Clinical Topics & News

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

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

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

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

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

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

A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.

“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, and senior research scientist at the Vancouver Prostate Center, told this news organization.

“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”

The study was published in Nature.
 

Test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors wrote, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.

Dr. Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.

The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.

The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.

“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Dr. Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
 

Clinical trials

The study authors wrote that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.

The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.

“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, both in Kingston, Ont., said in an interview.

Dr. Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and his colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Dr. Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Dr. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Dr. Mueller disclosed no relevant financial relationships.

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

A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.

“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, and senior research scientist at the Vancouver Prostate Center, told this news organization.

“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”

The study was published in Nature.
 

Test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors wrote, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.

Dr. Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.

The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.

The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.

“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Dr. Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
 

Clinical trials

The study authors wrote that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.

The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.

“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, both in Kingston, Ont., said in an interview.

Dr. Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and his colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Dr. Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Dr. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Dr. Mueller disclosed no relevant financial relationships.

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

A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.

“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, and senior research scientist at the Vancouver Prostate Center, told this news organization.

“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”

The study was published in Nature.
 

Test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors wrote, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.

Dr. Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.

The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.

The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.

“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Dr. Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
 

Clinical trials

The study authors wrote that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.

The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.

“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, both in Kingston, Ont., said in an interview.

Dr. Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and his colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Dr. Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Dr. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Dr. Mueller disclosed no relevant financial relationships.

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

Young women with a new diagnosis of node-negative triple-negative breast cancer (TNBC) who have high levels of stromal tumor-infiltrating lymphocytes (sTILs) have a very good long-term prognosis, and may be suitable candidates for reduced intensity pre- or postoperative chemotherapy, according to a team of European investigators.

Among 441 women in a Dutch cancer registry who were younger than 40 when they were diagnosed with node-negative TNBC and had not undergone systemic therapy, those who had 75% or more TILs in the intratumoral stromal area had a 15-year cumulative incidence of distant metastases or death of just 2.1%, and every 10% increase in sTILs was associated with a 19% decrease in the risk of death.

In contrast, the 15-year cumulative incidence of distant metastases was 38.4% for women with stromal TIL scores of less than 30%, according to researchers writing in the Journal of Clinical Oncology.

“These data could be used as a starting point for designing a randomized controlled chemotherapy de-escalation trial. The current study confirms the importance of sTILs as a valuable addition to the set of standard prognostic factors in patients with TNBC,” wrote the researchers, who were led by Sabine C. Linn, MD, of the Netherlands Cancer Institute, Amsterdam.
 

Markers for immune response

Stromal TILs, a mixture of mononuclear immune cells, have been shown in previous studies to be prognostic for outcomes in patients with early-stage TNBC treated either with or without neoadjuvant or adjuvant chemotherapy.

For example, investigators cited a study published in JCO in 2014, that showed among women with TNBC enrolled in the phase 3 ECOG 2197 clinical trial and the related ECOG 119 clinical trial, after a nearly 11-year follow-up, higher sTIL scores were associated with significantly better prognosis with every 10% increase translating into a 14% reduction in the risk of recurrence or death (P = .02).

“The prognostic importance of sTILs is, however, unexplored in patients diagnosed under age 40 years, let alone in the subgroup of systemic therapy–naive patients,” Dr. Linn and colleagues wrote.
 

Retrospective study

To see whether the prognostic value of sTILs was as strong among young, systemic therapy–naive women, the investigators conducted a retrospective study of women enrolled in the Netherlands Cancer Registry who were diagnosed with node-negative TNBC from 1989 to 2000. The patients selected had undergone only locoregional treatment, including axillary node dissection, but had not received any systemic therapy.

Pathologists reviewed samples, with TILs reported for the stromal compartment. The samples were grouped by sTIL score categories of high (75% or greater), intermediate (30% to less than 75%), or low (less than 30%). The investigators looked at overall survival (OS) and distant metastasis-free survival (DMFS) stratified by sTIL scores,

During a median follow-up of 15 years, 107 women died or developed distant metastases, and 78 experienced a second primary cancer.

The results were as noted, with patients in the highest category of sTILs having very low rates of either death or distant metastases during follow-up.

“We confirm the prognostic value of sTILs in young patients with early-stage N0 TNBC who are systemic therapy naive by taking advantage of a prospectively collected population-based cohort. Increasing sTILs are significantly associated with improved OS and DMFS. Patients with high sTILs (> 75%) had an excellent 10-year overall survival and a very low 10-year incidence of distant metastasis or death.

The study was supported by grants from The Netherlands Organization for Health Research and Development, A Sister’s Hope, De Vrienden van UMC Utrecht, Agilent Technologies, the Dutch Cancer Society, and Breast Cancer Research Foundation. Dr. Linn reported consulting with and receiving compensation from Daiichi Sankyo, as well as receiving research funding from Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia, and Novartis.

Young women with a new diagnosis of node-negative triple-negative breast cancer (TNBC) who have high levels of stromal tumor-infiltrating lymphocytes (sTILs) have a very good long-term prognosis, and may be suitable candidates for reduced intensity pre- or postoperative chemotherapy, according to a team of European investigators.

Among 441 women in a Dutch cancer registry who were younger than 40 when they were diagnosed with node-negative TNBC and had not undergone systemic therapy, those who had 75% or more TILs in the intratumoral stromal area had a 15-year cumulative incidence of distant metastases or death of just 2.1%, and every 10% increase in sTILs was associated with a 19% decrease in the risk of death.

In contrast, the 15-year cumulative incidence of distant metastases was 38.4% for women with stromal TIL scores of less than 30%, according to researchers writing in the Journal of Clinical Oncology.

“These data could be used as a starting point for designing a randomized controlled chemotherapy de-escalation trial. The current study confirms the importance of sTILs as a valuable addition to the set of standard prognostic factors in patients with TNBC,” wrote the researchers, who were led by Sabine C. Linn, MD, of the Netherlands Cancer Institute, Amsterdam.
 

Markers for immune response

Stromal TILs, a mixture of mononuclear immune cells, have been shown in previous studies to be prognostic for outcomes in patients with early-stage TNBC treated either with or without neoadjuvant or adjuvant chemotherapy.

For example, investigators cited a study published in JCO in 2014, that showed among women with TNBC enrolled in the phase 3 ECOG 2197 clinical trial and the related ECOG 119 clinical trial, after a nearly 11-year follow-up, higher sTIL scores were associated with significantly better prognosis with every 10% increase translating into a 14% reduction in the risk of recurrence or death (P = .02).

“The prognostic importance of sTILs is, however, unexplored in patients diagnosed under age 40 years, let alone in the subgroup of systemic therapy–naive patients,” Dr. Linn and colleagues wrote.
 

Retrospective study

To see whether the prognostic value of sTILs was as strong among young, systemic therapy–naive women, the investigators conducted a retrospective study of women enrolled in the Netherlands Cancer Registry who were diagnosed with node-negative TNBC from 1989 to 2000. The patients selected had undergone only locoregional treatment, including axillary node dissection, but had not received any systemic therapy.

Pathologists reviewed samples, with TILs reported for the stromal compartment. The samples were grouped by sTIL score categories of high (75% or greater), intermediate (30% to less than 75%), or low (less than 30%). The investigators looked at overall survival (OS) and distant metastasis-free survival (DMFS) stratified by sTIL scores,

During a median follow-up of 15 years, 107 women died or developed distant metastases, and 78 experienced a second primary cancer.

The results were as noted, with patients in the highest category of sTILs having very low rates of either death or distant metastases during follow-up.

“We confirm the prognostic value of sTILs in young patients with early-stage N0 TNBC who are systemic therapy naive by taking advantage of a prospectively collected population-based cohort. Increasing sTILs are significantly associated with improved OS and DMFS. Patients with high sTILs (> 75%) had an excellent 10-year overall survival and a very low 10-year incidence of distant metastasis or death.

The study was supported by grants from The Netherlands Organization for Health Research and Development, A Sister’s Hope, De Vrienden van UMC Utrecht, Agilent Technologies, the Dutch Cancer Society, and Breast Cancer Research Foundation. Dr. Linn reported consulting with and receiving compensation from Daiichi Sankyo, as well as receiving research funding from Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia, and Novartis.

Young women with a new diagnosis of node-negative triple-negative breast cancer (TNBC) who have high levels of stromal tumor-infiltrating lymphocytes (sTILs) have a very good long-term prognosis, and may be suitable candidates for reduced intensity pre- or postoperative chemotherapy, according to a team of European investigators.

Among 441 women in a Dutch cancer registry who were younger than 40 when they were diagnosed with node-negative TNBC and had not undergone systemic therapy, those who had 75% or more TILs in the intratumoral stromal area had a 15-year cumulative incidence of distant metastases or death of just 2.1%, and every 10% increase in sTILs was associated with a 19% decrease in the risk of death.

In contrast, the 15-year cumulative incidence of distant metastases was 38.4% for women with stromal TIL scores of less than 30%, according to researchers writing in the Journal of Clinical Oncology.

“These data could be used as a starting point for designing a randomized controlled chemotherapy de-escalation trial. The current study confirms the importance of sTILs as a valuable addition to the set of standard prognostic factors in patients with TNBC,” wrote the researchers, who were led by Sabine C. Linn, MD, of the Netherlands Cancer Institute, Amsterdam.
 

Markers for immune response

Stromal TILs, a mixture of mononuclear immune cells, have been shown in previous studies to be prognostic for outcomes in patients with early-stage TNBC treated either with or without neoadjuvant or adjuvant chemotherapy.

For example, investigators cited a study published in JCO in 2014, that showed among women with TNBC enrolled in the phase 3 ECOG 2197 clinical trial and the related ECOG 119 clinical trial, after a nearly 11-year follow-up, higher sTIL scores were associated with significantly better prognosis with every 10% increase translating into a 14% reduction in the risk of recurrence or death (P = .02).

“The prognostic importance of sTILs is, however, unexplored in patients diagnosed under age 40 years, let alone in the subgroup of systemic therapy–naive patients,” Dr. Linn and colleagues wrote.
 

Retrospective study

To see whether the prognostic value of sTILs was as strong among young, systemic therapy–naive women, the investigators conducted a retrospective study of women enrolled in the Netherlands Cancer Registry who were diagnosed with node-negative TNBC from 1989 to 2000. The patients selected had undergone only locoregional treatment, including axillary node dissection, but had not received any systemic therapy.

Pathologists reviewed samples, with TILs reported for the stromal compartment. The samples were grouped by sTIL score categories of high (75% or greater), intermediate (30% to less than 75%), or low (less than 30%). The investigators looked at overall survival (OS) and distant metastasis-free survival (DMFS) stratified by sTIL scores,

During a median follow-up of 15 years, 107 women died or developed distant metastases, and 78 experienced a second primary cancer.

The results were as noted, with patients in the highest category of sTILs having very low rates of either death or distant metastases during follow-up.

“We confirm the prognostic value of sTILs in young patients with early-stage N0 TNBC who are systemic therapy naive by taking advantage of a prospectively collected population-based cohort. Increasing sTILs are significantly associated with improved OS and DMFS. Patients with high sTILs (> 75%) had an excellent 10-year overall survival and a very low 10-year incidence of distant metastasis or death.

The study was supported by grants from The Netherlands Organization for Health Research and Development, A Sister’s Hope, De Vrienden van UMC Utrecht, Agilent Technologies, the Dutch Cancer Society, and Breast Cancer Research Foundation. Dr. Linn reported consulting with and receiving compensation from Daiichi Sankyo, as well as receiving research funding from Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia, and Novartis.

Adding to a growing body of evidence that elevated remnant cholesterol (remnant-C) provides additional and independent risk prediction for major cardiovascular events (MACE), a new analysis has this shown this biomarker has prognostic value specifically in patients with type 2 diabetes (T2D).

In a post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, each standard-deviation increase in remnant-C was associated with a 7% increased risk in MACE (P = .004) after adjustment for several risk factors including other cholesterol values.

“In type 2 diabetes, remnant-C levels are associated with MACE regardless of LDL-C,” reported a team of investigators led by Liyao Fu, MD, Second Xiangya Hospital of Central South University, Changsha, China .

Remnant-C is one component of triglyceride-rich lipoproteins. Within triglyceride-rich lipoproteins, remnant-C has become a major focus of efforts to explain cardiovascular (CV) residual risk, according to the investigators.

Residual risk is a term used to explain why cardiovascular events occur after all known modifiable factors, such as LDL cholesterol (LDL-C), are controlled.

“Our primary findings indicate that baseline estimated remnant-C levels were associated with MACE regardless of clinical phenotypes, lifestyle confounders relative to CV risk, and lipid-lowering treatment,” said the authors of the analysis.

In the post hoc analysis of the ACCORD trial, which evaluated the effects of intensive glucose lowering in T2D more than 10 years ago, there were data on remnant-C over a median of 8.8 years of follow-up in 9,650 T2D patients. Over this period, 1,815 (17.8%) developed MACE.

Multiple analyses support prognostic value of remnant-C

In addition to the 7% rise in MACE for each standard-deviation increase in remnant-C when calculated as a continuous variable, other analyses told the same story.

This included an assessment by remnant-C tertiles. Not only was there a significant trend (P < .001) for greater risk with each higher baseline tertile of remnant-C, those in the highest tertile had a 38% greater risk of MACE relative to those in the lowest tertile (hazard ratio, 1.38; P < .001) after adjustment for confounders.

The same pattern was seen for several components of MACE, such as CV death and nonfatal myocardial infarction, when remnant-C tertiles were compared.

