COVID-19 vaccines should not be withheld from people who are pregnant or lactating and want to be vaccinated, despite a lack of safety data in these populations, according to guidance from the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine.

Thye Aun Ngo/Fotolia.com

Pregnant women who opt not to receive the vaccine should be supported in that decision as well, a practice advisory from ACOG recommends.

“Pregnant women who experience fever following vaccination should be counseled to take acetaminophen,” the advisory notes.

In addition, women do not need to avoid pregnancy after receiving the Pfizer-BioNTech COVID-19 vaccine, according to the CDC’s interim clinical considerations for its use. The U.S. Food and Drug Administration issued an emergency use authorization for the vaccine on Dec. 11.

Although investigators excluded pregnant women from clinical trials, experts believe that mRNA vaccines, which are not live vaccines, “are unlikely to pose a risk for people who are pregnant” and “are not thought to be a risk to the breastfeeding infant,” the CDC notes.

Meanwhile, women who are pregnant may be at greater risk of severe COVID-19, even though the absolute risk of severe illness is low. COVID-19 also may increase the risk of adverse pregnancy outcomes, such as preterm birth, although the data have been mixed with some studies finding an association and others not.

“If pregnant people are part of a group that is recommended to receive a COVID-19 vaccine (e.g., health care personnel), they may choose to be vaccinated,” the CDC advises. “A conversation between the patient and their clinical team may assist with decisions regarding the use of vaccines approved under EUA for the prevention of COVID-19. While a conversation with a health care provider may be helpful, it is not required prior to vaccination.”
 

Acknowledging side effects and uncertainty

ACOG’s advisory reiterates that approach. The group notes that, based on the mRNA vaccine’s mechanism of action and its safety and efficacy in clinical trials, “it is expected that the safety and efficacy profile of the vaccine for pregnant individuals would be similar to that observed in nonpregnant individuals ... That said, there are no safety data specific to mRNA vaccine use in pregnant or lactating individuals and the potential risks to a pregnant individual and the fetus are unknown.” 

In clinical trials, most participants experienced mild influenza-like symptoms following vaccination, including injection site reactions, fatigue, chills, muscle and joint pain, and headache. Among participants aged 18-55 years, fever greater than 38°C occurred in 3.7% of participants after the first dose and in 15.8% after the second dose. Most symptoms resolved within a few days. 

Women who are pregnant should treat fever with acetaminophen because “fever has been associated with adverse pregnancy outcomes,” according to the ACOG guidance. “Acetaminophen has been proven to be safe for use in pregnancy and does not appear to impact antibody response to COVID-19 vaccines.” Patients may treat other vaccine side effects, such as injection-site soreness with acetaminophen as well.

When counseling patients, clinicians should explain that side effects are a normal part of developing antibodies to protect against COVID-19. “Regardless of their decision,” the group says, “these conversations provide an opportunity to remind patients about the importance of other prevention measures such as hand washing, physical distancing, and wearing a mask.”
 

More data expected

Data from developmental and reproductive toxicity studies in animals are expected soon, the CDC said. In addition, the manufacturer is following clinical trial participants who became pregnant during the study. 

Women who are pregnant and their physicians should weigh factors such as the extent of COVID-19 transmission in the community, the patient’s risk of contracting COVID-19, risks of COVID-19 to the patient and fetus, vaccine efficacy and side effects, and the lack of data about COVID-19 vaccination during pregnancy.

The Society for Maternal-Fetal Medicine recommends that pregnant and lactating women have access to COVID-19 vaccines in general and has advocated for the inclusion of women who are pregnant or lactating in vaccine trials. The society has suggested that health care professionals “counsel their patients that the theoretical risk of fetal harm from mRNA vaccines is very low.” It published resources this week for physicians and patients focused on COVID-19 vaccination and pregnancy.

In a review published online Dec. 10 in the American Journal of Obstetrics & Gynecology MFM, Amanda M. Craig, MD, of Duke University Health System in Durham, N.C., and coauthors note that there “is a theoretical risk for fetal harm from any untested medical intervention and this is no different for COVID-19 vaccines.”

“Pregnant individuals should be given the opportunity, along with their obstetric provider, to weigh the potential risk of severe maternal disease against the unknown risk of fetal exposure, and make an autonomous decision about whether or not to accept vaccine until pregnancy safety data are available,” they write.

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

COVID-19 vaccines should not be withheld from people who are pregnant or lactating and want to be vaccinated, despite a lack of safety data in these populations, according to guidance from the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine.

Thye Aun Ngo/Fotolia.com

Pregnant women who opt not to receive the vaccine should be supported in that decision as well, a practice advisory from ACOG recommends.

“Pregnant women who experience fever following vaccination should be counseled to take acetaminophen,” the advisory notes.

In addition, women do not need to avoid pregnancy after receiving the Pfizer-BioNTech COVID-19 vaccine, according to the CDC’s interim clinical considerations for its use. The U.S. Food and Drug Administration issued an emergency use authorization for the vaccine on Dec. 11.

Although investigators excluded pregnant women from clinical trials, experts believe that mRNA vaccines, which are not live vaccines, “are unlikely to pose a risk for people who are pregnant” and “are not thought to be a risk to the breastfeeding infant,” the CDC notes.

Meanwhile, women who are pregnant may be at greater risk of severe COVID-19, even though the absolute risk of severe illness is low. COVID-19 also may increase the risk of adverse pregnancy outcomes, such as preterm birth, although the data have been mixed with some studies finding an association and others not.

“If pregnant people are part of a group that is recommended to receive a COVID-19 vaccine (e.g., health care personnel), they may choose to be vaccinated,” the CDC advises. “A conversation between the patient and their clinical team may assist with decisions regarding the use of vaccines approved under EUA for the prevention of COVID-19. While a conversation with a health care provider may be helpful, it is not required prior to vaccination.”
 

Acknowledging side effects and uncertainty

ACOG’s advisory reiterates that approach. The group notes that, based on the mRNA vaccine’s mechanism of action and its safety and efficacy in clinical trials, “it is expected that the safety and efficacy profile of the vaccine for pregnant individuals would be similar to that observed in nonpregnant individuals ... That said, there are no safety data specific to mRNA vaccine use in pregnant or lactating individuals and the potential risks to a pregnant individual and the fetus are unknown.” 

In clinical trials, most participants experienced mild influenza-like symptoms following vaccination, including injection site reactions, fatigue, chills, muscle and joint pain, and headache. Among participants aged 18-55 years, fever greater than 38°C occurred in 3.7% of participants after the first dose and in 15.8% after the second dose. Most symptoms resolved within a few days. 

Women who are pregnant should treat fever with acetaminophen because “fever has been associated with adverse pregnancy outcomes,” according to the ACOG guidance. “Acetaminophen has been proven to be safe for use in pregnancy and does not appear to impact antibody response to COVID-19 vaccines.” Patients may treat other vaccine side effects, such as injection-site soreness with acetaminophen as well.

When counseling patients, clinicians should explain that side effects are a normal part of developing antibodies to protect against COVID-19. “Regardless of their decision,” the group says, “these conversations provide an opportunity to remind patients about the importance of other prevention measures such as hand washing, physical distancing, and wearing a mask.”
 

More data expected

Data from developmental and reproductive toxicity studies in animals are expected soon, the CDC said. In addition, the manufacturer is following clinical trial participants who became pregnant during the study. 

Women who are pregnant and their physicians should weigh factors such as the extent of COVID-19 transmission in the community, the patient’s risk of contracting COVID-19, risks of COVID-19 to the patient and fetus, vaccine efficacy and side effects, and the lack of data about COVID-19 vaccination during pregnancy.

The Society for Maternal-Fetal Medicine recommends that pregnant and lactating women have access to COVID-19 vaccines in general and has advocated for the inclusion of women who are pregnant or lactating in vaccine trials. The society has suggested that health care professionals “counsel their patients that the theoretical risk of fetal harm from mRNA vaccines is very low.” It published resources this week for physicians and patients focused on COVID-19 vaccination and pregnancy.

In a review published online Dec. 10 in the American Journal of Obstetrics & Gynecology MFM, Amanda M. Craig, MD, of Duke University Health System in Durham, N.C., and coauthors note that there “is a theoretical risk for fetal harm from any untested medical intervention and this is no different for COVID-19 vaccines.”

“Pregnant individuals should be given the opportunity, along with their obstetric provider, to weigh the potential risk of severe maternal disease against the unknown risk of fetal exposure, and make an autonomous decision about whether or not to accept vaccine until pregnancy safety data are available,” they write.

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

COVID-19 vaccines should not be withheld from people who are pregnant or lactating and want to be vaccinated, despite a lack of safety data in these populations, according to guidance from the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine.

Thye Aun Ngo/Fotolia.com

Pregnant women who opt not to receive the vaccine should be supported in that decision as well, a practice advisory from ACOG recommends.

“Pregnant women who experience fever following vaccination should be counseled to take acetaminophen,” the advisory notes.

In addition, women do not need to avoid pregnancy after receiving the Pfizer-BioNTech COVID-19 vaccine, according to the CDC’s interim clinical considerations for its use. The U.S. Food and Drug Administration issued an emergency use authorization for the vaccine on Dec. 11.

Although investigators excluded pregnant women from clinical trials, experts believe that mRNA vaccines, which are not live vaccines, “are unlikely to pose a risk for people who are pregnant” and “are not thought to be a risk to the breastfeeding infant,” the CDC notes.

Meanwhile, women who are pregnant may be at greater risk of severe COVID-19, even though the absolute risk of severe illness is low. COVID-19 also may increase the risk of adverse pregnancy outcomes, such as preterm birth, although the data have been mixed with some studies finding an association and others not.

“If pregnant people are part of a group that is recommended to receive a COVID-19 vaccine (e.g., health care personnel), they may choose to be vaccinated,” the CDC advises. “A conversation between the patient and their clinical team may assist with decisions regarding the use of vaccines approved under EUA for the prevention of COVID-19. While a conversation with a health care provider may be helpful, it is not required prior to vaccination.”
 

Acknowledging side effects and uncertainty

ACOG’s advisory reiterates that approach. The group notes that, based on the mRNA vaccine’s mechanism of action and its safety and efficacy in clinical trials, “it is expected that the safety and efficacy profile of the vaccine for pregnant individuals would be similar to that observed in nonpregnant individuals ... That said, there are no safety data specific to mRNA vaccine use in pregnant or lactating individuals and the potential risks to a pregnant individual and the fetus are unknown.” 

In clinical trials, most participants experienced mild influenza-like symptoms following vaccination, including injection site reactions, fatigue, chills, muscle and joint pain, and headache. Among participants aged 18-55 years, fever greater than 38°C occurred in 3.7% of participants after the first dose and in 15.8% after the second dose. Most symptoms resolved within a few days. 

Women who are pregnant should treat fever with acetaminophen because “fever has been associated with adverse pregnancy outcomes,” according to the ACOG guidance. “Acetaminophen has been proven to be safe for use in pregnancy and does not appear to impact antibody response to COVID-19 vaccines.” Patients may treat other vaccine side effects, such as injection-site soreness with acetaminophen as well.

When counseling patients, clinicians should explain that side effects are a normal part of developing antibodies to protect against COVID-19. “Regardless of their decision,” the group says, “these conversations provide an opportunity to remind patients about the importance of other prevention measures such as hand washing, physical distancing, and wearing a mask.”
 

More data expected

Data from developmental and reproductive toxicity studies in animals are expected soon, the CDC said. In addition, the manufacturer is following clinical trial participants who became pregnant during the study. 

Women who are pregnant and their physicians should weigh factors such as the extent of COVID-19 transmission in the community, the patient’s risk of contracting COVID-19, risks of COVID-19 to the patient and fetus, vaccine efficacy and side effects, and the lack of data about COVID-19 vaccination during pregnancy.

The Society for Maternal-Fetal Medicine recommends that pregnant and lactating women have access to COVID-19 vaccines in general and has advocated for the inclusion of women who are pregnant or lactating in vaccine trials. The society has suggested that health care professionals “counsel their patients that the theoretical risk of fetal harm from mRNA vaccines is very low.” It published resources this week for physicians and patients focused on COVID-19 vaccination and pregnancy.

In a review published online Dec. 10 in the American Journal of Obstetrics & Gynecology MFM, Amanda M. Craig, MD, of Duke University Health System in Durham, N.C., and coauthors note that there “is a theoretical risk for fetal harm from any untested medical intervention and this is no different for COVID-19 vaccines.”

“Pregnant individuals should be given the opportunity, along with their obstetric provider, to weigh the potential risk of severe maternal disease against the unknown risk of fetal exposure, and make an autonomous decision about whether or not to accept vaccine until pregnancy safety data are available,” they write.

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

COVID-19 has thrown a wrench in standard treatment protocols for patients with chronic lymphocytic leukemia (CLL). These patients already face a greater risk of dying from infections, and recent research suggests they tend to have risk factors that increase their likelihood of complications and death from COVID-19.

In August, a group of oncologists from the United States and Europe published a literature-informed expert opinion to help their colleagues navigate this new CLL treatment landscape. It offers a roadmap for balancing patients’ therapeutic needs against their risk for viral infection and outlines the safest course of action for patients who test positive for COVID-19.

Mazyar Shadman, MD, MPH, an associate professor in the Clinical Research Division of the Fred Hutchinson Cancer Research Center and the Division of Medical Oncology at the University of Washington School of Medicine, in Seattle, Washington, was contacted for comment to break down what clinicians need to know about treating CLL during the pandemic. This interview has been edited for length and clarity.
 

Question: What prompted you and colleagues from the United States and Europe to write these recommendations?

Dr. Shadman: When we began the collaboration earlier this year, our colleagues in Italy and the rest of Europe had more experience with COVID-19, so they led the effort. We wanted to help oncologists manage their patients with CLL during the pandemic based on the evidence we had at the time and the unknowns we faced.
 

What’s an example of how the available evidence informed your recommendations?

At the time, we didn’t know whether patients with CLL were more likely to get COVID-19, compared to the general population, but we did have evidence already that cancer increases patients’ risk of bad outcomes and death from COVID-19. CLL, for example, can increase risk factors for infection, including hypogammaglobulinemia, innate immune dysfunction, and neutropenia, which may be exacerbated by anticancer treatments. Patients’ existing immune suppression might prevent or delay their ability to react to or cope with the virus. And many patients with CLL have other conditions that increase their risk of a severe response to COVID-19, including older age (70% of CLL patients are older than 65 years), hypertension (21%), and diabetes (26%).

These factors informed our recommendations to limit patients’ exposure to COVID-19 by reducing or postponing the number of in-person visits and routine in-hospital follow-ups, especially if they could be substituted with virtual check-ins.
 

The expert opinion recommendations are divided into three main categories: patients who are newly diagnosed with CLL but have not begun receiving therapy, those already receiving therapy but are free of COVID-19, and those who test positive for COVID-19. Let’s start with the first category. What do the recommendations say about waiting versus proceeding for newly diagnosed patients?

Our priority was balancing the negative impacts of getting COVID-19 with the negative impacts of postponing cancer treatment. We suggested taking each new CLL case on a patient-by-patient basis to determine who needed treatment tomorrow and who could wait a few weeks or months. Fortunately, CLL rarely requires immediate therapy, so the preference was to postpone treatment a few weeks, depending on the local COVID-19 outbreak situation.

In my practice, for instance, we tried to postpone visits as much as we could. Before the pandemic, patients with CLL in the watch-and-wait phase – those diagnosed but who don’t require treatment immediately – would come in for bloodwork and exams every 3-6 months. But when the pandemic hit, we skipped 3-month visits for patients with stable lab results and switched to telehealth visits instead. For those who needed blood draws, we used local labs closer to the patient’s home to minimize their exposure and transportation requirements.

When treatment cannot be deferred, we’ve recommended starting patients on therapies that require fewer in-person visits and are less immune suppressive. We recommended oncologists consider Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib and acalabrutinib, as well as venetoclax. Some research suggests these inhibitors may be protective against COVID-19 by blunting a patient’s hyperinflammatory response to the virus. These drugs also require minimal routine treatment and lab visits, which helps limit patients’ potential exposure to COVID-19.

But there are risks to waiting. Even during the peak of the pandemic here in Seattle, if patients needed treatment immediately, we did not delay. Patients with significant drops in their platelet or neutrophil count or those with bulky disease, for instance, do require therapy.

It’s important to mention that we did have bad experiences with patients who needed immediate treatment and their treating physicians decided to wait because of COVID-19 risks. These patients who came in with aggressive CLL and experienced delays in care had much more complicated CLL treatment than if they had started treatment earlier.

When organ function became abnormal, for example, some patients could no longer receive certain therapies. If someone’s kidney function becomes abnormal, I wouldn’t recommend giving a drug like venetoclax. Although rare, some patients on venetoclax develop tumor lysis syndrome, which can lead to kidney failure.

Bottom line: Don’t just assume it’s a low-grade disease and that you can wait.



What about patients already receiving treatment for CLL who are free of COVID-19?

For patients on active treatment, we suggested stopping or holding treatment with monoclonal antibodies, such as rituximab and obinutuzumab, and chemotherapy regimens, such as idelalisib plus rituximab and duvelisib, when possible. We recommended oncologists consider continuing treatment for patients on BTK inhibitors.



What happens if a patient with CLL tests positive for COVID-19?

If a patient tests positive for COVID-19 but is not yet on CLL treatment, we recommend postponing CLL care until they’ve recovered from the infection. If a patient is already receiving treatment, the recommendations are similar to those above for COVID-19–negative patients: Delay care for those on chemotherapy and monoclonal antibodies, but consider continuing treatment for patients on BTK inhibitors.
 

The expert opinion was submitted in May and ultimately published in August. How has our understanding of treating CLL during the pandemic changed since then? Would you change any recommendations?

When we published this paper, it was still early on in the pandemic, and we didn’t know as much about COVID-19 and CLL as we do now. Since we published the recommendations, we have received confirmation from several studies that patients with cancer have a more complicated course of COVID-19 and have worse outcomes. But I believe the recommendations we devised early in the pandemic still hold now. Decisions about delivering treatment should be influenced by the local COVID-19 numbers and hospital resources as well as the patient’s specific situation – whether they have more stable disease and can delay or postpone care or whether they need more immediate attention.

With a further surge in cases predicted as we move even deeper into flu season, what would you recommend for initiating treatment in newly diagnosed patients?

The pandemic has created a very fluid situation for treating CLL. What’s happening now in Seattle may not be the same story in New York, California, or elsewhere. In early November [when Dr. Shadman was first contacted], in Seattle, we were not postponing care because our COVID-19 numbers were fairly good. But, as of mid December, that is starting to change as the COVID-19 numbers fluctuate.
 

If we do experience a second peak of COVID-19 cases, we would need to modify our practice as we did during the initial surge earlier this year. That would mean avoiding treatment with monoclonal antibodies and chemotherapy, as well as minimizing blood draws and drugs that require frequent in-person visits.
 

How important is it for patients to be vaccinated against COVID-19?

There are two key things to consider about a vaccine. Is the vaccine safe from the general safety standpoint that everyone is worried about? And if the vaccine is not harmful, will it work in patients will CLL?

Because we don’t yet know the complete side-effect profile of a COVID-19 vaccine, we would need to assess each patient’s condition to limit adverse reactions and to see whether the vaccine alters a patient’s immune response to the CLL drug they’re taking.

At the University of Washington, Seattle, we have a plan to start studying the effectiveness of the Pfizer and Moderna vaccines in patients with CLL – carefully assessing patients’ response to the vaccine in terms of antibody response. We already know, based on small studies, that the antibody response to the flu vaccine, for instance, is not as strong in patients with CLL, compared to those without. But, overall, as long as the vaccine won’t cause harm, I would recommend my patients get it.

Dr. Shadman has disclosed no relevant financial relationships.

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

COVID-19 has thrown a wrench in standard treatment protocols for patients with chronic lymphocytic leukemia (CLL). These patients already face a greater risk of dying from infections, and recent research suggests they tend to have risk factors that increase their likelihood of complications and death from COVID-19.

In August, a group of oncologists from the United States and Europe published a literature-informed expert opinion to help their colleagues navigate this new CLL treatment landscape. It offers a roadmap for balancing patients’ therapeutic needs against their risk for viral infection and outlines the safest course of action for patients who test positive for COVID-19.

Mazyar Shadman, MD, MPH, an associate professor in the Clinical Research Division of the Fred Hutchinson Cancer Research Center and the Division of Medical Oncology at the University of Washington School of Medicine, in Seattle, Washington, was contacted for comment to break down what clinicians need to know about treating CLL during the pandemic. This interview has been edited for length and clarity.
 

Question: What prompted you and colleagues from the United States and Europe to write these recommendations?

Dr. Shadman: When we began the collaboration earlier this year, our colleagues in Italy and the rest of Europe had more experience with COVID-19, so they led the effort. We wanted to help oncologists manage their patients with CLL during the pandemic based on the evidence we had at the time and the unknowns we faced.
 

What’s an example of how the available evidence informed your recommendations?

At the time, we didn’t know whether patients with CLL were more likely to get COVID-19, compared to the general population, but we did have evidence already that cancer increases patients’ risk of bad outcomes and death from COVID-19. CLL, for example, can increase risk factors for infection, including hypogammaglobulinemia, innate immune dysfunction, and neutropenia, which may be exacerbated by anticancer treatments. Patients’ existing immune suppression might prevent or delay their ability to react to or cope with the virus. And many patients with CLL have other conditions that increase their risk of a severe response to COVID-19, including older age (70% of CLL patients are older than 65 years), hypertension (21%), and diabetes (26%).

