diagnosis of chronic phase CML, have an active order for a TKI, be on TKI therapy for ≥ 3 years, and have a stable molecular response (BCR-ABL1 ≤ 0.01% on the International Scale for ≥ 2 years with ≥ 4 tests done ≥ 3 months apart) as of October 1, 2024. Veterans were excluded if they had a history of advanced accelerated phase CML, previous TKI discontinuation trials, nonadherence to the TKI, or if they did not want to consider TKI discontinuation.

This analysis evaluated the potential cost avoidance associated with TKI discontinuation. Cost avoidance was calculated using the average wholesale price of each TKI. Secondary objectives evaluated health outcomes of TKI discontinuation including CML relapse, reported AEs, long-term remission, and TKI withdrawal syndrome. Health outcomes were determined through chart review of AEs and clinic notes documented in the electronic health record during the study time frame.

Baseline information for eligible patients was collected, including age, sex, and race, and chart reviews were completed to evaluate reported AEs associated with therapy. Oncology clinical pharmacy practitioners (CPPs) at each VISN 21 facility were notified of eligible patients to facilitate discussion with oncologists and establish monitoring if therapy was discontinued. Following TKI discontinuation, health outcomes were evaluated, including CML relapse, changes in reported AEs, long-term remission, and TKI withdrawal syndrome. Descriptive statistics were used to analyze the baseline characteristics. Cost avoidance was calculated using the average wholesale price for each TKI. The number of tablets required to reach each patient’s individual dose was taken into consideration when determining the cost avoidance. A dashboard was created using the query from the CDW and was developed in Microsoft Power BI.

Preliminary Results

In FY 2024, VISN 21 had 3819 oncology patients. Twenty-four patients had taken a TKI for ≥ 3 years, 20 had a stable molecular response, and 15 had not previously attempted to discontinue their TKI (Figure 1). Fifteen veterans were eligible for therapy discontinuation for a total potential annual cost avoidance of $1.2 million (Figure 2). Most of the cost avoidance, $935,057 (78%), was attributed to 3 patients on nilotinib. The mean age of the population was 74 years. All patients were male, and 12 (80%) were White. (Table 2). At baseline, 11 patients (73%) were taking imatinib. One patient received oncology care from a community care clinician. All 15 patients decided to remain on therapy.

DISCUSSION

As a multisite quality improvement initiative, this project raised awareness of TKI therapy discontinuation in select patients with CML. It also sparked collaboration among oncology CPPs and clinicians and stimulated conversations about CML treatment. The development of the TKI discontinuation dashboard provides a population health management tool for CPPs and clinicians to identify eligible patients in the future.

Adherence to TKIs is crucial for disease control and survival in patients with CML. Patients are counseled that poor adherence to therapy may contribute to worsening disease or suboptimal response, the development of resistance, and greater health care costs.¹³ Therefore, it was a challenge for patients to understand and accept that they could stop TKI therapy after achieving a stable deep molecular response. Discussions with patients about the goal of therapy—suppressing the BCR-ABL oncogene, which they have achieved—could encourage patients to trial therapy discontinuation.

Only small cohort studies have been completed to evaluate the outcomes of therapy discontinuation. Much remains unknown regarding the optimal dose-reduction strategy and the minimum effective dose of each agent. Additionally, understanding the qualities of a good candidate for TKI discontinuation remains a barrier. A similar project was conducted in VISN 17. Five patients were counseled on TKI discontinuation; however, only 1 discontinued TKI therapy. Unfortunately, soon after discontinuing treatment, the patient had to restart therapy. Additional literature will enhance understanding of therapy discontinuation.

An unexpected finding of TKI discontinuation trials has been a reversible phenomenon known as TKI withdrawal syndrome.⁹ It can occur regardless of the TKI used and results in pruritus and new or worsening musculoskeletal pain within several weeks of TKI discontinuation in about 30% of patients. Symptoms may last several months and may require acetaminophen or nonsteroidal anti-inflammatory drugs for pain control.^9,10,14

The potential cost avoidance of $1.2 million is an underestimation because VA contracts allow for greater cost savings. However, that information is confidential and therefore average wholesale price had to be used for this project. Most of the cost avoidance was due to 4 patients who could not tolerate imatinib and used nilotinib, which is more expensive.

