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Money, Ethnicity, and Access Linked to Cervical Cancer Disparities
These findings come from analyses of insurance data gathered via the Cervical Cancer Geo-Analyzer tool, a publicly available online instrument designed to provide visual representation of recurrent or metastatic cervical cancer burden across metropolitan statistical areas in the United States over multiple years.
[Reporting the findings of] “this study is the first step to optimize healthcare resources allocations, advocate for policy changes that will minimize access barriers, and tailor education for modern treatment options to help reduce and improve outcomes for cervical cancer in US patients,” said Tara Castellano, MD, an author and presenter of this new research, at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, held in San Diego.
Seeing Cancer Cases
Dr. Castellano and colleagues previously reported that the Geo-Analyzer tool effectively provides quantified evidence of cervical cancer disease burden and graphic representation of geographical variations across the United States for both incident and recurrent/metastatic cervical cancer.
In the current analysis, Dr. Castellano, of Louisiana State University School of Medicine in New Orleans, discussed potential factors related to cervical cancer incidence and geographic variations.
The study builds on previous studies that have shown that Black and Hispanic women have longer time to treatment and worse cervical cancer outcomes than White women.
For example, in a study published in the International Journal of Gynecologic Cancer, Marilyn Huang, MD, and colleagues from the University of Miami Miller School of Medicine, Miami, Florida, and other centers in Miami looked at time to treatment in a diverse population of 274 women starting therapy for cervical cancer.
They found that insurance type (private, public, or none) contributed to delay in treatment initiation regardless of the treatment modality, and that the patient’s language and institution of diagnosis also influenced time to treatment.
In a separate scientific poster presented at SGO 2024, Dr. Castellano and colleagues reported that, among women with newly diagnosed endometrial cancer, the median time to treatment was 7 days longer for both Hispanic and Black women, compared with non-Hispanic White women. In addition, Black women had a 7-day longer time to receiving their first therapy for advanced disease. All of these differences were statistically significant.
Dr. Castellano told this news organization that the time-to-treatment disparities in the endometrial cancer study were determined by diagnostic codes and the timing of insurance claims.
Reasons for the disparities may include more limited access to care and structural and systemic biases in the healthcare systems where the majority of Black and Hispanic patients live, she said.
Insurance Database
In the new study on cervical cancer, Dr. Castellano and her team defined cervical cancer burden as prevalent cervical cancer diagnosis per 100,000 eligible women enrolled in a commercial insurance plan, Medicaid, or Medicare Advantage. Recurrent or metastatic cancer was determined to be the proportion of patients with cervical cancer who initiated systemic therapy.
The goals of the study were to provide a visualization of geographical distribution of cervical cancer in the US, and to quantify associations between early or advanced cancers with screening rates, poverty level, race/ethnicity, and access to brachytherapy.
The administrative claims database queried for the study included information on 75,521 women (median age 53) with a first diagnosis of cervical cancer from 2015 through 2022, and 14,033 women with recurrent or metastatic malignancies (median age 59 years).
Distribution of cases was higher in the South compared with in other US regions (37% vs approximately 20% for other regions).
Looking at the association between screening rates and disease burden from 2017 through 2022, the Geo-Analyzer showed that higher screening rates were significantly associated with decreased burden of new cases only in the South, whereas higher screening rates were associated with lower recurrent/metastatic disease burden in the Midwest and South, but a higher disease burden in the West.
In all regions, there was a significant association between decreased early cancer burden in areas with high percentages of women of Asian heritage, and significantly increased burden in areas with large populations of women of Hispanic origin.
The only significant association of race/ethnicity with recurrent/metastatic burden was a decrease in the Midwest in populations with large Asian populations.
An analysis of the how poverty levels affected screening and disease burden showed that in areas with a high percentage of low-income households there were significant associations with decreased cervical cancer screening and higher burden of newly diagnosed cases.
Poverty levels were significantly associated with recurrent/metastatic cancers only in the South.
The investigators also found that the presence of one or more brachytherapy centers within a ZIP-3 region (that is, a large geographic area designated by the first 3 digits of ZIP codes rather than 5-digit city codes) was associated with a 2.7% reduction in recurrent or metastatic cervical cancer burden (P less than .001).
Demographic Marker?
Reasons for disparities are complex and may involve a combination of inadequate health literacy and social and economic circumstances, said Cesar Castro, MD, commenting on the new cervical cancer study.
He noted in an interview that “the concept that a single Pap smear is often insufficient to capture precancerous changes, and hence the need for serial testing every 3 years, can be lost on individuals who also have competing challenges securing paychecks and/or dependent care. Historical barriers such as perceptions of the underlying cause of cervical cancer, the HPV virus, being a sexually transmitted disease and hence a taboo subject, also underpin decision-making. These sentiments have also fueled resistance towards HPV vaccination in young girls and boys.”
Dr. Castro, who is Program Director for Gynecologic Oncology at the Mass General Cancer Center in Boston, pointed out that treatments for cervical cancer often involve surgery or a combination of chemotherapy and radiation, and that side effects from these interventions may be especially disruptive to the lives of women who are breadwinners or caregivers for their families.
“These are the shackles that poverty places on many Black and Hispanic women notably in under-resourced regions domestically and globally,” he said.
The study was supported by Seagen and Genmab. Dr. Castellano disclosed consulting fees from GSK and Nykode and grant support from BMS. Dr. Castro reported no relevant conflicts of interest and was not involved in either of the studies presented at the meeting.
These findings come from analyses of insurance data gathered via the Cervical Cancer Geo-Analyzer tool, a publicly available online instrument designed to provide visual representation of recurrent or metastatic cervical cancer burden across metropolitan statistical areas in the United States over multiple years.
[Reporting the findings of] “this study is the first step to optimize healthcare resources allocations, advocate for policy changes that will minimize access barriers, and tailor education for modern treatment options to help reduce and improve outcomes for cervical cancer in US patients,” said Tara Castellano, MD, an author and presenter of this new research, at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, held in San Diego.
Seeing Cancer Cases
Dr. Castellano and colleagues previously reported that the Geo-Analyzer tool effectively provides quantified evidence of cervical cancer disease burden and graphic representation of geographical variations across the United States for both incident and recurrent/metastatic cervical cancer.
In the current analysis, Dr. Castellano, of Louisiana State University School of Medicine in New Orleans, discussed potential factors related to cervical cancer incidence and geographic variations.
The study builds on previous studies that have shown that Black and Hispanic women have longer time to treatment and worse cervical cancer outcomes than White women.
For example, in a study published in the International Journal of Gynecologic Cancer, Marilyn Huang, MD, and colleagues from the University of Miami Miller School of Medicine, Miami, Florida, and other centers in Miami looked at time to treatment in a diverse population of 274 women starting therapy for cervical cancer.
They found that insurance type (private, public, or none) contributed to delay in treatment initiation regardless of the treatment modality, and that the patient’s language and institution of diagnosis also influenced time to treatment.
In a separate scientific poster presented at SGO 2024, Dr. Castellano and colleagues reported that, among women with newly diagnosed endometrial cancer, the median time to treatment was 7 days longer for both Hispanic and Black women, compared with non-Hispanic White women. In addition, Black women had a 7-day longer time to receiving their first therapy for advanced disease. All of these differences were statistically significant.
Dr. Castellano told this news organization that the time-to-treatment disparities in the endometrial cancer study were determined by diagnostic codes and the timing of insurance claims.
Reasons for the disparities may include more limited access to care and structural and systemic biases in the healthcare systems where the majority of Black and Hispanic patients live, she said.
Insurance Database
In the new study on cervical cancer, Dr. Castellano and her team defined cervical cancer burden as prevalent cervical cancer diagnosis per 100,000 eligible women enrolled in a commercial insurance plan, Medicaid, or Medicare Advantage. Recurrent or metastatic cancer was determined to be the proportion of patients with cervical cancer who initiated systemic therapy.
The goals of the study were to provide a visualization of geographical distribution of cervical cancer in the US, and to quantify associations between early or advanced cancers with screening rates, poverty level, race/ethnicity, and access to brachytherapy.
The administrative claims database queried for the study included information on 75,521 women (median age 53) with a first diagnosis of cervical cancer from 2015 through 2022, and 14,033 women with recurrent or metastatic malignancies (median age 59 years).
Distribution of cases was higher in the South compared with in other US regions (37% vs approximately 20% for other regions).
Looking at the association between screening rates and disease burden from 2017 through 2022, the Geo-Analyzer showed that higher screening rates were significantly associated with decreased burden of new cases only in the South, whereas higher screening rates were associated with lower recurrent/metastatic disease burden in the Midwest and South, but a higher disease burden in the West.
In all regions, there was a significant association between decreased early cancer burden in areas with high percentages of women of Asian heritage, and significantly increased burden in areas with large populations of women of Hispanic origin.
The only significant association of race/ethnicity with recurrent/metastatic burden was a decrease in the Midwest in populations with large Asian populations.
An analysis of the how poverty levels affected screening and disease burden showed that in areas with a high percentage of low-income households there were significant associations with decreased cervical cancer screening and higher burden of newly diagnosed cases.
Poverty levels were significantly associated with recurrent/metastatic cancers only in the South.
The investigators also found that the presence of one or more brachytherapy centers within a ZIP-3 region (that is, a large geographic area designated by the first 3 digits of ZIP codes rather than 5-digit city codes) was associated with a 2.7% reduction in recurrent or metastatic cervical cancer burden (P less than .001).
Demographic Marker?
Reasons for disparities are complex and may involve a combination of inadequate health literacy and social and economic circumstances, said Cesar Castro, MD, commenting on the new cervical cancer study.
He noted in an interview that “the concept that a single Pap smear is often insufficient to capture precancerous changes, and hence the need for serial testing every 3 years, can be lost on individuals who also have competing challenges securing paychecks and/or dependent care. Historical barriers such as perceptions of the underlying cause of cervical cancer, the HPV virus, being a sexually transmitted disease and hence a taboo subject, also underpin decision-making. These sentiments have also fueled resistance towards HPV vaccination in young girls and boys.”
Dr. Castro, who is Program Director for Gynecologic Oncology at the Mass General Cancer Center in Boston, pointed out that treatments for cervical cancer often involve surgery or a combination of chemotherapy and radiation, and that side effects from these interventions may be especially disruptive to the lives of women who are breadwinners or caregivers for their families.
“These are the shackles that poverty places on many Black and Hispanic women notably in under-resourced regions domestically and globally,” he said.
The study was supported by Seagen and Genmab. Dr. Castellano disclosed consulting fees from GSK and Nykode and grant support from BMS. Dr. Castro reported no relevant conflicts of interest and was not involved in either of the studies presented at the meeting.
These findings come from analyses of insurance data gathered via the Cervical Cancer Geo-Analyzer tool, a publicly available online instrument designed to provide visual representation of recurrent or metastatic cervical cancer burden across metropolitan statistical areas in the United States over multiple years.
[Reporting the findings of] “this study is the first step to optimize healthcare resources allocations, advocate for policy changes that will minimize access barriers, and tailor education for modern treatment options to help reduce and improve outcomes for cervical cancer in US patients,” said Tara Castellano, MD, an author and presenter of this new research, at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, held in San Diego.
Seeing Cancer Cases
Dr. Castellano and colleagues previously reported that the Geo-Analyzer tool effectively provides quantified evidence of cervical cancer disease burden and graphic representation of geographical variations across the United States for both incident and recurrent/metastatic cervical cancer.
In the current analysis, Dr. Castellano, of Louisiana State University School of Medicine in New Orleans, discussed potential factors related to cervical cancer incidence and geographic variations.
The study builds on previous studies that have shown that Black and Hispanic women have longer time to treatment and worse cervical cancer outcomes than White women.
For example, in a study published in the International Journal of Gynecologic Cancer, Marilyn Huang, MD, and colleagues from the University of Miami Miller School of Medicine, Miami, Florida, and other centers in Miami looked at time to treatment in a diverse population of 274 women starting therapy for cervical cancer.
They found that insurance type (private, public, or none) contributed to delay in treatment initiation regardless of the treatment modality, and that the patient’s language and institution of diagnosis also influenced time to treatment.
In a separate scientific poster presented at SGO 2024, Dr. Castellano and colleagues reported that, among women with newly diagnosed endometrial cancer, the median time to treatment was 7 days longer for both Hispanic and Black women, compared with non-Hispanic White women. In addition, Black women had a 7-day longer time to receiving their first therapy for advanced disease. All of these differences were statistically significant.
Dr. Castellano told this news organization that the time-to-treatment disparities in the endometrial cancer study were determined by diagnostic codes and the timing of insurance claims.
Reasons for the disparities may include more limited access to care and structural and systemic biases in the healthcare systems where the majority of Black and Hispanic patients live, she said.
Insurance Database
In the new study on cervical cancer, Dr. Castellano and her team defined cervical cancer burden as prevalent cervical cancer diagnosis per 100,000 eligible women enrolled in a commercial insurance plan, Medicaid, or Medicare Advantage. Recurrent or metastatic cancer was determined to be the proportion of patients with cervical cancer who initiated systemic therapy.
The goals of the study were to provide a visualization of geographical distribution of cervical cancer in the US, and to quantify associations between early or advanced cancers with screening rates, poverty level, race/ethnicity, and access to brachytherapy.
The administrative claims database queried for the study included information on 75,521 women (median age 53) with a first diagnosis of cervical cancer from 2015 through 2022, and 14,033 women with recurrent or metastatic malignancies (median age 59 years).
Distribution of cases was higher in the South compared with in other US regions (37% vs approximately 20% for other regions).
Looking at the association between screening rates and disease burden from 2017 through 2022, the Geo-Analyzer showed that higher screening rates were significantly associated with decreased burden of new cases only in the South, whereas higher screening rates were associated with lower recurrent/metastatic disease burden in the Midwest and South, but a higher disease burden in the West.
In all regions, there was a significant association between decreased early cancer burden in areas with high percentages of women of Asian heritage, and significantly increased burden in areas with large populations of women of Hispanic origin.
The only significant association of race/ethnicity with recurrent/metastatic burden was a decrease in the Midwest in populations with large Asian populations.
An analysis of the how poverty levels affected screening and disease burden showed that in areas with a high percentage of low-income households there were significant associations with decreased cervical cancer screening and higher burden of newly diagnosed cases.
Poverty levels were significantly associated with recurrent/metastatic cancers only in the South.
The investigators also found that the presence of one or more brachytherapy centers within a ZIP-3 region (that is, a large geographic area designated by the first 3 digits of ZIP codes rather than 5-digit city codes) was associated with a 2.7% reduction in recurrent or metastatic cervical cancer burden (P less than .001).
Demographic Marker?
Reasons for disparities are complex and may involve a combination of inadequate health literacy and social and economic circumstances, said Cesar Castro, MD, commenting on the new cervical cancer study.
He noted in an interview that “the concept that a single Pap smear is often insufficient to capture precancerous changes, and hence the need for serial testing every 3 years, can be lost on individuals who also have competing challenges securing paychecks and/or dependent care. Historical barriers such as perceptions of the underlying cause of cervical cancer, the HPV virus, being a sexually transmitted disease and hence a taboo subject, also underpin decision-making. These sentiments have also fueled resistance towards HPV vaccination in young girls and boys.”
Dr. Castro, who is Program Director for Gynecologic Oncology at the Mass General Cancer Center in Boston, pointed out that treatments for cervical cancer often involve surgery or a combination of chemotherapy and radiation, and that side effects from these interventions may be especially disruptive to the lives of women who are breadwinners or caregivers for their families.
“These are the shackles that poverty places on many Black and Hispanic women notably in under-resourced regions domestically and globally,” he said.
The study was supported by Seagen and Genmab. Dr. Castellano disclosed consulting fees from GSK and Nykode and grant support from BMS. Dr. Castro reported no relevant conflicts of interest and was not involved in either of the studies presented at the meeting.
FROM SGO 2024
It Takes a Village: Treating Patients for NSCLC Brain Metastases
Treatment decisions about the care of patients with non–small cell lung cancer (NSCLC) that has metastasized to the brain should always be made by a multidisciplinary team, according to a lung cancer research specialist.
The care of these patients can be quite complex, and the brain is still largely terra incognita, said Lizza Hendriks, MD, PhD, during a case-based session at the European Lung Cancer Congress (ELCC) 2024 in Prague, Czech Republic.
The approach to patients with NSCLC metastatic to the brain and central nervous system was the subject of the session presented by Dr. Hendriks of Maastricht University Medical Center in Maastricht, the Netherlands. During this session, she outlined what is known, what is believed to be true, and what is still unknown about the treatment of patients with NSCLC that has spread to the CNS.
“Immunotherapy has moderate efficacy in the brain, but it can result in long-term disease control,” she said. She added that the best treatment strategy using these agents, whether immunotherapy alone or combined with chemotherapy, is still unknown, even when patients have high levels of programmed death protein 1 (PD-1) in their tumors.
“Also, we don’t know the best sequence of treatments, and we really need more preclinical research regarding the tumor microenvironment in the CNS,” she said.
Next-generation tyrosine kinase inhibitors (TKIs) generally have good intracranial efficacy, except for KRAS G12C inhibitors, which need to be tweaked for better effectiveness in the brain. The optimal sequence for TKIs also still needs to be determined, she continued.
Decision Points
Dr. Hendriks summarized decision points for the case of a 60-year-old female patient, a smoker, who in February of 2021 was evaluated for multiple asymptomatic brain metastases. The patient, who had good performance status, had a diagnosis of stage IVB NSCLC of adenocarcinoma histology, with a tumor positive for a KRAS G12C mutation and with 50% of tumor cells expressing PD-1.
The patient was treated with whole-brain radiation therapy and single-agent immunotherapy, and, 8 months later, in October 2021, was diagnosed with extracranial progressive disease and was then started on the KRAS G12c inhibitor sotorasib (Lumakras).
In May 2023 the patient was diagnosed with CNS oligoprogressive disease (that is, isolated progressing lesions) and underwent stereotactic radiotherapy. In June 2023 the patient was found to have progressive disease and was then started on platinum-based chemotherapy, with disease progression again noted in December of that year. The patient was still alive at the time of the presentation.
The first decision point in this case, Dr. Hendriks said, was whether to treat the patient at the time of diagnosis of brain metastases with upfront systemic or local therapy for the metastases.
At the time of extracranial progressive disease, should the treatment be another immumotherapy, chemotherapy, or a targeted agent?
“And the last decision is what should we do [in the event of] CNS oligoprogression?,” she said.
First Decision
For cases such as that described by Dr. Hendriks the question is whether upfront local therapy is needed if the patient is initially asymptomatic. Other considerations concerning early local therapy include the risks for late toxicities and whether there is also extracranial disease that needs to be controlled.
If systemic therapy is considered at this point, clinicians need to consider intracranial response rates to specific agents, time to onset of response, risk of pseudoprogression, and the risk of toxicity if radiotherapy is delayed until later in the disease course.
“I think all of these patients with brain metastases really deserve multidisciplinary team decisions in order to maintain or to [move] to new treatments, improve the quality of life, and improve survival,” she said.
In the case described here, the patient had small but numerous metastases that indicated the need for extracranial control, she said.
European Society of Medical Oncology (ESMO) guidelines recommend that asymptomatic patients or those with oligosymptomatic NSCLC brain metastases with an oncogenic driver receive a brain-penetrating TKI. Those with no oncogenic drive but high PD-1 expression should receive upfront immunotherapy alone, while those with PD-1 ligand 1 (PD-L1) expression below 50% receive chemoimmunotherapy.
The joint American Society of Clinical Oncology (ASCO), Society for Neuro-Oncology (SNO), and American Society for Radiation Oncology (ASTRO) guideline for treatment of brain metastases recommends a CNS-penetrating TKI for patients with asymptomatic NSCLC brain metastases bearing EGFR or ALK alterations. If there is no oncogenic driver, the guideline recommends the option of pembrolizumab (Keytruda) with or without chemotherapy.
Both the US and European guidelines recommend initiating local treatment for patients with symptomatic metastases. The level of evidence for these recommendations is low, however.
Clinicians still need better evidence about the potential for upfront immunotherapy for these patients, more information about the NSCLC brain metastases immune environment and tumor microenvironment, data on the best treatment sequence, and new strategies for improving CNS penetration of systemic therapy, Dr. Hendriks said.
Second Decision
At the time of CNS progression, the question becomes whether patients would benefit from targeted therapy or chemotherapy.
“We quite often say that chemotherapy doesn’t work in the brain, but that’s not entirely true,” Dr. Hendriks said, noting that, depending on the regimen range, brain response rates range from 23% to as high as 50% in patients with previously untreated asymptomatic brain metastases, although the median survival times are fairly low, on the order of 4 to almost 13 months.
There is also preclinical evidence that chemotherapy uptake is higher for larger brain metastases, compared with normal tissue and cerebrospinal fluid, “so the blood-brain barrier opens if you have the larger brain metastases,” she said.
KRAS-positive NSCLC is associated with a high risk for brain metastases, and these metastases share the same mutation as the primary cancer, suggesting potential efficacy of KRAS G12c inhibitors. There is preclinical evidence that adagrasib (Krazati) has CNS penetration, and there was evidence for intracranial efficacy of the drug in the KRYSTAL-1b trial, Dr. Hendriks noted.
There are fewer data for the other Food and Drug Administration (FDA)–approved inhibitor, sotorasib, but there is evidence to suggest that its brain activity is restricted by ABCB1, a gene encoding for a transporter protein that shuttles substances out of cells.
Third Decision
For patients with CNS oligoprogression, the question is whether to adapt systemic therapy or use local therapy.