Visit-to-visit variability in remnant-C over the course of follow-up was also associated with greater risk of MACE. In logarithmic calculations, the risk of MACE climbed about 40% across all three models of risk adjustment. These models included adjustments for different sets of confounders, such as sex, age, blood pressure, CV disease history, and glucose levels. On an unadjusted basis, the risk was increased about 50% (HR, 1.52; P < .001).

For visit-to-visit variability in remnant-C, the greatest effect was on risk of nonfatal MI across models. In model 3, for example, which adjusted for the most confounders, the risk was nearly doubled (HR, 1.92; P < .001). In contrast, there did not appear to be a link between visit-to-visit variability and nonfatal stroke.

In a discordant analysis that was conducted to examine the relative risk of remnant-C independent of LDL-C, those who had a remnant-C level of at least 31 mg/dL were found to have a higher risk of MACE regardless of LDL-C level. Yet, the risk was higher if both remnant-C and LDL-C were elevated. For example, the risk was increased 22% for those with LDL-C at or below 100 mg/dL and remnant-C levels of at least 31 mg/dL (HR, 1.22; P = .015) but climbed to 37% for those with LDL-C above 100 mg/dL if remnant-C was at least 31 mg/dL (HR, 1.38; P = .007).
 

Remnant-C shows prognostic value in other risk groups

Although this study suggests an important prognostic value for remnant-C in T2D, there are numerous studies suggesting that it has prognostic value in other risk groups, such as those with a history of CV disease. This includes a study published earlier this year with 10 years of follow-up in 41,928 patients in Denmark. When combined with other risk factors, remnant-C substantially improved the accuracy of risk of events over time.

The investigators from this previous study, like the new study in patients with T2D, predict that remnant-C will be eventually included in guidelines.

According to Shi Tai, MD, a coauthor of the T2D study, remnant-C “may allow for the development of specific preventive and therapeutic approaches” to CV risk in patients with T2D.

T2D patients “with elevated plasma remnant-C levels represent a special population that deserves more attention regarding residual risk,” said Dr. Tai of the department of cardiovascular medicine at the Hospital of South Central China.
 

Great interest, but ready for guidelines?

This is an important direction of ongoing research, according to Christie M. Ballantyne, MD, professor of medicine, Baylor College of Medicine, Houston.

“There is a great deal of interest from both clinicians and trialists to find a simple way to identify patients with high residual risk who are on statin therapy,” he said. He thinks remnant-C has promise in this regard.

“Remnant-C is not in current guidelines,” he said in an interview, but he suggested that there is now a substantial body of evidence to suggest that it might be added if validated in further studies.

“Remnant-C is easy to calculate and may be helpful in practice now to identify patients who need more aggressive therapy to reduce risk and may be useful to identify patients for clinical trials who will benefit from new therapies that are in development,” he said.

However, the clinical relevance of therapies addressed at triglyceride-rich lipoproteins in general or their components, including triglycerides or remnant-C, has never been demonstrated, pointed out Peter W.F. Wilson, MD, PhD.

“Higher fasting or nonfasting triglyceride levels or their surrogates have been shown to be associated with increased risk for cardiovascular disease events in observational studies, but the importance of such measurements in persons already treated with very aggressive LDL-C lowering therapy is not known,” commented Dr. Wilson, director of epidemiology and genomic medicine, Emory School of Medicine, Atlanta.

Dr. Wilson was the coauthor of an editorial that accompanied the previously published Danish study of remnant-C. In his editorial, he suggested that remnant-C has promise for better understanding residual risk, but when contacted about these latest data he emphasized a lack of support so far for clinical relevance.

“Unfortunately, clinical trials have generally not shown that triglyceride lowering [to favorably alter remnant-C] in this situation favorably affects the risk of CV disease events,” he said in an interview. This does not preclude remnant-C as a targetable risk factor, but these data are needed.

Dr. Fu, Dr. Tai, and Dr. Wilson report no potential conflicts of interest. Dr. Ballantyne has financial relationships with more than 25 pharmaceutical companies, including several that produce products employed for the treatment of lipid abnormalities.

Adding to a growing body of evidence that elevated remnant cholesterol (remnant-C) provides additional and independent risk prediction for major cardiovascular events (MACE), a new analysis has this shown this biomarker has prognostic value specifically in patients with type 2 diabetes (T2D).

In a post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, each standard-deviation increase in remnant-C was associated with a 7% increased risk in MACE (P = .004) after adjustment for several risk factors including other cholesterol values.

“In type 2 diabetes, remnant-C levels are associated with MACE regardless of LDL-C,” reported a team of investigators led by Liyao Fu, MD, Second Xiangya Hospital of Central South University, Changsha, China .

Remnant-C is one component of triglyceride-rich lipoproteins. Within triglyceride-rich lipoproteins, remnant-C has become a major focus of efforts to explain cardiovascular (CV) residual risk, according to the investigators.

Residual risk is a term used to explain why cardiovascular events occur after all known modifiable factors, such as LDL cholesterol (LDL-C), are controlled.

“Our primary findings indicate that baseline estimated remnant-C levels were associated with MACE regardless of clinical phenotypes, lifestyle confounders relative to CV risk, and lipid-lowering treatment,” said the authors of the analysis.

In the post hoc analysis of the ACCORD trial, which evaluated the effects of intensive glucose lowering in T2D more than 10 years ago, there were data on remnant-C over a median of 8.8 years of follow-up in 9,650 T2D patients. Over this period, 1,815 (17.8%) developed MACE.

Multiple analyses support prognostic value of remnant-C

In addition to the 7% rise in MACE for each standard-deviation increase in remnant-C when calculated as a continuous variable, other analyses told the same story.

This included an assessment by remnant-C tertiles. Not only was there a significant trend (P < .001) for greater risk with each higher baseline tertile of remnant-C, those in the highest tertile had a 38% greater risk of MACE relative to those in the lowest tertile (hazard ratio, 1.38; P < .001) after adjustment for confounders.

The same pattern was seen for several components of MACE, such as CV death and nonfatal myocardial infarction, when remnant-C tertiles were compared.

Visit-to-visit variability in remnant-C over the course of follow-up was also associated with greater risk of MACE. In logarithmic calculations, the risk of MACE climbed about 40% across all three models of risk adjustment. These models included adjustments for different sets of confounders, such as sex, age, blood pressure, CV disease history, and glucose levels. On an unadjusted basis, the risk was increased about 50% (HR, 1.52; P < .001).

For visit-to-visit variability in remnant-C, the greatest effect was on risk of nonfatal MI across models. In model 3, for example, which adjusted for the most confounders, the risk was nearly doubled (HR, 1.92; P < .001). In contrast, there did not appear to be a link between visit-to-visit variability and nonfatal stroke.

In a discordant analysis that was conducted to examine the relative risk of remnant-C independent of LDL-C, those who had a remnant-C level of at least 31 mg/dL were found to have a higher risk of MACE regardless of LDL-C level. Yet, the risk was higher if both remnant-C and LDL-C were elevated. For example, the risk was increased 22% for those with LDL-C at or below 100 mg/dL and remnant-C levels of at least 31 mg/dL (HR, 1.22; P = .015) but climbed to 37% for those with LDL-C above 100 mg/dL if remnant-C was at least 31 mg/dL (HR, 1.38; P = .007).
 

Remnant-C shows prognostic value in other risk groups

Although this study suggests an important prognostic value for remnant-C in T2D, there are numerous studies suggesting that it has prognostic value in other risk groups, such as those with a history of CV disease. This includes a study published earlier this year with 10 years of follow-up in 41,928 patients in Denmark. When combined with other risk factors, remnant-C substantially improved the accuracy of risk of events over time.

The investigators from this previous study, like the new study in patients with T2D, predict that remnant-C will be eventually included in guidelines.

According to Shi Tai, MD, a coauthor of the T2D study, remnant-C “may allow for the development of specific preventive and therapeutic approaches” to CV risk in patients with T2D.

T2D patients “with elevated plasma remnant-C levels represent a special population that deserves more attention regarding residual risk,” said Dr. Tai of the department of cardiovascular medicine at the Hospital of South Central China.
 

Great interest, but ready for guidelines?

This is an important direction of ongoing research, according to Christie M. Ballantyne, MD, professor of medicine, Baylor College of Medicine, Houston.

“There is a great deal of interest from both clinicians and trialists to find a simple way to identify patients with high residual risk who are on statin therapy,” he said. He thinks remnant-C has promise in this regard.

“Remnant-C is not in current guidelines,” he said in an interview, but he suggested that there is now a substantial body of evidence to suggest that it might be added if validated in further studies.

“Remnant-C is easy to calculate and may be helpful in practice now to identify patients who need more aggressive therapy to reduce risk and may be useful to identify patients for clinical trials who will benefit from new therapies that are in development,” he said.

However, the clinical relevance of therapies addressed at triglyceride-rich lipoproteins in general or their components, including triglycerides or remnant-C, has never been demonstrated, pointed out Peter W.F. Wilson, MD, PhD.

“Higher fasting or nonfasting triglyceride levels or their surrogates have been shown to be associated with increased risk for cardiovascular disease events in observational studies, but the importance of such measurements in persons already treated with very aggressive LDL-C lowering therapy is not known,” commented Dr. Wilson, director of epidemiology and genomic medicine, Emory School of Medicine, Atlanta.

Dr. Wilson was the coauthor of an editorial that accompanied the previously published Danish study of remnant-C. In his editorial, he suggested that remnant-C has promise for better understanding residual risk, but when contacted about these latest data he emphasized a lack of support so far for clinical relevance.

“Unfortunately, clinical trials have generally not shown that triglyceride lowering [to favorably alter remnant-C] in this situation favorably affects the risk of CV disease events,” he said in an interview. This does not preclude remnant-C as a targetable risk factor, but these data are needed.

Dr. Fu, Dr. Tai, and Dr. Wilson report no potential conflicts of interest. Dr. Ballantyne has financial relationships with more than 25 pharmaceutical companies, including several that produce products employed for the treatment of lipid abnormalities.

Adding to a growing body of evidence that elevated remnant cholesterol (remnant-C) provides additional and independent risk prediction for major cardiovascular events (MACE), a new analysis has this shown this biomarker has prognostic value specifically in patients with type 2 diabetes (T2D).

In a post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, each standard-deviation increase in remnant-C was associated with a 7% increased risk in MACE (P = .004) after adjustment for several risk factors including other cholesterol values.

“In type 2 diabetes, remnant-C levels are associated with MACE regardless of LDL-C,” reported a team of investigators led by Liyao Fu, MD, Second Xiangya Hospital of Central South University, Changsha, China .

Remnant-C is one component of triglyceride-rich lipoproteins. Within triglyceride-rich lipoproteins, remnant-C has become a major focus of efforts to explain cardiovascular (CV) residual risk, according to the investigators.

Residual risk is a term used to explain why cardiovascular events occur after all known modifiable factors, such as LDL cholesterol (LDL-C), are controlled.

“Our primary findings indicate that baseline estimated remnant-C levels were associated with MACE regardless of clinical phenotypes, lifestyle confounders relative to CV risk, and lipid-lowering treatment,” said the authors of the analysis.

In the post hoc analysis of the ACCORD trial, which evaluated the effects of intensive glucose lowering in T2D more than 10 years ago, there were data on remnant-C over a median of 8.8 years of follow-up in 9,650 T2D patients. Over this period, 1,815 (17.8%) developed MACE.

Multiple analyses support prognostic value of remnant-C

In addition to the 7% rise in MACE for each standard-deviation increase in remnant-C when calculated as a continuous variable, other analyses told the same story.

This included an assessment by remnant-C tertiles. Not only was there a significant trend (P < .001) for greater risk with each higher baseline tertile of remnant-C, those in the highest tertile had a 38% greater risk of MACE relative to those in the lowest tertile (hazard ratio, 1.38; P < .001) after adjustment for confounders.

The same pattern was seen for several components of MACE, such as CV death and nonfatal myocardial infarction, when remnant-C tertiles were compared.

Visit-to-visit variability in remnant-C over the course of follow-up was also associated with greater risk of MACE. In logarithmic calculations, the risk of MACE climbed about 40% across all three models of risk adjustment. These models included adjustments for different sets of confounders, such as sex, age, blood pressure, CV disease history, and glucose levels. On an unadjusted basis, the risk was increased about 50% (HR, 1.52; P < .001).

For visit-to-visit variability in remnant-C, the greatest effect was on risk of nonfatal MI across models. In model 3, for example, which adjusted for the most confounders, the risk was nearly doubled (HR, 1.92; P < .001). In contrast, there did not appear to be a link between visit-to-visit variability and nonfatal stroke.

In a discordant analysis that was conducted to examine the relative risk of remnant-C independent of LDL-C, those who had a remnant-C level of at least 31 mg/dL were found to have a higher risk of MACE regardless of LDL-C level. Yet, the risk was higher if both remnant-C and LDL-C were elevated. For example, the risk was increased 22% for those with LDL-C at or below 100 mg/dL and remnant-C levels of at least 31 mg/dL (HR, 1.22; P = .015) but climbed to 37% for those with LDL-C above 100 mg/dL if remnant-C was at least 31 mg/dL (HR, 1.38; P = .007).
 

Remnant-C shows prognostic value in other risk groups

Although this study suggests an important prognostic value for remnant-C in T2D, there are numerous studies suggesting that it has prognostic value in other risk groups, such as those with a history of CV disease. This includes a study published earlier this year with 10 years of follow-up in 41,928 patients in Denmark. When combined with other risk factors, remnant-C substantially improved the accuracy of risk of events over time.