These factors informed our recommendations to limit patients’ exposure to COVID-19 by reducing or postponing the number of in-person visits and routine in-hospital follow-ups, especially if they could be substituted with virtual check-ins.
 

The expert opinion recommendations are divided into three main categories: patients who are newly diagnosed with CLL but have not begun receiving therapy, those already receiving therapy but are free of COVID-19, and those who test positive for COVID-19. Let’s start with the first category. What do the recommendations say about waiting versus proceeding for newly diagnosed patients?

Our priority was balancing the negative impacts of getting COVID-19 with the negative impacts of postponing cancer treatment. We suggested taking each new CLL case on a patient-by-patient basis to determine who needed treatment tomorrow and who could wait a few weeks or months. Fortunately, CLL rarely requires immediate therapy, so the preference was to postpone treatment a few weeks, depending on the local COVID-19 outbreak situation.

In my practice, for instance, we tried to postpone visits as much as we could. Before the pandemic, patients with CLL in the watch-and-wait phase – those diagnosed but who don’t require treatment immediately – would come in for bloodwork and exams every 3-6 months. But when the pandemic hit, we skipped 3-month visits for patients with stable lab results and switched to telehealth visits instead. For those who needed blood draws, we used local labs closer to the patient’s home to minimize their exposure and transportation requirements.

When treatment cannot be deferred, we’ve recommended starting patients on therapies that require fewer in-person visits and are less immune suppressive. We recommended oncologists consider Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib and acalabrutinib, as well as venetoclax. Some research suggests these inhibitors may be protective against COVID-19 by blunting a patient’s hyperinflammatory response to the virus. These drugs also require minimal routine treatment and lab visits, which helps limit patients’ potential exposure to COVID-19.

But there are risks to waiting. Even during the peak of the pandemic here in Seattle, if patients needed treatment immediately, we did not delay. Patients with significant drops in their platelet or neutrophil count or those with bulky disease, for instance, do require therapy.

It’s important to mention that we did have bad experiences with patients who needed immediate treatment and their treating physicians decided to wait because of COVID-19 risks. These patients who came in with aggressive CLL and experienced delays in care had much more complicated CLL treatment than if they had started treatment earlier.

When organ function became abnormal, for example, some patients could no longer receive certain therapies. If someone’s kidney function becomes abnormal, I wouldn’t recommend giving a drug like venetoclax. Although rare, some patients on venetoclax develop tumor lysis syndrome, which can lead to kidney failure.

Bottom line: Don’t just assume it’s a low-grade disease and that you can wait.



What about patients already receiving treatment for CLL who are free of COVID-19?

For patients on active treatment, we suggested stopping or holding treatment with monoclonal antibodies, such as rituximab and obinutuzumab, and chemotherapy regimens, such as idelalisib plus rituximab and duvelisib, when possible. We recommended oncologists consider continuing treatment for patients on BTK inhibitors.



What happens if a patient with CLL tests positive for COVID-19?

If a patient tests positive for COVID-19 but is not yet on CLL treatment, we recommend postponing CLL care until they’ve recovered from the infection. If a patient is already receiving treatment, the recommendations are similar to those above for COVID-19–negative patients: Delay care for those on chemotherapy and monoclonal antibodies, but consider continuing treatment for patients on BTK inhibitors.
 

The expert opinion was submitted in May and ultimately published in August. How has our understanding of treating CLL during the pandemic changed since then? Would you change any recommendations?

When we published this paper, it was still early on in the pandemic, and we didn’t know as much about COVID-19 and CLL as we do now. Since we published the recommendations, we have received confirmation from several studies that patients with cancer have a more complicated course of COVID-19 and have worse outcomes. But I believe the recommendations we devised early in the pandemic still hold now. Decisions about delivering treatment should be influenced by the local COVID-19 numbers and hospital resources as well as the patient’s specific situation – whether they have more stable disease and can delay or postpone care or whether they need more immediate attention.

With a further surge in cases predicted as we move even deeper into flu season, what would you recommend for initiating treatment in newly diagnosed patients?

The pandemic has created a very fluid situation for treating CLL. What’s happening now in Seattle may not be the same story in New York, California, or elsewhere. In early November [when Dr. Shadman was first contacted], in Seattle, we were not postponing care because our COVID-19 numbers were fairly good. But, as of mid December, that is starting to change as the COVID-19 numbers fluctuate.
 

If we do experience a second peak of COVID-19 cases, we would need to modify our practice as we did during the initial surge earlier this year. That would mean avoiding treatment with monoclonal antibodies and chemotherapy, as well as minimizing blood draws and drugs that require frequent in-person visits.
 

How important is it for patients to be vaccinated against COVID-19?

There are two key things to consider about a vaccine. Is the vaccine safe from the general safety standpoint that everyone is worried about? And if the vaccine is not harmful, will it work in patients will CLL?

Because we don’t yet know the complete side-effect profile of a COVID-19 vaccine, we would need to assess each patient’s condition to limit adverse reactions and to see whether the vaccine alters a patient’s immune response to the CLL drug they’re taking.

At the University of Washington, Seattle, we have a plan to start studying the effectiveness of the Pfizer and Moderna vaccines in patients with CLL – carefully assessing patients’ response to the vaccine in terms of antibody response. We already know, based on small studies, that the antibody response to the flu vaccine, for instance, is not as strong in patients with CLL, compared to those without. But, overall, as long as the vaccine won’t cause harm, I would recommend my patients get it.

Dr. Shadman has disclosed no relevant financial relationships.

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

COVID-19 has thrown a wrench in standard treatment protocols for patients with chronic lymphocytic leukemia (CLL). These patients already face a greater risk of dying from infections, and recent research suggests they tend to have risk factors that increase their likelihood of complications and death from COVID-19.

In August, a group of oncologists from the United States and Europe published a literature-informed expert opinion to help their colleagues navigate this new CLL treatment landscape. It offers a roadmap for balancing patients’ therapeutic needs against their risk for viral infection and outlines the safest course of action for patients who test positive for COVID-19.

Mazyar Shadman, MD, MPH, an associate professor in the Clinical Research Division of the Fred Hutchinson Cancer Research Center and the Division of Medical Oncology at the University of Washington School of Medicine, in Seattle, Washington, was contacted for comment to break down what clinicians need to know about treating CLL during the pandemic. This interview has been edited for length and clarity.
 

Question: What prompted you and colleagues from the United States and Europe to write these recommendations?

Dr. Shadman: When we began the collaboration earlier this year, our colleagues in Italy and the rest of Europe had more experience with COVID-19, so they led the effort. We wanted to help oncologists manage their patients with CLL during the pandemic based on the evidence we had at the time and the unknowns we faced.
 

What’s an example of how the available evidence informed your recommendations?

At the time, we didn’t know whether patients with CLL were more likely to get COVID-19, compared to the general population, but we did have evidence already that cancer increases patients’ risk of bad outcomes and death from COVID-19. CLL, for example, can increase risk factors for infection, including hypogammaglobulinemia, innate immune dysfunction, and neutropenia, which may be exacerbated by anticancer treatments. Patients’ existing immune suppression might prevent or delay their ability to react to or cope with the virus. And many patients with CLL have other conditions that increase their risk of a severe response to COVID-19, including older age (70% of CLL patients are older than 65 years), hypertension (21%), and diabetes (26%).

These factors informed our recommendations to limit patients’ exposure to COVID-19 by reducing or postponing the number of in-person visits and routine in-hospital follow-ups, especially if they could be substituted with virtual check-ins.
 

The expert opinion recommendations are divided into three main categories: patients who are newly diagnosed with CLL but have not begun receiving therapy, those already receiving therapy but are free of COVID-19, and those who test positive for COVID-19. Let’s start with the first category. What do the recommendations say about waiting versus proceeding for newly diagnosed patients?

Our priority was balancing the negative impacts of getting COVID-19 with the negative impacts of postponing cancer treatment. We suggested taking each new CLL case on a patient-by-patient basis to determine who needed treatment tomorrow and who could wait a few weeks or months. Fortunately, CLL rarely requires immediate therapy, so the preference was to postpone treatment a few weeks, depending on the local COVID-19 outbreak situation.

In my practice, for instance, we tried to postpone visits as much as we could. Before the pandemic, patients with CLL in the watch-and-wait phase – those diagnosed but who don’t require treatment immediately – would come in for bloodwork and exams every 3-6 months. But when the pandemic hit, we skipped 3-month visits for patients with stable lab results and switched to telehealth visits instead. For those who needed blood draws, we used local labs closer to the patient’s home to minimize their exposure and transportation requirements.

When treatment cannot be deferred, we’ve recommended starting patients on therapies that require fewer in-person visits and are less immune suppressive. We recommended oncologists consider Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib and acalabrutinib, as well as venetoclax. Some research suggests these inhibitors may be protective against COVID-19 by blunting a patient’s hyperinflammatory response to the virus. These drugs also require minimal routine treatment and lab visits, which helps limit patients’ potential exposure to COVID-19.

But there are risks to waiting. Even during the peak of the pandemic here in Seattle, if patients needed treatment immediately, we did not delay. Patients with significant drops in their platelet or neutrophil count or those with bulky disease, for instance, do require therapy.

It’s important to mention that we did have bad experiences with patients who needed immediate treatment and their treating physicians decided to wait because of COVID-19 risks. These patients who came in with aggressive CLL and experienced delays in care had much more complicated CLL treatment than if they had started treatment earlier.

When organ function became abnormal, for example, some patients could no longer receive certain therapies. If someone’s kidney function becomes abnormal, I wouldn’t recommend giving a drug like venetoclax. Although rare, some patients on venetoclax develop tumor lysis syndrome, which can lead to kidney failure.

Bottom line: Don’t just assume it’s a low-grade disease and that you can wait.



What about patients already receiving treatment for CLL who are free of COVID-19?

For patients on active treatment, we suggested stopping or holding treatment with monoclonal antibodies, such as rituximab and obinutuzumab, and chemotherapy regimens, such as idelalisib plus rituximab and duvelisib, when possible. We recommended oncologists consider continuing treatment for patients on BTK inhibitors.



What happens if a patient with CLL tests positive for COVID-19?

If a patient tests positive for COVID-19 but is not yet on CLL treatment, we recommend postponing CLL care until they’ve recovered from the infection. If a patient is already receiving treatment, the recommendations are similar to those above for COVID-19–negative patients: Delay care for those on chemotherapy and monoclonal antibodies, but consider continuing treatment for patients on BTK inhibitors.
 

The expert opinion was submitted in May and ultimately published in August. How has our understanding of treating CLL during the pandemic changed since then? Would you change any recommendations?

When we published this paper, it was still early on in the pandemic, and we didn’t know as much about COVID-19 and CLL as we do now. Since we published the recommendations, we have received confirmation from several studies that patients with cancer have a more complicated course of COVID-19 and have worse outcomes. But I believe the recommendations we devised early in the pandemic still hold now. Decisions about delivering treatment should be influenced by the local COVID-19 numbers and hospital resources as well as the patient’s specific situation – whether they have more stable disease and can delay or postpone care or whether they need more immediate attention.

With a further surge in cases predicted as we move even deeper into flu season, what would you recommend for initiating treatment in newly diagnosed patients?

The pandemic has created a very fluid situation for treating CLL. What’s happening now in Seattle may not be the same story in New York, California, or elsewhere. In early November [when Dr. Shadman was first contacted], in Seattle, we were not postponing care because our COVID-19 numbers were fairly good. But, as of mid December, that is starting to change as the COVID-19 numbers fluctuate.
 

If we do experience a second peak of COVID-19 cases, we would need to modify our practice as we did during the initial surge earlier this year. That would mean avoiding treatment with monoclonal antibodies and chemotherapy, as well as minimizing blood draws and drugs that require frequent in-person visits.
 

How important is it for patients to be vaccinated against COVID-19?

There are two key things to consider about a vaccine. Is the vaccine safe from the general safety standpoint that everyone is worried about? And if the vaccine is not harmful, will it work in patients will CLL?

Because we don’t yet know the complete side-effect profile of a COVID-19 vaccine, we would need to assess each patient’s condition to limit adverse reactions and to see whether the vaccine alters a patient’s immune response to the CLL drug they’re taking.

At the University of Washington, Seattle, we have a plan to start studying the effectiveness of the Pfizer and Moderna vaccines in patients with CLL – carefully assessing patients’ response to the vaccine in terms of antibody response. We already know, based on small studies, that the antibody response to the flu vaccine, for instance, is not as strong in patients with CLL, compared to those without. But, overall, as long as the vaccine won’t cause harm, I would recommend my patients get it.

Dr. Shadman has disclosed no relevant financial relationships.

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

I have learned a lot about crisis management and leadership in the rapidly changing COVID health care environment. I have learned how to make quick and imperfect decisions with limited information, and how to move on swiftly. I have learned how to quickly fade out memories of how we used to run our business, and pivot to unknown and untested delivery modalities. I have learned how to take regulatory standards as guidance, not doctrine. And I have learned how tell longstanding loyal colleagues that they are being laid off.

Many of these leadership challenges are not new, but the rapidity of change and the weight and magnitude of decision making is unparalleled in my relatively short career. In some ways, it reminds me of some solid lessons I have learned over time as a lifetime runner, with many analogies and applications to leadership.

Some people ask me why I run. “You must get a runner’s high.” The truth is, I have never had a runner’s high. I feel every step. In fact, the very nature of running makes a person feel like they are being pulled under water. Runners are typically tachycardic and short of breath the whole time they are running. But what running does allow for is to ignore some of the signals your body is sending, and wholly and completely focus on other things. I often have my most creative and innovative thoughts while running. So that is why I run. But back to the point of what running and leadership have in common – and how lessons learned can translate between the two:

They are both really hard. As I mentioned above, running literally makes you feel like you are drowning. But when you finish running, it is amazing how easy everything else feels! Similar to leadership, it should feel hard, but not too hard. I have seen firsthand the effects of under- and over-delegating, and both are dysfunctional. Good leadership is a blend of being humble and servant, but also ensuring self-care and endurance. It is also important to acknowledge the difficulty of leadership. Dr. Tom Lee, currently chief medical officer at Press Ganey, is a leader I have always admired. He once said, “Leadership can be very lonely.” At the time, I did not quite understand that, but I have come to experience that feeling occasionally. The other aspect of leadership that I find really hard is that often, people’s anger is misdirected at leaders as a natural outlet for that anger. Part of being a leader is enduring such anger, gaining an understanding for it, and doing what you can to help people through it.

They both work better when you are restored. It sounds generic and cliché, but you can’t be a good runner or a good leader when you are totally depleted.

They both require efficiency. When I was running my first marathon, a complete stranger ran up beside me and started giving me advice. I thought it was sort of strange advice at the time, but it turned out to be sound and useful. He noticed my running pattern of “sticking to the road,” and he told me I should rather “run as the crow flies.” What he meant was to run in as straight of a line as possible, regardless of the road, to preserve energy and save steps. He recommended picking a point on the horizon and running toward that point as straight as possible. As he sped off ahead of me in the next mile, his parting words were, “You’ll thank me at mile 24…” To this day, I still use that tactic, which I find very steadying and calming during running. The same can be said for leadership; as you pick a point on the horizon, keep yourself and your team heading toward that point with intense focus, and before you realize it, you’ve reached your destination.

They both require having a goal. That same stranger who gave me advice on running efficiently also asked what my goal was. It caught me off guard a bit, as I realized my only goal was to finish. He encouraged me to make a goal for the run, which could serve as a motivator when the going got tough. This was another piece of lasting advice I have used for both running and for leadership.

They both can be endured by committing to continuous forward motion. Running and leadership both become psychologically much easier when you realize all you really have to do is maintain continuous forward motion. Some days require less effort than others, but I can always convince myself I am capable of some forward motion.

They both are easier if you don’t overthink things. When I first started in a leadership position, I would have moments of anxiety if I thought too hard about what I was responsible for. Similar to running, it works best if you don’t overthink what difficulties it may bring; rather, just put on your shoes and get going.

In the end, leading during COVID is like stepping onto a new trail. Despite the new terrain and foreign path, my prior training and trusty pair of sneakers – like my leadership skills and past experiences – will get me through this journey, one step at a time.

Dr. Scheurer is chief quality officer and professor of medicine at the Medical University of South Carolina, Charleston. She is president of SHM.

I have learned a lot about crisis management and leadership in the rapidly changing COVID health care environment. I have learned how to make quick and imperfect decisions with limited information, and how to move on swiftly. I have learned how to quickly fade out memories of how we used to run our business, and pivot to unknown and untested delivery modalities. I have learned how to take regulatory standards as guidance, not doctrine. And I have learned how tell longstanding loyal colleagues that they are being laid off.

Many of these leadership challenges are not new, but the rapidity of change and the weight and magnitude of decision making is unparalleled in my relatively short career. In some ways, it reminds me of some solid lessons I have learned over time as a lifetime runner, with many analogies and applications to leadership.

Some people ask me why I run. “You must get a runner’s high.” The truth is, I have never had a runner’s high. I feel every step. In fact, the very nature of running makes a person feel like they are being pulled under water. Runners are typically tachycardic and short of breath the whole time they are running. But what running does allow for is to ignore some of the signals your body is sending, and wholly and completely focus on other things. I often have my most creative and innovative thoughts while running. So that is why I run. But back to the point of what running and leadership have in common – and how lessons learned can translate between the two:

They are both really hard. As I mentioned above, running literally makes you feel like you are drowning. But when you finish running, it is amazing how easy everything else feels! Similar to leadership, it should feel hard, but not too hard. I have seen firsthand the effects of under- and over-delegating, and both are dysfunctional. Good leadership is a blend of being humble and servant, but also ensuring self-care and endurance. It is also important to acknowledge the difficulty of leadership. Dr. Tom Lee, currently chief medical officer at Press Ganey, is a leader I have always admired. He once said, “Leadership can be very lonely.” At the time, I did not quite understand that, but I have come to experience that feeling occasionally. The other aspect of leadership that I find really hard is that often, people’s anger is misdirected at leaders as a natural outlet for that anger. Part of being a leader is enduring such anger, gaining an understanding for it, and doing what you can to help people through it.

They both work better when you are restored. It sounds generic and cliché, but you can’t be a good runner or a good leader when you are totally depleted.

They both require efficiency. When I was running my first marathon, a complete stranger ran up beside me and started giving me advice. I thought it was sort of strange advice at the time, but it turned out to be sound and useful. He noticed my running pattern of “sticking to the road,” and he told me I should rather “run as the crow flies.” What he meant was to run in as straight of a line as possible, regardless of the road, to preserve energy and save steps. He recommended picking a point on the horizon and running toward that point as straight as possible. As he sped off ahead of me in the next mile, his parting words were, “You’ll thank me at mile 24…” To this day, I still use that tactic, which I find very steadying and calming during running. The same can be said for leadership; as you pick a point on the horizon, keep yourself and your team heading toward that point with intense focus, and before you realize it, you’ve reached your destination.

They both require having a goal. That same stranger who gave me advice on running efficiently also asked what my goal was. It caught me off guard a bit, as I realized my only goal was to finish. He encouraged me to make a goal for the run, which could serve as a motivator when the going got tough. This was another piece of lasting advice I have used for both running and for leadership.

They both can be endured by committing to continuous forward motion. Running and leadership both become psychologically much easier when you realize all you really have to do is maintain continuous forward motion. Some days require less effort than others, but I can always convince myself I am capable of some forward motion.

They both are easier if you don’t overthink things. When I first started in a leadership position, I would have moments of anxiety if I thought too hard about what I was responsible for. Similar to running, it works best if you don’t overthink what difficulties it may bring; rather, just put on your shoes and get going.

In the end, leading during COVID is like stepping onto a new trail. Despite the new terrain and foreign path, my prior training and trusty pair of sneakers – like my leadership skills and past experiences – will get me through this journey, one step at a time.

Dr. Scheurer is chief quality officer and professor of medicine at the Medical University of South Carolina, Charleston. She is president of SHM.

I have learned a lot about crisis management and leadership in the rapidly changing COVID health care environment. I have learned how to make quick and imperfect decisions with limited information, and how to move on swiftly. I have learned how to quickly fade out memories of how we used to run our business, and pivot to unknown and untested delivery modalities. I have learned how to take regulatory standards as guidance, not doctrine. And I have learned how tell longstanding loyal colleagues that they are being laid off.

Many of these leadership challenges are not new, but the rapidity of change and the weight and magnitude of decision making is unparalleled in my relatively short career. In some ways, it reminds me of some solid lessons I have learned over time as a lifetime runner, with many analogies and applications to leadership.

Some people ask me why I run. “You must get a runner’s high.” The truth is, I have never had a runner’s high. I feel every step. In fact, the very nature of running makes a person feel like they are being pulled under water. Runners are typically tachycardic and short of breath the whole time they are running. But what running does allow for is to ignore some of the signals your body is sending, and wholly and completely focus on other things. I often have my most creative and innovative thoughts while running. So that is why I run. But back to the point of what running and leadership have in common – and how lessons learned can translate between the two:

They are both really hard. As I mentioned above, running literally makes you feel like you are drowning. But when you finish running, it is amazing how easy everything else feels! Similar to leadership, it should feel hard, but not too hard. I have seen firsthand the effects of under- and over-delegating, and both are dysfunctional. Good leadership is a blend of being humble and servant, but also ensuring self-care and endurance. It is also important to acknowledge the difficulty of leadership. Dr. Tom Lee, currently chief medical officer at Press Ganey, is a leader I have always admired. He once said, “Leadership can be very lonely.” At the time, I did not quite understand that, but I have come to experience that feeling occasionally. The other aspect of leadership that I find really hard is that often, people’s anger is misdirected at leaders as a natural outlet for that anger. Part of being a leader is enduring such anger, gaining an understanding for it, and doing what you can to help people through it.