There is some evidence to support dose escalation for patients with oligoprogression of tumors with EGFR or ALK alterations, but no data to support such a strategy for those with KRAS alterations, she said.
In these situations, data support dose escalation of osimertinib (Tagrisso), especially for patients with leptomeningeal disease, and brigatinib (Alunbrig), but there is very little evidence to support dose escalation for any other drugs that might be tried, she said.
In the question-and-answer part of the session, Antonin Levy, MD, from Gustave Roussy in Villejuif, France, who also presented during the session, asked Dr. Hendriks what she would recommend for a patient with a long-term response to chemoimmunotherapy for whom treatment cessation may be recommended, but who still has oligopersistent brain metastases.
“The difficulty is that with immunotherapy patients can have persistent lesions without any tumor activity, and in the brain I think there is no reliable technique to evaluate this type of thing,” she said.
Dr. Hendriks added that she would continue to follow the patient, but also closely evaluate disease progression by reviewing all scans over the course of therapy to determine whether the tumor is truly stable, follow the patient with brain imaging, and then “don’t do anything.”
Dr. Hendriks disclosed grants/research support and financial relationships with multiple companies. Dr. Levy disclosed research grants from Beigene, AstraZeneca, PharmaMar, and Roche.
Treatment decisions about the care of patients with non–small cell lung cancer (NSCLC) that has metastasized to the brain should always be made by a multidisciplinary team, according to a lung cancer research specialist.
The care of these patients can be quite complex, and the brain is still largely terra incognita, said Lizza Hendriks, MD, PhD, during a case-based session at the European Lung Cancer Congress (ELCC) 2024 in Prague, Czech Republic.
The approach to patients with NSCLC metastatic to the brain and central nervous system was the subject of the session presented by Dr. Hendriks of Maastricht University Medical Center in Maastricht, the Netherlands. During this session, she outlined what is known, what is believed to be true, and what is still unknown about the treatment of patients with NSCLC that has spread to the CNS.
“Immunotherapy has moderate efficacy in the brain, but it can result in long-term disease control,” she said. She added that the best treatment strategy using these agents, whether immunotherapy alone or combined with chemotherapy, is still unknown, even when patients have high levels of programmed death protein 1 (PD-1) in their tumors.
“Also, we don’t know the best sequence of treatments, and we really need more preclinical research regarding the tumor microenvironment in the CNS,” she said.
Next-generation tyrosine kinase inhibitors (TKIs) generally have good intracranial efficacy, except for KRAS G12C inhibitors, which need to be tweaked for better effectiveness in the brain. The optimal sequence for TKIs also still needs to be determined, she continued.
Decision Points
Dr. Hendriks summarized decision points for the case of a 60-year-old female patient, a smoker, who in February of 2021 was evaluated for multiple asymptomatic brain metastases. The patient, who had good performance status, had a diagnosis of stage IVB NSCLC of adenocarcinoma histology, with a tumor positive for a KRAS G12C mutation and with 50% of tumor cells expressing PD-1.
The patient was treated with whole-brain radiation therapy and single-agent immunotherapy, and, 8 months later, in October 2021, was diagnosed with extracranial progressive disease and was then started on the KRAS G12c inhibitor sotorasib (Lumakras).
In May 2023 the patient was diagnosed with CNS oligoprogressive disease (that is, isolated progressing lesions) and underwent stereotactic radiotherapy. In June 2023 the patient was found to have progressive disease and was then started on platinum-based chemotherapy, with disease progression again noted in December of that year. The patient was still alive at the time of the presentation.
The first decision point in this case, Dr. Hendriks said, was whether to treat the patient at the time of diagnosis of brain metastases with upfront systemic or local therapy for the metastases.
At the time of extracranial progressive disease, should the treatment be another immumotherapy, chemotherapy, or a targeted agent?
“And the last decision is what should we do [in the event of] CNS oligoprogression?,” she said.
First Decision
For cases such as that described by Dr. Hendriks the question is whether upfront local therapy is needed if the patient is initially asymptomatic. Other considerations concerning early local therapy include the risks for late toxicities and whether there is also extracranial disease that needs to be controlled.
If systemic therapy is considered at this point, clinicians need to consider intracranial response rates to specific agents, time to onset of response, risk of pseudoprogression, and the risk of toxicity if radiotherapy is delayed until later in the disease course.
“I think all of these patients with brain metastases really deserve multidisciplinary team decisions in order to maintain or to [move] to new treatments, improve the quality of life, and improve survival,” she said.
In the case described here, the patient had small but numerous metastases that indicated the need for extracranial control, she said.
European Society of Medical Oncology (ESMO) guidelines recommend that asymptomatic patients or those with oligosymptomatic NSCLC brain metastases with an oncogenic driver receive a brain-penetrating TKI. Those with no oncogenic drive but high PD-1 expression should receive upfront immunotherapy alone, while those with PD-1 ligand 1 (PD-L1) expression below 50% receive chemoimmunotherapy.
The joint American Society of Clinical Oncology (ASCO), Society for Neuro-Oncology (SNO), and American Society for Radiation Oncology (ASTRO) guideline for treatment of brain metastases recommends a CNS-penetrating TKI for patients with asymptomatic NSCLC brain metastases bearing EGFR or ALK alterations. If there is no oncogenic driver, the guideline recommends the option of pembrolizumab (Keytruda) with or without chemotherapy.
Both the US and European guidelines recommend initiating local treatment for patients with symptomatic metastases. The level of evidence for these recommendations is low, however.
Clinicians still need better evidence about the potential for upfront immunotherapy for these patients, more information about the NSCLC brain metastases immune environment and tumor microenvironment, data on the best treatment sequence, and new strategies for improving CNS penetration of systemic therapy, Dr. Hendriks said.
Second Decision
At the time of CNS progression, the question becomes whether patients would benefit from targeted therapy or chemotherapy.
“We quite often say that chemotherapy doesn’t work in the brain, but that’s not entirely true,” Dr. Hendriks said, noting that, depending on the regimen range, brain response rates range from 23% to as high as 50% in patients with previously untreated asymptomatic brain metastases, although the median survival times are fairly low, on the order of 4 to almost 13 months.
There is also preclinical evidence that chemotherapy uptake is higher for larger brain metastases, compared with normal tissue and cerebrospinal fluid, “so the blood-brain barrier opens if you have the larger brain metastases,” she said.
KRAS-positive NSCLC is associated with a high risk for brain metastases, and these metastases share the same mutation as the primary cancer, suggesting potential efficacy of KRAS G12c inhibitors. There is preclinical evidence that adagrasib (Krazati) has CNS penetration, and there was evidence for intracranial efficacy of the drug in the KRYSTAL-1b trial, Dr. Hendriks noted.
There are fewer data for the other Food and Drug Administration (FDA)–approved inhibitor, sotorasib, but there is evidence to suggest that its brain activity is restricted by ABCB1, a gene encoding for a transporter protein that shuttles substances out of cells.
Third Decision
For patients with CNS oligoprogression, the question is whether to adapt systemic therapy or use local therapy.
There is some evidence to support dose escalation for patients with oligoprogression of tumors with EGFR or ALK alterations, but no data to support such a strategy for those with KRAS alterations, she said.
In these situations, data support dose escalation of osimertinib (Tagrisso), especially for patients with leptomeningeal disease, and brigatinib (Alunbrig), but there is very little evidence to support dose escalation for any other drugs that might be tried, she said.
In the question-and-answer part of the session, Antonin Levy, MD, from Gustave Roussy in Villejuif, France, who also presented during the session, asked Dr. Hendriks what she would recommend for a patient with a long-term response to chemoimmunotherapy for whom treatment cessation may be recommended, but who still has oligopersistent brain metastases.
“The difficulty is that with immunotherapy patients can have persistent lesions without any tumor activity, and in the brain I think there is no reliable technique to evaluate this type of thing,” she said.
Dr. Hendriks added that she would continue to follow the patient, but also closely evaluate disease progression by reviewing all scans over the course of therapy to determine whether the tumor is truly stable, follow the patient with brain imaging, and then “don’t do anything.”
Dr. Hendriks disclosed grants/research support and financial relationships with multiple companies. Dr. Levy disclosed research grants from Beigene, AstraZeneca, PharmaMar, and Roche.
Treatment decisions about the care of patients with non–small cell lung cancer (NSCLC) that has metastasized to the brain should always be made by a multidisciplinary team, according to a lung cancer research specialist.
The care of these patients can be quite complex, and the brain is still largely terra incognita, said Lizza Hendriks, MD, PhD, during a case-based session at the European Lung Cancer Congress (ELCC) 2024 in Prague, Czech Republic.
The approach to patients with NSCLC metastatic to the brain and central nervous system was the subject of the session presented by Dr. Hendriks of Maastricht University Medical Center in Maastricht, the Netherlands. During this session, she outlined what is known, what is believed to be true, and what is still unknown about the treatment of patients with NSCLC that has spread to the CNS.
“Immunotherapy has moderate efficacy in the brain, but it can result in long-term disease control,” she said. She added that the best treatment strategy using these agents, whether immunotherapy alone or combined with chemotherapy, is still unknown, even when patients have high levels of programmed death protein 1 (PD-1) in their tumors.
“Also, we don’t know the best sequence of treatments, and we really need more preclinical research regarding the tumor microenvironment in the CNS,” she said.
Next-generation tyrosine kinase inhibitors (TKIs) generally have good intracranial efficacy, except for KRAS G12C inhibitors, which need to be tweaked for better effectiveness in the brain. The optimal sequence for TKIs also still needs to be determined, she continued.
Decision Points
Dr. Hendriks summarized decision points for the case of a 60-year-old female patient, a smoker, who in February of 2021 was evaluated for multiple asymptomatic brain metastases. The patient, who had good performance status, had a diagnosis of stage IVB NSCLC of adenocarcinoma histology, with a tumor positive for a KRAS G12C mutation and with 50% of tumor cells expressing PD-1.
The patient was treated with whole-brain radiation therapy and single-agent immunotherapy, and, 8 months later, in October 2021, was diagnosed with extracranial progressive disease and was then started on the KRAS G12c inhibitor sotorasib (Lumakras).
In May 2023 the patient was diagnosed with CNS oligoprogressive disease (that is, isolated progressing lesions) and underwent stereotactic radiotherapy. In June 2023 the patient was found to have progressive disease and was then started on platinum-based chemotherapy, with disease progression again noted in December of that year. The patient was still alive at the time of the presentation.
The first decision point in this case, Dr. Hendriks said, was whether to treat the patient at the time of diagnosis of brain metastases with upfront systemic or local therapy for the metastases.
At the time of extracranial progressive disease, should the treatment be another immumotherapy, chemotherapy, or a targeted agent?
“And the last decision is what should we do [in the event of] CNS oligoprogression?,” she said.
First Decision
For cases such as that described by Dr. Hendriks the question is whether upfront local therapy is needed if the patient is initially asymptomatic. Other considerations concerning early local therapy include the risks for late toxicities and whether there is also extracranial disease that needs to be controlled.
If systemic therapy is considered at this point, clinicians need to consider intracranial response rates to specific agents, time to onset of response, risk of pseudoprogression, and the risk of toxicity if radiotherapy is delayed until later in the disease course.
“I think all of these patients with brain metastases really deserve multidisciplinary team decisions in order to maintain or to [move] to new treatments, improve the quality of life, and improve survival,” she said.
In the case described here, the patient had small but numerous metastases that indicated the need for extracranial control, she said.
European Society of Medical Oncology (ESMO) guidelines recommend that asymptomatic patients or those with oligosymptomatic NSCLC brain metastases with an oncogenic driver receive a brain-penetrating TKI. Those with no oncogenic drive but high PD-1 expression should receive upfront immunotherapy alone, while those with PD-1 ligand 1 (PD-L1) expression below 50% receive chemoimmunotherapy.
The joint American Society of Clinical Oncology (ASCO), Society for Neuro-Oncology (SNO), and American Society for Radiation Oncology (ASTRO) guideline for treatment of brain metastases recommends a CNS-penetrating TKI for patients with asymptomatic NSCLC brain metastases bearing EGFR or ALK alterations. If there is no oncogenic driver, the guideline recommends the option of pembrolizumab (Keytruda) with or without chemotherapy.
Both the US and European guidelines recommend initiating local treatment for patients with symptomatic metastases. The level of evidence for these recommendations is low, however.
Clinicians still need better evidence about the potential for upfront immunotherapy for these patients, more information about the NSCLC brain metastases immune environment and tumor microenvironment, data on the best treatment sequence, and new strategies for improving CNS penetration of systemic therapy, Dr. Hendriks said.
Second Decision
At the time of CNS progression, the question becomes whether patients would benefit from targeted therapy or chemotherapy.
“We quite often say that chemotherapy doesn’t work in the brain, but that’s not entirely true,” Dr. Hendriks said, noting that, depending on the regimen range, brain response rates range from 23% to as high as 50% in patients with previously untreated asymptomatic brain metastases, although the median survival times are fairly low, on the order of 4 to almost 13 months.
There is also preclinical evidence that chemotherapy uptake is higher for larger brain metastases, compared with normal tissue and cerebrospinal fluid, “so the blood-brain barrier opens if you have the larger brain metastases,” she said.
KRAS-positive NSCLC is associated with a high risk for brain metastases, and these metastases share the same mutation as the primary cancer, suggesting potential efficacy of KRAS G12c inhibitors. There is preclinical evidence that adagrasib (Krazati) has CNS penetration, and there was evidence for intracranial efficacy of the drug in the KRYSTAL-1b trial, Dr. Hendriks noted.
There are fewer data for the other Food and Drug Administration (FDA)–approved inhibitor, sotorasib, but there is evidence to suggest that its brain activity is restricted by ABCB1, a gene encoding for a transporter protein that shuttles substances out of cells.
Third Decision
For patients with CNS oligoprogression, the question is whether to adapt systemic therapy or use local therapy.
There is some evidence to support dose escalation for patients with oligoprogression of tumors with EGFR or ALK alterations, but no data to support such a strategy for those with KRAS alterations, she said.
In these situations, data support dose escalation of osimertinib (Tagrisso), especially for patients with leptomeningeal disease, and brigatinib (Alunbrig), but there is very little evidence to support dose escalation for any other drugs that might be tried, she said.
In the question-and-answer part of the session, Antonin Levy, MD, from Gustave Roussy in Villejuif, France, who also presented during the session, asked Dr. Hendriks what she would recommend for a patient with a long-term response to chemoimmunotherapy for whom treatment cessation may be recommended, but who still has oligopersistent brain metastases.
“The difficulty is that with immunotherapy patients can have persistent lesions without any tumor activity, and in the brain I think there is no reliable technique to evaluate this type of thing,” she said.
Dr. Hendriks added that she would continue to follow the patient, but also closely evaluate disease progression by reviewing all scans over the course of therapy to determine whether the tumor is truly stable, follow the patient with brain imaging, and then “don’t do anything.”
Dr. Hendriks disclosed grants/research support and financial relationships with multiple companies. Dr. Levy disclosed research grants from Beigene, AstraZeneca, PharmaMar, and Roche.
FROM ELCC 2024
Debate: Does ctDNA Have Role in Monitoring Tx Efficacy in Lung Cancer?
The clinical utility of circulating tumor DNA (ctDNA) for detecting minimal residual disease (MRD) and for treatment planning postoperatively was a topic of debate at the European Lung Cancer Congress 2024, held in Prague, Czech Republic.
PRO: Prognostic Value
Enriqueta Felip, MD, PhD, of Vall d’Hebron Institute of Oncology in Barcelona, Spain, argued in favor of using liquid biopsy for disease surveillance and decision making about adjuvant therapy.
“In early stage non–small cell lung cancer I think the evidence shows that pretreatment baseline ctDNA levels are clearly prognostic, and also, after surgical resection, the MRD predicts relapse, so we know that at present ctDNA and MRD are strong prognostic markers,” she said.
“I think ctDNA is useful as a noninvasive tool in both settings — at baseline pre surgery and also post surgery — to guide adjuvant therapy decision making,” she added.
Dr. Felip noted that so-called “tumor-informed” assays, such as sequencing of tumor tissue to identify mutations that can then be tracked in plasma samples, are high sensitivity methods, but have a long turnaround time, and approximately one in five patients does not have adequate tumor tissues for analysis.
In contrast, “tumor agnostic” methods rely on epigenetic features such as DNA methylation and cell-free DNA fragmentation patterns to detect tumor-derived DNA, but don’t rely on tumor tissue sample.
Dr. Felip cited a 2017 study published in Cancer Discovery showing that in patients with localized lung cancer post treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months. In addition, the investigators found that 53% of patients had ctDNA mutation profiles that suggested they would respond favorably to tyrosine kinase inhibitors or immune checkpoint inhibitors.
She also pointed to 2022 European Society for Medical Oncology (ESMO) recommendations on the use of ctDNA in patients with cancer, which state that detection of residual tumor DNA after NSCLC therapy with curative intent is associated with a high risk of future relapse, as supported by evidence from multiple studies. The recommendation also states, however, that there is insufficient evidence to recommend ctDNA testing in routine clinical practice in the absence of evidence from prospective clinical trials.
Evidence to support a benefit of ctDNA detection for treatment planning in the adjuvant setting come from several clinical studies, Dr. Felip said. For example, in a 2020 study published in Nature Cancer, investigators found that patients with detectable ctDNA after chemoradiotherapy who had treatment consolidation with an immune checkpoint inhibitor had significantly better freedom from progression compared with patients who had detectable ctDNA but did not receive consolidation immunotherapy.
In the IMpower010 trial, patients who were ctDNA-positive post surgery and received adjuvant atezolizumab (Tecentriq) had a median disease-free survival of 19.1 months, compared with 7.9 months for patients who did not get the immune checkpoint inhibitor, further indicating the value of ctDNA in the adjuvant setting, she said.
Wrapping up her argument, Dr. Felip acknowledged that currently the negative predictive value of ctDNA/MRD is suboptimal.
“However, we have seen that high ctDNA levels pre surgery predict poor outcome, and MRD-positive following definitive therapy is strongly prognostic and has extremely high positive predictive value for recurrence,” she said.
Taken together, the evidence suggests that patients who are ctDNA-positive preoperatively should be considered for neoadjuvant chemotherapy and immune checkpoint inhibition. If ctDNA persists after neoadjuvant therapy, patients should have extensive re-staging before surgery, because their options for pathologic complete response are limited. Patients who are MRD-positive after surgery should be treated with the same therapeutic approach as for patients with metastatic disease, Dr. Felip concluded.
CON: No Data Supporting OS Benefit
Offering counterpoint to Dr. Felip’s argument, Jordi Remon Masip, MD, PhD, of Gustave Roussy cancer treatment center in Villejuif, France, said that the currently available evidence suggests that MRD helps identify a high-risk population, but that its utility in the clinic is still uncertain.
“Today, I am a believer that we need prospective clinical trials, but one of the most important points today is to elucidate if the minimal residual disease is just prognostic or whether we really can use this minimal residual disease for making treatment decisions, not only escalating [but] also de-escalating treatment strategies in early stage non–small cell lung cancer,” he said.
Risk stratification may help to identify those patients who can most benefit from intensive therapy, but it appears to be much more difficult to risk stratify patients with early stage NSCLC, he said, pointing to the International Tailored Chemotherapy Adjuvant (ITACA) trial, a phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy versus standard adjuvant chemotherapy in patients with completely resected stage II-IIIA NSCLC. In this study, chemotherapy customized to individual patients according to molecular diagnostic analysis after surgery did not improve overall survival outcomes.
Dr. Masip said that as a clinician he would like to have any reliable tool that could help him to decide which patients need more therapy and which can do well with less.
He agreed that MRD-positivity as signaled by ctDNA after surgery or by a tumor-informed method correlates with poor prognosis, but he noted that MRD status depends on clinical characteristics such as sex, smoking status, age, stage, tumor size, histology, and many other factors that need to be taken into account if the assay is to have value in clinical practice.
“It’s true that the minimal residual disease may capture a poor prognostic population. However, even if we apply the minimal residual disease in our daily clinical practice, we can only capture, or we can only rescue 20% of the patients with the wild type or oncogenic early stage non–small cell lung cancer,” he said.
In addition, as Dr. Felip acknowledged, the negative predictive value of MRD is not infallible, with a 63% false negative rate compared with only a 2% false-positive rate.
“Half of the patients with the recurrence of the disease have a very, very low circulating tumor DNA, and the techniques are not sensitive enough to capture this minimal residual disease,” Dr. Masip said.
It would also be a mistake to forgo giving adjuvant therapy to those patients deemed to be MRD-negative on the basis of ctDNA, given the high false-negative rates, he said.
Oncologists also have to put themselves in their patients’ shoes:
“If our patients accept that with minimal residual disease I can only improve the disease-free survival without improving the overall survival, they would accept having less toxicity but the same survival that they would if they started the treatment later, and also what would happen if the patient is randomized to no adjuvant treatment because the minimal residual disease is negative, and some months later there is a recurrence of disease?” Dr. Masip said.
“I think we need more prospective data, but we really, really need a more sensitive test to avoid or to decrease the percentage of patients with false-negative results, and also we need very motivated patients that would accept to be randomized to de-escalate treatment strategies,” he concluded.
Dr. Felip disclosed advisory or speakers bureau roles for AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffman-La Roche, Genentech, Gilead, GlaxoSmithKline, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Novartis, PeerVoice, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics. She has served as a board member of Grifols. Dr. Masip disclosed research support from MSD, AstraZeneca, and Sanofi, and other financial relationships with AstraZeneca, Sanofi, Takeda Roche, and Janssen.