The investigators from this previous study, like the new study in patients with T2D, predict that remnant-C will be eventually included in guidelines.

According to Shi Tai, MD, a coauthor of the T2D study, remnant-C “may allow for the development of specific preventive and therapeutic approaches” to CV risk in patients with T2D.

T2D patients “with elevated plasma remnant-C levels represent a special population that deserves more attention regarding residual risk,” said Dr. Tai of the department of cardiovascular medicine at the Hospital of South Central China.
 

Great interest, but ready for guidelines?

This is an important direction of ongoing research, according to Christie M. Ballantyne, MD, professor of medicine, Baylor College of Medicine, Houston.

“There is a great deal of interest from both clinicians and trialists to find a simple way to identify patients with high residual risk who are on statin therapy,” he said. He thinks remnant-C has promise in this regard.

“Remnant-C is not in current guidelines,” he said in an interview, but he suggested that there is now a substantial body of evidence to suggest that it might be added if validated in further studies.

“Remnant-C is easy to calculate and may be helpful in practice now to identify patients who need more aggressive therapy to reduce risk and may be useful to identify patients for clinical trials who will benefit from new therapies that are in development,” he said.

However, the clinical relevance of therapies addressed at triglyceride-rich lipoproteins in general or their components, including triglycerides or remnant-C, has never been demonstrated, pointed out Peter W.F. Wilson, MD, PhD.

“Higher fasting or nonfasting triglyceride levels or their surrogates have been shown to be associated with increased risk for cardiovascular disease events in observational studies, but the importance of such measurements in persons already treated with very aggressive LDL-C lowering therapy is not known,” commented Dr. Wilson, director of epidemiology and genomic medicine, Emory School of Medicine, Atlanta.

Dr. Wilson was the coauthor of an editorial that accompanied the previously published Danish study of remnant-C. In his editorial, he suggested that remnant-C has promise for better understanding residual risk, but when contacted about these latest data he emphasized a lack of support so far for clinical relevance.

“Unfortunately, clinical trials have generally not shown that triglyceride lowering [to favorably alter remnant-C] in this situation favorably affects the risk of CV disease events,” he said in an interview. This does not preclude remnant-C as a targetable risk factor, but these data are needed.

Dr. Fu, Dr. Tai, and Dr. Wilson report no potential conflicts of interest. Dr. Ballantyne has financial relationships with more than 25 pharmaceutical companies, including several that produce products employed for the treatment of lipid abnormalities.

It was 2 a.m. And Rebecca Shatsky, MD, could not sleep.

The breast oncologist was thinking about a patient of hers with metastatic cancer.

The patient’s disease had been asymptomatic for some time. Then without warning, her cancer suddenly exploded. Her bone marrow was failing, and her liver was not far behind.

Dr. Shatsky had a treatment plan ready to go but still, she felt uneasy.

“I had to be honest with her that I didn’t know if this plan would work,” says Dr. Shatsky, a medical oncologist at University of California, San Diego (UCSD).

That night, after visiting the patient in the hospital, Dr. Shatsky lay awake going over her next move, making sure it was the right one and hoping it would help keep the disease at bay.

“It’s so much pressure when someone is depending on you to make life or death decisions,” Dr. Shatsky said.

And in the quiet hours of night, these concerns grow louder.

Dr. Shatsky is not alone. Oncologists face difficult decisions every day, and many wrestle with these choices long after their day in the clinic is over.

“There’s no off button,” says Aaron Goodman, MD, a hematologist at UCSD Health who goes by “Papa Heme” on Twitter. “I’m always thinking about my patients. Constantly.”

The public rarely gets a glimpse of these private moments. On occasion, oncologists will share a personal story, but more often, insights come from broad research on the ethical, emotional, and psychological toll of practicing medicine.

Many oncologists carry this baggage home with them because they have no other option.

“There is simply no time to process the weight of the day when I’ve got seven more patients who need my full attention before lunch,” Mark Lewis, MD, director, department of gastrointestinal oncology, Intermountain Healthcare, Salt Lake City, Utah. “That is why my processing happens outside of the office, when my brain can be quiet.”
 

What am I missing?

Dr. Goodman recognizes the gravity of each decision he makes. He pores over every detail of a patient’s scans, lab results, history, and symptoms.

But no matter how many times he checks and rechecks, one question nags at him: What am I missing?

For Dr. Goodman, this exhaustive level of attention is worth it.

“When errors are made, it’s someone’s life,” Dr. Goodman said. “Nothing would have prepared me for this responsibility. Until it lies on you, it’s impossible to understand how much trust patients put into us.”

That trust becomes most apparent for Dr. Goodman when facing a decision about how to treat a patient with acute myeloid leukemia who’s in remission.

Give more chemotherapy to root out the leukemia cells still lurking in the body, and the patient faces a high risk of the cancer returning. Pick stem cell transplant, and the chance of being cured goes up significantly, but the patient could also die within 100 days of the transplant.

“All together, the data show I’m helping patients with a transplant, but for the individual, I could be causing harm. Someone could be living less because of a decision I made,” Dr. Goodman said.

For patients with advanced cancer, oncologists may need to think several moves ahead. Mapping out a patient’s treatment options can feel like a game of chess. Dr. Shatsky is always trying to anticipate how the tumor will behave, what is driving it, and how lifestyle factors may influence a patient’s response in the present and the future.

“It is a mind game,” she says. “Like in chess, I try to outsmart my opponent. But with advanced cancer, there are not necessarily clear-cut guidelines or one way to manage the disease, and I have to do the best I can with drugs I have.”

That’s the art of oncology: Balancing the many knowns and unknowns of a person’s cancer alongside the toxicities of treatment and a patient’s hopes and goals.

Throughout the year, Don Dizon, MD, will see a number of patients with advanced disease. In these instances, the question he often wrestles with is if the patient can’t be cured, whether more treatment will just cause greater harm.

Dr. Dizon recently faced this dilemma with an older patient with metastatic disease who had not done well with an initial treatment regimen. After outlining the risks for more chemotherapy, he explained one option would be to forgo it and simply treat her symptoms.

“It’s an impossible choice,” says Dr. Dizon, director of women’s cancers at Lifespan Cancer Institute and director of medical oncology at Rhode Island Hospital, Providence.

Chemotherapy can provide symptom relief, but it can also be toxic – and patients may be so frail, they can die from more therapy.

“I told my patient, if in your heart, you want to try more therapy, that’s okay. But it’s also okay if you don’t,” Dr. Dizon recalled.

Her response: “You’re supposed to give me the answer.”

However, for patients approaching the end of life, there often is no right answer. 

“It’s part of the discomfort you live with as a patient and oncologist, and when I leave the clinic, that’s one thing that follows me home,” Dr. Dizon said. “At the end of the day, I need to look in the mirror and know I did the best I could.”
 

The difficult conversation

Every Sunday, Dr. Lewis feels the weight of the week ahead. He and his wife, a pediatrician, call it the “Sunday scaries.”

It’s when Dr. Lewis begins thinking about the delicate conversations to come, rehearsing how he’s going to share the news that a person has advanced cancer or that a cancer, once in remission, has returned.

“Before the pandemic, I had 36 people come to a visit where I delivered some very heavy news and it became a Greek chorus of sobbing,” he recalls.

For every oncologist, delivering bad news is an integral part of the job. But after spending months, sometimes years, with a patient and the family, Dr. Lewis knows how to take the temperature of the room – who will likely prefer a more blunt style and who might need a gentler touch.

“The longer you know a patient and family, the better you can gauge the best approach,” Dr. Lewis said. “And for some, you know it’ll be complete devastation no matter what.”

When Jennifer Lycette, MD, prepares for a difficult conversation, she’ll run down all the possible ways it could go. Sometimes her brain will get stuck in a loop, cycling through the different trajectories on repeat.

“For years, I didn’t know how to cope with that,” said Dr. Lycette, medical director at Providence Oncology and Hematology Care Clinic in Seaside, Ore. “I wasn’t taught the tools to cope with that in my medical training. It took midcareer professional coaching that I sought out on my own to learn to remind myself that no matter what the person says, I have the experience and skill set to handle what comes next and to simply be present in the moment with the patient.”

The question that now sits with Dr. Lycette hours after a visit is what she could have done better. She knows from experience how important it is to choose her words carefully.

Early in her career, Dr. Lycette had a patient with stage IV cancer who wanted to know more about the death process. Because most people ask about pain, she assured him that he likely wouldn’t experience too much pain with his type of cancer.

“It will probably be like falling asleep,” said Dr. Lycette, hoping she was offering comfort. “When I saw him next, he told me he hadn’t slept.”

He was afraid that if he did, he wouldn’t wake up.

In that moment, Dr. Lycette realized the power that her words carry and the importance of trying to understand the inner lives of her patients.
 

Life outside the clinic

Sometimes an oncologist’s late-night ruminations have little to do with cancer itself.

Manali Patel, MD, finds herself worrying if her patients will have enough to eat and whether she will be able to help.

“I was up at 3 a.m. one morning, thinking about how we’re going to fund a project for patients from low-income households who we discovered were experiencing severe food insecurity – what grants we need, what foundations we can work with,” said Dr. Patel, a medical oncologist at Stanford Hospital and Clinics and the VA Palo Alto Health Care System in California.

The past few years of the pandemic have added a new layer of worry for Dr. Patel.

“I don’t want my patients to die from a preventable virus when they’ve already been through so much suffering,” Dr. Patel said.

This thought feeds worries about how her actions outside the clinic could unintentionally harm her patients. Should she go to a big medical conference? A family gathering? The grocery store?

“There are some places you can’t avoid, but these decisions have caused a lot of strife for me,” she said. “The health and safety of our patients – that’s in our wheelhouse – but so many of the policies are outside of our control.”
 

The inevitable losses and the wins

For patients with metastatic disease, eventually the treatment options will run out.

Dr. Shatsky likes to be up front with patients about that reality: “There will come a day when I will tell you there’s nothing more I can do, and you need to trust that I’m being honest with you and that’s the truth.”

For Dr. Goodman, the devastation that bad news brings patients and families is glaring. He knows there will be no more normalcy in their lives.

“I see a lot of suffering, but I know the suffering happens regardless of whether I see it or not,” Dr. Goodman said.

That’s why holding on to the victories can be so important. Dr. Goodman recalled a young patient who came to him with a 20-cm tumor and is now cured. “Had I not met that individual and done what I had done, he’d be dead, but now he’s going to live his life,” Dr. Goodman said. “But I don’t wake up at 2 a.m. thinking about that.”

Dr. Shatsky gets a lot of joy from the wins – the patients who do really well, the times when she can help a friend or colleagues – and those moments go a long way to outweigh the hurt, worry, and workload.

When dealing with so much gray, “the wins are important, knowing you can make a difference is important,” Dr. Dizon said.

And there’s a delicate balance.

“I think patients want an oncologist who cares and is genuinely invested in their outcomes but not someone who is so sad all the time,” Dr. Lewis said. “When I lose a patient, I still grieve each loss, but I can’t mourn every patient’s death like it’s a family member. Otherwise, I’d break.”

What would you do if you had terminal cancer?

Dr. Dizon recalled how a friend handled the news. She went home and made dinner, he said.

Ultimately, she lived for many years. She saw her kids get married, met her first grandchild, and had time to prepare, something not everyone gets the chance to do.

That’s why it’s important to “do what you normally do as long as you can,” Dr. Dizon said. “Live your life.”

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

It was 2 a.m. And Rebecca Shatsky, MD, could not sleep.

The breast oncologist was thinking about a patient of hers with metastatic cancer.

The patient’s disease had been asymptomatic for some time. Then without warning, her cancer suddenly exploded. Her bone marrow was failing, and her liver was not far behind.

Dr. Shatsky had a treatment plan ready to go but still, she felt uneasy.

“I had to be honest with her that I didn’t know if this plan would work,” says Dr. Shatsky, a medical oncologist at University of California, San Diego (UCSD).

That night, after visiting the patient in the hospital, Dr. Shatsky lay awake going over her next move, making sure it was the right one and hoping it would help keep the disease at bay.

“It’s so much pressure when someone is depending on you to make life or death decisions,” Dr. Shatsky said.

And in the quiet hours of night, these concerns grow louder.

Dr. Shatsky is not alone. Oncologists face difficult decisions every day, and many wrestle with these choices long after their day in the clinic is over.

“There’s no off button,” says Aaron Goodman, MD, a hematologist at UCSD Health who goes by “Papa Heme” on Twitter. “I’m always thinking about my patients. Constantly.”

The public rarely gets a glimpse of these private moments. On occasion, oncologists will share a personal story, but more often, insights come from broad research on the ethical, emotional, and psychological toll of practicing medicine.

Many oncologists carry this baggage home with them because they have no other option.

“There is simply no time to process the weight of the day when I’ve got seven more patients who need my full attention before lunch,” Mark Lewis, MD, director, department of gastrointestinal oncology, Intermountain Healthcare, Salt Lake City, Utah. “That is why my processing happens outside of the office, when my brain can be quiet.”
 

What am I missing?

Dr. Goodman recognizes the gravity of each decision he makes. He pores over every detail of a patient’s scans, lab results, history, and symptoms.

But no matter how many times he checks and rechecks, one question nags at him: What am I missing?

For Dr. Goodman, this exhaustive level of attention is worth it.