They both work better when you are restored. It sounds generic and cliché, but you can’t be a good runner or a good leader when you are totally depleted.

They both require efficiency. When I was running my first marathon, a complete stranger ran up beside me and started giving me advice. I thought it was sort of strange advice at the time, but it turned out to be sound and useful. He noticed my running pattern of “sticking to the road,” and he told me I should rather “run as the crow flies.” What he meant was to run in as straight of a line as possible, regardless of the road, to preserve energy and save steps. He recommended picking a point on the horizon and running toward that point as straight as possible. As he sped off ahead of me in the next mile, his parting words were, “You’ll thank me at mile 24…” To this day, I still use that tactic, which I find very steadying and calming during running. The same can be said for leadership; as you pick a point on the horizon, keep yourself and your team heading toward that point with intense focus, and before you realize it, you’ve reached your destination.

They both require having a goal. That same stranger who gave me advice on running efficiently also asked what my goal was. It caught me off guard a bit, as I realized my only goal was to finish. He encouraged me to make a goal for the run, which could serve as a motivator when the going got tough. This was another piece of lasting advice I have used for both running and for leadership.

They both can be endured by committing to continuous forward motion. Running and leadership both become psychologically much easier when you realize all you really have to do is maintain continuous forward motion. Some days require less effort than others, but I can always convince myself I am capable of some forward motion.

They both are easier if you don’t overthink things. When I first started in a leadership position, I would have moments of anxiety if I thought too hard about what I was responsible for. Similar to running, it works best if you don’t overthink what difficulties it may bring; rather, just put on your shoes and get going.

In the end, leading during COVID is like stepping onto a new trail. Despite the new terrain and foreign path, my prior training and trusty pair of sneakers – like my leadership skills and past experiences – will get me through this journey, one step at a time.

Dr. Scheurer is chief quality officer and professor of medicine at the Medical University of South Carolina, Charleston. She is president of SHM.

Caring for LGBTQ+ pediatric patients often requires physicians to consider issues – such as preservation of fertility for transgender youth and resource allocation to sexual-minority youth in the foster-care system – that they may not think about as frequently with their other patients.

monkeybusinessimages/Getty Images

“It’s important to engage transgender and gender-diverse youth and families in fertility counseling early in their gender affirmation process,” but it does not happen as often as it should, said Jason Rafferty, MD (he/him/his), a clinical assistant professor of psychiatry and human behavior at the Warren Alpert Medical School of Brown University, Providence, R.I. Dr. Rafferty discussed two studies at the annual meeting of the American Academy of Pediatrics, held virtually this year: one on fertility outcomes among a small transgender sample and another finding that sexual-minority youth are 2.5 times more likely to be involved in the foster-care system.

“We need to recognize and address disparities in health that place sexual-minority youth at increased risk for child welfare involvement,” he told attendees.
 

Fertility preservation and counseling for transgender patients

Evidence suggests gender-affirming hormone treatment affects gonadal structures and functions in ways that may decrease fertility potential, Dr. Rafferty said. “Yet, there’s very little [research] into the reversibility or thresholds above which fertility potential is affected.”

The World Professional Association for Transgender Health (WPATH) recommends that doctors discuss the possible adverse health effects of feminizing or masculinizing treatments and the patient’s reproductive options before starting hormone therapy, although the extent to which this therapy may impair fertility isn’t known.

The first study Dr. Rafferty discussed was an assessment of semen cryopreservation outcomes among youth asserting a female identity. The researchers conducted a retrospective chart review on a convenience sample of 11 transgender and gender-diverse adolescents and young adults who had been referred for fertility preservation between January 2015 and September 2018 at the University of Pittsburgh Medical Center Children’s Hospital and the UPMC Magee-Womens Hospital in Pittsburgh.

Of the 11, 1 did not provide a sample, and another discarded their sample after 4 months. The seven patients without prior gender-affirming hormone treatment (average age 19 at time of fertility consultation) were all able to produce a semen sample, which showed normal parameters, except for some abnormal morphology. The significance of that one abnormal finding was unclear without a control group, Dr. Rafferty said. All seven began gonadotropin-releasing hormone (GnRH) agonist therapy, and four also began estradiol therapy, although Dr. Rafferty questioned why GnRH agonist therapy was started at such late ages.

Regardless, he said, the takeaway from this first group was the efficiency and effectiveness of getting a semen sample before beginning gender-affirming hormone therapy. The second group offered a different takeaway.

“What I think is probably the most unique aspect of this study is this second group of two individuals who had previously received hormones or blockers,” Dr. Rafferty told attendees. The first patient was 13 years of age at gender dysphoria onset and 18 years at the time of their fertility consultation. They had been on GnRH agonists for 6 months before semen collection. Their first sample, at 3 months after discontinuing hormones, was low-quality, but they did produce a viable sample 2 months later.

The other patient, who underwent fertility consultation at age 19, had taken estrogen and spironolactone for 26 months before semen collection and were not able to produce sperm 4 months after stopping the treatment. They did not try again because they underwent an orchiectomy.

Despite the small sample size and lack of confounding data, such as smoking and stress, the study remains the first to show successful sampling after gender-affirming hormone therapy in a teen, Dr. Rafferty said. It also shows that sampling after beginning hormone therapy may require discontinuation for several months before a successful sample is possible, thereby supporting WPATH’s recommendation for early fertility counseling.

“However, the standard of providing fertility counseling before intervention does not always occur,” Dr. Rafferty said, citing research that found low percentages of teens had received fertility counseling or discussed negative effects of therapy on fertility prior to starting it. These low numbers may result from changes in youths’ interest in fertility throughout development, but they could also relate to youths’ reluctance to discuss family planning while they feel uncomfortable in their bodies.

“My experience, and there is some empirical evidence for this, is that many transgender and gender-diverse youth feel more comfortable conceptualizing and pursuing intimate partner relationships and family planning after they start gender affirmation interventions,” Dr. Rafferty said. The stress associated with gender dysphoria can further complicate fertility discussions, and providers have to consider whether it’s more stressful to hold off on gender-affirming hormone therapy until the patient gets a successful semen sample or to start therapy and then discontinue for several months to get a sample later.

While decisions about fertility services should be fully up to the patient, in reality, multiple barriers – such as high cost, low insurance coverage, a dearth of specialists who can do the procedures, and inaccurate assumptions about transgender people’s interest in family planning – complicate the decision,.

“Systemically denying a marginalized population the ability to reproduce, or at least the ability to make a free choice about reproduction and family planning, is a reproductive justice issue that’s not getting the attention it deserves,” Dr. Rafferty said.

Clair Kronk, BSc, a session attendee from the University of Cincinnati College of Medicine and Cincinnati Children’s Hospital and Medical Center, said in an interview that she appreciated the session even while she lamented the lack of adequate evidence on transgender and gender-diverse care.

“I do feel like there are a lot of provider-based questions with no sufficient guidelines right now when it comes to transgender care,” Ms. Kronk said. “Despite being nearly a century old, treatment of trans patients is somehow still a ‘Wild West’ of medical care, which is sad to see.” She is grateful to see attention finally reaching this population.

“It is imperative that medical institutions focus on real, advanceable diversity, equity, and inclusion initiatives which center marginalized groups,” she said. “Centering minoritized and marginalized peoples in improving care is the only way lasting change will happen.”
 

Sexual-minority youth in foster care

The second study Dr. Rafferty discussed was the first nationally representative systemic assessment of the prevalence of sexual-minority youth in foster care, child welfare, and out-of-home placement. Anecdotal evidence and community samples already suggest that a disproportionately higher number of sexual-minority youth enter foster care, he said, possibly resulting in part from family conflict about sexual orientation. In addition, LGBTQ+ youth already experience higher rates of psychological and physical abuse at home – a top reason for entry into child welfare – and this population has high rates of running away, particularly around the time of coming out.

Past research has found that sexual-minority youth experience higher rates of maltreatment and discrimination than do their peers from foster parents, siblings, and agency staff, which translates to fewer support services and lower levels of reunification or adoption.

In the National Longitudinal Study of Adolescent to Adult Health involving 14,154 respondents, 6.3% reported any same-sex attraction, and 2.1% were involved in the foster-care system. The researchers determined that 4.3% of sexual-minority youth were involved in foster care, compared with just 1.9% of heterosexual youth (P = .002) – a 2.5 times greater rate – with a stronger effect among those with exclusively same-sex attraction.

In the second part of the study, the researchers looked at 1,014 youths in the foster-care system, of whom 80% had experienced an out-of-home placement. The 16% of youth in foster care reporting same sex attraction did not have a higher rate of out-of-home placement than did heterosexual youth within the system. However, there were twice as many sexual-minority youth in child welfare and four times as many in out-of-home placement, compared with their heterosexual peers, possibly suggesting that sexual-minority youth are less likely to exit the system, Dr. Rafferty said.

“Many studies have shown that family acceptance is a critical factor in building resiliency, while rejection is tied to poor physical and emotional outcomes,” he said. “It would follow that we’re identifying a critical at-risk group of sexual-minority youth lacking in fundamental and essential family support.”

This population “experiences the intersection of multiple forces of marginalization, including out-of-home placement, socioeconomic stress, sexual minority status, and likely, race,” Dr. Rafferty said.

Ms. Kronk commented during the session that fertility services and collection are extremely expensive, often forcing trans people into the absurd situation of having to choose between paying for hormone therapy or paying for fertility treatment.

“This makes a really strong argument for resource allocation based on risk” and has ramifications for the higher proportions of sexual-minority youth facing transition without adequate support services, Dr. Rafferty said.

It also suggests the need for providers to help patients feel comfortable and safe talking about their needs, Ms. Kronk said.

“Unfortunately, LGBTQIA+ health care is not taught very comprehensively in the United States [and most other countries],” she said. “Oftentimes, this leads to awkward situations where patients are more knowledgeable than their providers. Listening, learning, supporting, and being open to change are what every provider should take to heart.”

Dr. Rafferty and Ms. Kronk had no relevant financial disclosures.

Caring for LGBTQ+ pediatric patients often requires physicians to consider issues – such as preservation of fertility for transgender youth and resource allocation to sexual-minority youth in the foster-care system – that they may not think about as frequently with their other patients.

monkeybusinessimages/Getty Images

“It’s important to engage transgender and gender-diverse youth and families in fertility counseling early in their gender affirmation process,” but it does not happen as often as it should, said Jason Rafferty, MD (he/him/his), a clinical assistant professor of psychiatry and human behavior at the Warren Alpert Medical School of Brown University, Providence, R.I. Dr. Rafferty discussed two studies at the annual meeting of the American Academy of Pediatrics, held virtually this year: one on fertility outcomes among a small transgender sample and another finding that sexual-minority youth are 2.5 times more likely to be involved in the foster-care system.

“We need to recognize and address disparities in health that place sexual-minority youth at increased risk for child welfare involvement,” he told attendees.
 

Fertility preservation and counseling for transgender patients

Evidence suggests gender-affirming hormone treatment affects gonadal structures and functions in ways that may decrease fertility potential, Dr. Rafferty said. “Yet, there’s very little [research] into the reversibility or thresholds above which fertility potential is affected.”

The World Professional Association for Transgender Health (WPATH) recommends that doctors discuss the possible adverse health effects of feminizing or masculinizing treatments and the patient’s reproductive options before starting hormone therapy, although the extent to which this therapy may impair fertility isn’t known.

The first study Dr. Rafferty discussed was an assessment of semen cryopreservation outcomes among youth asserting a female identity. The researchers conducted a retrospective chart review on a convenience sample of 11 transgender and gender-diverse adolescents and young adults who had been referred for fertility preservation between January 2015 and September 2018 at the University of Pittsburgh Medical Center Children’s Hospital and the UPMC Magee-Womens Hospital in Pittsburgh.

Of the 11, 1 did not provide a sample, and another discarded their sample after 4 months. The seven patients without prior gender-affirming hormone treatment (average age 19 at time of fertility consultation) were all able to produce a semen sample, which showed normal parameters, except for some abnormal morphology. The significance of that one abnormal finding was unclear without a control group, Dr. Rafferty said. All seven began gonadotropin-releasing hormone (GnRH) agonist therapy, and four also began estradiol therapy, although Dr. Rafferty questioned why GnRH agonist therapy was started at such late ages.

Regardless, he said, the takeaway from this first group was the efficiency and effectiveness of getting a semen sample before beginning gender-affirming hormone therapy. The second group offered a different takeaway.

“What I think is probably the most unique aspect of this study is this second group of two individuals who had previously received hormones or blockers,” Dr. Rafferty told attendees. The first patient was 13 years of age at gender dysphoria onset and 18 years at the time of their fertility consultation. They had been on GnRH agonists for 6 months before semen collection. Their first sample, at 3 months after discontinuing hormones, was low-quality, but they did produce a viable sample 2 months later.

The other patient, who underwent fertility consultation at age 19, had taken estrogen and spironolactone for 26 months before semen collection and were not able to produce sperm 4 months after stopping the treatment. They did not try again because they underwent an orchiectomy.

Despite the small sample size and lack of confounding data, such as smoking and stress, the study remains the first to show successful sampling after gender-affirming hormone therapy in a teen, Dr. Rafferty said. It also shows that sampling after beginning hormone therapy may require discontinuation for several months before a successful sample is possible, thereby supporting WPATH’s recommendation for early fertility counseling.

“However, the standard of providing fertility counseling before intervention does not always occur,” Dr. Rafferty said, citing research that found low percentages of teens had received fertility counseling or discussed negative effects of therapy on fertility prior to starting it. These low numbers may result from changes in youths’ interest in fertility throughout development, but they could also relate to youths’ reluctance to discuss family planning while they feel uncomfortable in their bodies.

“My experience, and there is some empirical evidence for this, is that many transgender and gender-diverse youth feel more comfortable conceptualizing and pursuing intimate partner relationships and family planning after they start gender affirmation interventions,” Dr. Rafferty said. The stress associated with gender dysphoria can further complicate fertility discussions, and providers have to consider whether it’s more stressful to hold off on gender-affirming hormone therapy until the patient gets a successful semen sample or to start therapy and then discontinue for several months to get a sample later.

While decisions about fertility services should be fully up to the patient, in reality, multiple barriers – such as high cost, low insurance coverage, a dearth of specialists who can do the procedures, and inaccurate assumptions about transgender people’s interest in family planning – complicate the decision,.

“Systemically denying a marginalized population the ability to reproduce, or at least the ability to make a free choice about reproduction and family planning, is a reproductive justice issue that’s not getting the attention it deserves,” Dr. Rafferty said.

Clair Kronk, BSc, a session attendee from the University of Cincinnati College of Medicine and Cincinnati Children’s Hospital and Medical Center, said in an interview that she appreciated the session even while she lamented the lack of adequate evidence on transgender and gender-diverse care.

“I do feel like there are a lot of provider-based questions with no sufficient guidelines right now when it comes to transgender care,” Ms. Kronk said. “Despite being nearly a century old, treatment of trans patients is somehow still a ‘Wild West’ of medical care, which is sad to see.” She is grateful to see attention finally reaching this population.

“It is imperative that medical institutions focus on real, advanceable diversity, equity, and inclusion initiatives which center marginalized groups,” she said. “Centering minoritized and marginalized peoples in improving care is the only way lasting change will happen.”
 

Sexual-minority youth in foster care

The second study Dr. Rafferty discussed was the first nationally representative systemic assessment of the prevalence of sexual-minority youth in foster care, child welfare, and out-of-home placement. Anecdotal evidence and community samples already suggest that a disproportionately higher number of sexual-minority youth enter foster care, he said, possibly resulting in part from family conflict about sexual orientation. In addition, LGBTQ+ youth already experience higher rates of psychological and physical abuse at home – a top reason for entry into child welfare – and this population has high rates of running away, particularly around the time of coming out.

Past research has found that sexual-minority youth experience higher rates of maltreatment and discrimination than do their peers from foster parents, siblings, and agency staff, which translates to fewer support services and lower levels of reunification or adoption.

In the National Longitudinal Study of Adolescent to Adult Health involving 14,154 respondents, 6.3% reported any same-sex attraction, and 2.1% were involved in the foster-care system. The researchers determined that 4.3% of sexual-minority youth were involved in foster care, compared with just 1.9% of heterosexual youth (P = .002) – a 2.5 times greater rate – with a stronger effect among those with exclusively same-sex attraction.

In the second part of the study, the researchers looked at 1,014 youths in the foster-care system, of whom 80% had experienced an out-of-home placement. The 16% of youth in foster care reporting same sex attraction did not have a higher rate of out-of-home placement than did heterosexual youth within the system. However, there were twice as many sexual-minority youth in child welfare and four times as many in out-of-home placement, compared with their heterosexual peers, possibly suggesting that sexual-minority youth are less likely to exit the system, Dr. Rafferty said.

“Many studies have shown that family acceptance is a critical factor in building resiliency, while rejection is tied to poor physical and emotional outcomes,” he said. “It would follow that we’re identifying a critical at-risk group of sexual-minority youth lacking in fundamental and essential family support.”

This population “experiences the intersection of multiple forces of marginalization, including out-of-home placement, socioeconomic stress, sexual minority status, and likely, race,” Dr. Rafferty said.

Ms. Kronk commented during the session that fertility services and collection are extremely expensive, often forcing trans people into the absurd situation of having to choose between paying for hormone therapy or paying for fertility treatment.

“This makes a really strong argument for resource allocation based on risk” and has ramifications for the higher proportions of sexual-minority youth facing transition without adequate support services, Dr. Rafferty said.

It also suggests the need for providers to help patients feel comfortable and safe talking about their needs, Ms. Kronk said.

“Unfortunately, LGBTQIA+ health care is not taught very comprehensively in the United States [and most other countries],” she said. “Oftentimes, this leads to awkward situations where patients are more knowledgeable than their providers. Listening, learning, supporting, and being open to change are what every provider should take to heart.”

Dr. Rafferty and Ms. Kronk had no relevant financial disclosures.

Caring for LGBTQ+ pediatric patients often requires physicians to consider issues – such as preservation of fertility for transgender youth and resource allocation to sexual-minority youth in the foster-care system – that they may not think about as frequently with their other patients.

monkeybusinessimages/Getty Images

“It’s important to engage transgender and gender-diverse youth and families in fertility counseling early in their gender affirmation process,” but it does not happen as often as it should, said Jason Rafferty, MD (he/him/his), a clinical assistant professor of psychiatry and human behavior at the Warren Alpert Medical School of Brown University, Providence, R.I. Dr. Rafferty discussed two studies at the annual meeting of the American Academy of Pediatrics, held virtually this year: one on fertility outcomes among a small transgender sample and another finding that sexual-minority youth are 2.5 times more likely to be involved in the foster-care system.

“We need to recognize and address disparities in health that place sexual-minority youth at increased risk for child welfare involvement,” he told attendees.
 

Fertility preservation and counseling for transgender patients

Evidence suggests gender-affirming hormone treatment affects gonadal structures and functions in ways that may decrease fertility potential, Dr. Rafferty said. “Yet, there’s very little [research] into the reversibility or thresholds above which fertility potential is affected.”

The World Professional Association for Transgender Health (WPATH) recommends that doctors discuss the possible adverse health effects of feminizing or masculinizing treatments and the patient’s reproductive options before starting hormone therapy, although the extent to which this therapy may impair fertility isn’t known.

The first study Dr. Rafferty discussed was an assessment of semen cryopreservation outcomes among youth asserting a female identity. The researchers conducted a retrospective chart review on a convenience sample of 11 transgender and gender-diverse adolescents and young adults who had been referred for fertility preservation between January 2015 and September 2018 at the University of Pittsburgh Medical Center Children’s Hospital and the UPMC Magee-Womens Hospital in Pittsburgh.

Of the 11, 1 did not provide a sample, and another discarded their sample after 4 months. The seven patients without prior gender-affirming hormone treatment (average age 19 at time of fertility consultation) were all able to produce a semen sample, which showed normal parameters, except for some abnormal morphology. The significance of that one abnormal finding was unclear without a control group, Dr. Rafferty said. All seven began gonadotropin-releasing hormone (GnRH) agonist therapy, and four also began estradiol therapy, although Dr. Rafferty questioned why GnRH agonist therapy was started at such late ages.

Regardless, he said, the takeaway from this first group was the efficiency and effectiveness of getting a semen sample before beginning gender-affirming hormone therapy. The second group offered a different takeaway.

“What I think is probably the most unique aspect of this study is this second group of two individuals who had previously received hormones or blockers,” Dr. Rafferty told attendees. The first patient was 13 years of age at gender dysphoria onset and 18 years at the time of their fertility consultation. They had been on GnRH agonists for 6 months before semen collection. Their first sample, at 3 months after discontinuing hormones, was low-quality, but they did produce a viable sample 2 months later.

The other patient, who underwent fertility consultation at age 19, had taken estrogen and spironolactone for 26 months before semen collection and were not able to produce sperm 4 months after stopping the treatment. They did not try again because they underwent an orchiectomy.

Despite the small sample size and lack of confounding data, such as smoking and stress, the study remains the first to show successful sampling after gender-affirming hormone therapy in a teen, Dr. Rafferty said. It also shows that sampling after beginning hormone therapy may require discontinuation for several months before a successful sample is possible, thereby supporting WPATH’s recommendation for early fertility counseling.

“However, the standard of providing fertility counseling before intervention does not always occur,” Dr. Rafferty said, citing research that found low percentages of teens had received fertility counseling or discussed negative effects of therapy on fertility prior to starting it. These low numbers may result from changes in youths’ interest in fertility throughout development, but they could also relate to youths’ reluctance to discuss family planning while they feel uncomfortable in their bodies.