Limitations

The small sample size presented some limitations. Of the 3819 oncology patients within VISN 21 in FY 2024, 186 received a TKI and only 15 were eligible for discontinuation. Additionally, challenges emerged when discussing discontinuation with community care clinicians and patients. Community care clinicians were difficult to contact, making it challenging to discuss the project with them. CPPs noted hesitancy among VA clinicians and patients to discontinue a medication for which adherence was continually emphasized.

Conclusions

Discussions about CML TKI discontinuation led to collaboration with the oncology care team and could lead to significant cost avoidance. Barriers to TKI discontinuation included patients’ concern for relapse, risk of discontinuation syndrome, the requirement for close monitoring, and clinician buy-in. Outcome studies are needed to gain a greater understanding of the benefits and risks of therapy discontinuation. In the future, evaluation of possible clinical and biological predictors of successful TKI discontinuation may be beneficial.

Chronic myeloid leukemia (CML) is a hematologic malignancy resulting from an acquired mutation. The mutation results in a reciprocal translocation between the long arms of chromosomes 9 and 22 and is known as the Philadelphia chromosome (Ph), or Ph-positive (Ph+) when present. The translocation results in the formation of a BCR-ABL fusion oncogene, which leads to continuous cell cycling and proliferation, altered differentiation, and a loss of apoptosis.^1,2

Until the 1980s, CML was considered fatal.³ The mainstay of treatment consisted of 2 oral chemotherapeutic agents, busulfan and hydroxyurea. These medications did not prevent blast crisis, a fatal form of leukemia.^4,5 The introduction of tyrosine kinase inhibitors (TKIs) transformed CML management and improved 10-year overall survival from about 20% to > 80% by delaying the transition to blast crisis. Now, the risk of death from general health conditions or comorbidities is higher than that of CML.⁶

TKIs target the root cause of CML through inhibition of the BCR-ABL oncoprotein.^1,2 For CML, the goals of treatment include maintaining hematologic, cytogenetic, and molecular remission; preventing progression to accelerated phase or blast crisis; minimizing toxicity; and enabling potential cessation of therapy in carefully selected patients.^7,8

Small cohort studies suggest that dose reduction of TKIs in patients who achieve optimal responses may reduce the risk of long-term adverse effects (AEs). However, optimal dose-reduction and minimum effective dose of each agent are unknown.⁷ The ability to maintain undetectable minimal residual disease or disease detectable at a stable low level after TKI discontinuation has been called treatment-free remission. Studies suggest that about 40% to 50% of patients who have achieved a stable deep molecular response remain in treatment-free remission after stopping first-line treatment.^9,10 Of the patients who relapse following TKI discontinuation, 80% relapse within the first 6 months of treatment cessation. Molecular response is regained in almost all patients when treatment is resumed with the same TKI.¹¹

The National Comprehensive Cancer Network (NCCN) recommends considering discontinuation of TKI therapy only outside the setting of a clinical trial and only in patients who consent to discontinuation after a thorough discussion of the potential risks and benefits. The NCCN criteria for patients who may be eligible for discontinuation are listed in Table 1. The Life After Stopping TKIs study reported that 80% of patients with well-controlled chronic phase CML who discontinued TKIs had a clinically meaningful improvement in fatigue. Patients also reported clinically meaningful improvements in depression, diarrhea, sleep disturbance, and pain interference. These symptoms worsened after restarting TKI therapy.¹²

TKI DISCONTINUATION

Electronic health record data were extracted using structured query language from the US Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW). To be eligible for discontinuation, veterans had to be aged > 18 years, receive oncology care within a Veterans Integrated Services Network (VISN) 21 health care system (HCS) (VA Sierra Nevada HCS, VA Southern Nevada HCS, VA Central California HCS, VA Palo Alto HCS, VA Northern California HCS, and VA San Francisco HCS) or be a veteran referred to a community-based oncology practitioner. Patients had to have a documented diagnosis of chronic phase CML, have an active order for a TKI, be on TKI therapy for ≥ 3 years, and have a stable molecular response (BCR-ABL1 ≤ 0.01% on the International Scale for ≥ 2 years with ≥ 4 tests done ≥ 3 months apart) as of October 1, 2024. Veterans were excluded if they had a history of advanced accelerated phase CML, previous TKI discontinuation trials, nonadherence to the TKI, or if they did not want to consider TKI discontinuation.