“When errors are made, it’s someone’s life,” Dr. Goodman said. “Nothing would have prepared me for this responsibility. Until it lies on you, it’s impossible to understand how much trust patients put into us.”

That trust becomes most apparent for Dr. Goodman when facing a decision about how to treat a patient with acute myeloid leukemia who’s in remission.

Give more chemotherapy to root out the leukemia cells still lurking in the body, and the patient faces a high risk of the cancer returning. Pick stem cell transplant, and the chance of being cured goes up significantly, but the patient could also die within 100 days of the transplant.

“All together, the data show I’m helping patients with a transplant, but for the individual, I could be causing harm. Someone could be living less because of a decision I made,” Dr. Goodman said.

For patients with advanced cancer, oncologists may need to think several moves ahead. Mapping out a patient’s treatment options can feel like a game of chess. Dr. Shatsky is always trying to anticipate how the tumor will behave, what is driving it, and how lifestyle factors may influence a patient’s response in the present and the future.

“It is a mind game,” she says. “Like in chess, I try to outsmart my opponent. But with advanced cancer, there are not necessarily clear-cut guidelines or one way to manage the disease, and I have to do the best I can with drugs I have.”

That’s the art of oncology: Balancing the many knowns and unknowns of a person’s cancer alongside the toxicities of treatment and a patient’s hopes and goals.

Throughout the year, Don Dizon, MD, will see a number of patients with advanced disease. In these instances, the question he often wrestles with is if the patient can’t be cured, whether more treatment will just cause greater harm.

Dr. Dizon recently faced this dilemma with an older patient with metastatic disease who had not done well with an initial treatment regimen. After outlining the risks for more chemotherapy, he explained one option would be to forgo it and simply treat her symptoms.

“It’s an impossible choice,” says Dr. Dizon, director of women’s cancers at Lifespan Cancer Institute and director of medical oncology at Rhode Island Hospital, Providence.

Chemotherapy can provide symptom relief, but it can also be toxic – and patients may be so frail, they can die from more therapy.

“I told my patient, if in your heart, you want to try more therapy, that’s okay. But it’s also okay if you don’t,” Dr. Dizon recalled.

Her response: “You’re supposed to give me the answer.”

However, for patients approaching the end of life, there often is no right answer. 

“It’s part of the discomfort you live with as a patient and oncologist, and when I leave the clinic, that’s one thing that follows me home,” Dr. Dizon said. “At the end of the day, I need to look in the mirror and know I did the best I could.”
 

The difficult conversation

Every Sunday, Dr. Lewis feels the weight of the week ahead. He and his wife, a pediatrician, call it the “Sunday scaries.”

It’s when Dr. Lewis begins thinking about the delicate conversations to come, rehearsing how he’s going to share the news that a person has advanced cancer or that a cancer, once in remission, has returned.

“Before the pandemic, I had 36 people come to a visit where I delivered some very heavy news and it became a Greek chorus of sobbing,” he recalls.

For every oncologist, delivering bad news is an integral part of the job. But after spending months, sometimes years, with a patient and the family, Dr. Lewis knows how to take the temperature of the room – who will likely prefer a more blunt style and who might need a gentler touch.

“The longer you know a patient and family, the better you can gauge the best approach,” Dr. Lewis said. “And for some, you know it’ll be complete devastation no matter what.”

When Jennifer Lycette, MD, prepares for a difficult conversation, she’ll run down all the possible ways it could go. Sometimes her brain will get stuck in a loop, cycling through the different trajectories on repeat.

“For years, I didn’t know how to cope with that,” said Dr. Lycette, medical director at Providence Oncology and Hematology Care Clinic in Seaside, Ore. “I wasn’t taught the tools to cope with that in my medical training. It took midcareer professional coaching that I sought out on my own to learn to remind myself that no matter what the person says, I have the experience and skill set to handle what comes next and to simply be present in the moment with the patient.”

The question that now sits with Dr. Lycette hours after a visit is what she could have done better. She knows from experience how important it is to choose her words carefully.

Early in her career, Dr. Lycette had a patient with stage IV cancer who wanted to know more about the death process. Because most people ask about pain, she assured him that he likely wouldn’t experience too much pain with his type of cancer.

“It will probably be like falling asleep,” said Dr. Lycette, hoping she was offering comfort. “When I saw him next, he told me he hadn’t slept.”

He was afraid that if he did, he wouldn’t wake up.

In that moment, Dr. Lycette realized the power that her words carry and the importance of trying to understand the inner lives of her patients.
 

Life outside the clinic

Sometimes an oncologist’s late-night ruminations have little to do with cancer itself.

Manali Patel, MD, finds herself worrying if her patients will have enough to eat and whether she will be able to help.

“I was up at 3 a.m. one morning, thinking about how we’re going to fund a project for patients from low-income households who we discovered were experiencing severe food insecurity – what grants we need, what foundations we can work with,” said Dr. Patel, a medical oncologist at Stanford Hospital and Clinics and the VA Palo Alto Health Care System in California.

The past few years of the pandemic have added a new layer of worry for Dr. Patel.

“I don’t want my patients to die from a preventable virus when they’ve already been through so much suffering,” Dr. Patel said.

This thought feeds worries about how her actions outside the clinic could unintentionally harm her patients. Should she go to a big medical conference? A family gathering? The grocery store?

“There are some places you can’t avoid, but these decisions have caused a lot of strife for me,” she said. “The health and safety of our patients – that’s in our wheelhouse – but so many of the policies are outside of our control.”
 

The inevitable losses and the wins

For patients with metastatic disease, eventually the treatment options will run out.

Dr. Shatsky likes to be up front with patients about that reality: “There will come a day when I will tell you there’s nothing more I can do, and you need to trust that I’m being honest with you and that’s the truth.”

For Dr. Goodman, the devastation that bad news brings patients and families is glaring. He knows there will be no more normalcy in their lives.

“I see a lot of suffering, but I know the suffering happens regardless of whether I see it or not,” Dr. Goodman said.

That’s why holding on to the victories can be so important. Dr. Goodman recalled a young patient who came to him with a 20-cm tumor and is now cured. “Had I not met that individual and done what I had done, he’d be dead, but now he’s going to live his life,” Dr. Goodman said. “But I don’t wake up at 2 a.m. thinking about that.”

Dr. Shatsky gets a lot of joy from the wins – the patients who do really well, the times when she can help a friend or colleagues – and those moments go a long way to outweigh the hurt, worry, and workload.

When dealing with so much gray, “the wins are important, knowing you can make a difference is important,” Dr. Dizon said.

And there’s a delicate balance.

“I think patients want an oncologist who cares and is genuinely invested in their outcomes but not someone who is so sad all the time,” Dr. Lewis said. “When I lose a patient, I still grieve each loss, but I can’t mourn every patient’s death like it’s a family member. Otherwise, I’d break.”

What would you do if you had terminal cancer?

Dr. Dizon recalled how a friend handled the news. She went home and made dinner, he said.

Ultimately, she lived for many years. She saw her kids get married, met her first grandchild, and had time to prepare, something not everyone gets the chance to do.

That’s why it’s important to “do what you normally do as long as you can,” Dr. Dizon said. “Live your life.”

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

It was 2 a.m. And Rebecca Shatsky, MD, could not sleep.

The breast oncologist was thinking about a patient of hers with metastatic cancer.

The patient’s disease had been asymptomatic for some time. Then without warning, her cancer suddenly exploded. Her bone marrow was failing, and her liver was not far behind.

Dr. Shatsky had a treatment plan ready to go but still, she felt uneasy.

“I had to be honest with her that I didn’t know if this plan would work,” says Dr. Shatsky, a medical oncologist at University of California, San Diego (UCSD).

That night, after visiting the patient in the hospital, Dr. Shatsky lay awake going over her next move, making sure it was the right one and hoping it would help keep the disease at bay.

“It’s so much pressure when someone is depending on you to make life or death decisions,” Dr. Shatsky said.

And in the quiet hours of night, these concerns grow louder.

Dr. Shatsky is not alone. Oncologists face difficult decisions every day, and many wrestle with these choices long after their day in the clinic is over.

“There’s no off button,” says Aaron Goodman, MD, a hematologist at UCSD Health who goes by “Papa Heme” on Twitter. “I’m always thinking about my patients. Constantly.”

The public rarely gets a glimpse of these private moments. On occasion, oncologists will share a personal story, but more often, insights come from broad research on the ethical, emotional, and psychological toll of practicing medicine.

Many oncologists carry this baggage home with them because they have no other option.

“There is simply no time to process the weight of the day when I’ve got seven more patients who need my full attention before lunch,” Mark Lewis, MD, director, department of gastrointestinal oncology, Intermountain Healthcare, Salt Lake City, Utah. “That is why my processing happens outside of the office, when my brain can be quiet.”
 

What am I missing?

Dr. Goodman recognizes the gravity of each decision he makes. He pores over every detail of a patient’s scans, lab results, history, and symptoms.

But no matter how many times he checks and rechecks, one question nags at him: What am I missing?

For Dr. Goodman, this exhaustive level of attention is worth it.

“When errors are made, it’s someone’s life,” Dr. Goodman said. “Nothing would have prepared me for this responsibility. Until it lies on you, it’s impossible to understand how much trust patients put into us.”

That trust becomes most apparent for Dr. Goodman when facing a decision about how to treat a patient with acute myeloid leukemia who’s in remission.

Give more chemotherapy to root out the leukemia cells still lurking in the body, and the patient faces a high risk of the cancer returning. Pick stem cell transplant, and the chance of being cured goes up significantly, but the patient could also die within 100 days of the transplant.

“All together, the data show I’m helping patients with a transplant, but for the individual, I could be causing harm. Someone could be living less because of a decision I made,” Dr. Goodman said.

For patients with advanced cancer, oncologists may need to think several moves ahead. Mapping out a patient’s treatment options can feel like a game of chess. Dr. Shatsky is always trying to anticipate how the tumor will behave, what is driving it, and how lifestyle factors may influence a patient’s response in the present and the future.

“It is a mind game,” she says. “Like in chess, I try to outsmart my opponent. But with advanced cancer, there are not necessarily clear-cut guidelines or one way to manage the disease, and I have to do the best I can with drugs I have.”

That’s the art of oncology: Balancing the many knowns and unknowns of a person’s cancer alongside the toxicities of treatment and a patient’s hopes and goals.

Throughout the year, Don Dizon, MD, will see a number of patients with advanced disease. In these instances, the question he often wrestles with is if the patient can’t be cured, whether more treatment will just cause greater harm.

Dr. Dizon recently faced this dilemma with an older patient with metastatic disease who had not done well with an initial treatment regimen. After outlining the risks for more chemotherapy, he explained one option would be to forgo it and simply treat her symptoms.

“It’s an impossible choice,” says Dr. Dizon, director of women’s cancers at Lifespan Cancer Institute and director of medical oncology at Rhode Island Hospital, Providence.

Chemotherapy can provide symptom relief, but it can also be toxic – and patients may be so frail, they can die from more therapy.

“I told my patient, if in your heart, you want to try more therapy, that’s okay. But it’s also okay if you don’t,” Dr. Dizon recalled.

Her response: “You’re supposed to give me the answer.”

However, for patients approaching the end of life, there often is no right answer. 

“It’s part of the discomfort you live with as a patient and oncologist, and when I leave the clinic, that’s one thing that follows me home,” Dr. Dizon said. “At the end of the day, I need to look in the mirror and know I did the best I could.”
 

The difficult conversation

Every Sunday, Dr. Lewis feels the weight of the week ahead. He and his wife, a pediatrician, call it the “Sunday scaries.”

It’s when Dr. Lewis begins thinking about the delicate conversations to come, rehearsing how he’s going to share the news that a person has advanced cancer or that a cancer, once in remission, has returned.

“Before the pandemic, I had 36 people come to a visit where I delivered some very heavy news and it became a Greek chorus of sobbing,” he recalls.

For every oncologist, delivering bad news is an integral part of the job. But after spending months, sometimes years, with a patient and the family, Dr. Lewis knows how to take the temperature of the room – who will likely prefer a more blunt style and who might need a gentler touch.

“The longer you know a patient and family, the better you can gauge the best approach,” Dr. Lewis said. “And for some, you know it’ll be complete devastation no matter what.”

When Jennifer Lycette, MD, prepares for a difficult conversation, she’ll run down all the possible ways it could go. Sometimes her brain will get stuck in a loop, cycling through the different trajectories on repeat.

“For years, I didn’t know how to cope with that,” said Dr. Lycette, medical director at Providence Oncology and Hematology Care Clinic in Seaside, Ore. “I wasn’t taught the tools to cope with that in my medical training. It took midcareer professional coaching that I sought out on my own to learn to remind myself that no matter what the person says, I have the experience and skill set to handle what comes next and to simply be present in the moment with the patient.”

The question that now sits with Dr. Lycette hours after a visit is what she could have done better. She knows from experience how important it is to choose her words carefully.

Early in her career, Dr. Lycette had a patient with stage IV cancer who wanted to know more about the death process. Because most people ask about pain, she assured him that he likely wouldn’t experience too much pain with his type of cancer.

“It will probably be like falling asleep,” said Dr. Lycette, hoping she was offering comfort. “When I saw him next, he told me he hadn’t slept.”

He was afraid that if he did, he wouldn’t wake up.

In that moment, Dr. Lycette realized the power that her words carry and the importance of trying to understand the inner lives of her patients.
 

Life outside the clinic

Sometimes an oncologist’s late-night ruminations have little to do with cancer itself.