“My experience, and there is some empirical evidence for this, is that many transgender and gender-diverse youth feel more comfortable conceptualizing and pursuing intimate partner relationships and family planning after they start gender affirmation interventions,” Dr. Rafferty said. The stress associated with gender dysphoria can further complicate fertility discussions, and providers have to consider whether it’s more stressful to hold off on gender-affirming hormone therapy until the patient gets a successful semen sample or to start therapy and then discontinue for several months to get a sample later.

While decisions about fertility services should be fully up to the patient, in reality, multiple barriers – such as high cost, low insurance coverage, a dearth of specialists who can do the procedures, and inaccurate assumptions about transgender people’s interest in family planning – complicate the decision,.

“Systemically denying a marginalized population the ability to reproduce, or at least the ability to make a free choice about reproduction and family planning, is a reproductive justice issue that’s not getting the attention it deserves,” Dr. Rafferty said.

Clair Kronk, BSc, a session attendee from the University of Cincinnati College of Medicine and Cincinnati Children’s Hospital and Medical Center, said in an interview that she appreciated the session even while she lamented the lack of adequate evidence on transgender and gender-diverse care.

“I do feel like there are a lot of provider-based questions with no sufficient guidelines right now when it comes to transgender care,” Ms. Kronk said. “Despite being nearly a century old, treatment of trans patients is somehow still a ‘Wild West’ of medical care, which is sad to see.” She is grateful to see attention finally reaching this population.

“It is imperative that medical institutions focus on real, advanceable diversity, equity, and inclusion initiatives which center marginalized groups,” she said. “Centering minoritized and marginalized peoples in improving care is the only way lasting change will happen.”
 

Sexual-minority youth in foster care

The second study Dr. Rafferty discussed was the first nationally representative systemic assessment of the prevalence of sexual-minority youth in foster care, child welfare, and out-of-home placement. Anecdotal evidence and community samples already suggest that a disproportionately higher number of sexual-minority youth enter foster care, he said, possibly resulting in part from family conflict about sexual orientation. In addition, LGBTQ+ youth already experience higher rates of psychological and physical abuse at home – a top reason for entry into child welfare – and this population has high rates of running away, particularly around the time of coming out.

Past research has found that sexual-minority youth experience higher rates of maltreatment and discrimination than do their peers from foster parents, siblings, and agency staff, which translates to fewer support services and lower levels of reunification or adoption.

In the National Longitudinal Study of Adolescent to Adult Health involving 14,154 respondents, 6.3% reported any same-sex attraction, and 2.1% were involved in the foster-care system. The researchers determined that 4.3% of sexual-minority youth were involved in foster care, compared with just 1.9% of heterosexual youth (P = .002) – a 2.5 times greater rate – with a stronger effect among those with exclusively same-sex attraction.

In the second part of the study, the researchers looked at 1,014 youths in the foster-care system, of whom 80% had experienced an out-of-home placement. The 16% of youth in foster care reporting same sex attraction did not have a higher rate of out-of-home placement than did heterosexual youth within the system. However, there were twice as many sexual-minority youth in child welfare and four times as many in out-of-home placement, compared with their heterosexual peers, possibly suggesting that sexual-minority youth are less likely to exit the system, Dr. Rafferty said.

“Many studies have shown that family acceptance is a critical factor in building resiliency, while rejection is tied to poor physical and emotional outcomes,” he said. “It would follow that we’re identifying a critical at-risk group of sexual-minority youth lacking in fundamental and essential family support.”

This population “experiences the intersection of multiple forces of marginalization, including out-of-home placement, socioeconomic stress, sexual minority status, and likely, race,” Dr. Rafferty said.

Ms. Kronk commented during the session that fertility services and collection are extremely expensive, often forcing trans people into the absurd situation of having to choose between paying for hormone therapy or paying for fertility treatment.

“This makes a really strong argument for resource allocation based on risk” and has ramifications for the higher proportions of sexual-minority youth facing transition without adequate support services, Dr. Rafferty said.

It also suggests the need for providers to help patients feel comfortable and safe talking about their needs, Ms. Kronk said.

“Unfortunately, LGBTQIA+ health care is not taught very comprehensively in the United States [and most other countries],” she said. “Oftentimes, this leads to awkward situations where patients are more knowledgeable than their providers. Listening, learning, supporting, and being open to change are what every provider should take to heart.”

Dr. Rafferty and Ms. Kronk had no relevant financial disclosures.

What is more stressful in the mind of a patient – a diagnosis of cancer or infertility? An infertile woman’s anxiety and depression scores are equivalent to one with cancer (J Psychosom Obstet Gynecol. 1993;14 Suppl:45-52). These two diseases intersect in the burgeoning field of oncofertility, the collaboration of oncology with reproductive endocrinology to offer patients the option of fertility preservation. The term oncofertility was first coined by Teresa Woodruff, PhD, in 2005 during her invited lecture at the University of Calgary symposium called “Pushing the Boundaries – Advances that Will Change the World in 20 Years.” Her prediction has reached its fruition. This article will review fertility preservation options for female oncology patients.

The ability for oncofertility to exist is the result of improved cancer survival rates and advances in reproductive medicine. Improvements in the treatment of cancer enable many young women to survive and focus on the potential of having a family. Malignancies striking young people, particularly breast, lymphoma, and melanoma, have encouraging 5-year survival rates. If invasive cancer is located only in the breast (affecting 62% of women diagnosed), the 5-year survival rate is 99%. For all with Hodgkin lymphoma, the 5-year survival is 87%, increasing to 92% if the cancer is found in its earliest stages. Among all people with melanoma of the skin, from the time of initial diagnosis, the 5-year survival is 92%.

Long-term survival is expected for 80% of children and adolescents diagnosed with cancer (Obstet Gynecol. 2010;116: 1171-83).
 

Iatrogenic effects

The reproductive risk of cancer treatment is gonadotoxicity and the subsequent iatrogenic primary ovarian insufficiency (POI, prior termed premature ovarian failure) or infertility.

Chemotherapy with alkylating agents, such as cyclophosphamide, is associated with the greatest chance of amenorrhea (Breast Cancer Res Treat. 2014;145:113-28). Chemotherapy with cyclophosphamide, methotrexate, and 5 fluorouracil (CMF – commonly used for the treatment of breast cancer) will usually result in loss of ovarian function in 33% of women under age 30, 50% of women aged 30-35, 75% of women aged 35-40, and 95% of women over age 40 (J Clin Oncol. 2006;24:5769-79).

The dose at which 50% of oocytes are lost due to radiation is under 2 Gy (Hum Reprod. 2003;18:117-21). Unfortunately, the minimum dose decreases with advancing age of the woman, contributed by natural diminishing reserve and an increase in radiosensitivity of oocytes. Age, proximity of the radiation field to the ovaries, and total dose are important factors determining risk of POI. For brain tumors, cranial irradiation may result in hypothalamic amenorrhea.
 

Protection

The use of GnRH agonist for 6 months during chemotherapy has been controversial with mixed results in avoiding ovarian failure. A recent study suggests a GnRH agonist does reduce the prevalence of POI (J Clin Oncol. 2018;36:1981-90) in women treated for breast cancer but the subsequent ovarian reserve is low (Ann Oncol. 2017;28:1811-6). There are not enough data now to consider this the sole viable option for all patients to preserve fertility.

Patients requiring local pelvic radiation treatment may benefit from transposition of the ovaries to sites away from maximal radiation exposure.
 

Oocyte cryopreservation (OC) and ovarian tissue cryopreservation (OTC)

Since 2012, the American Society for Reproductive Medicine lifted the experimental designation on OC and, last year, the society removed the same label for OTC, providing an additional fertility preservation option.

Ovarian stimulation and egg retrieval for OC can now occur literally within 2 weeks because of a random start protocol whereby women are stimulated any day in their cycle, pre- and post ovulation. Studies have shown equivalent yield of oocytes.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a routine matter with egg donation cycles. While there remains debate over whether live birth rates using frozen eggs are inferior to fresh eggs, a learning curve with the new technology may be the important factor (Obstet Gynecol. 2020;135:709-16).

When urgent cancer treatment precludes ovarian stimulation for OC, then OTC is a viable option. Another population that could benefit from OTC are prepubertal girls facing gonadotoxic therapy. More research is required to determine the quality of eggs obtained through ovarian stimulation in adolescent and young adult patients. While leukemic patients are eligible for OTC, there is concern about reseeding malignant cells with future autologous transplantation of tissue.

OTC involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. To date, live birth rates are modest (Fertil Steril. 2015;104:1097-8).

Recent research has combined the freezing of both mature and immature eggs, the latter undergoing IVM (in-vitro maturation) to maximize the potential for fertilizable eggs. Women with polycystic ovary syndrome and certain cancers or medical conditions that warrant avoiding supraphysiologic levels of estradiol from ovarian stimulation, may benefit from the retrieval of immature eggs from unstimulated ovaries.

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans are not known but animal studies suggest there may be higher rates of miscarriage and birth defects.
 

Breast cancer – a special scenario

With every breast cancer patient, I review the theoretical concern over increasing estradiol levels during an IVF stimulation cycle with the potential impact on her cancer prognosis. Fortunately, the literature has not demonstrated an increased risk of breast cancer or recurrence after undergoing an IVF cycle. Currently, the use of aromatase inhibitors with gonadotropins along with a GnRH-antagonist is the protocol to maintain a lower estradiol level during stimulation, which may be of benefit for breast cancer prognosis. The use of aromatase inhibitors is an off-label indication for fertility with no definitive evidence of teratogenicity. Preimplantation genetic testing of embryos is available and approved by the American Society for Reproductive Medicine for BRCA gene mutation patients.

Oncofertility is an exciting field to allow cancer survivors the option for a biological child. We recommend all our cancer patients meet with our reproductive psychologist to assist in coping with the overwhelming information presented in a short time frame.
 

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and associate professor of obstetrics and gynecology at the University of Central Florida, Orlando.

What is more stressful in the mind of a patient – a diagnosis of cancer or infertility? An infertile woman’s anxiety and depression scores are equivalent to one with cancer (J Psychosom Obstet Gynecol. 1993;14 Suppl:45-52). These two diseases intersect in the burgeoning field of oncofertility, the collaboration of oncology with reproductive endocrinology to offer patients the option of fertility preservation. The term oncofertility was first coined by Teresa Woodruff, PhD, in 2005 during her invited lecture at the University of Calgary symposium called “Pushing the Boundaries – Advances that Will Change the World in 20 Years.” Her prediction has reached its fruition. This article will review fertility preservation options for female oncology patients.

The ability for oncofertility to exist is the result of improved cancer survival rates and advances in reproductive medicine. Improvements in the treatment of cancer enable many young women to survive and focus on the potential of having a family. Malignancies striking young people, particularly breast, lymphoma, and melanoma, have encouraging 5-year survival rates. If invasive cancer is located only in the breast (affecting 62% of women diagnosed), the 5-year survival rate is 99%. For all with Hodgkin lymphoma, the 5-year survival is 87%, increasing to 92% if the cancer is found in its earliest stages. Among all people with melanoma of the skin, from the time of initial diagnosis, the 5-year survival is 92%.

Long-term survival is expected for 80% of children and adolescents diagnosed with cancer (Obstet Gynecol. 2010;116: 1171-83).
 

Iatrogenic effects

The reproductive risk of cancer treatment is gonadotoxicity and the subsequent iatrogenic primary ovarian insufficiency (POI, prior termed premature ovarian failure) or infertility.

Chemotherapy with alkylating agents, such as cyclophosphamide, is associated with the greatest chance of amenorrhea (Breast Cancer Res Treat. 2014;145:113-28). Chemotherapy with cyclophosphamide, methotrexate, and 5 fluorouracil (CMF – commonly used for the treatment of breast cancer) will usually result in loss of ovarian function in 33% of women under age 30, 50% of women aged 30-35, 75% of women aged 35-40, and 95% of women over age 40 (J Clin Oncol. 2006;24:5769-79).

The dose at which 50% of oocytes are lost due to radiation is under 2 Gy (Hum Reprod. 2003;18:117-21). Unfortunately, the minimum dose decreases with advancing age of the woman, contributed by natural diminishing reserve and an increase in radiosensitivity of oocytes. Age, proximity of the radiation field to the ovaries, and total dose are important factors determining risk of POI. For brain tumors, cranial irradiation may result in hypothalamic amenorrhea.
 

Protection

The use of GnRH agonist for 6 months during chemotherapy has been controversial with mixed results in avoiding ovarian failure. A recent study suggests a GnRH agonist does reduce the prevalence of POI (J Clin Oncol. 2018;36:1981-90) in women treated for breast cancer but the subsequent ovarian reserve is low (Ann Oncol. 2017;28:1811-6). There are not enough data now to consider this the sole viable option for all patients to preserve fertility.

Patients requiring local pelvic radiation treatment may benefit from transposition of the ovaries to sites away from maximal radiation exposure.
 

Oocyte cryopreservation (OC) and ovarian tissue cryopreservation (OTC)

Since 2012, the American Society for Reproductive Medicine lifted the experimental designation on OC and, last year, the society removed the same label for OTC, providing an additional fertility preservation option.

Ovarian stimulation and egg retrieval for OC can now occur literally within 2 weeks because of a random start protocol whereby women are stimulated any day in their cycle, pre- and post ovulation. Studies have shown equivalent yield of oocytes.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a routine matter with egg donation cycles. While there remains debate over whether live birth rates using frozen eggs are inferior to fresh eggs, a learning curve with the new technology may be the important factor (Obstet Gynecol. 2020;135:709-16).

When urgent cancer treatment precludes ovarian stimulation for OC, then OTC is a viable option. Another population that could benefit from OTC are prepubertal girls facing gonadotoxic therapy. More research is required to determine the quality of eggs obtained through ovarian stimulation in adolescent and young adult patients. While leukemic patients are eligible for OTC, there is concern about reseeding malignant cells with future autologous transplantation of tissue.

OTC involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. To date, live birth rates are modest (Fertil Steril. 2015;104:1097-8).

Recent research has combined the freezing of both mature and immature eggs, the latter undergoing IVM (in-vitro maturation) to maximize the potential for fertilizable eggs. Women with polycystic ovary syndrome and certain cancers or medical conditions that warrant avoiding supraphysiologic levels of estradiol from ovarian stimulation, may benefit from the retrieval of immature eggs from unstimulated ovaries.

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans are not known but animal studies suggest there may be higher rates of miscarriage and birth defects.
 

Breast cancer – a special scenario

With every breast cancer patient, I review the theoretical concern over increasing estradiol levels during an IVF stimulation cycle with the potential impact on her cancer prognosis. Fortunately, the literature has not demonstrated an increased risk of breast cancer or recurrence after undergoing an IVF cycle. Currently, the use of aromatase inhibitors with gonadotropins along with a GnRH-antagonist is the protocol to maintain a lower estradiol level during stimulation, which may be of benefit for breast cancer prognosis. The use of aromatase inhibitors is an off-label indication for fertility with no definitive evidence of teratogenicity. Preimplantation genetic testing of embryos is available and approved by the American Society for Reproductive Medicine for BRCA gene mutation patients.

Oncofertility is an exciting field to allow cancer survivors the option for a biological child. We recommend all our cancer patients meet with our reproductive psychologist to assist in coping with the overwhelming information presented in a short time frame.
 

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and associate professor of obstetrics and gynecology at the University of Central Florida, Orlando.

What is more stressful in the mind of a patient – a diagnosis of cancer or infertility? An infertile woman’s anxiety and depression scores are equivalent to one with cancer (J Psychosom Obstet Gynecol. 1993;14 Suppl:45-52). These two diseases intersect in the burgeoning field of oncofertility, the collaboration of oncology with reproductive endocrinology to offer patients the option of fertility preservation. The term oncofertility was first coined by Teresa Woodruff, PhD, in 2005 during her invited lecture at the University of Calgary symposium called “Pushing the Boundaries – Advances that Will Change the World in 20 Years.” Her prediction has reached its fruition. This article will review fertility preservation options for female oncology patients.

The ability for oncofertility to exist is the result of improved cancer survival rates and advances in reproductive medicine. Improvements in the treatment of cancer enable many young women to survive and focus on the potential of having a family. Malignancies striking young people, particularly breast, lymphoma, and melanoma, have encouraging 5-year survival rates. If invasive cancer is located only in the breast (affecting 62% of women diagnosed), the 5-year survival rate is 99%. For all with Hodgkin lymphoma, the 5-year survival is 87%, increasing to 92% if the cancer is found in its earliest stages. Among all people with melanoma of the skin, from the time of initial diagnosis, the 5-year survival is 92%.

Long-term survival is expected for 80% of children and adolescents diagnosed with cancer (Obstet Gynecol. 2010;116: 1171-83).
 

Iatrogenic effects

The reproductive risk of cancer treatment is gonadotoxicity and the subsequent iatrogenic primary ovarian insufficiency (POI, prior termed premature ovarian failure) or infertility.

Chemotherapy with alkylating agents, such as cyclophosphamide, is associated with the greatest chance of amenorrhea (Breast Cancer Res Treat. 2014;145:113-28). Chemotherapy with cyclophosphamide, methotrexate, and 5 fluorouracil (CMF – commonly used for the treatment of breast cancer) will usually result in loss of ovarian function in 33% of women under age 30, 50% of women aged 30-35, 75% of women aged 35-40, and 95% of women over age 40 (J Clin Oncol. 2006;24:5769-79).

The dose at which 50% of oocytes are lost due to radiation is under 2 Gy (Hum Reprod. 2003;18:117-21). Unfortunately, the minimum dose decreases with advancing age of the woman, contributed by natural diminishing reserve and an increase in radiosensitivity of oocytes. Age, proximity of the radiation field to the ovaries, and total dose are important factors determining risk of POI. For brain tumors, cranial irradiation may result in hypothalamic amenorrhea.
 

Protection

The use of GnRH agonist for 6 months during chemotherapy has been controversial with mixed results in avoiding ovarian failure. A recent study suggests a GnRH agonist does reduce the prevalence of POI (J Clin Oncol. 2018;36:1981-90) in women treated for breast cancer but the subsequent ovarian reserve is low (Ann Oncol. 2017;28:1811-6). There are not enough data now to consider this the sole viable option for all patients to preserve fertility.

Patients requiring local pelvic radiation treatment may benefit from transposition of the ovaries to sites away from maximal radiation exposure.
 

Oocyte cryopreservation (OC) and ovarian tissue cryopreservation (OTC)

Since 2012, the American Society for Reproductive Medicine lifted the experimental designation on OC and, last year, the society removed the same label for OTC, providing an additional fertility preservation option.

Ovarian stimulation and egg retrieval for OC can now occur literally within 2 weeks because of a random start protocol whereby women are stimulated any day in their cycle, pre- and post ovulation. Studies have shown equivalent yield of oocytes.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a routine matter with egg donation cycles. While there remains debate over whether live birth rates using frozen eggs are inferior to fresh eggs, a learning curve with the new technology may be the important factor (Obstet Gynecol. 2020;135:709-16).

When urgent cancer treatment precludes ovarian stimulation for OC, then OTC is a viable option. Another population that could benefit from OTC are prepubertal girls facing gonadotoxic therapy. More research is required to determine the quality of eggs obtained through ovarian stimulation in adolescent and young adult patients. While leukemic patients are eligible for OTC, there is concern about reseeding malignant cells with future autologous transplantation of tissue.

OTC involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. To date, live birth rates are modest (Fertil Steril. 2015;104:1097-8).

Recent research has combined the freezing of both mature and immature eggs, the latter undergoing IVM (in-vitro maturation) to maximize the potential for fertilizable eggs. Women with polycystic ovary syndrome and certain cancers or medical conditions that warrant avoiding supraphysiologic levels of estradiol from ovarian stimulation, may benefit from the retrieval of immature eggs from unstimulated ovaries.

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans are not known but animal studies suggest there may be higher rates of miscarriage and birth defects.
 

Breast cancer – a special scenario

With every breast cancer patient, I review the theoretical concern over increasing estradiol levels during an IVF stimulation cycle with the potential impact on her cancer prognosis. Fortunately, the literature has not demonstrated an increased risk of breast cancer or recurrence after undergoing an IVF cycle. Currently, the use of aromatase inhibitors with gonadotropins along with a GnRH-antagonist is the protocol to maintain a lower estradiol level during stimulation, which may be of benefit for breast cancer prognosis. The use of aromatase inhibitors is an off-label indication for fertility with no definitive evidence of teratogenicity. Preimplantation genetic testing of embryos is available and approved by the American Society for Reproductive Medicine for BRCA gene mutation patients.

Oncofertility is an exciting field to allow cancer survivors the option for a biological child. We recommend all our cancer patients meet with our reproductive psychologist to assist in coping with the overwhelming information presented in a short time frame.
 

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and associate professor of obstetrics and gynecology at the University of Central Florida, Orlando.

Although there is an effective vaccine against Bordetella pertussis, whooping cough remains a leading cause of death. Cases are increasing, and scientists face challenges in developing new vaccines.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Dimitri Diavatopoulos, PhD, associate professor at the Radboud University Medical Centre Nijmegen, the Netherlands, summarized the pertussis vaccination problem and what the Pertussis Correlates of Protection Europe (PERISCOPE) project seeks to achieve. Dr. Diavatopoulos has a longstanding interest in pertussis and immunity and will soon take over as the scientific coordinator of PERISCOPE.