This analysis evaluated the potential cost avoidance associated with TKI discontinuation. Cost avoidance was calculated using the average wholesale price of each TKI. Secondary objectives evaluated health outcomes of TKI discontinuation including CML relapse, reported AEs, long-term remission, and TKI withdrawal syndrome. Health outcomes were determined through chart review of AEs and clinic notes documented in the electronic health record during the study time frame.

Baseline information for eligible patients was collected, including age, sex, and race, and chart reviews were completed to evaluate reported AEs associated with therapy. Oncology clinical pharmacy practitioners (CPPs) at each VISN 21 facility were notified of eligible patients to facilitate discussion with oncologists and establish monitoring if therapy was discontinued. Following TKI discontinuation, health outcomes were evaluated, including CML relapse, changes in reported AEs, long-term remission, and TKI withdrawal syndrome. Descriptive statistics were used to analyze the baseline characteristics. Cost avoidance was calculated using the average wholesale price for each TKI. The number of tablets required to reach each patient’s individual dose was taken into consideration when determining the cost avoidance. A dashboard was created using the query from the CDW and was developed in Microsoft Power BI.

Preliminary Results

In FY 2024, VISN 21 had 3819 oncology patients. Twenty-four patients had taken a TKI for ≥ 3 years, 20 had a stable molecular response, and 15 had not previously attempted to discontinue their TKI (Figure 1). Fifteen veterans were eligible for therapy discontinuation for a total potential annual cost avoidance of $1.2 million (Figure 2). Most of the cost avoidance, $935,057 (78%), was attributed to 3 patients on nilotinib. The mean age of the population was 74 years. All patients were male, and 12 (80%) were White. (Table 2). At baseline, 11 patients (73%) were taking imatinib. One patient received oncology care from a community care clinician. All 15 patients decided to remain on therapy.

DISCUSSION

As a multisite quality improvement initiative, this project raised awareness of TKI therapy discontinuation in select patients with CML. It also sparked collaboration among oncology CPPs and clinicians and stimulated conversations about CML treatment. The development of the TKI discontinuation dashboard provides a population health management tool for CPPs and clinicians to identify eligible patients in the future.

Adherence to TKIs is crucial for disease control and survival in patients with CML. Patients are counseled that poor adherence to therapy may contribute to worsening disease or suboptimal response, the development of resistance, and greater health care costs.¹³ Therefore, it was a challenge for patients to understand and accept that they could stop TKI therapy after achieving a stable deep molecular response. Discussions with patients about the goal of therapy—suppressing the BCR-ABL oncogene, which they have achieved—could encourage patients to trial therapy discontinuation.

Only small cohort studies have been completed to evaluate the outcomes of therapy discontinuation. Much remains unknown regarding the optimal dose-reduction strategy and the minimum effective dose of each agent. Additionally, understanding the qualities of a good candidate for TKI discontinuation remains a barrier. A similar project was conducted in VISN 17. Five patients were counseled on TKI discontinuation; however, only 1 discontinued TKI therapy. Unfortunately, soon after discontinuing treatment, the patient had to restart therapy. Additional literature will enhance understanding of therapy discontinuation.

An unexpected finding of TKI discontinuation trials has been a reversible phenomenon known as TKI withdrawal syndrome.⁹ It can occur regardless of the TKI used and results in pruritus and new or worsening musculoskeletal pain within several weeks of TKI discontinuation in about 30% of patients. Symptoms may last several months and may require acetaminophen or nonsteroidal anti-inflammatory drugs for pain control.^9,10,14

The potential cost avoidance of $1.2 million is an underestimation because VA contracts allow for greater cost savings. However, that information is confidential and therefore average wholesale price had to be used for this project. Most of the cost avoidance was due to 4 patients who could not tolerate imatinib and used nilotinib, which is more expensive.

Limitations

The small sample size presented some limitations. Of the 3819 oncology patients within VISN 21 in FY 2024, 186 received a TKI and only 15 were eligible for discontinuation. Additionally, challenges emerged when discussing discontinuation with community care clinicians and patients. Community care clinicians were difficult to contact, making it challenging to discuss the project with them. CPPs noted hesitancy among VA clinicians and patients to discontinue a medication for which adherence was continually emphasized.