Manali Patel, MD, finds herself worrying if her patients will have enough to eat and whether she will be able to help.

“I was up at 3 a.m. one morning, thinking about how we’re going to fund a project for patients from low-income households who we discovered were experiencing severe food insecurity – what grants we need, what foundations we can work with,” said Dr. Patel, a medical oncologist at Stanford Hospital and Clinics and the VA Palo Alto Health Care System in California.

The past few years of the pandemic have added a new layer of worry for Dr. Patel.

“I don’t want my patients to die from a preventable virus when they’ve already been through so much suffering,” Dr. Patel said.

This thought feeds worries about how her actions outside the clinic could unintentionally harm her patients. Should she go to a big medical conference? A family gathering? The grocery store?

“There are some places you can’t avoid, but these decisions have caused a lot of strife for me,” she said. “The health and safety of our patients – that’s in our wheelhouse – but so many of the policies are outside of our control.”
 

The inevitable losses and the wins

For patients with metastatic disease, eventually the treatment options will run out.

Dr. Shatsky likes to be up front with patients about that reality: “There will come a day when I will tell you there’s nothing more I can do, and you need to trust that I’m being honest with you and that’s the truth.”

For Dr. Goodman, the devastation that bad news brings patients and families is glaring. He knows there will be no more normalcy in their lives.

“I see a lot of suffering, but I know the suffering happens regardless of whether I see it or not,” Dr. Goodman said.

That’s why holding on to the victories can be so important. Dr. Goodman recalled a young patient who came to him with a 20-cm tumor and is now cured. “Had I not met that individual and done what I had done, he’d be dead, but now he’s going to live his life,” Dr. Goodman said. “But I don’t wake up at 2 a.m. thinking about that.”

Dr. Shatsky gets a lot of joy from the wins – the patients who do really well, the times when she can help a friend or colleagues – and those moments go a long way to outweigh the hurt, worry, and workload.

When dealing with so much gray, “the wins are important, knowing you can make a difference is important,” Dr. Dizon said.

And there’s a delicate balance.

“I think patients want an oncologist who cares and is genuinely invested in their outcomes but not someone who is so sad all the time,” Dr. Lewis said. “When I lose a patient, I still grieve each loss, but I can’t mourn every patient’s death like it’s a family member. Otherwise, I’d break.”

What would you do if you had terminal cancer?

Dr. Dizon recalled how a friend handled the news. She went home and made dinner, he said.

Ultimately, she lived for many years. She saw her kids get married, met her first grandchild, and had time to prepare, something not everyone gets the chance to do.

That’s why it’s important to “do what you normally do as long as you can,” Dr. Dizon said. “Live your life.”

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

U.S. Medicare beneficiaries with type 2 diabetes who had health coverage through a Medicare Advantage (MA) plan received treatment with an sodium-glucose cotransporter 2 inhibitor or glucagonlike peptide–1 receptor agonist significantly less often than patients with traditional fee-for-service (FFS) Medicare coverage in 2014-2019, according to a study of more than 411,000 patients.

“MA beneficiaries had modestly but significantly poorer intermediate health outcomes and were less likely to be treated with newer evidence-based antihyperglycemic therapies, compared with Medicare FFS beneficiaries,” concluded Utibe R. Essien, MD, and coauthors in a study published in Diabetes Care.

The report comes as the U.S. Congress is looking closely at the MA program and evidence that insurance companies that provide these policies sometimes impose inappropriate barriers on enrolled beneficiaries by denying or limiting access to treatments and interventions in ways that run counter to Medicare’s coverage policies.

According to Representative Diana DeGette (D-Colo.), who chaired a hearing on MA plans on June 28 by the House of Representatives’ Energy and Commerce Subcommittee on Oversight and Investigations, beneficiaries who are covered through an MA plan “do not always get the care that they are entitled to.”

The study by Dr. Essien and colleagues also documents some positives of care delivered through MA plans for patients with type 2 diabetes, compared with what FFS Medicare beneficiaries generally receive, such as significantly higher rates of screening for nephropathy and ophthalmologic disorders, and foot examinations.

But the apparently dampened use of SGLT2 inhibitors and GLP-1 receptor agonists among MA beneficiaries stand out as notable shortcomings, Dr. Essien maintained.
 

Cost containment may limit use

“The differences in health outcomes and in treatments in MA plans are important to highlight,” Dr. Essien said in an interview. “We worry that the cost-containment challenges [associated with MA plans] may be limiting use of these newer treatments.”

The study was based on 2014-2019 data from the Diabetes Collaborative Registry, which collects information from more than 5,000 U.S. clinicians whose practices include patients with diabetes, as well as claims data recorded by the Centers for Medicare and Medicaid Services during 2014-2017.

The main analysis focused on 345,911 Medicare beneficiaries with diabetes, which included 34% with MA coverage and 66% with FFS coverage. The two subgroups had similar ages, about 75 years old, and roughly half were women in both subgroups. The rate at which both subgroups received statin treatment was nearly the same: 72% for those with MA coverage and 71% for those with FFS Medicare.

But MA beneficiaries differed from those with FFS coverage in several other ways. MA beneficiaries had a higher prevalence of Medicaid eligibility than the FFS group (20% vs 12%) and lower rates of consultations with cardiologists (41% vs. 45%) or endocrinologists (7% vs. 10%).

Some of the positive differences in the care received by MA beneficiaries, compared with FFS beneficiaries, after adjustment for potential clinical and sociodemographic confounders, included:

• Screening for nephropathy, at a significant 14% higher relative rate.
• Screening for ophthalmologic disorders, at a significant 8% higher relative rate.
• Undergoing a diabetic foot examination, at a significant 13% higher relative rate.
• Receiving smoking-cessation counseling, at a significant 5% higher relative rate.
• Receiving treatment with an ACE inhibitor or angiotensin-receptor blocker (87% vs. 81%).
• More consistently receiving treatment with metformin, with rates of 72% versus 69% in 2017.

However, these positive differences were accompanied by these relative shortcomings for those with MA, compared with FFS coverage:

• Lower rates of treatment with an SGLT2 inhibitor (5.4% vs. 6.7%), a significant 9% relative difference after adjustment.
• Lower rates of treatment with a GLP-1 agonist (6.9% vs. 9.0%), a significant 20% relative difference after adjustment.
• Higher average levels of LDL cholesterol (81.5 vs. 78.9 mg/dL), a significantly higher average hemoglobin A1c level (7.1% vs. 7.0%), and a trend toward a lower prevalence of blood pressure control (70.3% vs. 71.5%).

Researchers also highlight that the lower rate at which people with MA coverage received SGLT2 inhibitors or GLP-1 agonists was consistent in patients with established cardiovascular or kidney disease, for whom these agents are particularly recommended.

In addition, a secondary analysis of data for another 65,000 Medicare beneficiaries in 2018 and 2019 showed the disparity in use of agents from these two drug classes continued.
 

Low systemic use of SGLT2 inhibitors, GLP-1 agonists

Dr. Essien acknowledged that, even in people with FFS Medicare coverage, use of SGLT2 inhibitors and GLP-1 agonists was low, but the difference between those with MA coverage is “important.”

Researchers offered four factors that might drive reduced prescribing of agents from these two classes for patients with type 2 diabetes with MA coverage: cost-containment strategies put in place by MA plans; the lower rate of consultations with specialists (cardiologists and endocrinologists); possible exclusion of clinicians from MA provider networks who tend to prescribe these higher-price agents; and lower household incomes of people with MA plans, which may lead to cost-related nonadherence.

Most SGLT2 inhibitors have an average retail cost of about $6,000/year, and some GLP-1 agonists cost more than $10,000/year.

In general, MA coverage includes more oversight of care and its cost than occurs with FFS coverage, noted Dr. Essien, an internal medicine physician at the University of Pittsburgh and a researcher at the Center for Health Equity Research and Promotion of the VA Pittsburgh Healthcare System.

“Incentives for using these more expensive treatments may not be there in MA plans,” he explained. Overcoming cost-related barriers is a challenge that will require “bold policy changes,” as well as better education of clinicians so they make correct treatment decisions, and of patients to resolve possible concerns about treatment safety.

Rep. DeGette hinted during her remarks at the June hearing that policy changes may be coming from Congress.

“Our seniors and their doctors should not be required to jump through numerous hoops to get coverage for straightforward and medically necessary procedures,” she said.

The study received no commercial funding. Dr. Essien reported no relevant financial relationships.

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

U.S. Medicare beneficiaries with type 2 diabetes who had health coverage through a Medicare Advantage (MA) plan received treatment with an sodium-glucose cotransporter 2 inhibitor or glucagonlike peptide–1 receptor agonist significantly less often than patients with traditional fee-for-service (FFS) Medicare coverage in 2014-2019, according to a study of more than 411,000 patients.

“MA beneficiaries had modestly but significantly poorer intermediate health outcomes and were less likely to be treated with newer evidence-based antihyperglycemic therapies, compared with Medicare FFS beneficiaries,” concluded Utibe R. Essien, MD, and coauthors in a study published in Diabetes Care.

The report comes as the U.S. Congress is looking closely at the MA program and evidence that insurance companies that provide these policies sometimes impose inappropriate barriers on enrolled beneficiaries by denying or limiting access to treatments and interventions in ways that run counter to Medicare’s coverage policies.

According to Representative Diana DeGette (D-Colo.), who chaired a hearing on MA plans on June 28 by the House of Representatives’ Energy and Commerce Subcommittee on Oversight and Investigations, beneficiaries who are covered through an MA plan “do not always get the care that they are entitled to.”

The study by Dr. Essien and colleagues also documents some positives of care delivered through MA plans for patients with type 2 diabetes, compared with what FFS Medicare beneficiaries generally receive, such as significantly higher rates of screening for nephropathy and ophthalmologic disorders, and foot examinations.

But the apparently dampened use of SGLT2 inhibitors and GLP-1 receptor agonists among MA beneficiaries stand out as notable shortcomings, Dr. Essien maintained.
 

Cost containment may limit use

“The differences in health outcomes and in treatments in MA plans are important to highlight,” Dr. Essien said in an interview. “We worry that the cost-containment challenges [associated with MA plans] may be limiting use of these newer treatments.”

The study was based on 2014-2019 data from the Diabetes Collaborative Registry, which collects information from more than 5,000 U.S. clinicians whose practices include patients with diabetes, as well as claims data recorded by the Centers for Medicare and Medicaid Services during 2014-2017.

The main analysis focused on 345,911 Medicare beneficiaries with diabetes, which included 34% with MA coverage and 66% with FFS coverage. The two subgroups had similar ages, about 75 years old, and roughly half were women in both subgroups. The rate at which both subgroups received statin treatment was nearly the same: 72% for those with MA coverage and 71% for those with FFS Medicare.

But MA beneficiaries differed from those with FFS coverage in several other ways. MA beneficiaries had a higher prevalence of Medicaid eligibility than the FFS group (20% vs 12%) and lower rates of consultations with cardiologists (41% vs. 45%) or endocrinologists (7% vs. 10%).

Some of the positive differences in the care received by MA beneficiaries, compared with FFS beneficiaries, after adjustment for potential clinical and sociodemographic confounders, included:

• Screening for nephropathy, at a significant 14% higher relative rate.
• Screening for ophthalmologic disorders, at a significant 8% higher relative rate.
• Undergoing a diabetic foot examination, at a significant 13% higher relative rate.
• Receiving smoking-cessation counseling, at a significant 5% higher relative rate.
• Receiving treatment with an ACE inhibitor or angiotensin-receptor blocker (87% vs. 81%).
• More consistently receiving treatment with metformin, with rates of 72% versus 69% in 2017.

However, these positive differences were accompanied by these relative shortcomings for those with MA, compared with FFS coverage:

• Lower rates of treatment with an SGLT2 inhibitor (5.4% vs. 6.7%), a significant 9% relative difference after adjustment.
• Lower rates of treatment with a GLP-1 agonist (6.9% vs. 9.0%), a significant 20% relative difference after adjustment.
• Higher average levels of LDL cholesterol (81.5 vs. 78.9 mg/dL), a significantly higher average hemoglobin A1c level (7.1% vs. 7.0%), and a trend toward a lower prevalence of blood pressure control (70.3% vs. 71.5%).

Researchers also highlight that the lower rate at which people with MA coverage received SGLT2 inhibitors or GLP-1 agonists was consistent in patients with established cardiovascular or kidney disease, for whom these agents are particularly recommended.

In addition, a secondary analysis of data for another 65,000 Medicare beneficiaries in 2018 and 2019 showed the disparity in use of agents from these two drug classes continued.
 

Low systemic use of SGLT2 inhibitors, GLP-1 agonists

Dr. Essien acknowledged that, even in people with FFS Medicare coverage, use of SGLT2 inhibitors and GLP-1 agonists was low, but the difference between those with MA coverage is “important.”

Researchers offered four factors that might drive reduced prescribing of agents from these two classes for patients with type 2 diabetes with MA coverage: cost-containment strategies put in place by MA plans; the lower rate of consultations with specialists (cardiologists and endocrinologists); possible exclusion of clinicians from MA provider networks who tend to prescribe these higher-price agents; and lower household incomes of people with MA plans, which may lead to cost-related nonadherence.

Most SGLT2 inhibitors have an average retail cost of about $6,000/year, and some GLP-1 agonists cost more than $10,000/year.