Pertussis is a highly contagious infectious disease that causes uncontrollable coughing. The disease begins with an atypical cough and rhinorrhea before entering a paroxysmal stage characterized by cyanosis, lymphocytosis, vomiting, and whoops. Generally, fever is absent and coughing increases at night. Finally, after weeks to months, the patient enters a convalescent stage. The World Health Organization estimates that there are 16 million pertussis cases annually and approximately 195,000 deaths in children. Most cases are caused by Bordetella pertussis and are preventable by vaccination.

In the United States, following the introduction of a national immunization program using a whole-cell vaccine in the 1950s, cases fell significantly. After a lag phase, the adoption of an acellular vaccine in the United States in 1997 and the Netherlands in 2005 – usually in combination with diphtheria and tetanus via DTaP – saw an increase in case numbers. Dr. Diavatopoulos stated that control is no longer as good, compared with other infectious diseases prevented by the MMR vaccine, such as mumps, measles, and rubella.

In the face of increasing numbers, how do we move to the next generation of vaccines to improve control? There are several barriers to licensure, including the following:

• Universal recommendation for pertussis prevention means that more than 90% of the population will have received DTaP (usually in combination with polio and Haemophilus influenzae B) and be protected for several years after vaccination.

• Because DTaP vaccines are only efficacious for a limited time, the problem is not immediately apparent.

• Pertussis epidemics are cyclical, occurring every 3-5 years. These peaks and troughs complicate the development of epidemiological studies.

What this means is that large-scale Phase III efficacy studies, in which disease is used as the endpoint, are not feasible. Also, formal correlates of protection have not been identified.

The PERISCOPE Project started in March 2016 and is designed to respond to some of these issues. Funding is made available by a public private consortium involving the Bill & Melinda Gates foundation, the European Union, and European Federation of Pharmaceutical Industries and Associations (EFPIA) partners, and in this case, GlaxoSmithKline and Sanofi Pasteur. In total, there are 22 partners in this project.

The strategic objectives of this partnership include the following:

• Foster expertise and increase capacity in Europe to evaluate new pertussis vaccines both in clinical and preclinical models.

• Identify early biomarkers of long-lasting protective immunity to pertussis in humans. (This step will accelerate and de-risk clinical development of next generation pertussis vaccines.)

• Investigate the impact of maternal vaccination on infant response to pertussis vaccination.

The problem is that there is no one single study design that addresses all questions about the pertussis vaccine. For example, in PERISCOPE, the results of preclinical studies using the baboon or mouse models and addressing disease and colonization endpoints or immunogenicity do not perfectly model human infection and disease.

By comparison, controlled human infection studies provide information on colonization but not disease endpoints. Such studies, however, do provide information on immunogenicity endpoints. Also available are booster vaccination studies and infant vaccination studies providing data on immunogenicity, as well as safety information.

Finally, there are patient studies, such as household contact studies where immunogenicity can be correlated to disease endpoints. From these studies, it will be seen that what is needed is integration of evidence from clinical and preclinical studies to support a new vaccine registration.

PERISCOPE addresses these issues by developing novel, functional antibody and cellular assays and employing cutting-edge methods to characterize innate immune responses and cell-mediated systemic and mucosal immunity. PERISCOPE combines two major industrial partners with public researchers from academic and public health institutes and small and medium-sized enterprises with expertise in clinical trials, vaccinology, immunology, molecular microbiology, challenge models, and bioinformatics.

Andrew Gorringe, PhD, from Public Health England and the Research and Development Institute at Porton Down, Wiltshire, England, said, “Vaccines have greatly reduced the incidence of pertussis, but it remains the most prevalent ‘vaccine preventable’ disease. This is an exciting period for pertussis vaccine research as we find new ways to understand the immunity that protects from both infection and disease. The PERISCOPE project provides a collaborative environment that combines expertise across Europe to provide a route to the development of new, more effective vaccines.”

GSK and Sanofi Pasteur have cofunded the PERISCOPE Project. Dr. Diavatopoulos made no other financial disclosures.

Although there is an effective vaccine against Bordetella pertussis, whooping cough remains a leading cause of death. Cases are increasing, and scientists face challenges in developing new vaccines.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Dimitri Diavatopoulos, PhD, associate professor at the Radboud University Medical Centre Nijmegen, the Netherlands, summarized the pertussis vaccination problem and what the Pertussis Correlates of Protection Europe (PERISCOPE) project seeks to achieve. Dr. Diavatopoulos has a longstanding interest in pertussis and immunity and will soon take over as the scientific coordinator of PERISCOPE.

Pertussis is a highly contagious infectious disease that causes uncontrollable coughing. The disease begins with an atypical cough and rhinorrhea before entering a paroxysmal stage characterized by cyanosis, lymphocytosis, vomiting, and whoops. Generally, fever is absent and coughing increases at night. Finally, after weeks to months, the patient enters a convalescent stage. The World Health Organization estimates that there are 16 million pertussis cases annually and approximately 195,000 deaths in children. Most cases are caused by Bordetella pertussis and are preventable by vaccination.

In the United States, following the introduction of a national immunization program using a whole-cell vaccine in the 1950s, cases fell significantly. After a lag phase, the adoption of an acellular vaccine in the United States in 1997 and the Netherlands in 2005 – usually in combination with diphtheria and tetanus via DTaP – saw an increase in case numbers. Dr. Diavatopoulos stated that control is no longer as good, compared with other infectious diseases prevented by the MMR vaccine, such as mumps, measles, and rubella.

In the face of increasing numbers, how do we move to the next generation of vaccines to improve control? There are several barriers to licensure, including the following:

• Universal recommendation for pertussis prevention means that more than 90% of the population will have received DTaP (usually in combination with polio and Haemophilus influenzae B) and be protected for several years after vaccination.

• Because DTaP vaccines are only efficacious for a limited time, the problem is not immediately apparent.

• Pertussis epidemics are cyclical, occurring every 3-5 years. These peaks and troughs complicate the development of epidemiological studies.

What this means is that large-scale Phase III efficacy studies, in which disease is used as the endpoint, are not feasible. Also, formal correlates of protection have not been identified.

The PERISCOPE Project started in March 2016 and is designed to respond to some of these issues. Funding is made available by a public private consortium involving the Bill & Melinda Gates foundation, the European Union, and European Federation of Pharmaceutical Industries and Associations (EFPIA) partners, and in this case, GlaxoSmithKline and Sanofi Pasteur. In total, there are 22 partners in this project.

The strategic objectives of this partnership include the following:

• Foster expertise and increase capacity in Europe to evaluate new pertussis vaccines both in clinical and preclinical models.

• Identify early biomarkers of long-lasting protective immunity to pertussis in humans. (This step will accelerate and de-risk clinical development of next generation pertussis vaccines.)

• Investigate the impact of maternal vaccination on infant response to pertussis vaccination.

The problem is that there is no one single study design that addresses all questions about the pertussis vaccine. For example, in PERISCOPE, the results of preclinical studies using the baboon or mouse models and addressing disease and colonization endpoints or immunogenicity do not perfectly model human infection and disease.

By comparison, controlled human infection studies provide information on colonization but not disease endpoints. Such studies, however, do provide information on immunogenicity endpoints. Also available are booster vaccination studies and infant vaccination studies providing data on immunogenicity, as well as safety information.

Finally, there are patient studies, such as household contact studies where immunogenicity can be correlated to disease endpoints. From these studies, it will be seen that what is needed is integration of evidence from clinical and preclinical studies to support a new vaccine registration.

PERISCOPE addresses these issues by developing novel, functional antibody and cellular assays and employing cutting-edge methods to characterize innate immune responses and cell-mediated systemic and mucosal immunity. PERISCOPE combines two major industrial partners with public researchers from academic and public health institutes and small and medium-sized enterprises with expertise in clinical trials, vaccinology, immunology, molecular microbiology, challenge models, and bioinformatics.

Andrew Gorringe, PhD, from Public Health England and the Research and Development Institute at Porton Down, Wiltshire, England, said, “Vaccines have greatly reduced the incidence of pertussis, but it remains the most prevalent ‘vaccine preventable’ disease. This is an exciting period for pertussis vaccine research as we find new ways to understand the immunity that protects from both infection and disease. The PERISCOPE project provides a collaborative environment that combines expertise across Europe to provide a route to the development of new, more effective vaccines.”

GSK and Sanofi Pasteur have cofunded the PERISCOPE Project. Dr. Diavatopoulos made no other financial disclosures.

Although there is an effective vaccine against Bordetella pertussis, whooping cough remains a leading cause of death. Cases are increasing, and scientists face challenges in developing new vaccines.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Dimitri Diavatopoulos, PhD, associate professor at the Radboud University Medical Centre Nijmegen, the Netherlands, summarized the pertussis vaccination problem and what the Pertussis Correlates of Protection Europe (PERISCOPE) project seeks to achieve. Dr. Diavatopoulos has a longstanding interest in pertussis and immunity and will soon take over as the scientific coordinator of PERISCOPE.

Pertussis is a highly contagious infectious disease that causes uncontrollable coughing. The disease begins with an atypical cough and rhinorrhea before entering a paroxysmal stage characterized by cyanosis, lymphocytosis, vomiting, and whoops. Generally, fever is absent and coughing increases at night. Finally, after weeks to months, the patient enters a convalescent stage. The World Health Organization estimates that there are 16 million pertussis cases annually and approximately 195,000 deaths in children. Most cases are caused by Bordetella pertussis and are preventable by vaccination.

In the United States, following the introduction of a national immunization program using a whole-cell vaccine in the 1950s, cases fell significantly. After a lag phase, the adoption of an acellular vaccine in the United States in 1997 and the Netherlands in 2005 – usually in combination with diphtheria and tetanus via DTaP – saw an increase in case numbers. Dr. Diavatopoulos stated that control is no longer as good, compared with other infectious diseases prevented by the MMR vaccine, such as mumps, measles, and rubella.

In the face of increasing numbers, how do we move to the next generation of vaccines to improve control? There are several barriers to licensure, including the following:

• Universal recommendation for pertussis prevention means that more than 90% of the population will have received DTaP (usually in combination with polio and Haemophilus influenzae B) and be protected for several years after vaccination.

• Because DTaP vaccines are only efficacious for a limited time, the problem is not immediately apparent.

• Pertussis epidemics are cyclical, occurring every 3-5 years. These peaks and troughs complicate the development of epidemiological studies.

What this means is that large-scale Phase III efficacy studies, in which disease is used as the endpoint, are not feasible. Also, formal correlates of protection have not been identified.

The PERISCOPE Project started in March 2016 and is designed to respond to some of these issues. Funding is made available by a public private consortium involving the Bill & Melinda Gates foundation, the European Union, and European Federation of Pharmaceutical Industries and Associations (EFPIA) partners, and in this case, GlaxoSmithKline and Sanofi Pasteur. In total, there are 22 partners in this project.

The strategic objectives of this partnership include the following:

• Foster expertise and increase capacity in Europe to evaluate new pertussis vaccines both in clinical and preclinical models.

• Identify early biomarkers of long-lasting protective immunity to pertussis in humans. (This step will accelerate and de-risk clinical development of next generation pertussis vaccines.)

• Investigate the impact of maternal vaccination on infant response to pertussis vaccination.

The problem is that there is no one single study design that addresses all questions about the pertussis vaccine. For example, in PERISCOPE, the results of preclinical studies using the baboon or mouse models and addressing disease and colonization endpoints or immunogenicity do not perfectly model human infection and disease.

By comparison, controlled human infection studies provide information on colonization but not disease endpoints. Such studies, however, do provide information on immunogenicity endpoints. Also available are booster vaccination studies and infant vaccination studies providing data on immunogenicity, as well as safety information.

Finally, there are patient studies, such as household contact studies where immunogenicity can be correlated to disease endpoints. From these studies, it will be seen that what is needed is integration of evidence from clinical and preclinical studies to support a new vaccine registration.

PERISCOPE addresses these issues by developing novel, functional antibody and cellular assays and employing cutting-edge methods to characterize innate immune responses and cell-mediated systemic and mucosal immunity. PERISCOPE combines two major industrial partners with public researchers from academic and public health institutes and small and medium-sized enterprises with expertise in clinical trials, vaccinology, immunology, molecular microbiology, challenge models, and bioinformatics.

Andrew Gorringe, PhD, from Public Health England and the Research and Development Institute at Porton Down, Wiltshire, England, said, “Vaccines have greatly reduced the incidence of pertussis, but it remains the most prevalent ‘vaccine preventable’ disease. This is an exciting period for pertussis vaccine research as we find new ways to understand the immunity that protects from both infection and disease. The PERISCOPE project provides a collaborative environment that combines expertise across Europe to provide a route to the development of new, more effective vaccines.”

GSK and Sanofi Pasteur have cofunded the PERISCOPE Project. Dr. Diavatopoulos made no other financial disclosures.

The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) evaluated Moderna’s COVID-19 vaccine as highly effective with a favorable safety profile, based on interim data from an ongoing phase 3 trial.

The panel acknowledged that further studies will be required post issuance of an Emergency Use Authorization (EUA) to collect additional data on the safety and effectiveness of the vaccine. A briefing document released by the FDA on Dec. 17, 2020, summarized interim results and included recommendations from VRBPAC on use of Moderna’s mRNA-1273 COVID-19 vaccine.

“On November 30, 2020, ModernaTX (the Sponsor) submitted an EUA request to FDA for an investigational COVID-19 vaccine (mRNA-1273) intended to prevent COVID-19,” the committee wrote.
 

The mRNA-1273 vaccine trial

Among 30,351 individuals aged 18 years and older, the efficacy, safety, and immunogenicity of the mRNA-1273 vaccine candidate was evaluated in a randomized, stratified, observer-blind, placebo-controlled phase 3 study. Participants were randomly assigned (1:1) to receive two injections of either 100 mcg of mRNA-1273 (n = 15,181) or saline placebo (n = 15,170) administered intramuscularly on day 1 and day 29.

The primary efficacy endpoint was efficacy of mRNA-1273 against PCR-confirmed COVID-19 with onset at least 14 days following the second dose. The primary safety endpoint was to characterize the safety of the vaccine following one or two doses.
 

Efficacy

Among 27,817 subjects included in the first interim analysis (data cutoff: Nov. 7, 2020), 5 cases of COVID-19 with onset at least 14 days after the second dose occurred among vaccine recipients and 90 case occurred among placebo recipients, corresponding to 94.5% vaccine efficacy (95% confidence interval, 86.5%-97.8%).

“Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19,” they reported.

Data from the final scheduled analysis of the primary efficacy endpoint (data cutoff: Nov. 21, 2020; median follow-up of >2 months after dose 2), demonstrated 94.1% vaccine efficacy (95% confidence interval, 89.3%-96.8%), corresponding to 11 cases of COVID-19 in the vaccine group and 185 cases in the placebo group.

When stratified by age, the vaccine efficacy was 95.6% (95% CI, 90.6%-97.9%) for individuals 18-64 years of age and 86.4% (95% CI, 61.4%-95.5%) for those 65 years of age or older.

In addition, results from secondary analyses indicated benefit for mRNA-1273 in preventing severe COVID-19 cases, COVID-19 in those with prior SARS-CoV-2 infection, and infection after the first dose, but these data were not conclusive.
 

Safety

Among 30,350 subjects included in the first interim analysis (data cutoff: Nov. 11, 2020; median follow-up of 7 weeks post second dose), no specific safety concerns were observed that would prevent issuance of an EUA.

Additional safety data (data cutoff: Nov. 25, 2020; median follow-up of 9 weeks post second dose) were provided on Dec. 7, 2020, but did not change the conclusions from the first interim analysis.

The most common vaccine-related adverse reactions were injection site pain (91.6%), fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%).

“The frequency of serious adverse events (SAEs) was low (1.0% in the mRNA-1273 arm and 1.0% in the placebo arm), without meaningful imbalances between study arms,” they reported.

Myocardial infarction (0.03%), nephrolithiasis (0.02%), and cholecystitis (0.02%) were the most common SAEs that were numerically greater in the vaccine arm than the placebo arm; however, the small number of cases does not infer a casual relationship.

“The 2-dose vaccination regimen was highly effective in preventing PCR-confirmed COVID-19 occurring at least 14 days after receipt of the second dose,” the committee wrote. “[However], it is critical to continue to gather data about the vaccine even after it is made available under EUA.”

The associated phase 3 study was sponsored by ModernaTX.

SOURCE: FDA Briefing Document: Moderna COVID-19 Vaccine. FDA Vaccines and Related Biological Products Advisory Committee. Published Dec. 17, 2020.

The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) evaluated Moderna’s COVID-19 vaccine as highly effective with a favorable safety profile, based on interim data from an ongoing phase 3 trial.

The panel acknowledged that further studies will be required post issuance of an Emergency Use Authorization (EUA) to collect additional data on the safety and effectiveness of the vaccine. A briefing document released by the FDA on Dec. 17, 2020, summarized interim results and included recommendations from VRBPAC on use of Moderna’s mRNA-1273 COVID-19 vaccine.

“On November 30, 2020, ModernaTX (the Sponsor) submitted an EUA request to FDA for an investigational COVID-19 vaccine (mRNA-1273) intended to prevent COVID-19,” the committee wrote.
 

The mRNA-1273 vaccine trial

Among 30,351 individuals aged 18 years and older, the efficacy, safety, and immunogenicity of the mRNA-1273 vaccine candidate was evaluated in a randomized, stratified, observer-blind, placebo-controlled phase 3 study. Participants were randomly assigned (1:1) to receive two injections of either 100 mcg of mRNA-1273 (n = 15,181) or saline placebo (n = 15,170) administered intramuscularly on day 1 and day 29.

The primary efficacy endpoint was efficacy of mRNA-1273 against PCR-confirmed COVID-19 with onset at least 14 days following the second dose. The primary safety endpoint was to characterize the safety of the vaccine following one or two doses.
 

Efficacy

Among 27,817 subjects included in the first interim analysis (data cutoff: Nov. 7, 2020), 5 cases of COVID-19 with onset at least 14 days after the second dose occurred among vaccine recipients and 90 case occurred among placebo recipients, corresponding to 94.5% vaccine efficacy (95% confidence interval, 86.5%-97.8%).

“Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19,” they reported.

Data from the final scheduled analysis of the primary efficacy endpoint (data cutoff: Nov. 21, 2020; median follow-up of >2 months after dose 2), demonstrated 94.1% vaccine efficacy (95% confidence interval, 89.3%-96.8%), corresponding to 11 cases of COVID-19 in the vaccine group and 185 cases in the placebo group.

When stratified by age, the vaccine efficacy was 95.6% (95% CI, 90.6%-97.9%) for individuals 18-64 years of age and 86.4% (95% CI, 61.4%-95.5%) for those 65 years of age or older.

In addition, results from secondary analyses indicated benefit for mRNA-1273 in preventing severe COVID-19 cases, COVID-19 in those with prior SARS-CoV-2 infection, and infection after the first dose, but these data were not conclusive.
 

Safety

Among 30,350 subjects included in the first interim analysis (data cutoff: Nov. 11, 2020; median follow-up of 7 weeks post second dose), no specific safety concerns were observed that would prevent issuance of an EUA.

Additional safety data (data cutoff: Nov. 25, 2020; median follow-up of 9 weeks post second dose) were provided on Dec. 7, 2020, but did not change the conclusions from the first interim analysis.

The most common vaccine-related adverse reactions were injection site pain (91.6%), fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%).

“The frequency of serious adverse events (SAEs) was low (1.0% in the mRNA-1273 arm and 1.0% in the placebo arm), without meaningful imbalances between study arms,” they reported.

Myocardial infarction (0.03%), nephrolithiasis (0.02%), and cholecystitis (0.02%) were the most common SAEs that were numerically greater in the vaccine arm than the placebo arm; however, the small number of cases does not infer a casual relationship.

“The 2-dose vaccination regimen was highly effective in preventing PCR-confirmed COVID-19 occurring at least 14 days after receipt of the second dose,” the committee wrote. “[However], it is critical to continue to gather data about the vaccine even after it is made available under EUA.”

The associated phase 3 study was sponsored by ModernaTX.

SOURCE: FDA Briefing Document: Moderna COVID-19 Vaccine. FDA Vaccines and Related Biological Products Advisory Committee. Published Dec. 17, 2020.

The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) evaluated Moderna’s COVID-19 vaccine as highly effective with a favorable safety profile, based on interim data from an ongoing phase 3 trial.

The panel acknowledged that further studies will be required post issuance of an Emergency Use Authorization (EUA) to collect additional data on the safety and effectiveness of the vaccine. A briefing document released by the FDA on Dec. 17, 2020, summarized interim results and included recommendations from VRBPAC on use of Moderna’s mRNA-1273 COVID-19 vaccine.

“On November 30, 2020, ModernaTX (the Sponsor) submitted an EUA request to FDA for an investigational COVID-19 vaccine (mRNA-1273) intended to prevent COVID-19,” the committee wrote.
 

The mRNA-1273 vaccine trial

Among 30,351 individuals aged 18 years and older, the efficacy, safety, and immunogenicity of the mRNA-1273 vaccine candidate was evaluated in a randomized, stratified, observer-blind, placebo-controlled phase 3 study. Participants were randomly assigned (1:1) to receive two injections of either 100 mcg of mRNA-1273 (n = 15,181) or saline placebo (n = 15,170) administered intramuscularly on day 1 and day 29.

The primary efficacy endpoint was efficacy of mRNA-1273 against PCR-confirmed COVID-19 with onset at least 14 days following the second dose. The primary safety endpoint was to characterize the safety of the vaccine following one or two doses.
 