The clinical utility of circulating tumor DNA (ctDNA) for detecting minimal residual disease (MRD) and for treatment planning postoperatively was a topic of debate at the European Lung Cancer Congress 2024, held in Prague, Czech Republic.
PRO: Prognostic Value
Enriqueta Felip, MD, PhD, of Vall d’Hebron Institute of Oncology in Barcelona, Spain, argued in favor of using liquid biopsy for disease surveillance and decision making about adjuvant therapy.
“In early stage non–small cell lung cancer I think the evidence shows that pretreatment baseline ctDNA levels are clearly prognostic, and also, after surgical resection, the MRD predicts relapse, so we know that at present ctDNA and MRD are strong prognostic markers,” she said.
“I think ctDNA is useful as a noninvasive tool in both settings — at baseline pre surgery and also post surgery — to guide adjuvant therapy decision making,” she added.
Dr. Felip noted that so-called “tumor-informed” assays, such as sequencing of tumor tissue to identify mutations that can then be tracked in plasma samples, are high sensitivity methods, but have a long turnaround time, and approximately one in five patients does not have adequate tumor tissues for analysis.
In contrast, “tumor agnostic” methods rely on epigenetic features such as DNA methylation and cell-free DNA fragmentation patterns to detect tumor-derived DNA, but don’t rely on tumor tissue sample.
Dr. Felip cited a 2017 study published in Cancer Discovery showing that in patients with localized lung cancer post treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months. In addition, the investigators found that 53% of patients had ctDNA mutation profiles that suggested they would respond favorably to tyrosine kinase inhibitors or immune checkpoint inhibitors.
She also pointed to 2022 European Society for Medical Oncology (ESMO) recommendations on the use of ctDNA in patients with cancer, which state that detection of residual tumor DNA after NSCLC therapy with curative intent is associated with a high risk of future relapse, as supported by evidence from multiple studies. The recommendation also states, however, that there is insufficient evidence to recommend ctDNA testing in routine clinical practice in the absence of evidence from prospective clinical trials.
Evidence to support a benefit of ctDNA detection for treatment planning in the adjuvant setting come from several clinical studies, Dr. Felip said. For example, in a 2020 study published in Nature Cancer, investigators found that patients with detectable ctDNA after chemoradiotherapy who had treatment consolidation with an immune checkpoint inhibitor had significantly better freedom from progression compared with patients who had detectable ctDNA but did not receive consolidation immunotherapy.
In the IMpower010 trial, patients who were ctDNA-positive post surgery and received adjuvant atezolizumab (Tecentriq) had a median disease-free survival of 19.1 months, compared with 7.9 months for patients who did not get the immune checkpoint inhibitor, further indicating the value of ctDNA in the adjuvant setting, she said.
Wrapping up her argument, Dr. Felip acknowledged that currently the negative predictive value of ctDNA/MRD is suboptimal.
“However, we have seen that high ctDNA levels pre surgery predict poor outcome, and MRD-positive following definitive therapy is strongly prognostic and has extremely high positive predictive value for recurrence,” she said.
Taken together, the evidence suggests that patients who are ctDNA-positive preoperatively should be considered for neoadjuvant chemotherapy and immune checkpoint inhibition. If ctDNA persists after neoadjuvant therapy, patients should have extensive re-staging before surgery, because their options for pathologic complete response are limited. Patients who are MRD-positive after surgery should be treated with the same therapeutic approach as for patients with metastatic disease, Dr. Felip concluded.
CON: No Data Supporting OS Benefit
Offering counterpoint to Dr. Felip’s argument, Jordi Remon Masip, MD, PhD, of Gustave Roussy cancer treatment center in Villejuif, France, said that the currently available evidence suggests that MRD helps identify a high-risk population, but that its utility in the clinic is still uncertain.
“Today, I am a believer that we need prospective clinical trials, but one of the most important points today is to elucidate if the minimal residual disease is just prognostic or whether we really can use this minimal residual disease for making treatment decisions, not only escalating [but] also de-escalating treatment strategies in early stage non–small cell lung cancer,” he said.
Risk stratification may help to identify those patients who can most benefit from intensive therapy, but it appears to be much more difficult to risk stratify patients with early stage NSCLC, he said, pointing to the International Tailored Chemotherapy Adjuvant (ITACA) trial, a phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy versus standard adjuvant chemotherapy in patients with completely resected stage II-IIIA NSCLC. In this study, chemotherapy customized to individual patients according to molecular diagnostic analysis after surgery did not improve overall survival outcomes.
Dr. Masip said that as a clinician he would like to have any reliable tool that could help him to decide which patients need more therapy and which can do well with less.
He agreed that MRD-positivity as signaled by ctDNA after surgery or by a tumor-informed method correlates with poor prognosis, but he noted that MRD status depends on clinical characteristics such as sex, smoking status, age, stage, tumor size, histology, and many other factors that need to be taken into account if the assay is to have value in clinical practice.
“It’s true that the minimal residual disease may capture a poor prognostic population. However, even if we apply the minimal residual disease in our daily clinical practice, we can only capture, or we can only rescue 20% of the patients with the wild type or oncogenic early stage non–small cell lung cancer,” he said.
In addition, as Dr. Felip acknowledged, the negative predictive value of MRD is not infallible, with a 63% false negative rate compared with only a 2% false-positive rate.
“Half of the patients with the recurrence of the disease have a very, very low circulating tumor DNA, and the techniques are not sensitive enough to capture this minimal residual disease,” Dr. Masip said.
It would also be a mistake to forgo giving adjuvant therapy to those patients deemed to be MRD-negative on the basis of ctDNA, given the high false-negative rates, he said.
Oncologists also have to put themselves in their patients’ shoes:
“If our patients accept that with minimal residual disease I can only improve the disease-free survival without improving the overall survival, they would accept having less toxicity but the same survival that they would if they started the treatment later, and also what would happen if the patient is randomized to no adjuvant treatment because the minimal residual disease is negative, and some months later there is a recurrence of disease?” Dr. Masip said.
“I think we need more prospective data, but we really, really need a more sensitive test to avoid or to decrease the percentage of patients with false-negative results, and also we need very motivated patients that would accept to be randomized to de-escalate treatment strategies,” he concluded.
Dr. Felip disclosed advisory or speakers bureau roles for AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffman-La Roche, Genentech, Gilead, GlaxoSmithKline, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Novartis, PeerVoice, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics. She has served as a board member of Grifols. Dr. Masip disclosed research support from MSD, AstraZeneca, and Sanofi, and other financial relationships with AstraZeneca, Sanofi, Takeda Roche, and Janssen.
The clinical utility of circulating tumor DNA (ctDNA) for detecting minimal residual disease (MRD) and for treatment planning postoperatively was a topic of debate at the European Lung Cancer Congress 2024, held in Prague, Czech Republic.
PRO: Prognostic Value
Enriqueta Felip, MD, PhD, of Vall d’Hebron Institute of Oncology in Barcelona, Spain, argued in favor of using liquid biopsy for disease surveillance and decision making about adjuvant therapy.
“In early stage non–small cell lung cancer I think the evidence shows that pretreatment baseline ctDNA levels are clearly prognostic, and also, after surgical resection, the MRD predicts relapse, so we know that at present ctDNA and MRD are strong prognostic markers,” she said.
“I think ctDNA is useful as a noninvasive tool in both settings — at baseline pre surgery and also post surgery — to guide adjuvant therapy decision making,” she added.
Dr. Felip noted that so-called “tumor-informed” assays, such as sequencing of tumor tissue to identify mutations that can then be tracked in plasma samples, are high sensitivity methods, but have a long turnaround time, and approximately one in five patients does not have adequate tumor tissues for analysis.
In contrast, “tumor agnostic” methods rely on epigenetic features such as DNA methylation and cell-free DNA fragmentation patterns to detect tumor-derived DNA, but don’t rely on tumor tissue sample.
Dr. Felip cited a 2017 study published in Cancer Discovery showing that in patients with localized lung cancer post treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months. In addition, the investigators found that 53% of patients had ctDNA mutation profiles that suggested they would respond favorably to tyrosine kinase inhibitors or immune checkpoint inhibitors.
She also pointed to 2022 European Society for Medical Oncology (ESMO) recommendations on the use of ctDNA in patients with cancer, which state that detection of residual tumor DNA after NSCLC therapy with curative intent is associated with a high risk of future relapse, as supported by evidence from multiple studies. The recommendation also states, however, that there is insufficient evidence to recommend ctDNA testing in routine clinical practice in the absence of evidence from prospective clinical trials.
Evidence to support a benefit of ctDNA detection for treatment planning in the adjuvant setting come from several clinical studies, Dr. Felip said. For example, in a 2020 study published in Nature Cancer, investigators found that patients with detectable ctDNA after chemoradiotherapy who had treatment consolidation with an immune checkpoint inhibitor had significantly better freedom from progression compared with patients who had detectable ctDNA but did not receive consolidation immunotherapy.
In the IMpower010 trial, patients who were ctDNA-positive post surgery and received adjuvant atezolizumab (Tecentriq) had a median disease-free survival of 19.1 months, compared with 7.9 months for patients who did not get the immune checkpoint inhibitor, further indicating the value of ctDNA in the adjuvant setting, she said.
Wrapping up her argument, Dr. Felip acknowledged that currently the negative predictive value of ctDNA/MRD is suboptimal.
“However, we have seen that high ctDNA levels pre surgery predict poor outcome, and MRD-positive following definitive therapy is strongly prognostic and has extremely high positive predictive value for recurrence,” she said.
Taken together, the evidence suggests that patients who are ctDNA-positive preoperatively should be considered for neoadjuvant chemotherapy and immune checkpoint inhibition. If ctDNA persists after neoadjuvant therapy, patients should have extensive re-staging before surgery, because their options for pathologic complete response are limited. Patients who are MRD-positive after surgery should be treated with the same therapeutic approach as for patients with metastatic disease, Dr. Felip concluded.
CON: No Data Supporting OS Benefit
Offering counterpoint to Dr. Felip’s argument, Jordi Remon Masip, MD, PhD, of Gustave Roussy cancer treatment center in Villejuif, France, said that the currently available evidence suggests that MRD helps identify a high-risk population, but that its utility in the clinic is still uncertain.
“Today, I am a believer that we need prospective clinical trials, but one of the most important points today is to elucidate if the minimal residual disease is just prognostic or whether we really can use this minimal residual disease for making treatment decisions, not only escalating [but] also de-escalating treatment strategies in early stage non–small cell lung cancer,” he said.
Risk stratification may help to identify those patients who can most benefit from intensive therapy, but it appears to be much more difficult to risk stratify patients with early stage NSCLC, he said, pointing to the International Tailored Chemotherapy Adjuvant (ITACA) trial, a phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy versus standard adjuvant chemotherapy in patients with completely resected stage II-IIIA NSCLC. In this study, chemotherapy customized to individual patients according to molecular diagnostic analysis after surgery did not improve overall survival outcomes.
Dr. Masip said that as a clinician he would like to have any reliable tool that could help him to decide which patients need more therapy and which can do well with less.
He agreed that MRD-positivity as signaled by ctDNA after surgery or by a tumor-informed method correlates with poor prognosis, but he noted that MRD status depends on clinical characteristics such as sex, smoking status, age, stage, tumor size, histology, and many other factors that need to be taken into account if the assay is to have value in clinical practice.
“It’s true that the minimal residual disease may capture a poor prognostic population. However, even if we apply the minimal residual disease in our daily clinical practice, we can only capture, or we can only rescue 20% of the patients with the wild type or oncogenic early stage non–small cell lung cancer,” he said.
In addition, as Dr. Felip acknowledged, the negative predictive value of MRD is not infallible, with a 63% false negative rate compared with only a 2% false-positive rate.
“Half of the patients with the recurrence of the disease have a very, very low circulating tumor DNA, and the techniques are not sensitive enough to capture this minimal residual disease,” Dr. Masip said.
It would also be a mistake to forgo giving adjuvant therapy to those patients deemed to be MRD-negative on the basis of ctDNA, given the high false-negative rates, he said.
Oncologists also have to put themselves in their patients’ shoes:
“If our patients accept that with minimal residual disease I can only improve the disease-free survival without improving the overall survival, they would accept having less toxicity but the same survival that they would if they started the treatment later, and also what would happen if the patient is randomized to no adjuvant treatment because the minimal residual disease is negative, and some months later there is a recurrence of disease?” Dr. Masip said.
“I think we need more prospective data, but we really, really need a more sensitive test to avoid or to decrease the percentage of patients with false-negative results, and also we need very motivated patients that would accept to be randomized to de-escalate treatment strategies,” he concluded.
Dr. Felip disclosed advisory or speakers bureau roles for AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffman-La Roche, Genentech, Gilead, GlaxoSmithKline, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Novartis, PeerVoice, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics. She has served as a board member of Grifols. Dr. Masip disclosed research support from MSD, AstraZeneca, and Sanofi, and other financial relationships with AstraZeneca, Sanofi, Takeda Roche, and Janssen.
FROM ELCC 2024
Savolitinib Active Against MET Ex14 Mutated NSCLC
Savolitinib, a selective oral tyrosine kinase inhibitor, showed good activity against locally advanced or metastatic non–small cell lung cancer (NSCLC) bearing MET exon 14 mutations as both first-line therapy for treatment-naive patients and in second-line of therapy for previously treated patients
“The phase 3b study results further confirm savolitinib as a valuable targeted therapy option for naive and previously-treated non–small cell lung cancer with MET 14 exon mutations,” Yongchang Zhang, MD, said while presenting the final results of the trial at the European Lung Cancer Congress 2024.
For 87 previously untreated patients the objective response rate (ORR) as assessed by independent review, the primary endpoint, was 62.1%. For 79 patients receiving savolitinib in the second line, the ORR was 39.2%, reported Dr. Zhang, MD, of the Hunan Cancer Hospital in Changsha, China.
Preliminary results of this trial were reported at the World Conference on Lung Cancer in 2023.
Selective Inhibitor
Savolitinib (AZD6094, also called volitinib) is reported to be a highly selective oral inhibitor of the MET receptor tyrosine kinase (TKI). It is approved in China for the treatment of patients with NSCLC harboring MET exon 14 mutations that has progressed on prior systemic therapy, or patients who are unable to tolerate platinum-based chemotherapy.
In the phase 3b study, patients with MET ex14-positive tumors who were negative for EGFR, ALK or ROS1 alterations and were naive to a MET inhibitor were enrolled. Those who weighed 50 kg or greater received 600 mg savolitinib orally once daily for each 21-day cycle, while patients who weighed less than 50 kg received a 400-mg daily dose. Therapy continued until disease progression, death, or unacceptable toxicity.
Tumors were evaluated by investigators every 6 weeks for the first year, than every 12 weeks thereafter.
As noted before, ORR by independent review was 62.1% for treatment-naive patients and 39.2% for previously treated patients. The respective ORRs by investigator assessment were 59.8% and 43%. All responses in each arm were partial responses.
Median progression-free survival (PFS) after a median follow-up of 18 months for treatment-naive patients and 11 months for treatment-experienced patients was 13.7 months and 11 months, respectively.
Overall survival after a median follow-up of 20.8 months for treatment-naive patients and 12.5 months for previously treated patients was not reached in treatment-naive patients and not mature in treatment-experienced patients.
Grade 3 or greater treatment-emergent adverse events occurred in 74.1% of patients, including 3 events (1.8%) leading to death. Dose modifications were required for 74.7% of patients.
Grade 3 or greater adverse events included peripheral edema, liver enzyme elevations, abnormal liver function, decreased platelet and white blood cell counts, and vomiting.
Which TKI is Best?
Invited discussant Antonio Passaro, MD, PhD, from the European Institute of Oncology in Milan, noted that eligibility for treatment with savolitinib or other MET exon 14-targeting TKIs is limited to about 3% of patients with NSCLC of adenocarcinoma histology.
He said that savolitinib appears to be similar in performance to two other TKIs for NSCLC with MET exon-14 skipping mutations that are currently on the market in the United States, Europe, and Japan: capmatinib (Tabrecta) and tepotinib (Tepmetko).
“Globally, all the results show a numerically better performance when we use a selective TKI in first-line treatment over the second-line treatment, in particular for overall response rate,” he said.
Dr. Passaro noted that savolitinib differs from the other two MET TKIs in that PFS with savolitinib is similar for treatment-naive and previously treated patients.
He added, however, that “today it’s very difficult” to determine which is the “perfect” agent for a specific disease presentation, particularly since MET exon 14 skipping mutations can also be found in patients with squamous cell carcinomas and those with a history of smoking.
To get a better sense of which drug to use in a specific situation, it would be helpful to analyze trial results in the context of tumor histology, smoking history, programmed death protein 1-ligand 1 status, and co-mutations, he said.
The study was sponsored by Hutchmed. Dr. Zhang reported having no conflicts of interest. Dr. Passaro reported a consulting, advisory, or speakers bureau role for multiple companies, not including Hutchmed.
Savolitinib, a selective oral tyrosine kinase inhibitor, showed good activity against locally advanced or metastatic non–small cell lung cancer (NSCLC) bearing MET exon 14 mutations as both first-line therapy for treatment-naive patients and in second-line of therapy for previously treated patients
“The phase 3b study results further confirm savolitinib as a valuable targeted therapy option for naive and previously-treated non–small cell lung cancer with MET 14 exon mutations,” Yongchang Zhang, MD, said while presenting the final results of the trial at the European Lung Cancer Congress 2024.
For 87 previously untreated patients the objective response rate (ORR) as assessed by independent review, the primary endpoint, was 62.1%. For 79 patients receiving savolitinib in the second line, the ORR was 39.2%, reported Dr. Zhang, MD, of the Hunan Cancer Hospital in Changsha, China.
Preliminary results of this trial were reported at the World Conference on Lung Cancer in 2023.
Selective Inhibitor
Savolitinib (AZD6094, also called volitinib) is reported to be a highly selective oral inhibitor of the MET receptor tyrosine kinase (TKI). It is approved in China for the treatment of patients with NSCLC harboring MET exon 14 mutations that has progressed on prior systemic therapy, or patients who are unable to tolerate platinum-based chemotherapy.
In the phase 3b study, patients with MET ex14-positive tumors who were negative for EGFR, ALK or ROS1 alterations and were naive to a MET inhibitor were enrolled. Those who weighed 50 kg or greater received 600 mg savolitinib orally once daily for each 21-day cycle, while patients who weighed less than 50 kg received a 400-mg daily dose. Therapy continued until disease progression, death, or unacceptable toxicity.
Tumors were evaluated by investigators every 6 weeks for the first year, than every 12 weeks thereafter.
As noted before, ORR by independent review was 62.1% for treatment-naive patients and 39.2% for previously treated patients. The respective ORRs by investigator assessment were 59.8% and 43%. All responses in each arm were partial responses.
Median progression-free survival (PFS) after a median follow-up of 18 months for treatment-naive patients and 11 months for treatment-experienced patients was 13.7 months and 11 months, respectively.
Overall survival after a median follow-up of 20.8 months for treatment-naive patients and 12.5 months for previously treated patients was not reached in treatment-naive patients and not mature in treatment-experienced patients.
Grade 3 or greater treatment-emergent adverse events occurred in 74.1% of patients, including 3 events (1.8%) leading to death. Dose modifications were required for 74.7% of patients.
Grade 3 or greater adverse events included peripheral edema, liver enzyme elevations, abnormal liver function, decreased platelet and white blood cell counts, and vomiting.
Which TKI is Best?
Invited discussant Antonio Passaro, MD, PhD, from the European Institute of Oncology in Milan, noted that eligibility for treatment with savolitinib or other MET exon 14-targeting TKIs is limited to about 3% of patients with NSCLC of adenocarcinoma histology.
He said that savolitinib appears to be similar in performance to two other TKIs for NSCLC with MET exon-14 skipping mutations that are currently on the market in the United States, Europe, and Japan: capmatinib (Tabrecta) and tepotinib (Tepmetko).
“Globally, all the results show a numerically better performance when we use a selective TKI in first-line treatment over the second-line treatment, in particular for overall response rate,” he said.
Dr. Passaro noted that savolitinib differs from the other two MET TKIs in that PFS with savolitinib is similar for treatment-naive and previously treated patients.
He added, however, that “today it’s very difficult” to determine which is the “perfect” agent for a specific disease presentation, particularly since MET exon 14 skipping mutations can also be found in patients with squamous cell carcinomas and those with a history of smoking.
To get a better sense of which drug to use in a specific situation, it would be helpful to analyze trial results in the context of tumor histology, smoking history, programmed death protein 1-ligand 1 status, and co-mutations, he said.
The study was sponsored by Hutchmed. Dr. Zhang reported having no conflicts of interest. Dr. Passaro reported a consulting, advisory, or speakers bureau role for multiple companies, not including Hutchmed.
Savolitinib, a selective oral tyrosine kinase inhibitor, showed good activity against locally advanced or metastatic non–small cell lung cancer (NSCLC) bearing MET exon 14 mutations as both first-line therapy for treatment-naive patients and in second-line of therapy for previously treated patients
“The phase 3b study results further confirm savolitinib as a valuable targeted therapy option for naive and previously-treated non–small cell lung cancer with MET 14 exon mutations,” Yongchang Zhang, MD, said while presenting the final results of the trial at the European Lung Cancer Congress 2024.