In general, MA coverage includes more oversight of care and its cost than occurs with FFS coverage, noted Dr. Essien, an internal medicine physician at the University of Pittsburgh and a researcher at the Center for Health Equity Research and Promotion of the VA Pittsburgh Healthcare System.

“Incentives for using these more expensive treatments may not be there in MA plans,” he explained. Overcoming cost-related barriers is a challenge that will require “bold policy changes,” as well as better education of clinicians so they make correct treatment decisions, and of patients to resolve possible concerns about treatment safety.

Rep. DeGette hinted during her remarks at the June hearing that policy changes may be coming from Congress.

“Our seniors and their doctors should not be required to jump through numerous hoops to get coverage for straightforward and medically necessary procedures,” she said.

The study received no commercial funding. Dr. Essien reported no relevant financial relationships.

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

U.S. Medicare beneficiaries with type 2 diabetes who had health coverage through a Medicare Advantage (MA) plan received treatment with an sodium-glucose cotransporter 2 inhibitor or glucagonlike peptide–1 receptor agonist significantly less often than patients with traditional fee-for-service (FFS) Medicare coverage in 2014-2019, according to a study of more than 411,000 patients.

“MA beneficiaries had modestly but significantly poorer intermediate health outcomes and were less likely to be treated with newer evidence-based antihyperglycemic therapies, compared with Medicare FFS beneficiaries,” concluded Utibe R. Essien, MD, and coauthors in a study published in Diabetes Care.

The report comes as the U.S. Congress is looking closely at the MA program and evidence that insurance companies that provide these policies sometimes impose inappropriate barriers on enrolled beneficiaries by denying or limiting access to treatments and interventions in ways that run counter to Medicare’s coverage policies.

According to Representative Diana DeGette (D-Colo.), who chaired a hearing on MA plans on June 28 by the House of Representatives’ Energy and Commerce Subcommittee on Oversight and Investigations, beneficiaries who are covered through an MA plan “do not always get the care that they are entitled to.”

The study by Dr. Essien and colleagues also documents some positives of care delivered through MA plans for patients with type 2 diabetes, compared with what FFS Medicare beneficiaries generally receive, such as significantly higher rates of screening for nephropathy and ophthalmologic disorders, and foot examinations.

But the apparently dampened use of SGLT2 inhibitors and GLP-1 receptor agonists among MA beneficiaries stand out as notable shortcomings, Dr. Essien maintained.
 

Cost containment may limit use

“The differences in health outcomes and in treatments in MA plans are important to highlight,” Dr. Essien said in an interview. “We worry that the cost-containment challenges [associated with MA plans] may be limiting use of these newer treatments.”

The study was based on 2014-2019 data from the Diabetes Collaborative Registry, which collects information from more than 5,000 U.S. clinicians whose practices include patients with diabetes, as well as claims data recorded by the Centers for Medicare and Medicaid Services during 2014-2017.

The main analysis focused on 345,911 Medicare beneficiaries with diabetes, which included 34% with MA coverage and 66% with FFS coverage. The two subgroups had similar ages, about 75 years old, and roughly half were women in both subgroups. The rate at which both subgroups received statin treatment was nearly the same: 72% for those with MA coverage and 71% for those with FFS Medicare.

But MA beneficiaries differed from those with FFS coverage in several other ways. MA beneficiaries had a higher prevalence of Medicaid eligibility than the FFS group (20% vs 12%) and lower rates of consultations with cardiologists (41% vs. 45%) or endocrinologists (7% vs. 10%).

Some of the positive differences in the care received by MA beneficiaries, compared with FFS beneficiaries, after adjustment for potential clinical and sociodemographic confounders, included:

• Screening for nephropathy, at a significant 14% higher relative rate.
• Screening for ophthalmologic disorders, at a significant 8% higher relative rate.
• Undergoing a diabetic foot examination, at a significant 13% higher relative rate.
• Receiving smoking-cessation counseling, at a significant 5% higher relative rate.
• Receiving treatment with an ACE inhibitor or angiotensin-receptor blocker (87% vs. 81%).
• More consistently receiving treatment with metformin, with rates of 72% versus 69% in 2017.

However, these positive differences were accompanied by these relative shortcomings for those with MA, compared with FFS coverage:

• Lower rates of treatment with an SGLT2 inhibitor (5.4% vs. 6.7%), a significant 9% relative difference after adjustment.
• Lower rates of treatment with a GLP-1 agonist (6.9% vs. 9.0%), a significant 20% relative difference after adjustment.
• Higher average levels of LDL cholesterol (81.5 vs. 78.9 mg/dL), a significantly higher average hemoglobin A1c level (7.1% vs. 7.0%), and a trend toward a lower prevalence of blood pressure control (70.3% vs. 71.5%).

Researchers also highlight that the lower rate at which people with MA coverage received SGLT2 inhibitors or GLP-1 agonists was consistent in patients with established cardiovascular or kidney disease, for whom these agents are particularly recommended.

In addition, a secondary analysis of data for another 65,000 Medicare beneficiaries in 2018 and 2019 showed the disparity in use of agents from these two drug classes continued.
 

Low systemic use of SGLT2 inhibitors, GLP-1 agonists

Dr. Essien acknowledged that, even in people with FFS Medicare coverage, use of SGLT2 inhibitors and GLP-1 agonists was low, but the difference between those with MA coverage is “important.”

Researchers offered four factors that might drive reduced prescribing of agents from these two classes for patients with type 2 diabetes with MA coverage: cost-containment strategies put in place by MA plans; the lower rate of consultations with specialists (cardiologists and endocrinologists); possible exclusion of clinicians from MA provider networks who tend to prescribe these higher-price agents; and lower household incomes of people with MA plans, which may lead to cost-related nonadherence.

Most SGLT2 inhibitors have an average retail cost of about $6,000/year, and some GLP-1 agonists cost more than $10,000/year.

In general, MA coverage includes more oversight of care and its cost than occurs with FFS coverage, noted Dr. Essien, an internal medicine physician at the University of Pittsburgh and a researcher at the Center for Health Equity Research and Promotion of the VA Pittsburgh Healthcare System.

“Incentives for using these more expensive treatments may not be there in MA plans,” he explained. Overcoming cost-related barriers is a challenge that will require “bold policy changes,” as well as better education of clinicians so they make correct treatment decisions, and of patients to resolve possible concerns about treatment safety.

Rep. DeGette hinted during her remarks at the June hearing that policy changes may be coming from Congress.

“Our seniors and their doctors should not be required to jump through numerous hoops to get coverage for straightforward and medically necessary procedures,” she said.

The study received no commercial funding. Dr. Essien reported no relevant financial relationships.

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

Ongoing follow-up and lifestyle interventions are needed in lean patients with nonalcoholic fatty liver disease (NAFLD), suggests a panel of experts in a recent review.

They also urge screening for NAFLD in individuals who are older than 40 years with type 2 diabetes, even if they are not overweight.

NAFLD is a leading cause of chronic liver disease that affects more than 25% of the United States and worldwide populations, note lead author Michelle T. Long, MD, Boston Medical Center, Boston University, and colleagues.

Evidence-based approaches

The 15 best practice advice statements covered a wide range of clinical areas, first defining lean as a body mass index (BMI) less than 25 in non-Asian persons and less than 23 in Asian persons.

The authors go on to stipulate, for example, that lean individuals in the general population should not be screened for NAFLD but that screening should be considered for individuals older than 40 years with type 2 diabetes.

More broadly, they write that the condition should be considered in lean individuals with metabolic diseases, such as type 2 diabetes, dyslipidemia, and hypertension, as well as elevated values on liver biochemical tests or incidentally noted hepatic steatosis.

After other causes of liver diseases are ruled out, the authors note that clinicians should consider liver biopsy as the reference test if uncertainties remain about liver injury causes and/or liver fibrosis staging.

They also write that the NAFLD fibrosis score and Fibrosis-4 score, along with imaging techniques, may be used as alternatives to biopsy for staging and during follow-up.

The authors, who provide a diagnosis and management algorithm to aid clinicians, suggest that lean patients with NAFLD follow lifestyle interventions, such as exercise, diet modification, and avoidance of fructose- and sugar-sweetened drinks, to achieve weight loss of 3%-5%.

Vitamin E may be considered, they continue, in patients with biopsy-confirmed nonalcoholic steatohepatitis but without type 2 diabetes or cirrhosis. Additionally, oral pioglitazone may be considered in lean persons with biopsy-confirmed nonalcoholic steatohepatitis without cirrhosis.

In contrast, they write that the role of glucagonlike peptide 1 agonists and sodium-glucose cotransporter 2 inhibitors requires further investigation.

The advice also says that lean patients with NAFLD should be routinely evaluated for comorbid conditions, such as type 2 diabetes, dyslipidemia, and hypertension, and risk-stratified for hepatic fibrosis to identify those with advanced fibrosis or cirrhosis.

For lean patients with NAFLD and clinical markers compatible with liver cirrhosis, twice-yearly surveillance for hepatocellular carcinoma is also advised.

Fatty liver disease in lean people with metabolic conditions

Approached for comment, Liyun Yuan, MD, PhD, assistant professor of clinical medicine, University of Southern California, Los Angeles, said it is very important to have uniform guidelines for general practitioners and other specialties on NAFLD in lean individuals.

Dr. Yuan, who was not involved in the review, told this news organization that it is crucial to raise awareness of NAFLD, just like awareness of breast cancer screening among women of a certain age was increased, so that individuals are screened for metabolic conditions regardless of whether they have obesity or overweight.

Zobair Younossi, MD, MPH, professor of medicine, Virginia Commonwealth University, Inova Campus, Falls Church, Va., added that there is a lack of awareness that NAFLD occurs in lean individuals, especially in those who have diabetes.

He said in an interview that although it is accurate to define individuals as being lean in terms of their BMI, the best way is to look not only at BMI but also at waist circumference.

Dr. Younossi said that he and his colleagues have shown that when BMI is combined with waist circumference, the prediction of mortality risk in NAFLD is affected, such that lean individuals with an obese waist circumference have a higher risk for all-cause mortality.

Dr. Long is supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases, Doris Duke Charitable Foundation, Gilead Sciences Research Scholars Award, Boston University School of Medicine Department of Medicine Career Investment Award, and Boston University Clinical Translational Science Institute. Dr. Long declares relationships with Novo Nordisk, Echosens Corporation, and Gilead Sciences. Dr. Yuan declares relationships with Genfit, Intercept, and Gilead Sciences. Dr. Younossi declares no relevant relationships.

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

*This article was updated on July 27, 2022.

Ongoing follow-up and lifestyle interventions are needed in lean patients with nonalcoholic fatty liver disease (NAFLD), suggests a panel of experts in a recent review.

They also urge screening for NAFLD in individuals who are older than 40 years with type 2 diabetes, even if they are not overweight.

NAFLD is a leading cause of chronic liver disease that affects more than 25% of the United States and worldwide populations, note lead author Michelle T. Long, MD, Boston Medical Center, Boston University, and colleagues.

Evidence-based approaches

The 15 best practice advice statements covered a wide range of clinical areas, first defining lean as a body mass index (BMI) less than 25 in non-Asian persons and less than 23 in Asian persons.

The authors go on to stipulate, for example, that lean individuals in the general population should not be screened for NAFLD but that screening should be considered for individuals older than 40 years with type 2 diabetes.

More broadly, they write that the condition should be considered in lean individuals with metabolic diseases, such as type 2 diabetes, dyslipidemia, and hypertension, as well as elevated values on liver biochemical tests or incidentally noted hepatic steatosis.

After other causes of liver diseases are ruled out, the authors note that clinicians should consider liver biopsy as the reference test if uncertainties remain about liver injury causes and/or liver fibrosis staging.

They also write that the NAFLD fibrosis score and Fibrosis-4 score, along with imaging techniques, may be used as alternatives to biopsy for staging and during follow-up.

The authors, who provide a diagnosis and management algorithm to aid clinicians, suggest that lean patients with NAFLD follow lifestyle interventions, such as exercise, diet modification, and avoidance of fructose- and sugar-sweetened drinks, to achieve weight loss of 3%-5%.

Vitamin E may be considered, they continue, in patients with biopsy-confirmed nonalcoholic steatohepatitis but without type 2 diabetes or cirrhosis. Additionally, oral pioglitazone may be considered in lean persons with biopsy-confirmed nonalcoholic steatohepatitis without cirrhosis.

In contrast, they write that the role of glucagonlike peptide 1 agonists and sodium-glucose cotransporter 2 inhibitors requires further investigation.

The advice also says that lean patients with NAFLD should be routinely evaluated for comorbid conditions, such as type 2 diabetes, dyslipidemia, and hypertension, and risk-stratified for hepatic fibrosis to identify those with advanced fibrosis or cirrhosis.

For lean patients with NAFLD and clinical markers compatible with liver cirrhosis, twice-yearly surveillance for hepatocellular carcinoma is also advised.

Fatty liver disease in lean people with metabolic conditions

Approached for comment, Liyun Yuan, MD, PhD, assistant professor of clinical medicine, University of Southern California, Los Angeles, said it is very important to have uniform guidelines for general practitioners and other specialties on NAFLD in lean individuals.

Dr. Yuan, who was not involved in the review, told this news organization that it is crucial to raise awareness of NAFLD, just like awareness of breast cancer screening among women of a certain age was increased, so that individuals are screened for metabolic conditions regardless of whether they have obesity or overweight.

Zobair Younossi, MD, MPH, professor of medicine, Virginia Commonwealth University, Inova Campus, Falls Church, Va., added that there is a lack of awareness that NAFLD occurs in lean individuals, especially in those who have diabetes.