Conclusions

Discussions about CML TKI discontinuation led to collaboration with the oncology care team and could lead to significant cost avoidance. Barriers to TKI discontinuation included patients’ concern for relapse, risk of discontinuation syndrome, the requirement for close monitoring, and clinician buy-in. Outcome studies are needed to gain a greater understanding of the benefits and risks of therapy discontinuation. In the future, evaluation of possible clinical and biological predictors of successful TKI discontinuation may be beneficial.

Chronic myeloid leukemia (CML) is a hematologic malignancy resulting from an acquired mutation. The mutation results in a reciprocal translocation between the long arms of chromosomes 9 and 22 and is known as the Philadelphia chromosome (Ph), or Ph-positive (Ph+) when present. The translocation results in the formation of a BCR-ABL fusion oncogene, which leads to continuous cell cycling and proliferation, altered differentiation, and a loss of apoptosis.^1,2

Until the 1980s, CML was considered fatal.³ The mainstay of treatment consisted of 2 oral chemotherapeutic agents, busulfan and hydroxyurea. These medications did not prevent blast crisis, a fatal form of leukemia.^4,5 The introduction of tyrosine kinase inhibitors (TKIs) transformed CML management and improved 10-year overall survival from about 20% to > 80% by delaying the transition to blast crisis. Now, the risk of death from general health conditions or comorbidities is higher than that of CML.⁶

TKIs target the root cause of CML through inhibition of the BCR-ABL oncoprotein.^1,2 For CML, the goals of treatment include maintaining hematologic, cytogenetic, and molecular remission; preventing progression to accelerated phase or blast crisis; minimizing toxicity; and enabling potential cessation of therapy in carefully selected patients.^7,8

Small cohort studies suggest that dose reduction of TKIs in patients who achieve optimal responses may reduce the risk of long-term adverse effects (AEs). However, optimal dose-reduction and minimum effective dose of each agent are unknown.⁷ The ability to maintain undetectable minimal residual disease or disease detectable at a stable low level after TKI discontinuation has been called treatment-free remission. Studies suggest that about 40% to 50% of patients who have achieved a stable deep molecular response remain in treatment-free remission after stopping first-line treatment.^9,10 Of the patients who relapse following TKI discontinuation, 80% relapse within the first 6 months of treatment cessation. Molecular response is regained in almost all patients when treatment is resumed with the same TKI.¹¹

The National Comprehensive Cancer Network (NCCN) recommends considering discontinuation of TKI therapy only outside the setting of a clinical trial and only in patients who consent to discontinuation after a thorough discussion of the potential risks and benefits. The NCCN criteria for patients who may be eligible for discontinuation are listed in Table 1. The Life After Stopping TKIs study reported that 80% of patients with well-controlled chronic phase CML who discontinued TKIs had a clinically meaningful improvement in fatigue. Patients also reported clinically meaningful improvements in depression, diarrhea, sleep disturbance, and pain interference. These symptoms worsened after restarting TKI therapy.¹²

TKI DISCONTINUATION

Electronic health record data were extracted using structured query language from the US Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW). To be eligible for discontinuation, veterans had to be aged > 18 years, receive oncology care within a Veterans Integrated Services Network (VISN) 21 health care system (HCS) (VA Sierra Nevada HCS, VA Southern Nevada HCS, VA Central California HCS, VA Palo Alto HCS, VA Northern California HCS, and VA San Francisco HCS) or be a veteran referred to a community-based oncology practitioner. Patients had to have a documented diagnosis of chronic phase CML, have an active order for a TKI, be on TKI therapy for ≥ 3 years, and have a stable molecular response (BCR-ABL1 ≤ 0.01% on the International Scale for ≥ 2 years with ≥ 4 tests done ≥ 3 months apart) as of October 1, 2024. Veterans were excluded if they had a history of advanced accelerated phase CML, previous TKI discontinuation trials, nonadherence to the TKI, or if they did not want to consider TKI discontinuation.

This analysis evaluated the potential cost avoidance associated with TKI discontinuation. Cost avoidance was calculated using the average wholesale price of each TKI. Secondary objectives evaluated health outcomes of TKI discontinuation including CML relapse, reported AEs, long-term remission, and TKI withdrawal syndrome. Health outcomes were determined through chart review of AEs and clinic notes documented in the electronic health record during the study time frame.