For 87 previously untreated patients the objective response rate (ORR) as assessed by independent review, the primary endpoint, was 62.1%. For 79 patients receiving savolitinib in the second line, the ORR was 39.2%, reported Dr. Zhang, MD, of the Hunan Cancer Hospital in Changsha, China.
Preliminary results of this trial were reported at the World Conference on Lung Cancer in 2023.
Selective Inhibitor
Savolitinib (AZD6094, also called volitinib) is reported to be a highly selective oral inhibitor of the MET receptor tyrosine kinase (TKI). It is approved in China for the treatment of patients with NSCLC harboring MET exon 14 mutations that has progressed on prior systemic therapy, or patients who are unable to tolerate platinum-based chemotherapy.
In the phase 3b study, patients with MET ex14-positive tumors who were negative for EGFR, ALK or ROS1 alterations and were naive to a MET inhibitor were enrolled. Those who weighed 50 kg or greater received 600 mg savolitinib orally once daily for each 21-day cycle, while patients who weighed less than 50 kg received a 400-mg daily dose. Therapy continued until disease progression, death, or unacceptable toxicity.
Tumors were evaluated by investigators every 6 weeks for the first year, than every 12 weeks thereafter.
As noted before, ORR by independent review was 62.1% for treatment-naive patients and 39.2% for previously treated patients. The respective ORRs by investigator assessment were 59.8% and 43%. All responses in each arm were partial responses.
Median progression-free survival (PFS) after a median follow-up of 18 months for treatment-naive patients and 11 months for treatment-experienced patients was 13.7 months and 11 months, respectively.
Overall survival after a median follow-up of 20.8 months for treatment-naive patients and 12.5 months for previously treated patients was not reached in treatment-naive patients and not mature in treatment-experienced patients.
Grade 3 or greater treatment-emergent adverse events occurred in 74.1% of patients, including 3 events (1.8%) leading to death. Dose modifications were required for 74.7% of patients.
Grade 3 or greater adverse events included peripheral edema, liver enzyme elevations, abnormal liver function, decreased platelet and white blood cell counts, and vomiting.
Which TKI is Best?
Invited discussant Antonio Passaro, MD, PhD, from the European Institute of Oncology in Milan, noted that eligibility for treatment with savolitinib or other MET exon 14-targeting TKIs is limited to about 3% of patients with NSCLC of adenocarcinoma histology.
He said that savolitinib appears to be similar in performance to two other TKIs for NSCLC with MET exon-14 skipping mutations that are currently on the market in the United States, Europe, and Japan: capmatinib (Tabrecta) and tepotinib (Tepmetko).
“Globally, all the results show a numerically better performance when we use a selective TKI in first-line treatment over the second-line treatment, in particular for overall response rate,” he said.
Dr. Passaro noted that savolitinib differs from the other two MET TKIs in that PFS with savolitinib is similar for treatment-naive and previously treated patients.
He added, however, that “today it’s very difficult” to determine which is the “perfect” agent for a specific disease presentation, particularly since MET exon 14 skipping mutations can also be found in patients with squamous cell carcinomas and those with a history of smoking.
To get a better sense of which drug to use in a specific situation, it would be helpful to analyze trial results in the context of tumor histology, smoking history, programmed death protein 1-ligand 1 status, and co-mutations, he said.
The study was sponsored by Hutchmed. Dr. Zhang reported having no conflicts of interest. Dr. Passaro reported a consulting, advisory, or speakers bureau role for multiple companies, not including Hutchmed.
FROM ELCC 2024
Minimally Invasive Cytoreductive Approach Comparable to Open Surgery for Ovarian Cancer
This was a finding of a retrospective study presented by Judy Hayek, MD, during an oral abstract session at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, in San Diego.
Among 2,412 women in the National Cancer Database with tumor-free surgical margins (R0 resections) after interval debulking surgery (IDS), the median overall survival (OS) was 46 months for those who had undergone an open procedure or minimally invasive surgery (MIS) that was converted to an open procedure. In contrast, the median OS was 51 months for patients who underwent laparoscopic or robot-assisted minimally invasive surgery, reported Dr. Hayek, a gynecologic oncology fellow at SUNY Downstate Health Sciences University in Brooklyn, New York.
“R0 resection at the time of interval debulking surgery has similar survival outcomes by minimally invasive surgery versus laparotomy, while R0 resection via laparotomy is associated with higher perioperative mortality. There is no interaction between the extent of surgery and the impact of MIS on survival,” she said during her presentation.
The session included a debate on the pros and cons of minimally invasive vs. open surgery in this population.
Growing Use of MIS
Over the last decade, minimally invasive surgery for interval debulking was shown to be safe and feasible. More recently, two studies using National Cancer Database cohorts showed that survival was similar and perioperative outcomes were better with a minimally invasive approach at the time of IDS for patients with early disease, Dr. Hayek said (Obstet Gynecol 2017 Jul;130(1):71-79; and Gynecol Oncol 2023 May:172:130-137).
Potential limitations of MIS include the absence of haptic feedback compared with open surgery, and the possibility that limited visualization of the surgical field could lead to missed residual disease and subsequent poor outcomes for patients who were presumed to have complete gross resections, she said.
Outcomes Compared
Dr. Hayek and colleagues conducted their study to evaluate survival outcomes after R0 resections by MIS or laparotomy in IDS for patients with advanced epithelial ovarian cancer.
As noted before, they looked at outcomes for 2,412 women with stage IIIC or IV cancers of all histology types who were diagnosed from 2010 through 2019. A total of 624 patients (25.9%) had minimally invasive procedures, and 1,788 (74.1%) had open surgery or MIS that had been converted to open procedures.
Of the minimally invasive procedures, 48.7% were robot-assisted, and the remainder were laparoscopic.
Over the decade of the study, the frequency of minimally invasive surgery steadily increased, from 11.9% of all procedures in 2010 to 36.5% in 2019.
Also as noted, there was no difference in median overall survival, at 46 months for open/converted procedures vs. 51 months for minimally invasive procedures.
As might be expected, the mean length of stay was shorter with the less invasive surgery: 3.3 days compared with 5.3 days with open surgery (P less than .001). In addition, 30-day and 90-day mortality rates were also lower with MIS, at 0.8% and 1.9%, respectively, compared with 1.6% and 3.5% with laparotomy (P = .006 for 30-day mortality, and .003 for 90-day).
There were also no differences in overall survival between the procedure types when the cases were stratified according to extent of surgery. Within the minimally invasive surgery groups there were no differences in median OS for patients whose surgery was performed laparoscopically or with robotic assistance.
The study was limited by a lack of data on either patient-specific tumor burden, neoadjuvant chemotherapy use, progression-free survival, cause of death, or surgical morbidity, Dr. Hayek acknowledged.
MIS Use Debatable: CON
Despite the good outcomes with minimally invasive techniques in this favorable-risk population, critics contend that MIS interval cytoreduction is too risky in the majority of cases.
In the debate portion of the session, Kara Long Roche, MD, an associate attending in the section of ovarian cancer surgery at Memorial Sloan Kettering Cancer Center in New York, argued that the potential for MIS missing residual disease is too great.
“We know from almost every retrospective and prospective study done that the volume of residual disease after debulking, whether primary or interval, is the most important prognostic factor for our patients that we can modify,” she said.
Rather than debating morbidity, mortality, or criteria for resection, “I would argue that the question we need to debate is can MIS interval debulking achieve a completeness of resection, i.e., volume of residual disease?” she said.
Dr. Roche contended that retrospective studies such as that reported by Dr. Hayek cannot adequately answer this question because of selection bias. Patients selected for MIS have better responses to neoadjuvant chemotherapy and more favorable tumor biology; and, therefore, overall survival may not be the optimal endpoint for retrospective studies.
In addition, neoadjuvant chemotherapy does not automatically preclude the need for extensive upper abdominal surgery since almost half of patients who receive neoadjuvant chemotherapy are found to have bulky upper abdominal disease at the time of debulking.
Dr. Roche especially cautioned against what she called the WNL or “We Never Looked” phenomenon, in which patients are found on open surgery and organ mobilization to have disease that was not evident on presurgical imaging.
She acknowledged that for some patients the risks of laparotomy are likely to outweigh the benefit of a radical resection, and stressed that for such patients forgoing surgery or optimizing perioperative care may be more important than the size of the incision.
MIS IDS should be the exception, not the rule. We need prospective data with appropriate endpoints. We need surgical quality control in both arms, and we need to continue to focus on surgical education and training so that our trainees can graduate doing these procedures via any approach,” she concluded.
Debate: PRO
Arguing in favor of MIS for ovarian cancer, J. Alejandro Rauh-Hain, MD, MPH, associate professor of gynecologic oncology at the University of Texas MD Anderson Cancer Center in Houston, told attendees “the only bias I have is that I actually love doing open surgery, but I’m going to try to convince you that there is a potential role for minimally invasive surgery in the future for selected patients with ovarian cancer after neoadjuvant chemotherapy.”
He noted that several studies have convincingly shown that neoadjuvant chemotherapy does not adversely affect oncologic outcomes for patients with advanced-stage ovarian cancer, and decreases perioperative morbidity in patients who receive it, including reductions in serious adverse events, risk of stoma, and 30-day postoperative mortality.
In addition, low use of neoadjuvant chemotherapy is associated with increased risks for 90-day postoperative deaths in both low- and high surgical volume centers in the US, according to unpublished National Cancer Database data.
Dr. Rauh-Hain noted that neoadjuvant chemotherapy use has steadily increased from 2010 through 2020, and added that in 2022, 32% of interval cytoreductive surgeries in the United States were performed with a minimally invasive approach.
To get a better handle on the MIS vs. open-surgery question, Dr. Rauh-Hain and colleagues at MD Anderson and 13 other centers in the United States, Canada, and Europe are currently recruiting patients for the Laparoscopic Cytoreduction After Neoadjuvant Chemotherapy (LANCE) trial. In this phase 3 noninferiority study, patients with stage IIIC-IV ovarian, primary peritoneal, or fallopian tube cancer who have complete or partial responses and CA125 normalization after three or four cycles of neoadjuvant chemotherapy will be randomized to laparotomy or MIS, followed by adjuvant platinum- and taxane-based chemotherapy.
The study by Hayek et al. was internally supported. Dr. Hayek and Dr. Roche reported having no conflicts of interest. Dr. Rauh-Hain disclosed financial relationships with Guidepoint Consulting, and the Schlesinger Group.
This was a finding of a retrospective study presented by Judy Hayek, MD, during an oral abstract session at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, in San Diego.
Among 2,412 women in the National Cancer Database with tumor-free surgical margins (R0 resections) after interval debulking surgery (IDS), the median overall survival (OS) was 46 months for those who had undergone an open procedure or minimally invasive surgery (MIS) that was converted to an open procedure. In contrast, the median OS was 51 months for patients who underwent laparoscopic or robot-assisted minimally invasive surgery, reported Dr. Hayek, a gynecologic oncology fellow at SUNY Downstate Health Sciences University in Brooklyn, New York.
“R0 resection at the time of interval debulking surgery has similar survival outcomes by minimally invasive surgery versus laparotomy, while R0 resection via laparotomy is associated with higher perioperative mortality. There is no interaction between the extent of surgery and the impact of MIS on survival,” she said during her presentation.
The session included a debate on the pros and cons of minimally invasive vs. open surgery in this population.
Growing Use of MIS
Over the last decade, minimally invasive surgery for interval debulking was shown to be safe and feasible. More recently, two studies using National Cancer Database cohorts showed that survival was similar and perioperative outcomes were better with a minimally invasive approach at the time of IDS for patients with early disease, Dr. Hayek said (Obstet Gynecol 2017 Jul;130(1):71-79; and Gynecol Oncol 2023 May:172:130-137).
Potential limitations of MIS include the absence of haptic feedback compared with open surgery, and the possibility that limited visualization of the surgical field could lead to missed residual disease and subsequent poor outcomes for patients who were presumed to have complete gross resections, she said.
Outcomes Compared
Dr. Hayek and colleagues conducted their study to evaluate survival outcomes after R0 resections by MIS or laparotomy in IDS for patients with advanced epithelial ovarian cancer.
As noted before, they looked at outcomes for 2,412 women with stage IIIC or IV cancers of all histology types who were diagnosed from 2010 through 2019. A total of 624 patients (25.9%) had minimally invasive procedures, and 1,788 (74.1%) had open surgery or MIS that had been converted to open procedures.
Of the minimally invasive procedures, 48.7% were robot-assisted, and the remainder were laparoscopic.
Over the decade of the study, the frequency of minimally invasive surgery steadily increased, from 11.9% of all procedures in 2010 to 36.5% in 2019.
Also as noted, there was no difference in median overall survival, at 46 months for open/converted procedures vs. 51 months for minimally invasive procedures.
As might be expected, the mean length of stay was shorter with the less invasive surgery: 3.3 days compared with 5.3 days with open surgery (P less than .001). In addition, 30-day and 90-day mortality rates were also lower with MIS, at 0.8% and 1.9%, respectively, compared with 1.6% and 3.5% with laparotomy (P = .006 for 30-day mortality, and .003 for 90-day).
There were also no differences in overall survival between the procedure types when the cases were stratified according to extent of surgery. Within the minimally invasive surgery groups there were no differences in median OS for patients whose surgery was performed laparoscopically or with robotic assistance.
The study was limited by a lack of data on either patient-specific tumor burden, neoadjuvant chemotherapy use, progression-free survival, cause of death, or surgical morbidity, Dr. Hayek acknowledged.
MIS Use Debatable: CON
Despite the good outcomes with minimally invasive techniques in this favorable-risk population, critics contend that MIS interval cytoreduction is too risky in the majority of cases.
In the debate portion of the session, Kara Long Roche, MD, an associate attending in the section of ovarian cancer surgery at Memorial Sloan Kettering Cancer Center in New York, argued that the potential for MIS missing residual disease is too great.
“We know from almost every retrospective and prospective study done that the volume of residual disease after debulking, whether primary or interval, is the most important prognostic factor for our patients that we can modify,” she said.
Rather than debating morbidity, mortality, or criteria for resection, “I would argue that the question we need to debate is can MIS interval debulking achieve a completeness of resection, i.e., volume of residual disease?” she said.
Dr. Roche contended that retrospective studies such as that reported by Dr. Hayek cannot adequately answer this question because of selection bias. Patients selected for MIS have better responses to neoadjuvant chemotherapy and more favorable tumor biology; and, therefore, overall survival may not be the optimal endpoint for retrospective studies.
In addition, neoadjuvant chemotherapy does not automatically preclude the need for extensive upper abdominal surgery since almost half of patients who receive neoadjuvant chemotherapy are found to have bulky upper abdominal disease at the time of debulking.
Dr. Roche especially cautioned against what she called the WNL or “We Never Looked” phenomenon, in which patients are found on open surgery and organ mobilization to have disease that was not evident on presurgical imaging.
She acknowledged that for some patients the risks of laparotomy are likely to outweigh the benefit of a radical resection, and stressed that for such patients forgoing surgery or optimizing perioperative care may be more important than the size of the incision.
MIS IDS should be the exception, not the rule. We need prospective data with appropriate endpoints. We need surgical quality control in both arms, and we need to continue to focus on surgical education and training so that our trainees can graduate doing these procedures via any approach,” she concluded.
Debate: PRO
Arguing in favor of MIS for ovarian cancer, J. Alejandro Rauh-Hain, MD, MPH, associate professor of gynecologic oncology at the University of Texas MD Anderson Cancer Center in Houston, told attendees “the only bias I have is that I actually love doing open surgery, but I’m going to try to convince you that there is a potential role for minimally invasive surgery in the future for selected patients with ovarian cancer after neoadjuvant chemotherapy.”
He noted that several studies have convincingly shown that neoadjuvant chemotherapy does not adversely affect oncologic outcomes for patients with advanced-stage ovarian cancer, and decreases perioperative morbidity in patients who receive it, including reductions in serious adverse events, risk of stoma, and 30-day postoperative mortality.
In addition, low use of neoadjuvant chemotherapy is associated with increased risks for 90-day postoperative deaths in both low- and high surgical volume centers in the US, according to unpublished National Cancer Database data.
Dr. Rauh-Hain noted that neoadjuvant chemotherapy use has steadily increased from 2010 through 2020, and added that in 2022, 32% of interval cytoreductive surgeries in the United States were performed with a minimally invasive approach.
To get a better handle on the MIS vs. open-surgery question, Dr. Rauh-Hain and colleagues at MD Anderson and 13 other centers in the United States, Canada, and Europe are currently recruiting patients for the Laparoscopic Cytoreduction After Neoadjuvant Chemotherapy (LANCE) trial. In this phase 3 noninferiority study, patients with stage IIIC-IV ovarian, primary peritoneal, or fallopian tube cancer who have complete or partial responses and CA125 normalization after three or four cycles of neoadjuvant chemotherapy will be randomized to laparotomy or MIS, followed by adjuvant platinum- and taxane-based chemotherapy.
The study by Hayek et al. was internally supported. Dr. Hayek and Dr. Roche reported having no conflicts of interest. Dr. Rauh-Hain disclosed financial relationships with Guidepoint Consulting, and the Schlesinger Group.
This was a finding of a retrospective study presented by Judy Hayek, MD, during an oral abstract session at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, in San Diego.
Among 2,412 women in the National Cancer Database with tumor-free surgical margins (R0 resections) after interval debulking surgery (IDS), the median overall survival (OS) was 46 months for those who had undergone an open procedure or minimally invasive surgery (MIS) that was converted to an open procedure. In contrast, the median OS was 51 months for patients who underwent laparoscopic or robot-assisted minimally invasive surgery, reported Dr. Hayek, a gynecologic oncology fellow at SUNY Downstate Health Sciences University in Brooklyn, New York.
“R0 resection at the time of interval debulking surgery has similar survival outcomes by minimally invasive surgery versus laparotomy, while R0 resection via laparotomy is associated with higher perioperative mortality. There is no interaction between the extent of surgery and the impact of MIS on survival,” she said during her presentation.
The session included a debate on the pros and cons of minimally invasive vs. open surgery in this population.
Growing Use of MIS
Over the last decade, minimally invasive surgery for interval debulking was shown to be safe and feasible. More recently, two studies using National Cancer Database cohorts showed that survival was similar and perioperative outcomes were better with a minimally invasive approach at the time of IDS for patients with early disease, Dr. Hayek said (Obstet Gynecol 2017 Jul;130(1):71-79; and Gynecol Oncol 2023 May:172:130-137).
Potential limitations of MIS include the absence of haptic feedback compared with open surgery, and the possibility that limited visualization of the surgical field could lead to missed residual disease and subsequent poor outcomes for patients who were presumed to have complete gross resections, she said.
Outcomes Compared
Dr. Hayek and colleagues conducted their study to evaluate survival outcomes after R0 resections by MIS or laparotomy in IDS for patients with advanced epithelial ovarian cancer.
As noted before, they looked at outcomes for 2,412 women with stage IIIC or IV cancers of all histology types who were diagnosed from 2010 through 2019. A total of 624 patients (25.9%) had minimally invasive procedures, and 1,788 (74.1%) had open surgery or MIS that had been converted to open procedures.
Of the minimally invasive procedures, 48.7% were robot-assisted, and the remainder were laparoscopic.
Over the decade of the study, the frequency of minimally invasive surgery steadily increased, from 11.9% of all procedures in 2010 to 36.5% in 2019.
Also as noted, there was no difference in median overall survival, at 46 months for open/converted procedures vs. 51 months for minimally invasive procedures.
As might be expected, the mean length of stay was shorter with the less invasive surgery: 3.3 days compared with 5.3 days with open surgery (P less than .001). In addition, 30-day and 90-day mortality rates were also lower with MIS, at 0.8% and 1.9%, respectively, compared with 1.6% and 3.5% with laparotomy (P = .006 for 30-day mortality, and .003 for 90-day).
There were also no differences in overall survival between the procedure types when the cases were stratified according to extent of surgery. Within the minimally invasive surgery groups there were no differences in median OS for patients whose surgery was performed laparoscopically or with robotic assistance.
The study was limited by a lack of data on either patient-specific tumor burden, neoadjuvant chemotherapy use, progression-free survival, cause of death, or surgical morbidity, Dr. Hayek acknowledged.
MIS Use Debatable: CON
Despite the good outcomes with minimally invasive techniques in this favorable-risk population, critics contend that MIS interval cytoreduction is too risky in the majority of cases.
In the debate portion of the session, Kara Long Roche, MD, an associate attending in the section of ovarian cancer surgery at Memorial Sloan Kettering Cancer Center in New York, argued that the potential for MIS missing residual disease is too great.
“We know from almost every retrospective and prospective study done that the volume of residual disease after debulking, whether primary or interval, is the most important prognostic factor for our patients that we can modify,” she said.
Rather than debating morbidity, mortality, or criteria for resection, “I would argue that the question we need to debate is can MIS interval debulking achieve a completeness of resection, i.e., volume of residual disease?” she said.
Dr. Roche contended that retrospective studies such as that reported by Dr. Hayek cannot adequately answer this question because of selection bias. Patients selected for MIS have better responses to neoadjuvant chemotherapy and more favorable tumor biology; and, therefore, overall survival may not be the optimal endpoint for retrospective studies.
In addition, neoadjuvant chemotherapy does not automatically preclude the need for extensive upper abdominal surgery since almost half of patients who receive neoadjuvant chemotherapy are found to have bulky upper abdominal disease at the time of debulking.
Dr. Roche especially cautioned against what she called the WNL or “We Never Looked” phenomenon, in which patients are found on open surgery and organ mobilization to have disease that was not evident on presurgical imaging.