He said in an interview that although it is accurate to define individuals as being lean in terms of their BMI, the best way is to look not only at BMI but also at waist circumference.

Dr. Younossi said that he and his colleagues have shown that when BMI is combined with waist circumference, the prediction of mortality risk in NAFLD is affected, such that lean individuals with an obese waist circumference have a higher risk for all-cause mortality.

Dr. Long is supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases, Doris Duke Charitable Foundation, Gilead Sciences Research Scholars Award, Boston University School of Medicine Department of Medicine Career Investment Award, and Boston University Clinical Translational Science Institute. Dr. Long declares relationships with Novo Nordisk, Echosens Corporation, and Gilead Sciences. Dr. Yuan declares relationships with Genfit, Intercept, and Gilead Sciences. Dr. Younossi declares no relevant relationships.

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

*This article was updated on July 27, 2022.

Ongoing follow-up and lifestyle interventions are needed in lean patients with nonalcoholic fatty liver disease (NAFLD), suggests a panel of experts in a recent review.

They also urge screening for NAFLD in individuals who are older than 40 years with type 2 diabetes, even if they are not overweight.

NAFLD is a leading cause of chronic liver disease that affects more than 25% of the United States and worldwide populations, note lead author Michelle T. Long, MD, Boston Medical Center, Boston University, and colleagues.

Evidence-based approaches

The 15 best practice advice statements covered a wide range of clinical areas, first defining lean as a body mass index (BMI) less than 25 in non-Asian persons and less than 23 in Asian persons.

The authors go on to stipulate, for example, that lean individuals in the general population should not be screened for NAFLD but that screening should be considered for individuals older than 40 years with type 2 diabetes.

More broadly, they write that the condition should be considered in lean individuals with metabolic diseases, such as type 2 diabetes, dyslipidemia, and hypertension, as well as elevated values on liver biochemical tests or incidentally noted hepatic steatosis.

After other causes of liver diseases are ruled out, the authors note that clinicians should consider liver biopsy as the reference test if uncertainties remain about liver injury causes and/or liver fibrosis staging.

They also write that the NAFLD fibrosis score and Fibrosis-4 score, along with imaging techniques, may be used as alternatives to biopsy for staging and during follow-up.

The authors, who provide a diagnosis and management algorithm to aid clinicians, suggest that lean patients with NAFLD follow lifestyle interventions, such as exercise, diet modification, and avoidance of fructose- and sugar-sweetened drinks, to achieve weight loss of 3%-5%.

Vitamin E may be considered, they continue, in patients with biopsy-confirmed nonalcoholic steatohepatitis but without type 2 diabetes or cirrhosis. Additionally, oral pioglitazone may be considered in lean persons with biopsy-confirmed nonalcoholic steatohepatitis without cirrhosis.

In contrast, they write that the role of glucagonlike peptide 1 agonists and sodium-glucose cotransporter 2 inhibitors requires further investigation.

The advice also says that lean patients with NAFLD should be routinely evaluated for comorbid conditions, such as type 2 diabetes, dyslipidemia, and hypertension, and risk-stratified for hepatic fibrosis to identify those with advanced fibrosis or cirrhosis.

For lean patients with NAFLD and clinical markers compatible with liver cirrhosis, twice-yearly surveillance for hepatocellular carcinoma is also advised.

Fatty liver disease in lean people with metabolic conditions

Approached for comment, Liyun Yuan, MD, PhD, assistant professor of clinical medicine, University of Southern California, Los Angeles, said it is very important to have uniform guidelines for general practitioners and other specialties on NAFLD in lean individuals.

Dr. Yuan, who was not involved in the review, told this news organization that it is crucial to raise awareness of NAFLD, just like awareness of breast cancer screening among women of a certain age was increased, so that individuals are screened for metabolic conditions regardless of whether they have obesity or overweight.

Zobair Younossi, MD, MPH, professor of medicine, Virginia Commonwealth University, Inova Campus, Falls Church, Va., added that there is a lack of awareness that NAFLD occurs in lean individuals, especially in those who have diabetes.

He said in an interview that although it is accurate to define individuals as being lean in terms of their BMI, the best way is to look not only at BMI but also at waist circumference.

Dr. Younossi said that he and his colleagues have shown that when BMI is combined with waist circumference, the prediction of mortality risk in NAFLD is affected, such that lean individuals with an obese waist circumference have a higher risk for all-cause mortality.

Dr. Long is supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases, Doris Duke Charitable Foundation, Gilead Sciences Research Scholars Award, Boston University School of Medicine Department of Medicine Career Investment Award, and Boston University Clinical Translational Science Institute. Dr. Long declares relationships with Novo Nordisk, Echosens Corporation, and Gilead Sciences. Dr. Yuan declares relationships with Genfit, Intercept, and Gilead Sciences. Dr. Younossi declares no relevant relationships.

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

*This article was updated on July 27, 2022.

More than half of studies testing anticancer drugs against each other have rules with regard to dose modification and growth support that favor the experimental drug arm, a new analysis suggests.

“We found it sobering that this practice is so common,” Timothée Olivier, MD, with Geneva University Hospital and the University of California, San Francisco, said in an interview.

Trials may be “rigged” in a way where the new therapy appears more effective than if the trial would have been designed with fairer rules, he explained.

This leaves open the question of whether new drugs are truly superior to older ones or if instead different outcomes are caused by more aggressive dosing or growth factor support, the investigators said.

Dr. Olivier, with UCSF coinvestigators Alyson Haslam, PhD, and Vinay Prasad, MD, reported their findings online in the European Journal of Cancer.

‘Highly concerning’

Different drug modification rules or growth factor support guidance may affect the results of randomized controlled trials (RCTs) of testing new cancer agents.

For their study, Dr. Olivier and colleagues did a cross-sectional analysis of all 62 head-to-head registration RCTs that led to Food and Drug Administration approval between 2009 and 2021.

All of the trials examined anticancer drugs in the advanced or metastatic setting where a comparison was made between arms regarding either dose modification rules or myeloid growth factors recommendations.

The researchers assessed imbalance in drug modification rules, myeloid growth factor recommendations, or both, according to prespecified rules.

They discovered that 40 of the 62 trials (65%) had unequal rules for dose medication, granulocyte colony-stimulating factor (G-CSF) use, or both.

Six trials (10%) had rules favoring the control arm, while 34 (55%) had rules favoring the experimental arm. Among these, 50% had unequal drug modification rules, 41% had unequal G-CSF rules, and 9% had both.

Dr. Olivier said in an interview the results are “highly concerning because when you are investigating the effect of a new drug, you don’t want to have a false sense of a drug’s effect because of other factors not directly related to the drug’s efficacy.”

“If you introduce unfair rules about dose modification or supporting medication that favors the new drug, then you don’t know if a positive trial is due to the effect of the new drug or to the effect of differential dosing or supporting medication,” he added.
 

Blame industry?

Dr. Olivier said the fact that most registration trials are industry-sponsored is likely the primary explanation of the findings.

“Industry-sponsored trials may be designed so that the new drug has the best chance to get the largest ‘win,’ because this means more market share and more profit for the company that manufactures the drug. This is not a criticism of the industry, which runs on a business model that naturally aims to gain more market share and more profit,” Dr. Olivier said.

“However, it is the role and duty of regulators to reconcile industry incentives with the patients’ best interests, and there is accumulating data showing the regulators are failing to do so,” he added.

Addressing this problem will likely take buy-in from multiple stakeholders.

Awareness of the problem is a first step and understanding the influence of commercial incentives in drug development is also key, Dr. Olivier said.

Institutional review boards and drug regulators could also systematically evaluate drug dosing modification and supportive medication rules before a trial gets underway.

Regulators could also incentivize companies to implement balanced rules between arms by not granting drug approval based on trials suffering from such flaws.

“However, financial conflict of interest is present at many levels of drug development, including in drug regulation,” Dr. Olivier noted.

He pointed to a recent study that found when hematology-oncology medical reviewers working at the FDA leave the agency, more than half end up working or consulting for the pharmaceutical industry.

Dr. Olivier wondered: “How can one fairly and independently appraise a medical intervention if one’s current or future revenue depends on its source?”

The study was funded by Arnold Ventures, through a grant paid to UCSF. Dr. Olivier and Dr. Haslam had no relevant disclosures. Dr. Prasad reported receiving royalties from Arnold Ventures.

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

More than half of studies testing anticancer drugs against each other have rules with regard to dose modification and growth support that favor the experimental drug arm, a new analysis suggests.

“We found it sobering that this practice is so common,” Timothée Olivier, MD, with Geneva University Hospital and the University of California, San Francisco, said in an interview.

Trials may be “rigged” in a way where the new therapy appears more effective than if the trial would have been designed with fairer rules, he explained.

This leaves open the question of whether new drugs are truly superior to older ones or if instead different outcomes are caused by more aggressive dosing or growth factor support, the investigators said.

Dr. Olivier, with UCSF coinvestigators Alyson Haslam, PhD, and Vinay Prasad, MD, reported their findings online in the European Journal of Cancer.

‘Highly concerning’

Different drug modification rules or growth factor support guidance may affect the results of randomized controlled trials (RCTs) of testing new cancer agents.

For their study, Dr. Olivier and colleagues did a cross-sectional analysis of all 62 head-to-head registration RCTs that led to Food and Drug Administration approval between 2009 and 2021.

All of the trials examined anticancer drugs in the advanced or metastatic setting where a comparison was made between arms regarding either dose modification rules or myeloid growth factors recommendations.

The researchers assessed imbalance in drug modification rules, myeloid growth factor recommendations, or both, according to prespecified rules.

They discovered that 40 of the 62 trials (65%) had unequal rules for dose medication, granulocyte colony-stimulating factor (G-CSF) use, or both.

Six trials (10%) had rules favoring the control arm, while 34 (55%) had rules favoring the experimental arm. Among these, 50% had unequal drug modification rules, 41% had unequal G-CSF rules, and 9% had both.

Dr. Olivier said in an interview the results are “highly concerning because when you are investigating the effect of a new drug, you don’t want to have a false sense of a drug’s effect because of other factors not directly related to the drug’s efficacy.”

“If you introduce unfair rules about dose modification or supporting medication that favors the new drug, then you don’t know if a positive trial is due to the effect of the new drug or to the effect of differential dosing or supporting medication,” he added.
 

Blame industry?

Dr. Olivier said the fact that most registration trials are industry-sponsored is likely the primary explanation of the findings.

“Industry-sponsored trials may be designed so that the new drug has the best chance to get the largest ‘win,’ because this means more market share and more profit for the company that manufactures the drug. This is not a criticism of the industry, which runs on a business model that naturally aims to gain more market share and more profit,” Dr. Olivier said.

“However, it is the role and duty of regulators to reconcile industry incentives with the patients’ best interests, and there is accumulating data showing the regulators are failing to do so,” he added.

Addressing this problem will likely take buy-in from multiple stakeholders.

Awareness of the problem is a first step and understanding the influence of commercial incentives in drug development is also key, Dr. Olivier said.

Institutional review boards and drug regulators could also systematically evaluate drug dosing modification and supportive medication rules before a trial gets underway.

Regulators could also incentivize companies to implement balanced rules between arms by not granting drug approval based on trials suffering from such flaws.

“However, financial conflict of interest is present at many levels of drug development, including in drug regulation,” Dr. Olivier noted.

He pointed to a recent study that found when hematology-oncology medical reviewers working at the FDA leave the agency, more than half end up working or consulting for the pharmaceutical industry.

Dr. Olivier wondered: “How can one fairly and independently appraise a medical intervention if one’s current or future revenue depends on its source?”

The study was funded by Arnold Ventures, through a grant paid to UCSF. Dr. Olivier and Dr. Haslam had no relevant disclosures. Dr. Prasad reported receiving royalties from Arnold Ventures.

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

More than half of studies testing anticancer drugs against each other have rules with regard to dose modification and growth support that favor the experimental drug arm, a new analysis suggests.

“We found it sobering that this practice is so common,” Timothée Olivier, MD, with Geneva University Hospital and the University of California, San Francisco, said in an interview.

Trials may be “rigged” in a way where the new therapy appears more effective than if the trial would have been designed with fairer rules, he explained.

This leaves open the question of whether new drugs are truly superior to older ones or if instead different outcomes are caused by more aggressive dosing or growth factor support, the investigators said.

Dr. Olivier, with UCSF coinvestigators Alyson Haslam, PhD, and Vinay Prasad, MD, reported their findings online in the European Journal of Cancer.

‘Highly concerning’

Different drug modification rules or growth factor support guidance may affect the results of randomized controlled trials (RCTs) of testing new cancer agents.

For their study, Dr. Olivier and colleagues did a cross-sectional analysis of all 62 head-to-head registration RCTs that led to Food and Drug Administration approval between 2009 and 2021.

All of the trials examined anticancer drugs in the advanced or metastatic setting where a comparison was made between arms regarding either dose modification rules or myeloid growth factors recommendations.

The researchers assessed imbalance in drug modification rules, myeloid growth factor recommendations, or both, according to prespecified rules.

They discovered that 40 of the 62 trials (65%) had unequal rules for dose medication, granulocyte colony-stimulating factor (G-CSF) use, or both.

Six trials (10%) had rules favoring the control arm, while 34 (55%) had rules favoring the experimental arm. Among these, 50% had unequal drug modification rules, 41% had unequal G-CSF rules, and 9% had both.