Baseline information for eligible patients was collected, including age, sex, and race, and chart reviews were completed to evaluate reported AEs associated with therapy. Oncology clinical pharmacy practitioners (CPPs) at each VISN 21 facility were notified of eligible patients to facilitate discussion with oncologists and establish monitoring if therapy was discontinued. Following TKI discontinuation, health outcomes were evaluated, including CML relapse, changes in reported AEs, long-term remission, and TKI withdrawal syndrome. Descriptive statistics were used to analyze the baseline characteristics. Cost avoidance was calculated using the average wholesale price for each TKI. The number of tablets required to reach each patient’s individual dose was taken into consideration when determining the cost avoidance. A dashboard was created using the query from the CDW and was developed in Microsoft Power BI.

Preliminary Results

In FY 2024, VISN 21 had 3819 oncology patients. Twenty-four patients had taken a TKI for ≥ 3 years, 20 had a stable molecular response, and 15 had not previously attempted to discontinue their TKI (Figure 1). Fifteen veterans were eligible for therapy discontinuation for a total potential annual cost avoidance of $1.2 million (Figure 2). Most of the cost avoidance, $935,057 (78%), was attributed to 3 patients on nilotinib. The mean age of the population was 74 years. All patients were male, and 12 (80%) were White. (Table 2). At baseline, 11 patients (73%) were taking imatinib. One patient received oncology care from a community care clinician. All 15 patients decided to remain on therapy.

DISCUSSION

As a multisite quality improvement initiative, this project raised awareness of TKI therapy discontinuation in select patients with CML. It also sparked collaboration among oncology CPPs and clinicians and stimulated conversations about CML treatment. The development of the TKI discontinuation dashboard provides a population health management tool for CPPs and clinicians to identify eligible patients in the future.

Adherence to TKIs is crucial for disease control and survival in patients with CML. Patients are counseled that poor adherence to therapy may contribute to worsening disease or suboptimal response, the development of resistance, and greater health care costs.¹³ Therefore, it was a challenge for patients to understand and accept that they could stop TKI therapy after achieving a stable deep molecular response. Discussions with patients about the goal of therapy—suppressing the BCR-ABL oncogene, which they have achieved—could encourage patients to trial therapy discontinuation.

Only small cohort studies have been completed to evaluate the outcomes of therapy discontinuation. Much remains unknown regarding the optimal dose-reduction strategy and the minimum effective dose of each agent. Additionally, understanding the qualities of a good candidate for TKI discontinuation remains a barrier. A similar project was conducted in VISN 17. Five patients were counseled on TKI discontinuation; however, only 1 discontinued TKI therapy. Unfortunately, soon after discontinuing treatment, the patient had to restart therapy. Additional literature will enhance understanding of therapy discontinuation.

An unexpected finding of TKI discontinuation trials has been a reversible phenomenon known as TKI withdrawal syndrome.⁹ It can occur regardless of the TKI used and results in pruritus and new or worsening musculoskeletal pain within several weeks of TKI discontinuation in about 30% of patients. Symptoms may last several months and may require acetaminophen or nonsteroidal anti-inflammatory drugs for pain control.^9,10,14

The potential cost avoidance of $1.2 million is an underestimation because VA contracts allow for greater cost savings. However, that information is confidential and therefore average wholesale price had to be used for this project. Most of the cost avoidance was due to 4 patients who could not tolerate imatinib and used nilotinib, which is more expensive.

Limitations

The small sample size presented some limitations. Of the 3819 oncology patients within VISN 21 in FY 2024, 186 received a TKI and only 15 were eligible for discontinuation. Additionally, challenges emerged when discussing discontinuation with community care clinicians and patients. Community care clinicians were difficult to contact, making it challenging to discuss the project with them. CPPs noted hesitancy among VA clinicians and patients to discontinue a medication for which adherence was continually emphasized.

Conclusions

Discussions about CML TKI discontinuation led to collaboration with the oncology care team and could lead to significant cost avoidance. Barriers to TKI discontinuation included patients’ concern for relapse, risk of discontinuation syndrome, the requirement for close monitoring, and clinician buy-in. Outcome studies are needed to gain a greater understanding of the benefits and risks of therapy discontinuation. In the future, evaluation of possible clinical and biological predictors of successful TKI discontinuation may be beneficial.