She acknowledged that for some patients the risks of laparotomy are likely to outweigh the benefit of a radical resection, and stressed that for such patients forgoing surgery or optimizing perioperative care may be more important than the size of the incision.
MIS IDS should be the exception, not the rule. We need prospective data with appropriate endpoints. We need surgical quality control in both arms, and we need to continue to focus on surgical education and training so that our trainees can graduate doing these procedures via any approach,” she concluded.
Debate: PRO
Arguing in favor of MIS for ovarian cancer, J. Alejandro Rauh-Hain, MD, MPH, associate professor of gynecologic oncology at the University of Texas MD Anderson Cancer Center in Houston, told attendees “the only bias I have is that I actually love doing open surgery, but I’m going to try to convince you that there is a potential role for minimally invasive surgery in the future for selected patients with ovarian cancer after neoadjuvant chemotherapy.”
He noted that several studies have convincingly shown that neoadjuvant chemotherapy does not adversely affect oncologic outcomes for patients with advanced-stage ovarian cancer, and decreases perioperative morbidity in patients who receive it, including reductions in serious adverse events, risk of stoma, and 30-day postoperative mortality.
In addition, low use of neoadjuvant chemotherapy is associated with increased risks for 90-day postoperative deaths in both low- and high surgical volume centers in the US, according to unpublished National Cancer Database data.
Dr. Rauh-Hain noted that neoadjuvant chemotherapy use has steadily increased from 2010 through 2020, and added that in 2022, 32% of interval cytoreductive surgeries in the United States were performed with a minimally invasive approach.
To get a better handle on the MIS vs. open-surgery question, Dr. Rauh-Hain and colleagues at MD Anderson and 13 other centers in the United States, Canada, and Europe are currently recruiting patients for the Laparoscopic Cytoreduction After Neoadjuvant Chemotherapy (LANCE) trial. In this phase 3 noninferiority study, patients with stage IIIC-IV ovarian, primary peritoneal, or fallopian tube cancer who have complete or partial responses and CA125 normalization after three or four cycles of neoadjuvant chemotherapy will be randomized to laparotomy or MIS, followed by adjuvant platinum- and taxane-based chemotherapy.
The study by Hayek et al. was internally supported. Dr. Hayek and Dr. Roche reported having no conflicts of interest. Dr. Rauh-Hain disclosed financial relationships with Guidepoint Consulting, and the Schlesinger Group.
FROM SGO 2024
Therapeutic HPV16 vaccine clears virus in most patients with CIN
The vaccine, pNGVL4a-CRTE6E7L2, also showed signs of efficacy in patients living with HIV, reported Kimberly Lynn Levinson, MD, MPH, associate professor of obstetrics and gynecology at Johns Hopkins Medicine in Baltimore.
“We demonstrated a 78% rate of clearance for both histologic regression and HPV16, with some clearance of other HPV types,” she said in an oral abstract presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, held in San Diego.
Further evaluation of the vaccine in vulvar, vaginal, and other tissue types is required, and evaluation of immune response at the local and systemic is ongoing, Dr. Levinson said.
In contrast to HPV16 prophylactic vaccines, which form an antibody-specific response to HPV, therapeutic vaccines elicit a cell-mediated immunity, primarily focusing on the virus’ E6 and E7 proteins.
There are currently only three Food and Drug Administration–approved therapeutic vaccines for cancer, but none are as yet approved for treatment of gynecologic malignancies.
According to the US National Institutes of Health, there are multiple therapeutic HPV vaccines in development using either vector-based, peptide and protein-based, or nucleic-acid based approaches, or whole cell (dendritic cell) approaches.
Current Study
Dr. Levinson noted that “DNA vaccines are both well tolerated and simple to produce, and the addition of calreticulin enhances immune response.”
The investigational vaccine is delivered via an electoporation device (TriGrid delivery system) that stimulates muscle at the injection site to produce an enhanced immune response.
In preclinical studies the device was associated with an enhanced immune response compared with standard intramuscular injection. The enhance immune effect persisted despite CD4 T cell depletion.
The investigators conducted a phase 1 dose-escalation study, administering the vaccine to two separate cohorts: women without HIV who had HPV16-positive cervical dysplasia (CIN 2/3) and women living with HIV with HPV16-positive cervical or vulvovaginal dysplasia (CIN 2/3, VIN 2/3 or VAIN 2/3).
The vaccine was delivered at weeks 0, 4, and 8, at doses of 0.3 mg, 1.0 mg, or 3.0 mg. At week 12, all patients underwent site-specific biopsy to verify non-progression.
At 6 months, the patients then underwent definitive treatment with either loop electro excision or vulvar/vaginal excision. At 12 months, all patients had standard evaluations with biopsies.
Dr. Levinson reported results for the first 14 women enrolled, 10 of whom were HIV-negative and 4 of whom were HIV-positive.
Of nine women in the HIV-negative arm who had completed 6-month visits and were evaluable, two had HPV16 clearance by 2-month follow-up, and seven had clearance at 6 months. Other HPV subtypes cleared in two of five patients at 3 months and in three of five at 6 months.
In addition, seven of nine patients in this arm had histologic regression at 6 months.
In the HIV-positive arm, the two patients with CIN had no HPV16 clearance at 3 months, but both had clearance at 16 months. The vaccine did not clear other HPV subtypes in these patients, however.
Of the two women in this arm who had VIN, one had HPV16 clearance and histologic regression at 6 months. The other patient had neither viral clearance nor histologic regression.
All participants tolerated each vaccine well. Adverse events were all grade 1 in severity and resolved within 4 weeks. The most common event was tenderness at the injection site. There were also three cases of mild headache, two cases of drowsiness, and one of nausea.
What’s Next?
In the question-and-answer session following the presentation, Ronald D. Alvarez, MD, MBA, chairman and clinical service chief of obstetrics and gynecology at Vanderbilt University Medical Center in Nashville, Tennessee, asked Dr. Levinson how the vaccine development will proceed.
“Obviously, you have more data to collect and analyze, but how are you going to move forward with what looks like equal efficacy between the 1 milligram and the 3 milligram doses? Are you just going to go with the maximum tolerated dose, or consider a lower dose if it shows equal efficacy in terms of histologic regression as well as HPV clearance?” he asked.
“This is something we’re very interested in, and we do plan for the dose-expansion phase to go with the higher dose,” Dr. Levinson replied. “We need to evaluate it further and we may need to do further randomization between the medium dose and the highest dose to determine if there are differences both with systemic and local responses.”
Robert DeBernardo, MD, section head of obstetrics and gynecology and the Women’s Health Institute at the Cleveland Clinic, asked whether Dr. Levinson and colleagues were considering evaluating the vaccine in transplant recipients, “because we have a lot of persistent HPV in that subgroup.”
Dr. Levinson said that one of the dose-expansion cohorts for further study is a population of patients scheduled for transplantation.
“What we’re interested in is looking at whether we can ‘cure’ HPV prior to transplantation, and we think that’s going to be the best way to show that this vaccine potentially eliminates the virus, because if we can eliminate the virus and then take a population that’s going to be immunodeficient, then that would show that there’s no reactivation of the virus,” she said.
The study is supported by the National Institutes of Health. Dr. Levinson, Dr. Alvarez, and Dr. DeBernardo had no conflicts of interest to report.
The vaccine, pNGVL4a-CRTE6E7L2, also showed signs of efficacy in patients living with HIV, reported Kimberly Lynn Levinson, MD, MPH, associate professor of obstetrics and gynecology at Johns Hopkins Medicine in Baltimore.
“We demonstrated a 78% rate of clearance for both histologic regression and HPV16, with some clearance of other HPV types,” she said in an oral abstract presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, held in San Diego.
Further evaluation of the vaccine in vulvar, vaginal, and other tissue types is required, and evaluation of immune response at the local and systemic is ongoing, Dr. Levinson said.
In contrast to HPV16 prophylactic vaccines, which form an antibody-specific response to HPV, therapeutic vaccines elicit a cell-mediated immunity, primarily focusing on the virus’ E6 and E7 proteins.
There are currently only three Food and Drug Administration–approved therapeutic vaccines for cancer, but none are as yet approved for treatment of gynecologic malignancies.
According to the US National Institutes of Health, there are multiple therapeutic HPV vaccines in development using either vector-based, peptide and protein-based, or nucleic-acid based approaches, or whole cell (dendritic cell) approaches.
Current Study
Dr. Levinson noted that “DNA vaccines are both well tolerated and simple to produce, and the addition of calreticulin enhances immune response.”
The investigational vaccine is delivered via an electoporation device (TriGrid delivery system) that stimulates muscle at the injection site to produce an enhanced immune response.
In preclinical studies the device was associated with an enhanced immune response compared with standard intramuscular injection. The enhance immune effect persisted despite CD4 T cell depletion.
The investigators conducted a phase 1 dose-escalation study, administering the vaccine to two separate cohorts: women without HIV who had HPV16-positive cervical dysplasia (CIN 2/3) and women living with HIV with HPV16-positive cervical or vulvovaginal dysplasia (CIN 2/3, VIN 2/3 or VAIN 2/3).
The vaccine was delivered at weeks 0, 4, and 8, at doses of 0.3 mg, 1.0 mg, or 3.0 mg. At week 12, all patients underwent site-specific biopsy to verify non-progression.
At 6 months, the patients then underwent definitive treatment with either loop electro excision or vulvar/vaginal excision. At 12 months, all patients had standard evaluations with biopsies.
Dr. Levinson reported results for the first 14 women enrolled, 10 of whom were HIV-negative and 4 of whom were HIV-positive.
Of nine women in the HIV-negative arm who had completed 6-month visits and were evaluable, two had HPV16 clearance by 2-month follow-up, and seven had clearance at 6 months. Other HPV subtypes cleared in two of five patients at 3 months and in three of five at 6 months.
In addition, seven of nine patients in this arm had histologic regression at 6 months.
In the HIV-positive arm, the two patients with CIN had no HPV16 clearance at 3 months, but both had clearance at 16 months. The vaccine did not clear other HPV subtypes in these patients, however.
Of the two women in this arm who had VIN, one had HPV16 clearance and histologic regression at 6 months. The other patient had neither viral clearance nor histologic regression.
All participants tolerated each vaccine well. Adverse events were all grade 1 in severity and resolved within 4 weeks. The most common event was tenderness at the injection site. There were also three cases of mild headache, two cases of drowsiness, and one of nausea.
What’s Next?
In the question-and-answer session following the presentation, Ronald D. Alvarez, MD, MBA, chairman and clinical service chief of obstetrics and gynecology at Vanderbilt University Medical Center in Nashville, Tennessee, asked Dr. Levinson how the vaccine development will proceed.
“Obviously, you have more data to collect and analyze, but how are you going to move forward with what looks like equal efficacy between the 1 milligram and the 3 milligram doses? Are you just going to go with the maximum tolerated dose, or consider a lower dose if it shows equal efficacy in terms of histologic regression as well as HPV clearance?” he asked.
“This is something we’re very interested in, and we do plan for the dose-expansion phase to go with the higher dose,” Dr. Levinson replied. “We need to evaluate it further and we may need to do further randomization between the medium dose and the highest dose to determine if there are differences both with systemic and local responses.”
Robert DeBernardo, MD, section head of obstetrics and gynecology and the Women’s Health Institute at the Cleveland Clinic, asked whether Dr. Levinson and colleagues were considering evaluating the vaccine in transplant recipients, “because we have a lot of persistent HPV in that subgroup.”
Dr. Levinson said that one of the dose-expansion cohorts for further study is a population of patients scheduled for transplantation.
“What we’re interested in is looking at whether we can ‘cure’ HPV prior to transplantation, and we think that’s going to be the best way to show that this vaccine potentially eliminates the virus, because if we can eliminate the virus and then take a population that’s going to be immunodeficient, then that would show that there’s no reactivation of the virus,” she said.
The study is supported by the National Institutes of Health. Dr. Levinson, Dr. Alvarez, and Dr. DeBernardo had no conflicts of interest to report.
The vaccine, pNGVL4a-CRTE6E7L2, also showed signs of efficacy in patients living with HIV, reported Kimberly Lynn Levinson, MD, MPH, associate professor of obstetrics and gynecology at Johns Hopkins Medicine in Baltimore.
“We demonstrated a 78% rate of clearance for both histologic regression and HPV16, with some clearance of other HPV types,” she said in an oral abstract presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, held in San Diego.
Further evaluation of the vaccine in vulvar, vaginal, and other tissue types is required, and evaluation of immune response at the local and systemic is ongoing, Dr. Levinson said.
In contrast to HPV16 prophylactic vaccines, which form an antibody-specific response to HPV, therapeutic vaccines elicit a cell-mediated immunity, primarily focusing on the virus’ E6 and E7 proteins.
There are currently only three Food and Drug Administration–approved therapeutic vaccines for cancer, but none are as yet approved for treatment of gynecologic malignancies.
According to the US National Institutes of Health, there are multiple therapeutic HPV vaccines in development using either vector-based, peptide and protein-based, or nucleic-acid based approaches, or whole cell (dendritic cell) approaches.
Current Study
Dr. Levinson noted that “DNA vaccines are both well tolerated and simple to produce, and the addition of calreticulin enhances immune response.”
The investigational vaccine is delivered via an electoporation device (TriGrid delivery system) that stimulates muscle at the injection site to produce an enhanced immune response.
In preclinical studies the device was associated with an enhanced immune response compared with standard intramuscular injection. The enhance immune effect persisted despite CD4 T cell depletion.
The investigators conducted a phase 1 dose-escalation study, administering the vaccine to two separate cohorts: women without HIV who had HPV16-positive cervical dysplasia (CIN 2/3) and women living with HIV with HPV16-positive cervical or vulvovaginal dysplasia (CIN 2/3, VIN 2/3 or VAIN 2/3).
The vaccine was delivered at weeks 0, 4, and 8, at doses of 0.3 mg, 1.0 mg, or 3.0 mg. At week 12, all patients underwent site-specific biopsy to verify non-progression.
At 6 months, the patients then underwent definitive treatment with either loop electro excision or vulvar/vaginal excision. At 12 months, all patients had standard evaluations with biopsies.
Dr. Levinson reported results for the first 14 women enrolled, 10 of whom were HIV-negative and 4 of whom were HIV-positive.
Of nine women in the HIV-negative arm who had completed 6-month visits and were evaluable, two had HPV16 clearance by 2-month follow-up, and seven had clearance at 6 months. Other HPV subtypes cleared in two of five patients at 3 months and in three of five at 6 months.
In addition, seven of nine patients in this arm had histologic regression at 6 months.
In the HIV-positive arm, the two patients with CIN had no HPV16 clearance at 3 months, but both had clearance at 16 months. The vaccine did not clear other HPV subtypes in these patients, however.
Of the two women in this arm who had VIN, one had HPV16 clearance and histologic regression at 6 months. The other patient had neither viral clearance nor histologic regression.
All participants tolerated each vaccine well. Adverse events were all grade 1 in severity and resolved within 4 weeks. The most common event was tenderness at the injection site. There were also three cases of mild headache, two cases of drowsiness, and one of nausea.
What’s Next?
In the question-and-answer session following the presentation, Ronald D. Alvarez, MD, MBA, chairman and clinical service chief of obstetrics and gynecology at Vanderbilt University Medical Center in Nashville, Tennessee, asked Dr. Levinson how the vaccine development will proceed.
“Obviously, you have more data to collect and analyze, but how are you going to move forward with what looks like equal efficacy between the 1 milligram and the 3 milligram doses? Are you just going to go with the maximum tolerated dose, or consider a lower dose if it shows equal efficacy in terms of histologic regression as well as HPV clearance?” he asked.
“This is something we’re very interested in, and we do plan for the dose-expansion phase to go with the higher dose,” Dr. Levinson replied. “We need to evaluate it further and we may need to do further randomization between the medium dose and the highest dose to determine if there are differences both with systemic and local responses.”
Robert DeBernardo, MD, section head of obstetrics and gynecology and the Women’s Health Institute at the Cleveland Clinic, asked whether Dr. Levinson and colleagues were considering evaluating the vaccine in transplant recipients, “because we have a lot of persistent HPV in that subgroup.”
Dr. Levinson said that one of the dose-expansion cohorts for further study is a population of patients scheduled for transplantation.
“What we’re interested in is looking at whether we can ‘cure’ HPV prior to transplantation, and we think that’s going to be the best way to show that this vaccine potentially eliminates the virus, because if we can eliminate the virus and then take a population that’s going to be immunodeficient, then that would show that there’s no reactivation of the virus,” she said.
The study is supported by the National Institutes of Health. Dr. Levinson, Dr. Alvarez, and Dr. DeBernardo had no conflicts of interest to report.
FROM SGO 2024
ctDNA May Predict Early Response to Radiation of Gynecologic Cancers
Among 15 patients with vulvar, cervical, or endometrial malignancies who had serum ctDNA draws prior to, during, and after radiation therapy (RT) or chemoradiotherapy (CRT), both persistence or clearance of residual ctDNA were prognostic of patient outcomes from 3 to 6 months after the end of radiation therapy, reported A. Gabriella Wernicke, MD, MSc, a radiation oncologist at Lenox Hill Hospital in New York City.
“Our early findings in this limited cohort suggest that a mid-treatment ctDNA draw identified responders to radiation, and that may potentially serve as an early predictive biomarker of response. And clearly, these findings need to be validated in a prospective manner, a trial which will be starting in our center soon,” she said in an oral abstract session at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, held in San Diego, California.
Gynecologic malignancies are challenging to manage with radiotherapy because of the treatment’s toxicities and because outcomes may not be known until several months after the end of therapy. Early identification of responses to radiation therapy with simple blood draws has the potential to help clinicians identify those patients whose tumors are responding to radiation early in the course of therapy, she said.
Correlating treatment with responses
Dr. Wernicke and colleagues tested their hypothesis that the ctDNA is predictive of treatment response in patients receiving RT or CRT by retrospectively assessing the correlation of clinical responses to ctDNA detection and dynamics.
Their sample included 15 women with vulvar, cervical, or recurrent endometrial cancer who were treated with RT or CRT in 2022 and 2023.
The samples were collected prior to radiation therapy, mid-treatment, prior to boost dose with brachytherapy or stereotactic body radiation therapy, at the end of treatment, and at follow-up at 1, 3, and 6 months after the end of therapy and every 6 months thereafter.
The ctDNA analysis was performed with a personalized assay consisting of multiplex polymerase chain reaction and next-generation sequencing. The assays assessed clonal mutations found in the tumors of each patient.
Of the 15 patients, 5 had vulvar/vaginal tumors, all of squamous cell carcinoma histology. Six patients had squamous cell carcinoma of the cervix, and one had neuroendocrine cervical tumors. The two remaining patients had recurrent endometrial adenocarcinomas.
Eight of the patients had stage III disease, four had stage I or II, one had stage IV, and two had recurrent disease.
Results
At baseline 13 of the patients had detectable ctDNA, measured as greater than 0.00 mean tumor molecules per milliliter of plasma (MTM/mL).
There was a strong correlation between elevated ctDNA and measurable disease evaluated by standardized uptake values (SUV) on imaging pre treatment (correlation coefficient = 0.87, P less than .0001).
All patients had reductions in ctDNA from baseline to post-RT/CRT, with 2 having a reduction (partial metabolic response) and 13 having undetectable ctDNA (complete metabolic response) at the end of RT/CRT.
From the mid-treatment blood draw to the posttreatment draw 33% of patients had a partial metabolic response, and 67% had a complete response.
Reduction or clearance of ctDNA also correlated with a decrease in disease burden on MRI during the pre-boost phase of RT.
“Patients with undetectable ctDNA, meaning a complete metabolic response, at mid-radiation and at the end of radiation continued to be clinically without evidence of disease and with undetectable ctDNA at follow-up,” Dr. Wernicke said.
In contrast, the two patients who had partial metabolic responses had disease progression at the end of treatment. Dr. Wernicke noted that one of these patients, who was treated for a neuroendocrine carcinoma of the cervix and had undergone both systemic therapy and CRT, was found to have disease metastatic to the liver and lungs at the 3-month follow-up.
How to Use It?
Invited discussant Casey M. Cosgrove, MD, a gynecologic oncologist at Ohio State University Comprehensive Cancer Centers facility in Hilliard, Ohio, said that the reduction of ctDNA levels in all patients was “great,” but the question remains about how the information from ctDNA might be used to guide care in patients undergoing radiation therapy.
“The main questions I have are: If I don’t clear the ctDNA do I need to do more therapy? If I do clear does that mean I need to do less therapy? And if I have negative ctDNA to start what do I do?” he said.
The answers will be found only with further prospective studies, he emphasized.
“These technologies are only going to get better, and better, and better, and this is going to be a conversation that our patients are going to be bringing up, and this is going to be technology that we’re going to be using in our clinics in the very near future,” he added.
Session comoderator Michael Bookman, MD, a gynecology oncologist at Kaiser Permanente in San Francisco, said “it’s worth remembering that FDA approval of a diagnostic test can be obtained prior to showing any clinical benefit. So these are tests that measure what they say they’re measuring, but they haven’t been validated as improving clinical outcomes, which is the task that clearly lies ahead of us.”
The study was internally funded. Dr. Wernicke reported no relevant disclosures. Dr. Cosgrove reported a consulting or advisory role for Intuitive Ltd., GlaxoSmithKline, AstraZeneca, ImmunoGen, and Merck, and research fees from GSK. Dr. Bookman reported clinical trial advising/monitoring for Immunogen and Clovis Oncology, with fees paid to his institution.