Efficacy

Among 27,817 subjects included in the first interim analysis (data cutoff: Nov. 7, 2020), 5 cases of COVID-19 with onset at least 14 days after the second dose occurred among vaccine recipients and 90 case occurred among placebo recipients, corresponding to 94.5% vaccine efficacy (95% confidence interval, 86.5%-97.8%).

“Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19,” they reported.

Data from the final scheduled analysis of the primary efficacy endpoint (data cutoff: Nov. 21, 2020; median follow-up of >2 months after dose 2), demonstrated 94.1% vaccine efficacy (95% confidence interval, 89.3%-96.8%), corresponding to 11 cases of COVID-19 in the vaccine group and 185 cases in the placebo group.

When stratified by age, the vaccine efficacy was 95.6% (95% CI, 90.6%-97.9%) for individuals 18-64 years of age and 86.4% (95% CI, 61.4%-95.5%) for those 65 years of age or older.

In addition, results from secondary analyses indicated benefit for mRNA-1273 in preventing severe COVID-19 cases, COVID-19 in those with prior SARS-CoV-2 infection, and infection after the first dose, but these data were not conclusive.
 

Safety

Among 30,350 subjects included in the first interim analysis (data cutoff: Nov. 11, 2020; median follow-up of 7 weeks post second dose), no specific safety concerns were observed that would prevent issuance of an EUA.

Additional safety data (data cutoff: Nov. 25, 2020; median follow-up of 9 weeks post second dose) were provided on Dec. 7, 2020, but did not change the conclusions from the first interim analysis.

The most common vaccine-related adverse reactions were injection site pain (91.6%), fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%).

“The frequency of serious adverse events (SAEs) was low (1.0% in the mRNA-1273 arm and 1.0% in the placebo arm), without meaningful imbalances between study arms,” they reported.

Myocardial infarction (0.03%), nephrolithiasis (0.02%), and cholecystitis (0.02%) were the most common SAEs that were numerically greater in the vaccine arm than the placebo arm; however, the small number of cases does not infer a casual relationship.

“The 2-dose vaccination regimen was highly effective in preventing PCR-confirmed COVID-19 occurring at least 14 days after receipt of the second dose,” the committee wrote. “[However], it is critical to continue to gather data about the vaccine even after it is made available under EUA.”

The associated phase 3 study was sponsored by ModernaTX.

SOURCE: FDA Briefing Document: Moderna COVID-19 Vaccine. FDA Vaccines and Related Biological Products Advisory Committee. Published Dec. 17, 2020.

CASE Agitated and aggressive

Mr. X, age 61, who has Alzheimer’s disease, is brought to the emergency department (ED) by his family after he is found to be confused, becomes physically aggressive with family members, and threatens to burn the house down. His family reports that earlier that day, he was paranoid that somebody was trying to kill him and he tried to leave the house. Mr. X has been experiencing visual hallucinations and delusional thoughts that made him aggressive towards his son. After an initial laboratory workup in the ED, Mr. X’s bloodwork comes back positive for mild leukocytosis, indicating the possibility of an infectious etiology. Mr. X is admitted to the hospital for further evaluation of his altered mental status.

HISTORY Decline over 2 years

This is Mr. X’s third inpatient admission for agitation and psychosis. His current medications—twice daily divalproex sodium extended release (ER), 250 mg every morning and 500 mg at every bedtime, and prazosin, 2 mg/d at bedtime—have been only partially effective. His medical history includes osteoarthritis, back pain, and heterozygous factor V Leiden (not on anticoagulation). He quit smoking tobacco several years ago and has no history of substance use. He has no family history of dementia. Previous trials of cholinesterase inhibitors, antipsychotics, and antidepressants resulted in only minimal improvement in his agitation and psychosis.

A chart review shows that 2 years before his current hospital admission, Mr. X had presented to his primary care physician with slurred speech, forgetfulness, missing words, and transient reading difficulties. His initial laboratory workup and MRI came back normal. He was placed on short-term disability due to work-related errors. He was referred to the hospital’s Memory Clinic 2 years ago, where his Mini-Mental State Exam score was 20/30, indicating mild cognitive impairment. Stroke workup was negative. Due to significant language deficits, a differential diagnosis for Alzheimer’s disease vs primary progressive aphasia vs frontotemporal dementia was made. He screened positive for amyloid PET scan, which confirmed the diagnosis of Alzheimer’s disease.

Neuropsychological testing showed similarities with logopenic variant of primary progressive aphasia, which in many cases is present in Alzheimer’s disease. Mr. X was prescribed anticholinesterase inhibitors, including donepezil, 10 mg/d, and rivastigmine patch, 9.5 mg/d; and memantine, 10 mg/d, which he could not tolerate because of adverse effects. During the next year, Mr. X deteriorated and presented to the ED a few times with significant psychotic symptoms and aggression. He had a poor response to various pharmacologic and nonpharmacologic interventions during this time.

EVALUATION Continued problematic behaviors

During his hospitalization, Mr. X continues to be agitated and paranoid and is placed in restraints. He is unable to respond to his name and cannot follow simple verbal commands. Results of his laboratory workup are within normal limits. His mild leukocytosis resolves with no active signs of infection. Psychiatry is consulted for management of his behavioral and psychological symptoms of dementia (BPSD).

Continue to: Mr. X is started on olanzapine...

Mr. X is started on olanzapine and lorazepam as needed for agitation, and his twice daily divalproex sodium ER is increased to 250 every morning and 750 mg at every bedtime. However, Mr. X remains agitated and requires restraints. Olanzapine is switched from an as-needed dose to scheduled doses of 10 mg every morning and 15 mg at every bedtime, to address his psychosis and agitation.

On Day 24 of hospitalization, Mr. X’s ammonia levels are checked and are found to be 69 µ/dL, which is high (normal range: 15 to 45 µ/dL). Divalproex sodium ER is eventually tapered and discontinued. Mr. X is started on carbamazepine, which is titrated to 400 mg twice daily and results in some improvement in his behavior. He continues to receive carbamazepine and is started on dextromethorphan-quinidine, 10 mg/d, and increased to 10 mg twice daily; however, Mr. X continues to be verbally aggressive with staff, throws food, wanders around, and tries to leave the hospital unit, so he is placed in restraints and continues to require a sitter.

[polldaddy:10698428]

The authors' observations

Dementia typically affects older adults, but its onset can occur before age 60. It is a syndrome rather than a specific illness; the most common types are Alzheimer’s disease, vascular dementia, dementia with Lewy bodies, and frontotemporal dementia. Diagnostic clarity and an evidence-based treatment plan are crucial for improving the quality of life for both the patient and their caregivers. The Table outlines the differential diagnosis of cognitive deficits. New-onset cognitive deficits warrant neuro­imaging, and other testing may also be needed.

Behavioral and psychological symptoms of dementia

Noncognitive symptoms occur in 98% of individuals with dementia at some point in their disease and are often the most distressing to both caregivers and patients.¹ Behavioral and psychological symptoms of dementia, including apathy, depression, sleep disorders, hallucinations, delusions, psychosis, agitation, and aggression, are exceedingly prevalent.² Although these symptoms pose a significant burden, there are no clear published treatment guidelines; however, the American Psychiatric Association and the American Geriatric Society recommend using nonpharmacologic approaches as the first-line of treatment for patients with BPSD.^3,4

Nonpharmacologic treatments

Due to the unfavorable adverse effects profiles of medications commonly used to treat dementia, nonpharmacologic treatment approaches have always played a crucial role for managing BPSD. Interventions such as music therapy, aromatherapy, art therapy, behavioral therapy, reality orientation, tailored activities, and physical exercises, have shown promising results for alleviating BPSD.^5-7

Continue to: Pharmacologic therapies should be used...

Pharmacologic treatments

Pharmacologic therapies should be used when nonpharmacologic approaches are unsuccessful, or when a patient is at imminent risk to harm themselves or others.

Antipsychotics. Although there is conflicting data regarding the use of antipsychotics in older adults, these agents are the most common pharmacologic treatment for patients with BPSD. Several studies examining the efficacy of antipsychotics for treating BPSD have demonstrated an increased risk of cerebrovascular events, including stroke and death due to any cause.⁸ While the use of antipsychotics increases the risk of mortality in older adults, the absolute risk is still low.⁹

Antipsychotics used to treat BPSD include:

• Risperidone is well studied in older adults and has shown benefit for treating aggression, agitation, and psychosis.¹⁰
• Quetiapine has a favorable adverse effects profile and may help improve sleep and reduce anxiety.¹⁰
• Olanzapine. Low-dose olanzapine has been modestly effective in decreasing agitation and aggression in patients with Alzheimer’s and vascular dementias.¹¹
• Aripiprazole has shown modest benefit in treating psychosis and agitation in patients with dementia but may be associated with insomnia or activation symptoms at lower doses.¹⁰
• Ziprasidone. Case reports have found benefit with oral and injectable forms.¹²

Antidepressants. In the CitAD study, which was a placebo-controlled randomized trial, citalopram titrated to a target of 30 mg/d was found to be effective in reducing BPSD.¹³ However, QTc prolongation limits the use of citalopram. Sertraline was studied in 1 small, randomized trial against haloperidol but showed no additional benefit.¹⁴ 

Mood stabilizers. In a small, randomized trial, carbamazepine was helpful for patients with BPSD who were resistant to treatment with antipsychotics, with efficacy demonstrated over 6 weeks.¹⁵ No other mood stabilizers have had significant positive results in treating BPSD.¹⁶ 

Anxiolytic medications. Some research suggests that the occasional use of lorazepam, as necessary, is acceptable for patients with extreme agitation or aggression when behavioral interventions or sleep aids are ineffective.¹⁷ Various case reports and case series have suggested gabapentin may be effective for BPSD.¹⁸ 

Prazosin. In a small randomized placebo-controlled trial, the commonly used antihypertensive agent prazosin reduced agitation and aggression in patients with Alzheimer’s dementia, at doses from 1 to 6 mg/d.¹⁹ Postural hypotension, the main adverse effect associated with prazosin, can limit its use.

Trazodone. Some research suggests trazodone can reduce irritability and aggression in patients with Alzheimer’s disease.²⁰

Dextromethorphan/quinidine. In a 10-week phase 2 randomized clinical trial of patients with probable Alzheimer’s disease dementia, combination dextromethorphan/quinidine reduced agitation and was generally well tolerated.²¹

For patients such as Mr. X who do not respond to multiple pharmacologic treatments, electroconvulsive therapy (ECT) may be an option.

Continue to: Because Mr. X does not respond...

TREATMENT A trial of ECT

Because Mr. X does not respond to the standard treatment protocols, the treatment team and Mr. X’s family discuss the use of ECT to control his agitation. Consent is obtained from his legal guardian and Mr. X is medically cleared to receive ECT. Mr. X receives 3 ECT treatments per week. During the first week, Mr. X experiences post-treatment agitation and confusion. The frequency of ECT treatments is reduced to 2 treatments per week, and then 1 session per week. Mr. X starts to show improvement in his agitation and ECT is continued at 1 session per week for 7 weeks.

The authors’ observations

Electroconvulsive therapy has been an effective treatment for patients with treatment-resistant depression and has shown benefit in treating other psychiatric conditions such as acute mania, catatonia, psychotic disorders, and Parkinson’s disease.²² Its use as an off-label treatment for chronic neuropathic pain has also been well documented.²³ Although ECT is not indicated for treating agitation and aggression in patients with dementia, its effectiveness for these symptoms has been discussed extensively in the literature.^22,24-26

Electroconvulsive therapy treatment can be divided into 2 phases: an acute phase during which ECT is administered 2 to 3 times a week for 4 to 5 weeks, and a maintenance phase of weekly treatments for 4 weeks and then biweekly treatments for 8 weeks.²⁶ Although extensive research supports the safe use of ECT in older adults, concerns for worsening cognitive impairment can deter patients and families from agreeing to this treatment.

Adverse effects of ECT such as headaches and postictal confusion are generally mild and transient. Severe adverse effects such as seizures, severe confusion, and delirium are uncommon.²⁵ The number of ECT treatments required for a good effect ranges from 2 to 18, and the most common position for electrodes placement is bilateral. Outcomes can be measured by using rating scales such as the Cohen-Mansfield Agitation Inventory, Neuropsychiatric Inventory, Social Dysfunction and Aggression Scale, Clinical Global Impression scale, and Pittsford Agitation Scale.²⁵ Obtaining consent from patients with dementia is generally not possible because these patients generally lack the capacity to make medical decisions. Clinicians should refer to their state laws regarding medical-decision making in such cases. The patient’s next of kin or medical power of attorney should be contacted, and the risks and benefits should be discussed before starting ECT.

OUTCOME Lasting improvement

Due to Mr. X’s improvement after ECT, on hospital Day 124, the restraints are removed and he no longer requires a sitter. He starts responding to his name and following simple verbal commands. Electroconvulsive therapy is tapered to every other week, and eventually stopped as his status improves. Mr. X continues to do well and is maintained on the same dosages of olanzapine, carbamazepine, and dextromethorphan-quinidine he had been receiving prior to discharge.

Related Resources

• Van den Berg JF, Kruithof HC, Kok RM, et al. Electroconvulsive therapy for agitation and aggression in dementia: a systematic review. Am J Geriatr Psychiatry. 2018;26(4):419-434.
• Kales HC, Mulsant BH, Sajatovic M. Prescribing antipsychotics in geriatric patients: Focus on dementia. Current Psychiatry. 2017;16(12):24-30.

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Dextromethorphan- quinidine • Nuedexta
Divalproex sodium ER • Depakote
Donepezil • Aricept
Gabapentin • Neurontin
Haloperidol • Haldol
Lorazepam • Ativan
Memantine • Namenda
Olanzapine • Zyprexa
Prazosin • Minipress
Quetiapine • Seroquel
Risperidone • Risperdal
Rivastigmine • Exelon
Sertraline • Zoloft
Trazodone • Desyrel, Oleptro
Ziprasidone • Geodon

CASE Agitated and aggressive

Mr. X, age 61, who has Alzheimer’s disease, is brought to the emergency department (ED) by his family after he is found to be confused, becomes physically aggressive with family members, and threatens to burn the house down. His family reports that earlier that day, he was paranoid that somebody was trying to kill him and he tried to leave the house. Mr. X has been experiencing visual hallucinations and delusional thoughts that made him aggressive towards his son. After an initial laboratory workup in the ED, Mr. X’s bloodwork comes back positive for mild leukocytosis, indicating the possibility of an infectious etiology. Mr. X is admitted to the hospital for further evaluation of his altered mental status.

HISTORY Decline over 2 years

This is Mr. X’s third inpatient admission for agitation and psychosis. His current medications—twice daily divalproex sodium extended release (ER), 250 mg every morning and 500 mg at every bedtime, and prazosin, 2 mg/d at bedtime—have been only partially effective. His medical history includes osteoarthritis, back pain, and heterozygous factor V Leiden (not on anticoagulation). He quit smoking tobacco several years ago and has no history of substance use. He has no family history of dementia. Previous trials of cholinesterase inhibitors, antipsychotics, and antidepressants resulted in only minimal improvement in his agitation and psychosis.

A chart review shows that 2 years before his current hospital admission, Mr. X had presented to his primary care physician with slurred speech, forgetfulness, missing words, and transient reading difficulties. His initial laboratory workup and MRI came back normal. He was placed on short-term disability due to work-related errors. He was referred to the hospital’s Memory Clinic 2 years ago, where his Mini-Mental State Exam score was 20/30, indicating mild cognitive impairment. Stroke workup was negative. Due to significant language deficits, a differential diagnosis for Alzheimer’s disease vs primary progressive aphasia vs frontotemporal dementia was made. He screened positive for amyloid PET scan, which confirmed the diagnosis of Alzheimer’s disease.

Neuropsychological testing showed similarities with logopenic variant of primary progressive aphasia, which in many cases is present in Alzheimer’s disease. Mr. X was prescribed anticholinesterase inhibitors, including donepezil, 10 mg/d, and rivastigmine patch, 9.5 mg/d; and memantine, 10 mg/d, which he could not tolerate because of adverse effects. During the next year, Mr. X deteriorated and presented to the ED a few times with significant psychotic symptoms and aggression. He had a poor response to various pharmacologic and nonpharmacologic interventions during this time.

EVALUATION Continued problematic behaviors

During his hospitalization, Mr. X continues to be agitated and paranoid and is placed in restraints. He is unable to respond to his name and cannot follow simple verbal commands. Results of his laboratory workup are within normal limits. His mild leukocytosis resolves with no active signs of infection. Psychiatry is consulted for management of his behavioral and psychological symptoms of dementia (BPSD).

Continue to: Mr. X is started on olanzapine...

Mr. X is started on olanzapine and lorazepam as needed for agitation, and his twice daily divalproex sodium ER is increased to 250 every morning and 750 mg at every bedtime. However, Mr. X remains agitated and requires restraints. Olanzapine is switched from an as-needed dose to scheduled doses of 10 mg every morning and 15 mg at every bedtime, to address his psychosis and agitation.

On Day 24 of hospitalization, Mr. X’s ammonia levels are checked and are found to be 69 µ/dL, which is high (normal range: 15 to 45 µ/dL). Divalproex sodium ER is eventually tapered and discontinued. Mr. X is started on carbamazepine, which is titrated to 400 mg twice daily and results in some improvement in his behavior. He continues to receive carbamazepine and is started on dextromethorphan-quinidine, 10 mg/d, and increased to 10 mg twice daily; however, Mr. X continues to be verbally aggressive with staff, throws food, wanders around, and tries to leave the hospital unit, so he is placed in restraints and continues to require a sitter.

[polldaddy:10698428]

The authors' observations

Dementia typically affects older adults, but its onset can occur before age 60. It is a syndrome rather than a specific illness; the most common types are Alzheimer’s disease, vascular dementia, dementia with Lewy bodies, and frontotemporal dementia. Diagnostic clarity and an evidence-based treatment plan are crucial for improving the quality of life for both the patient and their caregivers. The Table outlines the differential diagnosis of cognitive deficits. New-onset cognitive deficits warrant neuro­imaging, and other testing may also be needed.

Behavioral and psychological symptoms of dementia

Noncognitive symptoms occur in 98% of individuals with dementia at some point in their disease and are often the most distressing to both caregivers and patients.¹ Behavioral and psychological symptoms of dementia, including apathy, depression, sleep disorders, hallucinations, delusions, psychosis, agitation, and aggression, are exceedingly prevalent.² Although these symptoms pose a significant burden, there are no clear published treatment guidelines; however, the American Psychiatric Association and the American Geriatric Society recommend using nonpharmacologic approaches as the first-line of treatment for patients with BPSD.^3,4

Nonpharmacologic treatments

Due to the unfavorable adverse effects profiles of medications commonly used to treat dementia, nonpharmacologic treatment approaches have always played a crucial role for managing BPSD. Interventions such as music therapy, aromatherapy, art therapy, behavioral therapy, reality orientation, tailored activities, and physical exercises, have shown promising results for alleviating BPSD.^5-7

Continue to: Pharmacologic therapies should be used...

Pharmacologic treatments

Pharmacologic therapies should be used when nonpharmacologic approaches are unsuccessful, or when a patient is at imminent risk to harm themselves or others.

Antipsychotics. Although there is conflicting data regarding the use of antipsychotics in older adults, these agents are the most common pharmacologic treatment for patients with BPSD. Several studies examining the efficacy of antipsychotics for treating BPSD have demonstrated an increased risk of cerebrovascular events, including stroke and death due to any cause.⁸ While the use of antipsychotics increases the risk of mortality in older adults, the absolute risk is still low.⁹

Antipsychotics used to treat BPSD include:

• Risperidone is well studied in older adults and has shown benefit for treating aggression, agitation, and psychosis.¹⁰
• Quetiapine has a favorable adverse effects profile and may help improve sleep and reduce anxiety.¹⁰
• Olanzapine. Low-dose olanzapine has been modestly effective in decreasing agitation and aggression in patients with Alzheimer’s and vascular dementias.¹¹
• Aripiprazole has shown modest benefit in treating psychosis and agitation in patients with dementia but may be associated with insomnia or activation symptoms at lower doses.¹⁰
• Ziprasidone. Case reports have found benefit with oral and injectable forms.¹²

Antidepressants. In the CitAD study, which was a placebo-controlled randomized trial, citalopram titrated to a target of 30 mg/d was found to be effective in reducing BPSD.¹³ However, QTc prolongation limits the use of citalopram. Sertraline was studied in 1 small, randomized trial against haloperidol but showed no additional benefit.¹⁴ 

Mood stabilizers. In a small, randomized trial, carbamazepine was helpful for patients with BPSD who were resistant to treatment with antipsychotics, with efficacy demonstrated over 6 weeks.¹⁵ No other mood stabilizers have had significant positive results in treating BPSD.¹⁶ 

Anxiolytic medications. Some research suggests that the occasional use of lorazepam, as necessary, is acceptable for patients with extreme agitation or aggression when behavioral interventions or sleep aids are ineffective.¹⁷ Various case reports and case series have suggested gabapentin may be effective for BPSD.¹⁸ 

Prazosin. In a small randomized placebo-controlled trial, the commonly used antihypertensive agent prazosin reduced agitation and aggression in patients with Alzheimer’s dementia, at doses from 1 to 6 mg/d.¹⁹ Postural hypotension, the main adverse effect associated with prazosin, can limit its use.

Trazodone. Some research suggests trazodone can reduce irritability and aggression in patients with Alzheimer’s disease.²⁰

Dextromethorphan/quinidine. In a 10-week phase 2 randomized clinical trial of patients with probable Alzheimer’s disease dementia, combination dextromethorphan/quinidine reduced agitation and was generally well tolerated.²¹

For patients such as Mr. X who do not respond to multiple pharmacologic treatments, electroconvulsive therapy (ECT) may be an option.