Among 15 patients with vulvar, cervical, or endometrial malignancies who had serum ctDNA draws prior to, during, and after radiation therapy (RT) or chemoradiotherapy (CRT), both persistence or clearance of residual ctDNA were prognostic of patient outcomes from 3 to 6 months after the end of radiation therapy, reported A. Gabriella Wernicke, MD, MSc, a radiation oncologist at Lenox Hill Hospital in New York City.
“Our early findings in this limited cohort suggest that a mid-treatment ctDNA draw identified responders to radiation, and that may potentially serve as an early predictive biomarker of response. And clearly, these findings need to be validated in a prospective manner, a trial which will be starting in our center soon,” she said in an oral abstract session at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, held in San Diego, California.
Gynecologic malignancies are challenging to manage with radiotherapy because of the treatment’s toxicities and because outcomes may not be known until several months after the end of therapy. Early identification of responses to radiation therapy with simple blood draws has the potential to help clinicians identify those patients whose tumors are responding to radiation early in the course of therapy, she said.
Correlating treatment with responses
Dr. Wernicke and colleagues tested their hypothesis that the ctDNA is predictive of treatment response in patients receiving RT or CRT by retrospectively assessing the correlation of clinical responses to ctDNA detection and dynamics.
Their sample included 15 women with vulvar, cervical, or recurrent endometrial cancer who were treated with RT or CRT in 2022 and 2023.
The samples were collected prior to radiation therapy, mid-treatment, prior to boost dose with brachytherapy or stereotactic body radiation therapy, at the end of treatment, and at follow-up at 1, 3, and 6 months after the end of therapy and every 6 months thereafter.
The ctDNA analysis was performed with a personalized assay consisting of multiplex polymerase chain reaction and next-generation sequencing. The assays assessed clonal mutations found in the tumors of each patient.
Of the 15 patients, 5 had vulvar/vaginal tumors, all of squamous cell carcinoma histology. Six patients had squamous cell carcinoma of the cervix, and one had neuroendocrine cervical tumors. The two remaining patients had recurrent endometrial adenocarcinomas.
Eight of the patients had stage III disease, four had stage I or II, one had stage IV, and two had recurrent disease.
Results
At baseline 13 of the patients had detectable ctDNA, measured as greater than 0.00 mean tumor molecules per milliliter of plasma (MTM/mL).
There was a strong correlation between elevated ctDNA and measurable disease evaluated by standardized uptake values (SUV) on imaging pre treatment (correlation coefficient = 0.87, P less than .0001).
All patients had reductions in ctDNA from baseline to post-RT/CRT, with 2 having a reduction (partial metabolic response) and 13 having undetectable ctDNA (complete metabolic response) at the end of RT/CRT.
From the mid-treatment blood draw to the posttreatment draw 33% of patients had a partial metabolic response, and 67% had a complete response.
Reduction or clearance of ctDNA also correlated with a decrease in disease burden on MRI during the pre-boost phase of RT.
“Patients with undetectable ctDNA, meaning a complete metabolic response, at mid-radiation and at the end of radiation continued to be clinically without evidence of disease and with undetectable ctDNA at follow-up,” Dr. Wernicke said.
In contrast, the two patients who had partial metabolic responses had disease progression at the end of treatment. Dr. Wernicke noted that one of these patients, who was treated for a neuroendocrine carcinoma of the cervix and had undergone both systemic therapy and CRT, was found to have disease metastatic to the liver and lungs at the 3-month follow-up.
How to Use It?
Invited discussant Casey M. Cosgrove, MD, a gynecologic oncologist at Ohio State University Comprehensive Cancer Centers facility in Hilliard, Ohio, said that the reduction of ctDNA levels in all patients was “great,” but the question remains about how the information from ctDNA might be used to guide care in patients undergoing radiation therapy.
“The main questions I have are: If I don’t clear the ctDNA do I need to do more therapy? If I do clear does that mean I need to do less therapy? And if I have negative ctDNA to start what do I do?” he said.
The answers will be found only with further prospective studies, he emphasized.
“These technologies are only going to get better, and better, and better, and this is going to be a conversation that our patients are going to be bringing up, and this is going to be technology that we’re going to be using in our clinics in the very near future,” he added.
Session comoderator Michael Bookman, MD, a gynecology oncologist at Kaiser Permanente in San Francisco, said “it’s worth remembering that FDA approval of a diagnostic test can be obtained prior to showing any clinical benefit. So these are tests that measure what they say they’re measuring, but they haven’t been validated as improving clinical outcomes, which is the task that clearly lies ahead of us.”
The study was internally funded. Dr. Wernicke reported no relevant disclosures. Dr. Cosgrove reported a consulting or advisory role for Intuitive Ltd., GlaxoSmithKline, AstraZeneca, ImmunoGen, and Merck, and research fees from GSK. Dr. Bookman reported clinical trial advising/monitoring for Immunogen and Clovis Oncology, with fees paid to his institution.
Among 15 patients with vulvar, cervical, or endometrial malignancies who had serum ctDNA draws prior to, during, and after radiation therapy (RT) or chemoradiotherapy (CRT), both persistence or clearance of residual ctDNA were prognostic of patient outcomes from 3 to 6 months after the end of radiation therapy, reported A. Gabriella Wernicke, MD, MSc, a radiation oncologist at Lenox Hill Hospital in New York City.
“Our early findings in this limited cohort suggest that a mid-treatment ctDNA draw identified responders to radiation, and that may potentially serve as an early predictive biomarker of response. And clearly, these findings need to be validated in a prospective manner, a trial which will be starting in our center soon,” she said in an oral abstract session at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, held in San Diego, California.
Gynecologic malignancies are challenging to manage with radiotherapy because of the treatment’s toxicities and because outcomes may not be known until several months after the end of therapy. Early identification of responses to radiation therapy with simple blood draws has the potential to help clinicians identify those patients whose tumors are responding to radiation early in the course of therapy, she said.
Correlating treatment with responses
Dr. Wernicke and colleagues tested their hypothesis that the ctDNA is predictive of treatment response in patients receiving RT or CRT by retrospectively assessing the correlation of clinical responses to ctDNA detection and dynamics.
Their sample included 15 women with vulvar, cervical, or recurrent endometrial cancer who were treated with RT or CRT in 2022 and 2023.
The samples were collected prior to radiation therapy, mid-treatment, prior to boost dose with brachytherapy or stereotactic body radiation therapy, at the end of treatment, and at follow-up at 1, 3, and 6 months after the end of therapy and every 6 months thereafter.
The ctDNA analysis was performed with a personalized assay consisting of multiplex polymerase chain reaction and next-generation sequencing. The assays assessed clonal mutations found in the tumors of each patient.
Of the 15 patients, 5 had vulvar/vaginal tumors, all of squamous cell carcinoma histology. Six patients had squamous cell carcinoma of the cervix, and one had neuroendocrine cervical tumors. The two remaining patients had recurrent endometrial adenocarcinomas.
Eight of the patients had stage III disease, four had stage I or II, one had stage IV, and two had recurrent disease.
Results
At baseline 13 of the patients had detectable ctDNA, measured as greater than 0.00 mean tumor molecules per milliliter of plasma (MTM/mL).
There was a strong correlation between elevated ctDNA and measurable disease evaluated by standardized uptake values (SUV) on imaging pre treatment (correlation coefficient = 0.87, P less than .0001).
All patients had reductions in ctDNA from baseline to post-RT/CRT, with 2 having a reduction (partial metabolic response) and 13 having undetectable ctDNA (complete metabolic response) at the end of RT/CRT.
From the mid-treatment blood draw to the posttreatment draw 33% of patients had a partial metabolic response, and 67% had a complete response.
Reduction or clearance of ctDNA also correlated with a decrease in disease burden on MRI during the pre-boost phase of RT.
“Patients with undetectable ctDNA, meaning a complete metabolic response, at mid-radiation and at the end of radiation continued to be clinically without evidence of disease and with undetectable ctDNA at follow-up,” Dr. Wernicke said.
In contrast, the two patients who had partial metabolic responses had disease progression at the end of treatment. Dr. Wernicke noted that one of these patients, who was treated for a neuroendocrine carcinoma of the cervix and had undergone both systemic therapy and CRT, was found to have disease metastatic to the liver and lungs at the 3-month follow-up.
How to Use It?
Invited discussant Casey M. Cosgrove, MD, a gynecologic oncologist at Ohio State University Comprehensive Cancer Centers facility in Hilliard, Ohio, said that the reduction of ctDNA levels in all patients was “great,” but the question remains about how the information from ctDNA might be used to guide care in patients undergoing radiation therapy.
“The main questions I have are: If I don’t clear the ctDNA do I need to do more therapy? If I do clear does that mean I need to do less therapy? And if I have negative ctDNA to start what do I do?” he said.
The answers will be found only with further prospective studies, he emphasized.
“These technologies are only going to get better, and better, and better, and this is going to be a conversation that our patients are going to be bringing up, and this is going to be technology that we’re going to be using in our clinics in the very near future,” he added.
Session comoderator Michael Bookman, MD, a gynecology oncologist at Kaiser Permanente in San Francisco, said “it’s worth remembering that FDA approval of a diagnostic test can be obtained prior to showing any clinical benefit. So these are tests that measure what they say they’re measuring, but they haven’t been validated as improving clinical outcomes, which is the task that clearly lies ahead of us.”
The study was internally funded. Dr. Wernicke reported no relevant disclosures. Dr. Cosgrove reported a consulting or advisory role for Intuitive Ltd., GlaxoSmithKline, AstraZeneca, ImmunoGen, and Merck, and research fees from GSK. Dr. Bookman reported clinical trial advising/monitoring for Immunogen and Clovis Oncology, with fees paid to his institution.
FROM SGO 2024
RUBY: ‘A Huge Win’ for Patients With Advanced or Recurrent Endometrial Cancer
The benefit of the combination of the programmed death protein 1 (PD-1) inhibitor dostarlimab (Jemperli) and chemotherapy was even more pronounced among patients with DNA mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) tumors.
These results, from the second interim analysis of the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial, were cheered by audience members when they were reported at the Society of Gynecologic Oncology (SGO)’s Annual Meeting on Women’s Cancer, held in San Diego, California.
“Overall survival benefit to the addition of PD-1 inhibitor to chemotherapy upfront for patients with advanced and recurrent MSI-high endometrial cancer: SOLD!” said invited discussant Gini Fleming, medical director of gynecologic oncology at the University of Chicago.
“I think this is a huge win for our patients. It’s something that none of us have seen before over many years of working with endometrial cancer and should be incorporated into everybody’s practice as of yesterday,” she said.
Continued Improvement
Results from the first interim analysis of the trial showed that dostarlimab and chemotherapy significantly improved progression-free survival (PFS) in the dMMR/MSI-H population, and there was an early trend toward improved overall survival, compared with chemotherapy plus placebo.
As Matthew A. Powell, MD from Washington University School of Medicine in Saint Louis, Missouri reported at SGO 2024, that early trend has become an undeniable survival advantage.
At a median follow-up of 37.2 months, the median overall survival was 44.6 months for patients randomized to the combination, compared with 28.2 months for those assigned to chemotherapy plus placebo.
The respective 3-year overall survival (OS) rates were 54.9% and 42.9%, translating into a hazard ratio (HR) for death with dostarlimab/chemotherapy of 0.69 (P = .002).
Among the subset of patients with dMMR/MSI-H tumors the survival benefit conferred by the combination was even greater, with median OS not reached in the dostarlimab group vs 31.4 months in the chemotherapy-alone arm, with respective 3-year OS rates of 78% and 46%. This difference translated into a HR for death with the combination of 0.32 (P = .0002) for patients with deficient mismatch-repair cancers.
“Dostarlimab plus carboplatin-paclitaxel chemotherapy demonstrated statistically significant and clinically meaningful overall survival improvements in the overall population, a substantial unprecedented overall survival benefit in patients with defective mismatch-repair tumors, and a clinically meaningful; 7-month improvement in the OS difference in patients with proficient mismatch-repair tumors,” Dr. Powell said.
RUBY Details
The trial was conducted in 494 patients with primary advanced stage III or IV or first recurrent endometrial cancer who received first-line treatment with standard chemotherapy with carboplatin (area under the concentration–time curve, 5 mg/mL per minute) and paclitaxel (175 mg/m2 of body surface area), every 3 weeks (six cycles). They were also randomized to receive either dostarlimab (1000 mg) or dostarlimab placebo every 6 weeks for up to 3 years.
Within the cohort, 118 patients (23.9%) had dMMR/MSI-H tumors.
At the time of the first interim analysis the estimated progression-free survival at 24 months in the dMMR–MSI-H subgroup was 61.4% in the dostarlimab group vs 15.7 in the placebo group (HR for progression or death, 0.28; P < .001). For the entire cohort, progression-free survival at 24 months was 36.1% vs 18.1% (HR, 0.64; P < .001).
A prespecified exploratory analysis of progression-free survival in proficient MMR, microsatellite stable (MSS) patients was also done, and a clinically relevant benefit was observed.
Overall survival at that time also favored dostarlimab, although it was only mature for 33% of the population. But at 24 months, OS rates were 71.3% vs 56.0% among placebo recipients; this difference approached but did not reach statistical significance.
The overall response rate in the dMMR–MSI-H population vs the placebo group was 77.6% vs 69%, respectively, and 68.1% and 63.4% in the pMMR/MSS population.
The most common adverse events observed were nausea, alopecia, and fatigue. Grade 3 and higher adverse events at the most recent follow-up were more frequent in the dostarlimab group than in the placebo group (72.2% vs 60.2%).
“Importantly, safety was maintained” at the second interim analysis, Dr. Powell said.
“No new safety signals were noted, no new deaths related to therapy were noted with the subsequent 1-year additional analysis time,” he said.
What’s Next?
Dr. Fleming reviewed potential strategies for further improving care of patients with advanced or recurrent endometrial cancer during her discussion.
“What are the next directions for patients with MSI-high disease? Well, obviously could we use immune checkpoint inhibitors without chemotherapy and not compromise results? There are two ongoing trials or trials that we’re awaiting results of that have compared single-agent immune checkpoint inhibitor to just chemotherapy in mismatch repair-deficient advanced disease, and hopefully we can extrapolate from these trials to determine if this might be a more patient-friendly and equally effective strategy, but we don’t yet know,” she said.
Dr. Fleming also noted that ongoing or planned clinical trials will address questions about potential options for patients with MSI-H tumors whose disease progresses on frontline chemotherapy and immunotherapy. Other trials are assessing whether combining radiotherapy with checkpoint inhibitors will be effective in treating patients with earlier-stage tumors, or whether the addition of a PARP inhibitor might offer additional benefit for these patients.
“Immune checkpoint inhibitor should be given first line to patients with advanced/recurrent microsatellite [instability] endometrial cancer, and they should be considered as front line in patients with microsatellite stable disease. At this point, unfortunately, we have no reasonable predictive factors to know which of those patients with microsatellite stable disease will truly benefit. Multiple other agents are being tested in this setting, and will hopefully prove useful in subgroups,” she said.
The study is funded by GlaxoSmithKline. Dr. Powell reports grants/research support from GSK and honoraria/consultation fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, and Merck. Dr. Fleming reports serving as an institutional principal investigator for trials sponsored by multiple companies, not including GSK.
The benefit of the combination of the programmed death protein 1 (PD-1) inhibitor dostarlimab (Jemperli) and chemotherapy was even more pronounced among patients with DNA mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) tumors.
These results, from the second interim analysis of the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial, were cheered by audience members when they were reported at the Society of Gynecologic Oncology (SGO)’s Annual Meeting on Women’s Cancer, held in San Diego, California.
“Overall survival benefit to the addition of PD-1 inhibitor to chemotherapy upfront for patients with advanced and recurrent MSI-high endometrial cancer: SOLD!” said invited discussant Gini Fleming, medical director of gynecologic oncology at the University of Chicago.
“I think this is a huge win for our patients. It’s something that none of us have seen before over many years of working with endometrial cancer and should be incorporated into everybody’s practice as of yesterday,” she said.
Continued Improvement
Results from the first interim analysis of the trial showed that dostarlimab and chemotherapy significantly improved progression-free survival (PFS) in the dMMR/MSI-H population, and there was an early trend toward improved overall survival, compared with chemotherapy plus placebo.
As Matthew A. Powell, MD from Washington University School of Medicine in Saint Louis, Missouri reported at SGO 2024, that early trend has become an undeniable survival advantage.
At a median follow-up of 37.2 months, the median overall survival was 44.6 months for patients randomized to the combination, compared with 28.2 months for those assigned to chemotherapy plus placebo.
The respective 3-year overall survival (OS) rates were 54.9% and 42.9%, translating into a hazard ratio (HR) for death with dostarlimab/chemotherapy of 0.69 (P = .002).
Among the subset of patients with dMMR/MSI-H tumors the survival benefit conferred by the combination was even greater, with median OS not reached in the dostarlimab group vs 31.4 months in the chemotherapy-alone arm, with respective 3-year OS rates of 78% and 46%. This difference translated into a HR for death with the combination of 0.32 (P = .0002) for patients with deficient mismatch-repair cancers.
“Dostarlimab plus carboplatin-paclitaxel chemotherapy demonstrated statistically significant and clinically meaningful overall survival improvements in the overall population, a substantial unprecedented overall survival benefit in patients with defective mismatch-repair tumors, and a clinically meaningful; 7-month improvement in the OS difference in patients with proficient mismatch-repair tumors,” Dr. Powell said.
RUBY Details
The trial was conducted in 494 patients with primary advanced stage III or IV or first recurrent endometrial cancer who received first-line treatment with standard chemotherapy with carboplatin (area under the concentration–time curve, 5 mg/mL per minute) and paclitaxel (175 mg/m2 of body surface area), every 3 weeks (six cycles). They were also randomized to receive either dostarlimab (1000 mg) or dostarlimab placebo every 6 weeks for up to 3 years.
Within the cohort, 118 patients (23.9%) had dMMR/MSI-H tumors.
At the time of the first interim analysis the estimated progression-free survival at 24 months in the dMMR–MSI-H subgroup was 61.4% in the dostarlimab group vs 15.7 in the placebo group (HR for progression or death, 0.28; P < .001). For the entire cohort, progression-free survival at 24 months was 36.1% vs 18.1% (HR, 0.64; P < .001).
A prespecified exploratory analysis of progression-free survival in proficient MMR, microsatellite stable (MSS) patients was also done, and a clinically relevant benefit was observed.
Overall survival at that time also favored dostarlimab, although it was only mature for 33% of the population. But at 24 months, OS rates were 71.3% vs 56.0% among placebo recipients; this difference approached but did not reach statistical significance.
The overall response rate in the dMMR–MSI-H population vs the placebo group was 77.6% vs 69%, respectively, and 68.1% and 63.4% in the pMMR/MSS population.
The most common adverse events observed were nausea, alopecia, and fatigue. Grade 3 and higher adverse events at the most recent follow-up were more frequent in the dostarlimab group than in the placebo group (72.2% vs 60.2%).
“Importantly, safety was maintained” at the second interim analysis, Dr. Powell said.
“No new safety signals were noted, no new deaths related to therapy were noted with the subsequent 1-year additional analysis time,” he said.
What’s Next?
Dr. Fleming reviewed potential strategies for further improving care of patients with advanced or recurrent endometrial cancer during her discussion.
“What are the next directions for patients with MSI-high disease? Well, obviously could we use immune checkpoint inhibitors without chemotherapy and not compromise results? There are two ongoing trials or trials that we’re awaiting results of that have compared single-agent immune checkpoint inhibitor to just chemotherapy in mismatch repair-deficient advanced disease, and hopefully we can extrapolate from these trials to determine if this might be a more patient-friendly and equally effective strategy, but we don’t yet know,” she said.
Dr. Fleming also noted that ongoing or planned clinical trials will address questions about potential options for patients with MSI-H tumors whose disease progresses on frontline chemotherapy and immunotherapy. Other trials are assessing whether combining radiotherapy with checkpoint inhibitors will be effective in treating patients with earlier-stage tumors, or whether the addition of a PARP inhibitor might offer additional benefit for these patients.
“Immune checkpoint inhibitor should be given first line to patients with advanced/recurrent microsatellite [instability] endometrial cancer, and they should be considered as front line in patients with microsatellite stable disease. At this point, unfortunately, we have no reasonable predictive factors to know which of those patients with microsatellite stable disease will truly benefit. Multiple other agents are being tested in this setting, and will hopefully prove useful in subgroups,” she said.
The study is funded by GlaxoSmithKline. Dr. Powell reports grants/research support from GSK and honoraria/consultation fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, and Merck. Dr. Fleming reports serving as an institutional principal investigator for trials sponsored by multiple companies, not including GSK.
The benefit of the combination of the programmed death protein 1 (PD-1) inhibitor dostarlimab (Jemperli) and chemotherapy was even more pronounced among patients with DNA mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) tumors.
These results, from the second interim analysis of the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial, were cheered by audience members when they were reported at the Society of Gynecologic Oncology (SGO)’s Annual Meeting on Women’s Cancer, held in San Diego, California.
“Overall survival benefit to the addition of PD-1 inhibitor to chemotherapy upfront for patients with advanced and recurrent MSI-high endometrial cancer: SOLD!” said invited discussant Gini Fleming, medical director of gynecologic oncology at the University of Chicago.
“I think this is a huge win for our patients. It’s something that none of us have seen before over many years of working with endometrial cancer and should be incorporated into everybody’s practice as of yesterday,” she said.
Continued Improvement
Results from the first interim analysis of the trial showed that dostarlimab and chemotherapy significantly improved progression-free survival (PFS) in the dMMR/MSI-H population, and there was an early trend toward improved overall survival, compared with chemotherapy plus placebo.
As Matthew A. Powell, MD from Washington University School of Medicine in Saint Louis, Missouri reported at SGO 2024, that early trend has become an undeniable survival advantage.
At a median follow-up of 37.2 months, the median overall survival was 44.6 months for patients randomized to the combination, compared with 28.2 months for those assigned to chemotherapy plus placebo.
The respective 3-year overall survival (OS) rates were 54.9% and 42.9%, translating into a hazard ratio (HR) for death with dostarlimab/chemotherapy of 0.69 (P = .002).
Among the subset of patients with dMMR/MSI-H tumors the survival benefit conferred by the combination was even greater, with median OS not reached in the dostarlimab group vs 31.4 months in the chemotherapy-alone arm, with respective 3-year OS rates of 78% and 46%. This difference translated into a HR for death with the combination of 0.32 (P = .0002) for patients with deficient mismatch-repair cancers.
“Dostarlimab plus carboplatin-paclitaxel chemotherapy demonstrated statistically significant and clinically meaningful overall survival improvements in the overall population, a substantial unprecedented overall survival benefit in patients with defective mismatch-repair tumors, and a clinically meaningful; 7-month improvement in the OS difference in patients with proficient mismatch-repair tumors,” Dr. Powell said.
RUBY Details
The trial was conducted in 494 patients with primary advanced stage III or IV or first recurrent endometrial cancer who received first-line treatment with standard chemotherapy with carboplatin (area under the concentration–time curve, 5 mg/mL per minute) and paclitaxel (175 mg/m2 of body surface area), every 3 weeks (six cycles). They were also randomized to receive either dostarlimab (1000 mg) or dostarlimab placebo every 6 weeks for up to 3 years.
Within the cohort, 118 patients (23.9%) had dMMR/MSI-H tumors.
At the time of the first interim analysis the estimated progression-free survival at 24 months in the dMMR–MSI-H subgroup was 61.4% in the dostarlimab group vs 15.7 in the placebo group (HR for progression or death, 0.28; P < .001). For the entire cohort, progression-free survival at 24 months was 36.1% vs 18.1% (HR, 0.64; P < .001).
A prespecified exploratory analysis of progression-free survival in proficient MMR, microsatellite stable (MSS) patients was also done, and a clinically relevant benefit was observed.
Overall survival at that time also favored dostarlimab, although it was only mature for 33% of the population. But at 24 months, OS rates were 71.3% vs 56.0% among placebo recipients; this difference approached but did not reach statistical significance.
The overall response rate in the dMMR–MSI-H population vs the placebo group was 77.6% vs 69%, respectively, and 68.1% and 63.4% in the pMMR/MSS population.
The most common adverse events observed were nausea, alopecia, and fatigue. Grade 3 and higher adverse events at the most recent follow-up were more frequent in the dostarlimab group than in the placebo group (72.2% vs 60.2%).
“Importantly, safety was maintained” at the second interim analysis, Dr. Powell said.
“No new safety signals were noted, no new deaths related to therapy were noted with the subsequent 1-year additional analysis time,” he said.
What’s Next?
Dr. Fleming reviewed potential strategies for further improving care of patients with advanced or recurrent endometrial cancer during her discussion.
“What are the next directions for patients with MSI-high disease? Well, obviously could we use immune checkpoint inhibitors without chemotherapy and not compromise results? There are two ongoing trials or trials that we’re awaiting results of that have compared single-agent immune checkpoint inhibitor to just chemotherapy in mismatch repair-deficient advanced disease, and hopefully we can extrapolate from these trials to determine if this might be a more patient-friendly and equally effective strategy, but we don’t yet know,” she said.
Dr. Fleming also noted that ongoing or planned clinical trials will address questions about potential options for patients with MSI-H tumors whose disease progresses on frontline chemotherapy and immunotherapy. Other trials are assessing whether combining radiotherapy with checkpoint inhibitors will be effective in treating patients with earlier-stage tumors, or whether the addition of a PARP inhibitor might offer additional benefit for these patients.
“Immune checkpoint inhibitor should be given first line to patients with advanced/recurrent microsatellite [instability] endometrial cancer, and they should be considered as front line in patients with microsatellite stable disease. At this point, unfortunately, we have no reasonable predictive factors to know which of those patients with microsatellite stable disease will truly benefit. Multiple other agents are being tested in this setting, and will hopefully prove useful in subgroups,” she said.
The study is funded by GlaxoSmithKline. Dr. Powell reports grants/research support from GSK and honoraria/consultation fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, and Merck. Dr. Fleming reports serving as an institutional principal investigator for trials sponsored by multiple companies, not including GSK.
FROM SGO 2024
Neurologists Read Signs to Diagnose Functional Neurological Disorders
They have gone by many different names over the centuries: hysteria, psychosomatic illnesses, psychogenic neurological disorders, conversion disorders, dissociative neurological symptom disorders. The terminology may change, but functional neurological disorders by any other name are still real and serious yet treatable phenomena.
Functional neurological disorders, or FNDs, live at the crossroads of neurology and psychiatry, and they are as much a product of the body as they are of the brain, say neurologists who specialize in treating these complex and clinically challenging conditions.
“Whether they’re easily recognized or not depends on someone’s training and experience in this regard,” said Mark Hallett, MD, of the Human Motor Control Section of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.
“The difficulty has been that there hasn’t been very good education about functional disorders over the last 50 years or so,” he said in an interview.
However, with training and experience, clinicians can learn to identify these common and disabling conditions, Dr. Hallett said.
Varying Definitions
The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) labels FND as “conversion disorder,” and lists diagnostic criteria that include “one or more symptoms of altered voluntary motor or sensory function; clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions; the symptom or deficit is not better explained by another medical or mental disorder;” and “the symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation.”
Dr. Hallett offers his own definition of FND, which includes the following characteristics:
- A neurological disorder, characterized by almost any type of neurological symptom
- Not voluntarily produced
- Caused by a brain network dysfunction that does not exclude the possibility of normal function
- Sometimes due in part to a psychological cause, and not explained by other neurological pathology that may or may not be present
- Symptoms may be inconsistent (variable) or incompatible (incongruent) with other known neurological disorders or human anatomy and physiology.
The two most common types of FND are psychogenic nonepileptic seizures and functional movement disorders, but patients may also have functional sensory, visual, auditory, speech, and urologic disorders, and even functional coma.
Dr. Hallett cited studies showing that an estimated 9% of neurology hospital admission are for FNDS, and that among patients in neurology clinics 5.4% had a diagnosis of FND, and 30% had an FND as part of the diagnosis.
Women comprise between 60% and 75% of the population with FNDs.
Diagnosis
FND is not, as once thought, a diagnosis of exclusion, but is based on signs and symptoms, which may be either inconsistent or irreversible and may occur in the absence of a stressor, said Sara Finkelstein, MD, MSc, of the Functional Neurological Disorder Unit in the Department of Neurology at Massachusetts General Hospital in Boston.
She emphasized that there are several diagnostic pitfalls that clinicians need to be aware of.
For example, “just because a patient has a psychiatric history does not mean that they have a functional neurological disorder,” she said in an interview.
Clinicians may also make unwarranted assumptions about a given patient, excluding an FND diagnosis in, say, a young woman with symptoms of anxiety. Alternatively, clinicians may either include or exclude a diagnosis based on personality factors or on a prior stressor, neither of which alone are sufficiently diagnostic.
Additionally, a clinician may be tempted to make the diagnosis of an FND based on the absence of findings on standard exams rather than on rule-in signs and symptoms, she emphasized.
Functional seizures
A definitive diagnosis can depend on the type of disorder.
“Many functional seizures have some clinical manifestations that are apparent, but as seizures are intermittent the doctor may not see one, and it may depend upon someone taking a video of the person with the seizure perhaps, or bringing them into a hospital and watching them until they do have the seizure,” Dr. Hallett said.
There are some manifestations that indicate the likelihood that a seizure has a functional origin, and when there is uncertainty EEG can help to nail down a diagnosis, he added.
Dr. Finkelstein noted that exam signs with good reliability for functional seizures include eye closure or resistance to opening; duration longer than 2 minutes; stopping and starting; asynchronous limb movements; patient maintenance of awareness during a generalized event; and ictal weeping.
Differential diagnoses included migraine with complex aura, dissociation related to posttraumatic stress disorder, or anxiety.
Functional movement disorders
Dr. Finkelstein cautioned that when evaluating patients for potential functional movement disorders, it’s important to not jump to conclusions.
For example, the amplitude of tremor can vary in Parkinson’s disease and essential tremor as well as in functional tremor. The clinician should not read too much into the observation that a patient’s tremor gets worse with increasing stress as stress can exacerbate most tremor types, she said.
One sign that tremor could be functional (dystonic tremor) is irregularity of amplitude and frequency, she noted.
When assessing patients with gait disorder, it’s important to understand that there is no single sign that is specially characteristic for a given disorder, and just because a patient has a “bizarre” gait, it doesn’t necessarily signal a functional disorder.
“A dystonic gait may improve with an alternate motor pattern or be inconsistent over time,” Dr. Finkelstein said.
Treatment
In a comprehensive review published in The Lancet: Neurology in 2022, Dr. Hallett and colleagues said that good doctor-patient communications and understanding of each patient’s needs and goals are essential for effective treatment of all FNDs.
“Neurologists have traditionally avoided taking responsibility for people with FND, although are often most appropriate to engage patients in treatment. Explaining the diagnosis with clarity, confidence, using the principles of a ‘rule in’ process, is a key step in treatment,” they wrote.
Treatment can take several forms, depending on the FND, and may include physiotherapy for patients with functional movement disorders and psychological therapy for patients with functional seizures.
“With increasing evidence-based treatment, the diagnosis of FND should be seen as a process of looking for potentially reversible cause of disability and distress whether or not an individual has abnormalities on conventional laboratory or radiological testing,” Dr. Hallett and colleagues concluded.
This article was based on interviews and from presentations by Dr. Hallett and Dr. Finkelstein at a 2023 meeting of the Indiana Neurological Society. Dr. Hallett and Dr. Finkelstein declared no conflicts of interest.
They have gone by many different names over the centuries: hysteria, psychosomatic illnesses, psychogenic neurological disorders, conversion disorders, dissociative neurological symptom disorders. The terminology may change, but functional neurological disorders by any other name are still real and serious yet treatable phenomena.
Functional neurological disorders, or FNDs, live at the crossroads of neurology and psychiatry, and they are as much a product of the body as they are of the brain, say neurologists who specialize in treating these complex and clinically challenging conditions.
“Whether they’re easily recognized or not depends on someone’s training and experience in this regard,” said Mark Hallett, MD, of the Human Motor Control Section of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.
“The difficulty has been that there hasn’t been very good education about functional disorders over the last 50 years or so,” he said in an interview.
However, with training and experience, clinicians can learn to identify these common and disabling conditions, Dr. Hallett said.
Varying Definitions
The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) labels FND as “conversion disorder,” and lists diagnostic criteria that include “one or more symptoms of altered voluntary motor or sensory function; clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions; the symptom or deficit is not better explained by another medical or mental disorder;” and “the symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation.”
Dr. Hallett offers his own definition of FND, which includes the following characteristics:
- A neurological disorder, characterized by almost any type of neurological symptom
- Not voluntarily produced
- Caused by a brain network dysfunction that does not exclude the possibility of normal function
- Sometimes due in part to a psychological cause, and not explained by other neurological pathology that may or may not be present
- Symptoms may be inconsistent (variable) or incompatible (incongruent) with other known neurological disorders or human anatomy and physiology.
The two most common types of FND are psychogenic nonepileptic seizures and functional movement disorders, but patients may also have functional sensory, visual, auditory, speech, and urologic disorders, and even functional coma.
Dr. Hallett cited studies showing that an estimated 9% of neurology hospital admission are for FNDS, and that among patients in neurology clinics 5.4% had a diagnosis of FND, and 30% had an FND as part of the diagnosis.
Women comprise between 60% and 75% of the population with FNDs.
Diagnosis
FND is not, as once thought, a diagnosis of exclusion, but is based on signs and symptoms, which may be either inconsistent or irreversible and may occur in the absence of a stressor, said Sara Finkelstein, MD, MSc, of the Functional Neurological Disorder Unit in the Department of Neurology at Massachusetts General Hospital in Boston.
She emphasized that there are several diagnostic pitfalls that clinicians need to be aware of.
For example, “just because a patient has a psychiatric history does not mean that they have a functional neurological disorder,” she said in an interview.
Clinicians may also make unwarranted assumptions about a given patient, excluding an FND diagnosis in, say, a young woman with symptoms of anxiety. Alternatively, clinicians may either include or exclude a diagnosis based on personality factors or on a prior stressor, neither of which alone are sufficiently diagnostic.
Additionally, a clinician may be tempted to make the diagnosis of an FND based on the absence of findings on standard exams rather than on rule-in signs and symptoms, she emphasized.
Functional seizures
A definitive diagnosis can depend on the type of disorder.
“Many functional seizures have some clinical manifestations that are apparent, but as seizures are intermittent the doctor may not see one, and it may depend upon someone taking a video of the person with the seizure perhaps, or bringing them into a hospital and watching them until they do have the seizure,” Dr. Hallett said.
There are some manifestations that indicate the likelihood that a seizure has a functional origin, and when there is uncertainty EEG can help to nail down a diagnosis, he added.
Dr. Finkelstein noted that exam signs with good reliability for functional seizures include eye closure or resistance to opening; duration longer than 2 minutes; stopping and starting; asynchronous limb movements; patient maintenance of awareness during a generalized event; and ictal weeping.
Differential diagnoses included migraine with complex aura, dissociation related to posttraumatic stress disorder, or anxiety.
Functional movement disorders
Dr. Finkelstein cautioned that when evaluating patients for potential functional movement disorders, it’s important to not jump to conclusions.
For example, the amplitude of tremor can vary in Parkinson’s disease and essential tremor as well as in functional tremor. The clinician should not read too much into the observation that a patient’s tremor gets worse with increasing stress as stress can exacerbate most tremor types, she said.
One sign that tremor could be functional (dystonic tremor) is irregularity of amplitude and frequency, she noted.
When assessing patients with gait disorder, it’s important to understand that there is no single sign that is specially characteristic for a given disorder, and just because a patient has a “bizarre” gait, it doesn’t necessarily signal a functional disorder.
“A dystonic gait may improve with an alternate motor pattern or be inconsistent over time,” Dr. Finkelstein said.
Treatment
In a comprehensive review published in The Lancet: Neurology in 2022, Dr. Hallett and colleagues said that good doctor-patient communications and understanding of each patient’s needs and goals are essential for effective treatment of all FNDs.
“Neurologists have traditionally avoided taking responsibility for people with FND, although are often most appropriate to engage patients in treatment. Explaining the diagnosis with clarity, confidence, using the principles of a ‘rule in’ process, is a key step in treatment,” they wrote.
Treatment can take several forms, depending on the FND, and may include physiotherapy for patients with functional movement disorders and psychological therapy for patients with functional seizures.
“With increasing evidence-based treatment, the diagnosis of FND should be seen as a process of looking for potentially reversible cause of disability and distress whether or not an individual has abnormalities on conventional laboratory or radiological testing,” Dr. Hallett and colleagues concluded.
This article was based on interviews and from presentations by Dr. Hallett and Dr. Finkelstein at a 2023 meeting of the Indiana Neurological Society. Dr. Hallett and Dr. Finkelstein declared no conflicts of interest.
They have gone by many different names over the centuries: hysteria, psychosomatic illnesses, psychogenic neurological disorders, conversion disorders, dissociative neurological symptom disorders. The terminology may change, but functional neurological disorders by any other name are still real and serious yet treatable phenomena.
Functional neurological disorders, or FNDs, live at the crossroads of neurology and psychiatry, and they are as much a product of the body as they are of the brain, say neurologists who specialize in treating these complex and clinically challenging conditions.
“Whether they’re easily recognized or not depends on someone’s training and experience in this regard,” said Mark Hallett, MD, of the Human Motor Control Section of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.
“The difficulty has been that there hasn’t been very good education about functional disorders over the last 50 years or so,” he said in an interview.
However, with training and experience, clinicians can learn to identify these common and disabling conditions, Dr. Hallett said.
Varying Definitions
The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) labels FND as “conversion disorder,” and lists diagnostic criteria that include “one or more symptoms of altered voluntary motor or sensory function; clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions; the symptom or deficit is not better explained by another medical or mental disorder;” and “the symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation.”
Dr. Hallett offers his own definition of FND, which includes the following characteristics:
- A neurological disorder, characterized by almost any type of neurological symptom
- Not voluntarily produced
- Caused by a brain network dysfunction that does not exclude the possibility of normal function
- Sometimes due in part to a psychological cause, and not explained by other neurological pathology that may or may not be present
- Symptoms may be inconsistent (variable) or incompatible (incongruent) with other known neurological disorders or human anatomy and physiology.
The two most common types of FND are psychogenic nonepileptic seizures and functional movement disorders, but patients may also have functional sensory, visual, auditory, speech, and urologic disorders, and even functional coma.
Dr. Hallett cited studies showing that an estimated 9% of neurology hospital admission are for FNDS, and that among patients in neurology clinics 5.4% had a diagnosis of FND, and 30% had an FND as part of the diagnosis.
Women comprise between 60% and 75% of the population with FNDs.
Diagnosis
FND is not, as once thought, a diagnosis of exclusion, but is based on signs and symptoms, which may be either inconsistent or irreversible and may occur in the absence of a stressor, said Sara Finkelstein, MD, MSc, of the Functional Neurological Disorder Unit in the Department of Neurology at Massachusetts General Hospital in Boston.
She emphasized that there are several diagnostic pitfalls that clinicians need to be aware of.
For example, “just because a patient has a psychiatric history does not mean that they have a functional neurological disorder,” she said in an interview.
Clinicians may also make unwarranted assumptions about a given patient, excluding an FND diagnosis in, say, a young woman with symptoms of anxiety. Alternatively, clinicians may either include or exclude a diagnosis based on personality factors or on a prior stressor, neither of which alone are sufficiently diagnostic.
Additionally, a clinician may be tempted to make the diagnosis of an FND based on the absence of findings on standard exams rather than on rule-in signs and symptoms, she emphasized.
Functional seizures
A definitive diagnosis can depend on the type of disorder.
“Many functional seizures have some clinical manifestations that are apparent, but as seizures are intermittent the doctor may not see one, and it may depend upon someone taking a video of the person with the seizure perhaps, or bringing them into a hospital and watching them until they do have the seizure,” Dr. Hallett said.
There are some manifestations that indicate the likelihood that a seizure has a functional origin, and when there is uncertainty EEG can help to nail down a diagnosis, he added.
Dr. Finkelstein noted that exam signs with good reliability for functional seizures include eye closure or resistance to opening; duration longer than 2 minutes; stopping and starting; asynchronous limb movements; patient maintenance of awareness during a generalized event; and ictal weeping.
Differential diagnoses included migraine with complex aura, dissociation related to posttraumatic stress disorder, or anxiety.
Functional movement disorders
Dr. Finkelstein cautioned that when evaluating patients for potential functional movement disorders, it’s important to not jump to conclusions.
For example, the amplitude of tremor can vary in Parkinson’s disease and essential tremor as well as in functional tremor. The clinician should not read too much into the observation that a patient’s tremor gets worse with increasing stress as stress can exacerbate most tremor types, she said.
One sign that tremor could be functional (dystonic tremor) is irregularity of amplitude and frequency, she noted.
When assessing patients with gait disorder, it’s important to understand that there is no single sign that is specially characteristic for a given disorder, and just because a patient has a “bizarre” gait, it doesn’t necessarily signal a functional disorder.
“A dystonic gait may improve with an alternate motor pattern or be inconsistent over time,” Dr. Finkelstein said.
Treatment
In a comprehensive review published in The Lancet: Neurology in 2022, Dr. Hallett and colleagues said that good doctor-patient communications and understanding of each patient’s needs and goals are essential for effective treatment of all FNDs.
“Neurologists have traditionally avoided taking responsibility for people with FND, although are often most appropriate to engage patients in treatment. Explaining the diagnosis with clarity, confidence, using the principles of a ‘rule in’ process, is a key step in treatment,” they wrote.
Treatment can take several forms, depending on the FND, and may include physiotherapy for patients with functional movement disorders and psychological therapy for patients with functional seizures.
“With increasing evidence-based treatment, the diagnosis of FND should be seen as a process of looking for potentially reversible cause of disability and distress whether or not an individual has abnormalities on conventional laboratory or radiological testing,” Dr. Hallett and colleagues concluded.
This article was based on interviews and from presentations by Dr. Hallett and Dr. Finkelstein at a 2023 meeting of the Indiana Neurological Society. Dr. Hallett and Dr. Finkelstein declared no conflicts of interest.
FROM THE INDIANA NEUROLOGICAL SOCIETY’S FUNCTIONAL NEUROLOGICAL DISORDERS CONFERENCE
Patients haunted by fears of living with and dying from severe lung disease
Many patients with chronic progressive pulmonary disease feel anxious and depressed as their conditions advance, as breathing becomes increasingly labored and difficult, and as performing even small daily tasks leaves them exhausted.