Continue to: Because Mr. X does not respond...

TREATMENT A trial of ECT

Because Mr. X does not respond to the standard treatment protocols, the treatment team and Mr. X’s family discuss the use of ECT to control his agitation. Consent is obtained from his legal guardian and Mr. X is medically cleared to receive ECT. Mr. X receives 3 ECT treatments per week. During the first week, Mr. X experiences post-treatment agitation and confusion. The frequency of ECT treatments is reduced to 2 treatments per week, and then 1 session per week. Mr. X starts to show improvement in his agitation and ECT is continued at 1 session per week for 7 weeks.

The authors’ observations

Electroconvulsive therapy has been an effective treatment for patients with treatment-resistant depression and has shown benefit in treating other psychiatric conditions such as acute mania, catatonia, psychotic disorders, and Parkinson’s disease.²² Its use as an off-label treatment for chronic neuropathic pain has also been well documented.²³ Although ECT is not indicated for treating agitation and aggression in patients with dementia, its effectiveness for these symptoms has been discussed extensively in the literature.^22,24-26

Electroconvulsive therapy treatment can be divided into 2 phases: an acute phase during which ECT is administered 2 to 3 times a week for 4 to 5 weeks, and a maintenance phase of weekly treatments for 4 weeks and then biweekly treatments for 8 weeks.²⁶ Although extensive research supports the safe use of ECT in older adults, concerns for worsening cognitive impairment can deter patients and families from agreeing to this treatment.

Adverse effects of ECT such as headaches and postictal confusion are generally mild and transient. Severe adverse effects such as seizures, severe confusion, and delirium are uncommon.²⁵ The number of ECT treatments required for a good effect ranges from 2 to 18, and the most common position for electrodes placement is bilateral. Outcomes can be measured by using rating scales such as the Cohen-Mansfield Agitation Inventory, Neuropsychiatric Inventory, Social Dysfunction and Aggression Scale, Clinical Global Impression scale, and Pittsford Agitation Scale.²⁵ Obtaining consent from patients with dementia is generally not possible because these patients generally lack the capacity to make medical decisions. Clinicians should refer to their state laws regarding medical-decision making in such cases. The patient’s next of kin or medical power of attorney should be contacted, and the risks and benefits should be discussed before starting ECT.

OUTCOME Lasting improvement

Due to Mr. X’s improvement after ECT, on hospital Day 124, the restraints are removed and he no longer requires a sitter. He starts responding to his name and following simple verbal commands. Electroconvulsive therapy is tapered to every other week, and eventually stopped as his status improves. Mr. X continues to do well and is maintained on the same dosages of olanzapine, carbamazepine, and dextromethorphan-quinidine he had been receiving prior to discharge.

Related Resources

• Van den Berg JF, Kruithof HC, Kok RM, et al. Electroconvulsive therapy for agitation and aggression in dementia: a systematic review. Am J Geriatr Psychiatry. 2018;26(4):419-434.
• Kales HC, Mulsant BH, Sajatovic M. Prescribing antipsychotics in geriatric patients: Focus on dementia. Current Psychiatry. 2017;16(12):24-30.

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Dextromethorphan- quinidine • Nuedexta
Divalproex sodium ER • Depakote
Donepezil • Aricept
Gabapentin • Neurontin
Haloperidol • Haldol
Lorazepam • Ativan
Memantine • Namenda
Olanzapine • Zyprexa
Prazosin • Minipress
Quetiapine • Seroquel
Risperidone • Risperdal
Rivastigmine • Exelon
Sertraline • Zoloft
Trazodone • Desyrel, Oleptro
Ziprasidone • Geodon

CASE Agitated and aggressive

Mr. X, age 61, who has Alzheimer’s disease, is brought to the emergency department (ED) by his family after he is found to be confused, becomes physically aggressive with family members, and threatens to burn the house down. His family reports that earlier that day, he was paranoid that somebody was trying to kill him and he tried to leave the house. Mr. X has been experiencing visual hallucinations and delusional thoughts that made him aggressive towards his son. After an initial laboratory workup in the ED, Mr. X’s bloodwork comes back positive for mild leukocytosis, indicating the possibility of an infectious etiology. Mr. X is admitted to the hospital for further evaluation of his altered mental status.

HISTORY Decline over 2 years

This is Mr. X’s third inpatient admission for agitation and psychosis. His current medications—twice daily divalproex sodium extended release (ER), 250 mg every morning and 500 mg at every bedtime, and prazosin, 2 mg/d at bedtime—have been only partially effective. His medical history includes osteoarthritis, back pain, and heterozygous factor V Leiden (not on anticoagulation). He quit smoking tobacco several years ago and has no history of substance use. He has no family history of dementia. Previous trials of cholinesterase inhibitors, antipsychotics, and antidepressants resulted in only minimal improvement in his agitation and psychosis.

A chart review shows that 2 years before his current hospital admission, Mr. X had presented to his primary care physician with slurred speech, forgetfulness, missing words, and transient reading difficulties. His initial laboratory workup and MRI came back normal. He was placed on short-term disability due to work-related errors. He was referred to the hospital’s Memory Clinic 2 years ago, where his Mini-Mental State Exam score was 20/30, indicating mild cognitive impairment. Stroke workup was negative. Due to significant language deficits, a differential diagnosis for Alzheimer’s disease vs primary progressive aphasia vs frontotemporal dementia was made. He screened positive for amyloid PET scan, which confirmed the diagnosis of Alzheimer’s disease.

Neuropsychological testing showed similarities with logopenic variant of primary progressive aphasia, which in many cases is present in Alzheimer’s disease. Mr. X was prescribed anticholinesterase inhibitors, including donepezil, 10 mg/d, and rivastigmine patch, 9.5 mg/d; and memantine, 10 mg/d, which he could not tolerate because of adverse effects. During the next year, Mr. X deteriorated and presented to the ED a few times with significant psychotic symptoms and aggression. He had a poor response to various pharmacologic and nonpharmacologic interventions during this time.

EVALUATION Continued problematic behaviors

During his hospitalization, Mr. X continues to be agitated and paranoid and is placed in restraints. He is unable to respond to his name and cannot follow simple verbal commands. Results of his laboratory workup are within normal limits. His mild leukocytosis resolves with no active signs of infection. Psychiatry is consulted for management of his behavioral and psychological symptoms of dementia (BPSD).

Continue to: Mr. X is started on olanzapine...

Mr. X is started on olanzapine and lorazepam as needed for agitation, and his twice daily divalproex sodium ER is increased to 250 every morning and 750 mg at every bedtime. However, Mr. X remains agitated and requires restraints. Olanzapine is switched from an as-needed dose to scheduled doses of 10 mg every morning and 15 mg at every bedtime, to address his psychosis and agitation.

On Day 24 of hospitalization, Mr. X’s ammonia levels are checked and are found to be 69 µ/dL, which is high (normal range: 15 to 45 µ/dL). Divalproex sodium ER is eventually tapered and discontinued. Mr. X is started on carbamazepine, which is titrated to 400 mg twice daily and results in some improvement in his behavior. He continues to receive carbamazepine and is started on dextromethorphan-quinidine, 10 mg/d, and increased to 10 mg twice daily; however, Mr. X continues to be verbally aggressive with staff, throws food, wanders around, and tries to leave the hospital unit, so he is placed in restraints and continues to require a sitter.

[polldaddy:10698428]

The authors' observations

Dementia typically affects older adults, but its onset can occur before age 60. It is a syndrome rather than a specific illness; the most common types are Alzheimer’s disease, vascular dementia, dementia with Lewy bodies, and frontotemporal dementia. Diagnostic clarity and an evidence-based treatment plan are crucial for improving the quality of life for both the patient and their caregivers. The Table outlines the differential diagnosis of cognitive deficits. New-onset cognitive deficits warrant neuro­imaging, and other testing may also be needed.

Behavioral and psychological symptoms of dementia

Noncognitive symptoms occur in 98% of individuals with dementia at some point in their disease and are often the most distressing to both caregivers and patients.¹ Behavioral and psychological symptoms of dementia, including apathy, depression, sleep disorders, hallucinations, delusions, psychosis, agitation, and aggression, are exceedingly prevalent.² Although these symptoms pose a significant burden, there are no clear published treatment guidelines; however, the American Psychiatric Association and the American Geriatric Society recommend using nonpharmacologic approaches as the first-line of treatment for patients with BPSD.^3,4

Nonpharmacologic treatments

Due to the unfavorable adverse effects profiles of medications commonly used to treat dementia, nonpharmacologic treatment approaches have always played a crucial role for managing BPSD. Interventions such as music therapy, aromatherapy, art therapy, behavioral therapy, reality orientation, tailored activities, and physical exercises, have shown promising results for alleviating BPSD.^5-7

Continue to: Pharmacologic therapies should be used...

Pharmacologic treatments

Pharmacologic therapies should be used when nonpharmacologic approaches are unsuccessful, or when a patient is at imminent risk to harm themselves or others.

Antipsychotics. Although there is conflicting data regarding the use of antipsychotics in older adults, these agents are the most common pharmacologic treatment for patients with BPSD. Several studies examining the efficacy of antipsychotics for treating BPSD have demonstrated an increased risk of cerebrovascular events, including stroke and death due to any cause.⁸ While the use of antipsychotics increases the risk of mortality in older adults, the absolute risk is still low.⁹

Antipsychotics used to treat BPSD include:

• Risperidone is well studied in older adults and has shown benefit for treating aggression, agitation, and psychosis.¹⁰
• Quetiapine has a favorable adverse effects profile and may help improve sleep and reduce anxiety.¹⁰
• Olanzapine. Low-dose olanzapine has been modestly effective in decreasing agitation and aggression in patients with Alzheimer’s and vascular dementias.¹¹
• Aripiprazole has shown modest benefit in treating psychosis and agitation in patients with dementia but may be associated with insomnia or activation symptoms at lower doses.¹⁰
• Ziprasidone. Case reports have found benefit with oral and injectable forms.¹²

Antidepressants. In the CitAD study, which was a placebo-controlled randomized trial, citalopram titrated to a target of 30 mg/d was found to be effective in reducing BPSD.¹³ However, QTc prolongation limits the use of citalopram. Sertraline was studied in 1 small, randomized trial against haloperidol but showed no additional benefit.¹⁴ 

Mood stabilizers. In a small, randomized trial, carbamazepine was helpful for patients with BPSD who were resistant to treatment with antipsychotics, with efficacy demonstrated over 6 weeks.¹⁵ No other mood stabilizers have had significant positive results in treating BPSD.¹⁶ 

Anxiolytic medications. Some research suggests that the occasional use of lorazepam, as necessary, is acceptable for patients with extreme agitation or aggression when behavioral interventions or sleep aids are ineffective.¹⁷ Various case reports and case series have suggested gabapentin may be effective for BPSD.¹⁸ 

Prazosin. In a small randomized placebo-controlled trial, the commonly used antihypertensive agent prazosin reduced agitation and aggression in patients with Alzheimer’s dementia, at doses from 1 to 6 mg/d.¹⁹ Postural hypotension, the main adverse effect associated with prazosin, can limit its use.

Trazodone. Some research suggests trazodone can reduce irritability and aggression in patients with Alzheimer’s disease.²⁰

Dextromethorphan/quinidine. In a 10-week phase 2 randomized clinical trial of patients with probable Alzheimer’s disease dementia, combination dextromethorphan/quinidine reduced agitation and was generally well tolerated.²¹

For patients such as Mr. X who do not respond to multiple pharmacologic treatments, electroconvulsive therapy (ECT) may be an option.

Continue to: Because Mr. X does not respond...

TREATMENT A trial of ECT

Because Mr. X does not respond to the standard treatment protocols, the treatment team and Mr. X’s family discuss the use of ECT to control his agitation. Consent is obtained from his legal guardian and Mr. X is medically cleared to receive ECT. Mr. X receives 3 ECT treatments per week. During the first week, Mr. X experiences post-treatment agitation and confusion. The frequency of ECT treatments is reduced to 2 treatments per week, and then 1 session per week. Mr. X starts to show improvement in his agitation and ECT is continued at 1 session per week for 7 weeks.

The authors’ observations

Electroconvulsive therapy has been an effective treatment for patients with treatment-resistant depression and has shown benefit in treating other psychiatric conditions such as acute mania, catatonia, psychotic disorders, and Parkinson’s disease.²² Its use as an off-label treatment for chronic neuropathic pain has also been well documented.²³ Although ECT is not indicated for treating agitation and aggression in patients with dementia, its effectiveness for these symptoms has been discussed extensively in the literature.^22,24-26

Electroconvulsive therapy treatment can be divided into 2 phases: an acute phase during which ECT is administered 2 to 3 times a week for 4 to 5 weeks, and a maintenance phase of weekly treatments for 4 weeks and then biweekly treatments for 8 weeks.²⁶ Although extensive research supports the safe use of ECT in older adults, concerns for worsening cognitive impairment can deter patients and families from agreeing to this treatment.

Adverse effects of ECT such as headaches and postictal confusion are generally mild and transient. Severe adverse effects such as seizures, severe confusion, and delirium are uncommon.²⁵ The number of ECT treatments required for a good effect ranges from 2 to 18, and the most common position for electrodes placement is bilateral. Outcomes can be measured by using rating scales such as the Cohen-Mansfield Agitation Inventory, Neuropsychiatric Inventory, Social Dysfunction and Aggression Scale, Clinical Global Impression scale, and Pittsford Agitation Scale.²⁵ Obtaining consent from patients with dementia is generally not possible because these patients generally lack the capacity to make medical decisions. Clinicians should refer to their state laws regarding medical-decision making in such cases. The patient’s next of kin or medical power of attorney should be contacted, and the risks and benefits should be discussed before starting ECT.

OUTCOME Lasting improvement

Due to Mr. X’s improvement after ECT, on hospital Day 124, the restraints are removed and he no longer requires a sitter. He starts responding to his name and following simple verbal commands. Electroconvulsive therapy is tapered to every other week, and eventually stopped as his status improves. Mr. X continues to do well and is maintained on the same dosages of olanzapine, carbamazepine, and dextromethorphan-quinidine he had been receiving prior to discharge.

Related Resources

• Van den Berg JF, Kruithof HC, Kok RM, et al. Electroconvulsive therapy for agitation and aggression in dementia: a systematic review. Am J Geriatr Psychiatry. 2018;26(4):419-434.
• Kales HC, Mulsant BH, Sajatovic M. Prescribing antipsychotics in geriatric patients: Focus on dementia. Current Psychiatry. 2017;16(12):24-30.

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Dextromethorphan- quinidine • Nuedexta
Divalproex sodium ER • Depakote
Donepezil • Aricept
Gabapentin • Neurontin
Haloperidol • Haldol
Lorazepam • Ativan
Memantine • Namenda
Olanzapine • Zyprexa
Prazosin • Minipress
Quetiapine • Seroquel
Risperidone • Risperdal
Rivastigmine • Exelon
Sertraline • Zoloft
Trazodone • Desyrel, Oleptro
Ziprasidone • Geodon

Dexamethasone can have a detrimental effect on survival in patients with glioblastoma who are receiving immunotherapy, according to a study published in Clinical Cancer Research.

Investigators found that baseline dexamethasone use was associated with poor overall survival (OS) in glioblastoma patients receiving anti–PD-1 or anti–PD-L1 therapy. In fact, in a multivariable analysis, baseline dexamethasone use was the strongest predictor of poor survival.

These results “support accumulating concerns that corticosteroids can be detrimental to immunotherapy for oncology patients,” wrote senior study author David Reardon, MD, of Dana-Farber Cancer Institute in Boston and colleagues.

The concerns are particularly relevant for glioblastoma patients because dexamethasone is a cornerstone of glioblastoma therapy, being used to reduce tumor-associated edema. Patients often receive dexamethasone early on and in significant doses for a protracted period of time to stay ahead of evolving symptoms.

However, the current study suggests dexamethasone and other corticosteroids may be contraindicated in glioblastoma patients on immunotherapy. Therefore, Dr. Reardon and colleagues recommended “careful evaluation of dexamethasone use” in these patients.

“If a glioblastoma patient requires corticosteroids, and they often do for debilitating symptoms, only use these drugs if the patient really needs them,” Dr. Reardon advised. “Start at a low dose and use the shortest treatment interval possible.”
 

Preclinical and clinical results

Dr. Reardon and colleagues initially evaluated the effects of dexamethasone when administered with PD-1 blockade and/or radiotherapy in an immunocompetent syngeneic mouse model.

Most mice that received anti–PD-1 monotherapy were cured, but the benefit of anti–PD-1 therapy was significantly diminished, in a dose-dependent manner, when dexamethasone was added.

At 100 days, the OS rate was about 76% in the anti–PD-1 monotherapy group, 47% when dexamethasone was given at 1 mg/kg, 31% with dexamethasone at 2.5 mg/kg, and 27% with dexamethasone at 10 mg/kg.

A mechanistic study, including analysis of immune cells in the spleen, showed that dexamethasone decreased intratumoral T cells and systemic levels of T cells, natural killer cells, and myeloid cells, while qualitatively impairing lymphocyte function. The mechanism of T-cell depletion included induction of apoptosis, which was noted as soon as 1 hour after the dexamethasone dose, Dr. Reardon said.

The researchers also evaluated 181 consecutive glioblastoma patients treated with PD-1– or PD-L1–targeted therapy. The study included a multivariable statistical analysis that accounted for age, performance status, extent of resection, size of tumor, bulk tumor burden, and MGMT promoter methylation status.

In an initial unadjusted analysis, baseline dexamethasone decreased the median OS to 8.1 months when it was given at less than 2 mg daily and 6.3 months when given at 2 mg or more daily. The median OS was 13.1 months for patients who did not receive dexamethasone.

After multivariable adjustment, baseline dexamethasone eliminated the survival benefit of immunotherapy, the researchers said. The hazard ratio was 2.16 (P = .003) when dexamethasone was given at less than 2 mg daily and 1.97 (P = .005) with dexamethasone at 2 mg or more daily, compared with no baseline dexamethasone.

In fact, the strongest negative risk factor for OS was the use of dexamethasone at initiation of checkpoint inhibitor therapy.
 

Implications: Use corticosteroids ‘very judiciously’

The results of this research suggest “corticosteroids can be detrimental when used along with checkpoint inhibitors,” Dr. Reardon said. He added that this effect could extend to other immunotherapies, such as vaccines, cellular therapies, and oncolytic viruses.

“We need to understand what is driving the inflammatory response,” Dr. Reardon said. “Other targets in the downstream pathway may be regulated to avoid the detrimental effect of corticosteroids.”

Ongoing prospective clinical trials need to build in whether concurrent use of corticosteroids leads to poorer outcomes, according to Dr. Reardon.

“We are validating this prospectively in ongoing clinical trials to evaluate differences in outcome in glioblastoma patients and exploring different types of immunotherapies,” he said.

Though questions remain, Dr. Reardon advises judicious use of corticosteroids or even substituting corticosteroids with bevacizumab in glioblastoma patients.

“If a glioblastoma patient develops debilitating symptoms due to swelling in the brain and is a candidate for immunotherapy, then consider using bevacizumab to avoid using corticosteroids,” Dr. Reardon said, adding that this is being tested prospectively in a clinical trial as well.

“We know corticosteroids have a host of side effects. An additional side effect may be limiting immune function in brain cancer patients and jeopardizing the potential benefits of immunotherapy going forward. I implore practicing oncologists to use corticosteroids very judiciously and as little as possible for as little time as possible,” Dr. Reardon said.

This research was funded by grants from the National Institutes of Health and support from various foundations and institutions. The researchers disclosed relationships with many pharmaceutical companies.

SOURCE: Iorgulescu JB et al. Clin Cancer Res. 2020 Nov 25. doi: 10.1158/1078-0432.CCR-20-2291.

Dexamethasone can have a detrimental effect on survival in patients with glioblastoma who are receiving immunotherapy, according to a study published in Clinical Cancer Research.

Investigators found that baseline dexamethasone use was associated with poor overall survival (OS) in glioblastoma patients receiving anti–PD-1 or anti–PD-L1 therapy. In fact, in a multivariable analysis, baseline dexamethasone use was the strongest predictor of poor survival.

These results “support accumulating concerns that corticosteroids can be detrimental to immunotherapy for oncology patients,” wrote senior study author David Reardon, MD, of Dana-Farber Cancer Institute in Boston and colleagues.

The concerns are particularly relevant for glioblastoma patients because dexamethasone is a cornerstone of glioblastoma therapy, being used to reduce tumor-associated edema. Patients often receive dexamethasone early on and in significant doses for a protracted period of time to stay ahead of evolving symptoms.

However, the current study suggests dexamethasone and other corticosteroids may be contraindicated in glioblastoma patients on immunotherapy. Therefore, Dr. Reardon and colleagues recommended “careful evaluation of dexamethasone use” in these patients.

“If a glioblastoma patient requires corticosteroids, and they often do for debilitating symptoms, only use these drugs if the patient really needs them,” Dr. Reardon advised. “Start at a low dose and use the shortest treatment interval possible.”
 

Preclinical and clinical results

Dr. Reardon and colleagues initially evaluated the effects of dexamethasone when administered with PD-1 blockade and/or radiotherapy in an immunocompetent syngeneic mouse model.

Most mice that received anti–PD-1 monotherapy were cured, but the benefit of anti–PD-1 therapy was significantly diminished, in a dose-dependent manner, when dexamethasone was added.

At 100 days, the OS rate was about 76% in the anti–PD-1 monotherapy group, 47% when dexamethasone was given at 1 mg/kg, 31% with dexamethasone at 2.5 mg/kg, and 27% with dexamethasone at 10 mg/kg.

A mechanistic study, including analysis of immune cells in the spleen, showed that dexamethasone decreased intratumoral T cells and systemic levels of T cells, natural killer cells, and myeloid cells, while qualitatively impairing lymphocyte function. The mechanism of T-cell depletion included induction of apoptosis, which was noted as soon as 1 hour after the dexamethasone dose, Dr. Reardon said.

The researchers also evaluated 181 consecutive glioblastoma patients treated with PD-1– or PD-L1–targeted therapy. The study included a multivariable statistical analysis that accounted for age, performance status, extent of resection, size of tumor, bulk tumor burden, and MGMT promoter methylation status.

In an initial unadjusted analysis, baseline dexamethasone decreased the median OS to 8.1 months when it was given at less than 2 mg daily and 6.3 months when given at 2 mg or more daily. The median OS was 13.1 months for patients who did not receive dexamethasone.

After multivariable adjustment, baseline dexamethasone eliminated the survival benefit of immunotherapy, the researchers said. The hazard ratio was 2.16 (P = .003) when dexamethasone was given at less than 2 mg daily and 1.97 (P = .005) with dexamethasone at 2 mg or more daily, compared with no baseline dexamethasone.

In fact, the strongest negative risk factor for OS was the use of dexamethasone at initiation of checkpoint inhibitor therapy.
 

Implications: Use corticosteroids ‘very judiciously’

The results of this research suggest “corticosteroids can be detrimental when used along with checkpoint inhibitors,” Dr. Reardon said. He added that this effect could extend to other immunotherapies, such as vaccines, cellular therapies, and oncolytic viruses.

“We need to understand what is driving the inflammatory response,” Dr. Reardon said. “Other targets in the downstream pathway may be regulated to avoid the detrimental effect of corticosteroids.”

Ongoing prospective clinical trials need to build in whether concurrent use of corticosteroids leads to poorer outcomes, according to Dr. Reardon.

“We are validating this prospectively in ongoing clinical trials to evaluate differences in outcome in glioblastoma patients and exploring different types of immunotherapies,” he said.

Though questions remain, Dr. Reardon advises judicious use of corticosteroids or even substituting corticosteroids with bevacizumab in glioblastoma patients.

“If a glioblastoma patient develops debilitating symptoms due to swelling in the brain and is a candidate for immunotherapy, then consider using bevacizumab to avoid using corticosteroids,” Dr. Reardon said, adding that this is being tested prospectively in a clinical trial as well.

“We know corticosteroids have a host of side effects. An additional side effect may be limiting immune function in brain cancer patients and jeopardizing the potential benefits of immunotherapy going forward. I implore practicing oncologists to use corticosteroids very judiciously and as little as possible for as little time as possible,” Dr. Reardon said.

This research was funded by grants from the National Institutes of Health and support from various foundations and institutions. The researchers disclosed relationships with many pharmaceutical companies.

SOURCE: Iorgulescu JB et al. Clin Cancer Res. 2020 Nov 25. doi: 10.1158/1078-0432.CCR-20-2291.

Dexamethasone can have a detrimental effect on survival in patients with glioblastoma who are receiving immunotherapy, according to a study published in Clinical Cancer Research.

Investigators found that baseline dexamethasone use was associated with poor overall survival (OS) in glioblastoma patients receiving anti–PD-1 or anti–PD-L1 therapy. In fact, in a multivariable analysis, baseline dexamethasone use was the strongest predictor of poor survival.

These results “support accumulating concerns that corticosteroids can be detrimental to immunotherapy for oncology patients,” wrote senior study author David Reardon, MD, of Dana-Farber Cancer Institute in Boston and colleagues.

The concerns are particularly relevant for glioblastoma patients because dexamethasone is a cornerstone of glioblastoma therapy, being used to reduce tumor-associated edema. Patients often receive dexamethasone early on and in significant doses for a protracted period of time to stay ahead of evolving symptoms.

However, the current study suggests dexamethasone and other corticosteroids may be contraindicated in glioblastoma patients on immunotherapy. Therefore, Dr. Reardon and colleagues recommended “careful evaluation of dexamethasone use” in these patients.

“If a glioblastoma patient requires corticosteroids, and they often do for debilitating symptoms, only use these drugs if the patient really needs them,” Dr. Reardon advised. “Start at a low dose and use the shortest treatment interval possible.”
 

Preclinical and clinical results

Dr. Reardon and colleagues initially evaluated the effects of dexamethasone when administered with PD-1 blockade and/or radiotherapy in an immunocompetent syngeneic mouse model.

Most mice that received anti–PD-1 monotherapy were cured, but the benefit of anti–PD-1 therapy was significantly diminished, in a dose-dependent manner, when dexamethasone was added.

At 100 days, the OS rate was about 76% in the anti–PD-1 monotherapy group, 47% when dexamethasone was given at 1 mg/kg, 31% with dexamethasone at 2.5 mg/kg, and 27% with dexamethasone at 10 mg/kg.

A mechanistic study, including analysis of immune cells in the spleen, showed that dexamethasone decreased intratumoral T cells and systemic levels of T cells, natural killer cells, and myeloid cells, while qualitatively impairing lymphocyte function. The mechanism of T-cell depletion included induction of apoptosis, which was noted as soon as 1 hour after the dexamethasone dose, Dr. Reardon said.

The researchers also evaluated 181 consecutive glioblastoma patients treated with PD-1– or PD-L1–targeted therapy. The study included a multivariable statistical analysis that accounted for age, performance status, extent of resection, size of tumor, bulk tumor burden, and MGMT promoter methylation status.

In an initial unadjusted analysis, baseline dexamethasone decreased the median OS to 8.1 months when it was given at less than 2 mg daily and 6.3 months when given at 2 mg or more daily. The median OS was 13.1 months for patients who did not receive dexamethasone.

After multivariable adjustment, baseline dexamethasone eliminated the survival benefit of immunotherapy, the researchers said. The hazard ratio was 2.16 (P = .003) when dexamethasone was given at less than 2 mg daily and 1.97 (P = .005) with dexamethasone at 2 mg or more daily, compared with no baseline dexamethasone.

In fact, the strongest negative risk factor for OS was the use of dexamethasone at initiation of checkpoint inhibitor therapy.
 

Implications: Use corticosteroids ‘very judiciously’

The results of this research suggest “corticosteroids can be detrimental when used along with checkpoint inhibitors,” Dr. Reardon said. He added that this effect could extend to other immunotherapies, such as vaccines, cellular therapies, and oncolytic viruses.

“We need to understand what is driving the inflammatory response,” Dr. Reardon said. “Other targets in the downstream pathway may be regulated to avoid the detrimental effect of corticosteroids.”

Ongoing prospective clinical trials need to build in whether concurrent use of corticosteroids leads to poorer outcomes, according to Dr. Reardon.

“We are validating this prospectively in ongoing clinical trials to evaluate differences in outcome in glioblastoma patients and exploring different types of immunotherapies,” he said.

Though questions remain, Dr. Reardon advises judicious use of corticosteroids or even substituting corticosteroids with bevacizumab in glioblastoma patients.

“If a glioblastoma patient develops debilitating symptoms due to swelling in the brain and is a candidate for immunotherapy, then consider using bevacizumab to avoid using corticosteroids,” Dr. Reardon said, adding that this is being tested prospectively in a clinical trial as well.

“We know corticosteroids have a host of side effects. An additional side effect may be limiting immune function in brain cancer patients and jeopardizing the potential benefits of immunotherapy going forward. I implore practicing oncologists to use corticosteroids very judiciously and as little as possible for as little time as possible,” Dr. Reardon said.

This research was funded by grants from the National Institutes of Health and support from various foundations and institutions. The researchers disclosed relationships with many pharmaceutical companies.

SOURCE: Iorgulescu JB et al. Clin Cancer Res. 2020 Nov 25. doi: 10.1158/1078-0432.CCR-20-2291.

The intensity of posttreatment surveillance of patients with rectal cancer managed by a watch-and-wait approach can be safely reduced if patients achieve and maintain a clinical complete response within the first 3 years of initiation of that approach, a retrospective, multicenter registry study suggests.

“The risk of local regrowth or distant metastases after a clinical complete response to neoadjuvant chemoradiotherapy after nonoperative management of rectal cancer remains an important drawback for the widespread uptake of watch and wait in clinical practice,” Laura Fernandez, MD, Champalimaud Clinical Center, Lisbon, and colleagues observe.

“Conditional survival analysis estimates suggest that patients who sustain a clinical complete response for 3 years have 5% or lower risk of developing a local regrowth and a less than 2% risk of developing systemic recurrence thereafter,” the investigators emphasize.

Achieving a complete clinical recovery and sustaining it for 1 year is the “most relevant protective factor” for patients with rectal cancer and places them in an “excellent prognostic stage,” Fernandez said in a press statement.

The study was published online Dec. 11 in The Lancet Oncology.
 

A watch-and-wait database

A total of 793 patients were identified from the International Watch and Wait Database, a large registry of patients who experience a clinical complete response after neoadjuvant chemotherapy and who are managed by a watch-and-wait strategy. The registry includes data from 47 clinics in 15 countries.

The main outcome measures were the probability of patients remaining free of local regrowth and distant metastasis for an additional 2 years after sustaining a clinical complete response for 1, 3, and 5 years after the start of watch-and-wait management.

Among patients who had sustained clinical complete response for 1 year, the probability of remaining local regrowth–free for an additional 2 years – in other words, for a total of 3 years – was 88.1%.

Local regrowth–free survival rates were in the high 90 percentages after sustaining a clinical response for 3 years and for 5 years.

“Similar results were observed for distant metastasis–free survival,” Dr. Fernandez and colleagues continue. For example, 2-year conditional distant metastasis–free survival rates among patients who remained free of distant metastasis from the time the decision was made to initiate watch-and-wait management for 1 year was 93.8%; for 3 years, it was 97.8%; and for 5 years, it was 96.6%, the investigators report.

The only risk factors identified in the study for local regrowth over time was baseline clinical tumor stage and total dose of radiotherapy received.

However, after patients have achieved and sustained a complete clinical response for 1 year, known risk factors for local regrowth, such as disease stage before any treatment and the dose of radiation received by the patient, “seem to become irrelevant,” said Dr. Fernandez.

The authors say that after a patient sustains a clinical complete response for more than 3 years, it is unlikely that intensive surveillance for the detection of local regrowth would be required.

Indeed, they suggest that those who have no sign of regrowth or distant metastases at 3 years post treatment could probably be followed in established follow-up programs for rectal cancer patients who are treated with standard therapy, including radical resection.
 

Study limitations

Asked for comment, Joshua Smith, MD, PhD, a colorectal surgeon with the Memorial Sloan Kettering Cancer Center, New York, cautioned that there are real limitations to retrospective data as used for the current analysis, including the heterogeneity of the definitions of a clinical complete response. The investigators also tried to assess response to treatment both before and after 2010. Before 2010, intrarectal ultrasound was used to stage rectal cancer; currently, MRI is used.

There was also heterogeneity of the radiation used across the study interval. All of these factors must be taken into consideration when interpreting the investigators’ conclusions, Smith cautioned. Nevertheless, he also noted that the group is very sophisticated and that the article was well written and, in his view, not terribly overstated. “I just would be cautious with what they are saying that after 3 years, you do not need to be as strict with your surveillance,” Dr. Smith told this news organization.

“I think we still have some patients with local regrowth after that period of time, so I wouldn’t say we’re out of the woods after 3 years – I think we still have to follow these patients very closely,” he emphasized.

“The data clearly show that the longer a patient doesn’t have a local regrowth, the lower their chances are that they will develop local regrowth,” Dr. Smith said.

The study also provides clinicians with data to discuss with potential watch-and-wait candidates, he added. “The decision we make should really depend on the patient – what their goals are and what their quality-of-life perspective is,” Dr. Smith said. More definitive data on patient outcomes are expected soon from the Organ Preservation in Rectal Adenocarcinoma (OPRA) Trial.

That trial prospectively evaluates the watch-and-wait approach. Results should reflect not only what surgeons can anticipate with respect to local regrowth and distant metastases, but it should also determine the real organ preservation rate – an important endpoint of the watch-and-wait approach.

“I think it will be a paradigm-changing trial,” Dr. Smith predicted.

The study was funded by the European Registration of Cancer Care, among others organizations. Dr. Fernandez has disclosed no relevant financial relationships. Dr. Smith has served as a clinical advisor to Guardant Health.

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

The intensity of posttreatment surveillance of patients with rectal cancer managed by a watch-and-wait approach can be safely reduced if patients achieve and maintain a clinical complete response within the first 3 years of initiation of that approach, a retrospective, multicenter registry study suggests.

“The risk of local regrowth or distant metastases after a clinical complete response to neoadjuvant chemoradiotherapy after nonoperative management of rectal cancer remains an important drawback for the widespread uptake of watch and wait in clinical practice,” Laura Fernandez, MD, Champalimaud Clinical Center, Lisbon, and colleagues observe.

“Conditional survival analysis estimates suggest that patients who sustain a clinical complete response for 3 years have 5% or lower risk of developing a local regrowth and a less than 2% risk of developing systemic recurrence thereafter,” the investigators emphasize.

Achieving a complete clinical recovery and sustaining it for 1 year is the “most relevant protective factor” for patients with rectal cancer and places them in an “excellent prognostic stage,” Fernandez said in a press statement.

The study was published online Dec. 11 in The Lancet Oncology.
 

A watch-and-wait database

A total of 793 patients were identified from the International Watch and Wait Database, a large registry of patients who experience a clinical complete response after neoadjuvant chemotherapy and who are managed by a watch-and-wait strategy. The registry includes data from 47 clinics in 15 countries.

The main outcome measures were the probability of patients remaining free of local regrowth and distant metastasis for an additional 2 years after sustaining a clinical complete response for 1, 3, and 5 years after the start of watch-and-wait management.

Among patients who had sustained clinical complete response for 1 year, the probability of remaining local regrowth–free for an additional 2 years – in other words, for a total of 3 years – was 88.1%.

Local regrowth–free survival rates were in the high 90 percentages after sustaining a clinical response for 3 years and for 5 years.

“Similar results were observed for distant metastasis–free survival,” Dr. Fernandez and colleagues continue. For example, 2-year conditional distant metastasis–free survival rates among patients who remained free of distant metastasis from the time the decision was made to initiate watch-and-wait management for 1 year was 93.8%; for 3 years, it was 97.8%; and for 5 years, it was 96.6%, the investigators report.

The only risk factors identified in the study for local regrowth over time was baseline clinical tumor stage and total dose of radiotherapy received.

However, after patients have achieved and sustained a complete clinical response for 1 year, known risk factors for local regrowth, such as disease stage before any treatment and the dose of radiation received by the patient, “seem to become irrelevant,” said Dr. Fernandez.

The authors say that after a patient sustains a clinical complete response for more than 3 years, it is unlikely that intensive surveillance for the detection of local regrowth would be required.

Indeed, they suggest that those who have no sign of regrowth or distant metastases at 3 years post treatment could probably be followed in established follow-up programs for rectal cancer patients who are treated with standard therapy, including radical resection.
 

Study limitations

Asked for comment, Joshua Smith, MD, PhD, a colorectal surgeon with the Memorial Sloan Kettering Cancer Center, New York, cautioned that there are real limitations to retrospective data as used for the current analysis, including the heterogeneity of the definitions of a clinical complete response. The investigators also tried to assess response to treatment both before and after 2010. Before 2010, intrarectal ultrasound was used to stage rectal cancer; currently, MRI is used.

There was also heterogeneity of the radiation used across the study interval. All of these factors must be taken into consideration when interpreting the investigators’ conclusions, Smith cautioned. Nevertheless, he also noted that the group is very sophisticated and that the article was well written and, in his view, not terribly overstated. “I just would be cautious with what they are saying that after 3 years, you do not need to be as strict with your surveillance,” Dr. Smith told this news organization.

“I think we still have some patients with local regrowth after that period of time, so I wouldn’t say we’re out of the woods after 3 years – I think we still have to follow these patients very closely,” he emphasized.

“The data clearly show that the longer a patient doesn’t have a local regrowth, the lower their chances are that they will develop local regrowth,” Dr. Smith said.

The study also provides clinicians with data to discuss with potential watch-and-wait candidates, he added. “The decision we make should really depend on the patient – what their goals are and what their quality-of-life perspective is,” Dr. Smith said. More definitive data on patient outcomes are expected soon from the Organ Preservation in Rectal Adenocarcinoma (OPRA) Trial.

That trial prospectively evaluates the watch-and-wait approach. Results should reflect not only what surgeons can anticipate with respect to local regrowth and distant metastases, but it should also determine the real organ preservation rate – an important endpoint of the watch-and-wait approach.

“I think it will be a paradigm-changing trial,” Dr. Smith predicted.

The study was funded by the European Registration of Cancer Care, among others organizations. Dr. Fernandez has disclosed no relevant financial relationships. Dr. Smith has served as a clinical advisor to Guardant Health.

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

The intensity of posttreatment surveillance of patients with rectal cancer managed by a watch-and-wait approach can be safely reduced if patients achieve and maintain a clinical complete response within the first 3 years of initiation of that approach, a retrospective, multicenter registry study suggests.

“The risk of local regrowth or distant metastases after a clinical complete response to neoadjuvant chemoradiotherapy after nonoperative management of rectal cancer remains an important drawback for the widespread uptake of watch and wait in clinical practice,” Laura Fernandez, MD, Champalimaud Clinical Center, Lisbon, and colleagues observe.

“Conditional survival analysis estimates suggest that patients who sustain a clinical complete response for 3 years have 5% or lower risk of developing a local regrowth and a less than 2% risk of developing systemic recurrence thereafter,” the investigators emphasize.

Achieving a complete clinical recovery and sustaining it for 1 year is the “most relevant protective factor” for patients with rectal cancer and places them in an “excellent prognostic stage,” Fernandez said in a press statement.

The study was published online Dec. 11 in The Lancet Oncology.
 

A watch-and-wait database

A total of 793 patients were identified from the International Watch and Wait Database, a large registry of patients who experience a clinical complete response after neoadjuvant chemotherapy and who are managed by a watch-and-wait strategy. The registry includes data from 47 clinics in 15 countries.

The main outcome measures were the probability of patients remaining free of local regrowth and distant metastasis for an additional 2 years after sustaining a clinical complete response for 1, 3, and 5 years after the start of watch-and-wait management.

Among patients who had sustained clinical complete response for 1 year, the probability of remaining local regrowth–free for an additional 2 years – in other words, for a total of 3 years – was 88.1%.

Local regrowth–free survival rates were in the high 90 percentages after sustaining a clinical response for 3 years and for 5 years.

“Similar results were observed for distant metastasis–free survival,” Dr. Fernandez and colleagues continue. For example, 2-year conditional distant metastasis–free survival rates among patients who remained free of distant metastasis from the time the decision was made to initiate watch-and-wait management for 1 year was 93.8%; for 3 years, it was 97.8%; and for 5 years, it was 96.6%, the investigators report.

The only risk factors identified in the study for local regrowth over time was baseline clinical tumor stage and total dose of radiotherapy received.

However, after patients have achieved and sustained a complete clinical response for 1 year, known risk factors for local regrowth, such as disease stage before any treatment and the dose of radiation received by the patient, “seem to become irrelevant,” said Dr. Fernandez.

The authors say that after a patient sustains a clinical complete response for more than 3 years, it is unlikely that intensive surveillance for the detection of local regrowth would be required.

Indeed, they suggest that those who have no sign of regrowth or distant metastases at 3 years post treatment could probably be followed in established follow-up programs for rectal cancer patients who are treated with standard therapy, including radical resection.
 

Study limitations

Asked for comment, Joshua Smith, MD, PhD, a colorectal surgeon with the Memorial Sloan Kettering Cancer Center, New York, cautioned that there are real limitations to retrospective data as used for the current analysis, including the heterogeneity of the definitions of a clinical complete response. The investigators also tried to assess response to treatment both before and after 2010. Before 2010, intrarectal ultrasound was used to stage rectal cancer; currently, MRI is used.

There was also heterogeneity of the radiation used across the study interval. All of these factors must be taken into consideration when interpreting the investigators’ conclusions, Smith cautioned. Nevertheless, he also noted that the group is very sophisticated and that the article was well written and, in his view, not terribly overstated. “I just would be cautious with what they are saying that after 3 years, you do not need to be as strict with your surveillance,” Dr. Smith told this news organization.

“I think we still have some patients with local regrowth after that period of time, so I wouldn’t say we’re out of the woods after 3 years – I think we still have to follow these patients very closely,” he emphasized.

“The data clearly show that the longer a patient doesn’t have a local regrowth, the lower their chances are that they will develop local regrowth,” Dr. Smith said.

The study also provides clinicians with data to discuss with potential watch-and-wait candidates, he added. “The decision we make should really depend on the patient – what their goals are and what their quality-of-life perspective is,” Dr. Smith said. More definitive data on patient outcomes are expected soon from the Organ Preservation in Rectal Adenocarcinoma (OPRA) Trial.

That trial prospectively evaluates the watch-and-wait approach. Results should reflect not only what surgeons can anticipate with respect to local regrowth and distant metastases, but it should also determine the real organ preservation rate – an important endpoint of the watch-and-wait approach.

“I think it will be a paradigm-changing trial,” Dr. Smith predicted.

The study was funded by the European Registration of Cancer Care, among others organizations. Dr. Fernandez has disclosed no relevant financial relationships. Dr. Smith has served as a clinical advisor to Guardant Health.

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