Disease-related mental distress can lead to increased disability, more frequent use of costly healthcare resources, higher morbidity, and elevated risk of death, investigators say.
“Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD. Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients,” wrote Abebaw Mengitsu Yohannes, PhD, then from Azusa Pacific University in Azusa, California, and colleagues in an article published jointly by The Journal of Family Practice and The Cleveland Clinic Journal of Medicine.
Patients with COPD may experience major depressive disorders, chronic mild depression (dysthymias), and minor depression, as well as generalized anxiety disorder, phobias, and panic disorders, the investigators say.
“Growing evidence suggests that the relationship between mood disorders — particularly depression — and COPD is bidirectional, meaning that mood disorders adversely impact prognosis in COPD, whereas COPD increases the risk of developing depression,” Yohannes et al. wrote.
Jamie Garfield, MD, professor of thoracic medicine and surgery at Temple University’s Lewis Katz School of Medicine in Philadelphia, Pennsylvania, told Chest Physician that the association between severe chronic diseases and mood disorders is well known.
“I don’t think that it’s specific to chronic lung diseases; in people with chronic heart disease or malignancies we see that coexistence of depression and anxiety will worsen the course of disease,” she said.
Dr. Johannes, who is currently a professor of physical therapy at the University of Alabama School of Health Professionals in Birmingham, said that depression and anxiety are often underdiagnosed and undertreated in patients with obstructive pulmonary diseases because the conditions can share symptoms such as dyspnea (for example, in anxiety) or fatigue (in depression).
“Therefore, unless one begins to explore further, it’s hard for physicians to be able to identify these conditions,” he said in an interview with Chest Physician.
Fears of dying (and living)
The causes of depression and anxiety among patients with obstructive pulmonary disorders are multifactorial, and may require a variety of treatment and coping strategies, according to Susann Strang, RN, PhD, and colleagues from the University of Gothenburg, Gothenburg, Sweden.
They conducted qualitative in-depth interviews with 31 men and women with stage III or IV COPD, and found that the majority of patients had anxiety associated with their disease.
“Analyses revealed three major themes: death anxiety, life anxiety, and counterweights to anxiety,” the investigators wrote in a study published in the journal Palliative and Supportive Care in 2014.
Factors contributing to anxiety surrounding death included fear of suffocation, awareness of impending death, fear of the process of death, and anxiety about being separated from loved ones.
In contrast, some patients expressed dread of living with the limitations and loneliness imposed on them by their disease — so-called “life anxiety.”
The patients also reported “counterweights” to anxiety as a way of coping. For some this involved trust in their healthcare professionals and adherence to medication, inhalers, and supplemental oxygen.
“The patients also placed hope in new treatments, better medication, surgery, stem cell treatment, or lung transplants,” Dr. Strang and colleagues reported.
Others reported avoiding talking about death, sleeping more, or using humor to “laugh off this difficult subject.”
Screening and diagnosis
Primary care practitioners are often the first health professionals that patients with COPD see, but these clinicians often don’t have the time to add screening to their already crammed schedules. In addition, “the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders),” can make it difficult for PCPs to detect and manage anxiety and depression in their patients with significant healthcare burdens from COPD and other obstructive lung diseases, Dr. Yohannes and colleagues noted.
In addition to commonly used screening tools for anxiety and depression such as the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ-9), there are at least two designed to evaluate patients with lung disease: the Anxiety Inventory for Respiratory (AIR) Disease scale, developed by Dr. Yohannes and colleagues, and the COPD Anxiety Questionnaire.
The COPD Assessment Test and Clinical COPD Questionnaire, while not specifically designed to screen for mental disorders, include questions that can point to symptoms of distress in patients with COPD, Dr. Yohannes said.
“In truth I think that there are few providers who will routinely do this on all their patients in terms of quantifying the severity or the presence or absence of depression, but in my own practice I very much ask questions that align with the questions in these tools to determine whether my patient appears to have high levels of anxiety and depression,” Dr. Garfield said.
Listen to patients and families
Among the most powerful tools that clinicians have at their disposal for treating anxiety and depression in patients with chronic lung disease are their ears and their minds, said Anthony Saleh, MD, a pulmonologist at New York-Presbyterian Brooklyn Methodist Hospital in Brooklyn, New York.
“I think just listening to the patient, that’s a little bit forgotten yet so important,” he said in an interview with CHEST Physician.
“When I have someone with advanced lung disease, like idiopathic pulmonary fibrosis, like advanced emphysema, one of the most important things I think is to listen to the patient, and not just to listen to the answers of your perfunctory ‘how’s your breathing? Any chest pain?’ and those sort of rote medical questions, but listen to their thoughts, and it will given them a safe space to say ‘Hey, I’m nervous, hey I’m worried about my family, hey I’m worried if I die what’s going to happen to my wife and kids,’ and that’s something I think is invaluable.”
It’s also vital to listen to the concerns of the patients family members, who may be the primary caregivers and may share the patient’s stresses and anxieties, he said.
Pulmonary Rehabilitation
All of the experts interviewed for this article agreed that a combination of medical, social and mental health support services is important for treatment for patients with chronic obstructive lung diseases.
One of the most effective means of helping patients with both acute breathing problems and with disease-related anxiety and depression is pulmonary rehabilitation. Depending on disease severity, this multidisciplinary approach may involve exercise, patient education, psychological and nutrition counseling, and training patients how to conserve energy and adopt breathing strategies to help them better manage their symptoms.
“I think that pulmonary rehabilitation is one of the first interventions that we should be recommending for our patients,” Dr. Garfield said. “It’s physical therapy for patients with chronic lung diseases, backed by respiratory therapists, and it offers not only physical rehabilitation — improving strength and coordination, but also it helps our patients get as much as possible out of what they’ve got.”
For example, patients can be taught how to decrease their respiratory rate when they’re feeling a sense of urgency or panic. Patients can also learn how to change body positions to help them breathe more effectively when they feel that their breath is limited or restricted, she said.
“Once you’re into medical interventions, pulmonary rehab is phenomenal,” Dr. Saleh said.
Pulmonary rehabilitation helps patients to feel better about themselves and about their abilities, but “unfortunately it’s not as available as we like,” he said.
Many patients don’t live near a pulmonary rehabilitation center, and the typical two to three weekly sessions for 4-12 weeks or longer can be a significant burden for patients and caregivers, he acknowledged.
“You have to sit [with the patient] and be honest and tell them it’s a lot of diligence involved and you have to be really motivated,” he said.
Other treatment options include pharmacological therapy with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and anxiolytic agents.
“SSRIs are the current first-line drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date. However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy,” Dr. Johannes and colleagues wrote.
Defiant joy
Importantly, even with the burden of life with COPD, many patients found ways to experience what Strang et al. called “a defiant joy.”
“It was remarkable that when the patients were asked about what gave their lives meaning today, many talked about what had given their life meaning in the past, prior to becoming ill. In the light of the things they had lost because of the disease, many felt that their previous sources of joy no longer existed. Despite this, many still hoped to be able to get out into the fresh air, to be able to do errands, or that tomorrow might be better,” the investigators wrote.
Dr. Yohannes, Dr. Garfield, and Dr. Saleh all reported having no relevant conflicts of interest to report.
Many patients with chronic progressive pulmonary disease feel anxious and depressed as their conditions advance, as breathing becomes increasingly labored and difficult, and as performing even small daily tasks leaves them exhausted.
Disease-related mental distress can lead to increased disability, more frequent use of costly healthcare resources, higher morbidity, and elevated risk of death, investigators say.
“Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD. Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients,” wrote Abebaw Mengitsu Yohannes, PhD, then from Azusa Pacific University in Azusa, California, and colleagues in an article published jointly by The Journal of Family Practice and The Cleveland Clinic Journal of Medicine.
Patients with COPD may experience major depressive disorders, chronic mild depression (dysthymias), and minor depression, as well as generalized anxiety disorder, phobias, and panic disorders, the investigators say.
“Growing evidence suggests that the relationship between mood disorders — particularly depression — and COPD is bidirectional, meaning that mood disorders adversely impact prognosis in COPD, whereas COPD increases the risk of developing depression,” Yohannes et al. wrote.
Jamie Garfield, MD, professor of thoracic medicine and surgery at Temple University’s Lewis Katz School of Medicine in Philadelphia, Pennsylvania, told Chest Physician that the association between severe chronic diseases and mood disorders is well known.
“I don’t think that it’s specific to chronic lung diseases; in people with chronic heart disease or malignancies we see that coexistence of depression and anxiety will worsen the course of disease,” she said.
Dr. Johannes, who is currently a professor of physical therapy at the University of Alabama School of Health Professionals in Birmingham, said that depression and anxiety are often underdiagnosed and undertreated in patients with obstructive pulmonary diseases because the conditions can share symptoms such as dyspnea (for example, in anxiety) or fatigue (in depression).
“Therefore, unless one begins to explore further, it’s hard for physicians to be able to identify these conditions,” he said in an interview with Chest Physician.
Fears of dying (and living)
The causes of depression and anxiety among patients with obstructive pulmonary disorders are multifactorial, and may require a variety of treatment and coping strategies, according to Susann Strang, RN, PhD, and colleagues from the University of Gothenburg, Gothenburg, Sweden.
They conducted qualitative in-depth interviews with 31 men and women with stage III or IV COPD, and found that the majority of patients had anxiety associated with their disease.
“Analyses revealed three major themes: death anxiety, life anxiety, and counterweights to anxiety,” the investigators wrote in a study published in the journal Palliative and Supportive Care in 2014.
Factors contributing to anxiety surrounding death included fear of suffocation, awareness of impending death, fear of the process of death, and anxiety about being separated from loved ones.
In contrast, some patients expressed dread of living with the limitations and loneliness imposed on them by their disease — so-called “life anxiety.”
The patients also reported “counterweights” to anxiety as a way of coping. For some this involved trust in their healthcare professionals and adherence to medication, inhalers, and supplemental oxygen.
“The patients also placed hope in new treatments, better medication, surgery, stem cell treatment, or lung transplants,” Dr. Strang and colleagues reported.
Others reported avoiding talking about death, sleeping more, or using humor to “laugh off this difficult subject.”
Screening and diagnosis
Primary care practitioners are often the first health professionals that patients with COPD see, but these clinicians often don’t have the time to add screening to their already crammed schedules. In addition, “the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders),” can make it difficult for PCPs to detect and manage anxiety and depression in their patients with significant healthcare burdens from COPD and other obstructive lung diseases, Dr. Yohannes and colleagues noted.
In addition to commonly used screening tools for anxiety and depression such as the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ-9), there are at least two designed to evaluate patients with lung disease: the Anxiety Inventory for Respiratory (AIR) Disease scale, developed by Dr. Yohannes and colleagues, and the COPD Anxiety Questionnaire.
The COPD Assessment Test and Clinical COPD Questionnaire, while not specifically designed to screen for mental disorders, include questions that can point to symptoms of distress in patients with COPD, Dr. Yohannes said.
“In truth I think that there are few providers who will routinely do this on all their patients in terms of quantifying the severity or the presence or absence of depression, but in my own practice I very much ask questions that align with the questions in these tools to determine whether my patient appears to have high levels of anxiety and depression,” Dr. Garfield said.
Listen to patients and families
Among the most powerful tools that clinicians have at their disposal for treating anxiety and depression in patients with chronic lung disease are their ears and their minds, said Anthony Saleh, MD, a pulmonologist at New York-Presbyterian Brooklyn Methodist Hospital in Brooklyn, New York.
“I think just listening to the patient, that’s a little bit forgotten yet so important,” he said in an interview with CHEST Physician.
“When I have someone with advanced lung disease, like idiopathic pulmonary fibrosis, like advanced emphysema, one of the most important things I think is to listen to the patient, and not just to listen to the answers of your perfunctory ‘how’s your breathing? Any chest pain?’ and those sort of rote medical questions, but listen to their thoughts, and it will given them a safe space to say ‘Hey, I’m nervous, hey I’m worried about my family, hey I’m worried if I die what’s going to happen to my wife and kids,’ and that’s something I think is invaluable.”
It’s also vital to listen to the concerns of the patients family members, who may be the primary caregivers and may share the patient’s stresses and anxieties, he said.
Pulmonary Rehabilitation
All of the experts interviewed for this article agreed that a combination of medical, social and mental health support services is important for treatment for patients with chronic obstructive lung diseases.
One of the most effective means of helping patients with both acute breathing problems and with disease-related anxiety and depression is pulmonary rehabilitation. Depending on disease severity, this multidisciplinary approach may involve exercise, patient education, psychological and nutrition counseling, and training patients how to conserve energy and adopt breathing strategies to help them better manage their symptoms.
“I think that pulmonary rehabilitation is one of the first interventions that we should be recommending for our patients,” Dr. Garfield said. “It’s physical therapy for patients with chronic lung diseases, backed by respiratory therapists, and it offers not only physical rehabilitation — improving strength and coordination, but also it helps our patients get as much as possible out of what they’ve got.”
For example, patients can be taught how to decrease their respiratory rate when they’re feeling a sense of urgency or panic. Patients can also learn how to change body positions to help them breathe more effectively when they feel that their breath is limited or restricted, she said.
“Once you’re into medical interventions, pulmonary rehab is phenomenal,” Dr. Saleh said.
Pulmonary rehabilitation helps patients to feel better about themselves and about their abilities, but “unfortunately it’s not as available as we like,” he said.
Many patients don’t live near a pulmonary rehabilitation center, and the typical two to three weekly sessions for 4-12 weeks or longer can be a significant burden for patients and caregivers, he acknowledged.
“You have to sit [with the patient] and be honest and tell them it’s a lot of diligence involved and you have to be really motivated,” he said.
Other treatment options include pharmacological therapy with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and anxiolytic agents.
“SSRIs are the current first-line drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date. However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy,” Dr. Johannes and colleagues wrote.
Defiant joy
Importantly, even with the burden of life with COPD, many patients found ways to experience what Strang et al. called “a defiant joy.”
“It was remarkable that when the patients were asked about what gave their lives meaning today, many talked about what had given their life meaning in the past, prior to becoming ill. In the light of the things they had lost because of the disease, many felt that their previous sources of joy no longer existed. Despite this, many still hoped to be able to get out into the fresh air, to be able to do errands, or that tomorrow might be better,” the investigators wrote.
Dr. Yohannes, Dr. Garfield, and Dr. Saleh all reported having no relevant conflicts of interest to report.
Many patients with chronic progressive pulmonary disease feel anxious and depressed as their conditions advance, as breathing becomes increasingly labored and difficult, and as performing even small daily tasks leaves them exhausted.
Disease-related mental distress can lead to increased disability, more frequent use of costly healthcare resources, higher morbidity, and elevated risk of death, investigators say.
“Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD. Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients,” wrote Abebaw Mengitsu Yohannes, PhD, then from Azusa Pacific University in Azusa, California, and colleagues in an article published jointly by The Journal of Family Practice and The Cleveland Clinic Journal of Medicine.
Patients with COPD may experience major depressive disorders, chronic mild depression (dysthymias), and minor depression, as well as generalized anxiety disorder, phobias, and panic disorders, the investigators say.
“Growing evidence suggests that the relationship between mood disorders — particularly depression — and COPD is bidirectional, meaning that mood disorders adversely impact prognosis in COPD, whereas COPD increases the risk of developing depression,” Yohannes et al. wrote.
Jamie Garfield, MD, professor of thoracic medicine and surgery at Temple University’s Lewis Katz School of Medicine in Philadelphia, Pennsylvania, told Chest Physician that the association between severe chronic diseases and mood disorders is well known.
“I don’t think that it’s specific to chronic lung diseases; in people with chronic heart disease or malignancies we see that coexistence of depression and anxiety will worsen the course of disease,” she said.
Dr. Johannes, who is currently a professor of physical therapy at the University of Alabama School of Health Professionals in Birmingham, said that depression and anxiety are often underdiagnosed and undertreated in patients with obstructive pulmonary diseases because the conditions can share symptoms such as dyspnea (for example, in anxiety) or fatigue (in depression).
“Therefore, unless one begins to explore further, it’s hard for physicians to be able to identify these conditions,” he said in an interview with Chest Physician.
Fears of dying (and living)
The causes of depression and anxiety among patients with obstructive pulmonary disorders are multifactorial, and may require a variety of treatment and coping strategies, according to Susann Strang, RN, PhD, and colleagues from the University of Gothenburg, Gothenburg, Sweden.
They conducted qualitative in-depth interviews with 31 men and women with stage III or IV COPD, and found that the majority of patients had anxiety associated with their disease.
“Analyses revealed three major themes: death anxiety, life anxiety, and counterweights to anxiety,” the investigators wrote in a study published in the journal Palliative and Supportive Care in 2014.
Factors contributing to anxiety surrounding death included fear of suffocation, awareness of impending death, fear of the process of death, and anxiety about being separated from loved ones.
In contrast, some patients expressed dread of living with the limitations and loneliness imposed on them by their disease — so-called “life anxiety.”
The patients also reported “counterweights” to anxiety as a way of coping. For some this involved trust in their healthcare professionals and adherence to medication, inhalers, and supplemental oxygen.
“The patients also placed hope in new treatments, better medication, surgery, stem cell treatment, or lung transplants,” Dr. Strang and colleagues reported.
Others reported avoiding talking about death, sleeping more, or using humor to “laugh off this difficult subject.”
Screening and diagnosis
Primary care practitioners are often the first health professionals that patients with COPD see, but these clinicians often don’t have the time to add screening to their already crammed schedules. In addition, “the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders),” can make it difficult for PCPs to detect and manage anxiety and depression in their patients with significant healthcare burdens from COPD and other obstructive lung diseases, Dr. Yohannes and colleagues noted.
In addition to commonly used screening tools for anxiety and depression such as the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ-9), there are at least two designed to evaluate patients with lung disease: the Anxiety Inventory for Respiratory (AIR) Disease scale, developed by Dr. Yohannes and colleagues, and the COPD Anxiety Questionnaire.
The COPD Assessment Test and Clinical COPD Questionnaire, while not specifically designed to screen for mental disorders, include questions that can point to symptoms of distress in patients with COPD, Dr. Yohannes said.
“In truth I think that there are few providers who will routinely do this on all their patients in terms of quantifying the severity or the presence or absence of depression, but in my own practice I very much ask questions that align with the questions in these tools to determine whether my patient appears to have high levels of anxiety and depression,” Dr. Garfield said.
Listen to patients and families
Among the most powerful tools that clinicians have at their disposal for treating anxiety and depression in patients with chronic lung disease are their ears and their minds, said Anthony Saleh, MD, a pulmonologist at New York-Presbyterian Brooklyn Methodist Hospital in Brooklyn, New York.
“I think just listening to the patient, that’s a little bit forgotten yet so important,” he said in an interview with CHEST Physician.
“When I have someone with advanced lung disease, like idiopathic pulmonary fibrosis, like advanced emphysema, one of the most important things I think is to listen to the patient, and not just to listen to the answers of your perfunctory ‘how’s your breathing? Any chest pain?’ and those sort of rote medical questions, but listen to their thoughts, and it will given them a safe space to say ‘Hey, I’m nervous, hey I’m worried about my family, hey I’m worried if I die what’s going to happen to my wife and kids,’ and that’s something I think is invaluable.”
It’s also vital to listen to the concerns of the patients family members, who may be the primary caregivers and may share the patient’s stresses and anxieties, he said.
Pulmonary Rehabilitation
All of the experts interviewed for this article agreed that a combination of medical, social and mental health support services is important for treatment for patients with chronic obstructive lung diseases.
One of the most effective means of helping patients with both acute breathing problems and with disease-related anxiety and depression is pulmonary rehabilitation. Depending on disease severity, this multidisciplinary approach may involve exercise, patient education, psychological and nutrition counseling, and training patients how to conserve energy and adopt breathing strategies to help them better manage their symptoms.
“I think that pulmonary rehabilitation is one of the first interventions that we should be recommending for our patients,” Dr. Garfield said. “It’s physical therapy for patients with chronic lung diseases, backed by respiratory therapists, and it offers not only physical rehabilitation — improving strength and coordination, but also it helps our patients get as much as possible out of what they’ve got.”
For example, patients can be taught how to decrease their respiratory rate when they’re feeling a sense of urgency or panic. Patients can also learn how to change body positions to help them breathe more effectively when they feel that their breath is limited or restricted, she said.
“Once you’re into medical interventions, pulmonary rehab is phenomenal,” Dr. Saleh said.
Pulmonary rehabilitation helps patients to feel better about themselves and about their abilities, but “unfortunately it’s not as available as we like,” he said.
Many patients don’t live near a pulmonary rehabilitation center, and the typical two to three weekly sessions for 4-12 weeks or longer can be a significant burden for patients and caregivers, he acknowledged.
“You have to sit [with the patient] and be honest and tell them it’s a lot of diligence involved and you have to be really motivated,” he said.
Other treatment options include pharmacological therapy with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and anxiolytic agents.
“SSRIs are the current first-line drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date. However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy,” Dr. Johannes and colleagues wrote.
Defiant joy
Importantly, even with the burden of life with COPD, many patients found ways to experience what Strang et al. called “a defiant joy.”
“It was remarkable that when the patients were asked about what gave their lives meaning today, many talked about what had given their life meaning in the past, prior to becoming ill. In the light of the things they had lost because of the disease, many felt that their previous sources of joy no longer existed. Despite this, many still hoped to be able to get out into the fresh air, to be able to do errands, or that tomorrow might be better,” the investigators wrote.
Dr. Yohannes, Dr. Garfield, and Dr. Saleh all reported having no relevant conflicts of interest to report.