Dr. Olivier said in an interview the results are “highly concerning because when you are investigating the effect of a new drug, you don’t want to have a false sense of a drug’s effect because of other factors not directly related to the drug’s efficacy.”

“If you introduce unfair rules about dose modification or supporting medication that favors the new drug, then you don’t know if a positive trial is due to the effect of the new drug or to the effect of differential dosing or supporting medication,” he added.
 

Blame industry?

Dr. Olivier said the fact that most registration trials are industry-sponsored is likely the primary explanation of the findings.

“Industry-sponsored trials may be designed so that the new drug has the best chance to get the largest ‘win,’ because this means more market share and more profit for the company that manufactures the drug. This is not a criticism of the industry, which runs on a business model that naturally aims to gain more market share and more profit,” Dr. Olivier said.

“However, it is the role and duty of regulators to reconcile industry incentives with the patients’ best interests, and there is accumulating data showing the regulators are failing to do so,” he added.

Addressing this problem will likely take buy-in from multiple stakeholders.

Awareness of the problem is a first step and understanding the influence of commercial incentives in drug development is also key, Dr. Olivier said.

Institutional review boards and drug regulators could also systematically evaluate drug dosing modification and supportive medication rules before a trial gets underway.

Regulators could also incentivize companies to implement balanced rules between arms by not granting drug approval based on trials suffering from such flaws.

“However, financial conflict of interest is present at many levels of drug development, including in drug regulation,” Dr. Olivier noted.

He pointed to a recent study that found when hematology-oncology medical reviewers working at the FDA leave the agency, more than half end up working or consulting for the pharmaceutical industry.

Dr. Olivier wondered: “How can one fairly and independently appraise a medical intervention if one’s current or future revenue depends on its source?”

The study was funded by Arnold Ventures, through a grant paid to UCSF. Dr. Olivier and Dr. Haslam had no relevant disclosures. Dr. Prasad reported receiving royalties from Arnold Ventures.

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

Emma Sherman, a 13-year-old girl in Ascot, England, woke up to a dizzying aura of blind spots and flashing lights in her field of vision. It was May 2020, and she also had crippling nausea and headaches. By August, her dizziness was so overwhelming, she couldn’t hold her head up, lying in her mother’s lap for hours, too fatigued to attend school.

The former competitive gymnast, who had hoped to try out for the cheerleading squad, now used a wheelchair and was a shadow of her former self. She had been diagnosed with COVID-induced postural orthostatic tachycardia syndrome, a condition often caused by an infection that results in a higher heart rate, extreme nausea, dizziness, and fatigue.

“I was so into sports before I got long COVID, and afterwards I could barely walk,” Emma said.

Even minor movements sent her heart rate sky-high. Her long chestnut hair turned gray and fell out in clumps. In the hospital, she was pricked and prodded, her blood tested for numerous conditions.

“They ran every scan known to man and took an MRI of her brain,” said Emma’s mother, Marie Sherman. “All was clear.”

Emma’s pediatrician determined that the teen had long COVID after having had a mild case of the virus in March, about 2 months before her puzzling symptoms began. But beyond a positive antibody test, doctors have found little evidence of what was causing Emma’s symptoms.

For Emma and others with long COVID, there are no medications shown to directly target the condition. Instead, caregivers target their symptoms, which include nausea, dizziness, fatigue, headaches, and a racing heart, said Laura Malone, MD, codirector of the Johns Hopkins Kennedy Krieger Pediatric Post–COVID-19 Rehabilitation Clinic in Baltimore.

“Right now, it’s a rehabilitation-based approach focused on improving symptoms and functioning so that kids can go back to their usual activities as much as possible,” she says.

Depression and anxiety are common, although doctors are struggling to figure out whether COVID is changing the brain or whether mental health symptoms result from all the life disruptions. There’s little research to show how may kids have depression because of long COVID. Dr. Malone said about half of her patients at the Kennedy Krieger Institute›s long COVID clinic are also dealing with mental health issues.

Patients with headaches, dizziness, and nausea are given pain and nausea medications and recommendations for a healthy diet with added fruits and vegetables, monounsaturated fats, lower sodium, unprocessed foods, and whole grains. Kids with irregular or racing heart rates are referred to cardiologists and potentially prescribed beta-blockers to treat their heart arrhythmias, while children with breathing problems may be referred to pulmonologists and those with depression to a psychiatrist.

Still, many patients like Emma go to their doctors with phantom symptoms that don’t show up on scans or blood tests.

“We’re not seeing any evidence of structural damage to the brain, for example,” said Dr. Malone. “When we do MRIs, they often come out normal.”

It’s possible that the virus lingers in some patients, said Rajeev Fernando, MD, an infectious disease specialist and a fellow at Harvard Medical School, Boston. Kids’ strong immune systems often fend off problems that can be noticed. But on the inside, dead fragments of the virus persist, floating in hidden parts of the body and activating the immune system long after the threat has passed.

The virus can be in the gut and in the brain, which may help explain why symptoms like brain fog and nausea can linger in children.

“The immune system doesn’t recognize whether fragments of the virus are dead or alive. It continues to think it’s fighting active COVID,” said Dr. Fernando.

There is little data on how long symptoms last, Dr. Fernando said, as well as how many kids get them and why some are more vulnerable than others. Some research has found that about 5%-15% of children with COVID may get long COVID, but the statistics vary globally.

“Children with long COVID have largely been ignored. And while we’re talking about it now, we’ve got some work to do,” said Dr. Fernando.

As for Emma, she recovered in January of 2021, heading back to school and her friends, although her cardiologist advised her to skip gym classes.

“For the first time in months, I was feeling like myself again,” she said.

But the coronavirus found its way to Emma again. Although she was fully vaccinated in the fall of 2021, when the Omicron variant swept the world late that year, she was infected again.

“When the wave of Omicron descended, Emma was like a sitting duck,” her mother said.

She was bedridden with a high fever and cough. The cold-like symptoms eventually went away, but the issues in her gut stuck around. Since then, Emma has had extreme nausea, losing most of the weight she had gained back.

For her part, Ms. Sherman has found solace in a group called Long COVID Kids, a nonprofit in Europe and the United States. The group is raising awareness about the condition in kids to increase funding, boost understanding, and improve treatment and outcomes.

“There’s nothing worse than watching your child suffer and not being able to do anything about it,” she said. “I tell Emma all the time: If I could just crawl in your body and take it, I would do it in a second.”

Emma is hoping for a fresh start with her family’s move in the coming weeks to Sotogrande in southern Spain.

“I miss the simplest things like going for a run, going to the fair with my friends, and just feeling well,” she said. “I have a long list of things I’ll do once this is all done.”

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

Emma Sherman, a 13-year-old girl in Ascot, England, woke up to a dizzying aura of blind spots and flashing lights in her field of vision. It was May 2020, and she also had crippling nausea and headaches. By August, her dizziness was so overwhelming, she couldn’t hold her head up, lying in her mother’s lap for hours, too fatigued to attend school.

The former competitive gymnast, who had hoped to try out for the cheerleading squad, now used a wheelchair and was a shadow of her former self. She had been diagnosed with COVID-induced postural orthostatic tachycardia syndrome, a condition often caused by an infection that results in a higher heart rate, extreme nausea, dizziness, and fatigue.

“I was so into sports before I got long COVID, and afterwards I could barely walk,” Emma said.

Even minor movements sent her heart rate sky-high. Her long chestnut hair turned gray and fell out in clumps. In the hospital, she was pricked and prodded, her blood tested for numerous conditions.

“They ran every scan known to man and took an MRI of her brain,” said Emma’s mother, Marie Sherman. “All was clear.”

Emma’s pediatrician determined that the teen had long COVID after having had a mild case of the virus in March, about 2 months before her puzzling symptoms began. But beyond a positive antibody test, doctors have found little evidence of what was causing Emma’s symptoms.

For Emma and others with long COVID, there are no medications shown to directly target the condition. Instead, caregivers target their symptoms, which include nausea, dizziness, fatigue, headaches, and a racing heart, said Laura Malone, MD, codirector of the Johns Hopkins Kennedy Krieger Pediatric Post–COVID-19 Rehabilitation Clinic in Baltimore.

“Right now, it’s a rehabilitation-based approach focused on improving symptoms and functioning so that kids can go back to their usual activities as much as possible,” she says.

Depression and anxiety are common, although doctors are struggling to figure out whether COVID is changing the brain or whether mental health symptoms result from all the life disruptions. There’s little research to show how may kids have depression because of long COVID. Dr. Malone said about half of her patients at the Kennedy Krieger Institute›s long COVID clinic are also dealing with mental health issues.

Patients with headaches, dizziness, and nausea are given pain and nausea medications and recommendations for a healthy diet with added fruits and vegetables, monounsaturated fats, lower sodium, unprocessed foods, and whole grains. Kids with irregular or racing heart rates are referred to cardiologists and potentially prescribed beta-blockers to treat their heart arrhythmias, while children with breathing problems may be referred to pulmonologists and those with depression to a psychiatrist.

Still, many patients like Emma go to their doctors with phantom symptoms that don’t show up on scans or blood tests.

“We’re not seeing any evidence of structural damage to the brain, for example,” said Dr. Malone. “When we do MRIs, they often come out normal.”

It’s possible that the virus lingers in some patients, said Rajeev Fernando, MD, an infectious disease specialist and a fellow at Harvard Medical School, Boston. Kids’ strong immune systems often fend off problems that can be noticed. But on the inside, dead fragments of the virus persist, floating in hidden parts of the body and activating the immune system long after the threat has passed.

The virus can be in the gut and in the brain, which may help explain why symptoms like brain fog and nausea can linger in children.

“The immune system doesn’t recognize whether fragments of the virus are dead or alive. It continues to think it’s fighting active COVID,” said Dr. Fernando.

There is little data on how long symptoms last, Dr. Fernando said, as well as how many kids get them and why some are more vulnerable than others. Some research has found that about 5%-15% of children with COVID may get long COVID, but the statistics vary globally.

“Children with long COVID have largely been ignored. And while we’re talking about it now, we’ve got some work to do,” said Dr. Fernando.

As for Emma, she recovered in January of 2021, heading back to school and her friends, although her cardiologist advised her to skip gym classes.

“For the first time in months, I was feeling like myself again,” she said.

But the coronavirus found its way to Emma again. Although she was fully vaccinated in the fall of 2021, when the Omicron variant swept the world late that year, she was infected again.

“When the wave of Omicron descended, Emma was like a sitting duck,” her mother said.

She was bedridden with a high fever and cough. The cold-like symptoms eventually went away, but the issues in her gut stuck around. Since then, Emma has had extreme nausea, losing most of the weight she had gained back.

For her part, Ms. Sherman has found solace in a group called Long COVID Kids, a nonprofit in Europe and the United States. The group is raising awareness about the condition in kids to increase funding, boost understanding, and improve treatment and outcomes.

“There’s nothing worse than watching your child suffer and not being able to do anything about it,” she said. “I tell Emma all the time: If I could just crawl in your body and take it, I would do it in a second.”

Emma is hoping for a fresh start with her family’s move in the coming weeks to Sotogrande in southern Spain.

“I miss the simplest things like going for a run, going to the fair with my friends, and just feeling well,” she said. “I have a long list of things I’ll do once this is all done.”

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

Emma Sherman, a 13-year-old girl in Ascot, England, woke up to a dizzying aura of blind spots and flashing lights in her field of vision. It was May 2020, and she also had crippling nausea and headaches. By August, her dizziness was so overwhelming, she couldn’t hold her head up, lying in her mother’s lap for hours, too fatigued to attend school.

The former competitive gymnast, who had hoped to try out for the cheerleading squad, now used a wheelchair and was a shadow of her former self. She had been diagnosed with COVID-induced postural orthostatic tachycardia syndrome, a condition often caused by an infection that results in a higher heart rate, extreme nausea, dizziness, and fatigue.

“I was so into sports before I got long COVID, and afterwards I could barely walk,” Emma said.

Even minor movements sent her heart rate sky-high. Her long chestnut hair turned gray and fell out in clumps. In the hospital, she was pricked and prodded, her blood tested for numerous conditions.

“They ran every scan known to man and took an MRI of her brain,” said Emma’s mother, Marie Sherman. “All was clear.”

Emma’s pediatrician determined that the teen had long COVID after having had a mild case of the virus in March, about 2 months before her puzzling symptoms began. But beyond a positive antibody test, doctors have found little evidence of what was causing Emma’s symptoms.

For Emma and others with long COVID, there are no medications shown to directly target the condition. Instead, caregivers target their symptoms, which include nausea, dizziness, fatigue, headaches, and a racing heart, said Laura Malone, MD, codirector of the Johns Hopkins Kennedy Krieger Pediatric Post–COVID-19 Rehabilitation Clinic in Baltimore.

“Right now, it’s a rehabilitation-based approach focused on improving symptoms and functioning so that kids can go back to their usual activities as much as possible,” she says.

Depression and anxiety are common, although doctors are struggling to figure out whether COVID is changing the brain or whether mental health symptoms result from all the life disruptions. There’s little research to show how may kids have depression because of long COVID. Dr. Malone said about half of her patients at the Kennedy Krieger Institute›s long COVID clinic are also dealing with mental health issues.

Patients with headaches, dizziness, and nausea are given pain and nausea medications and recommendations for a healthy diet with added fruits and vegetables, monounsaturated fats, lower sodium, unprocessed foods, and whole grains. Kids with irregular or racing heart rates are referred to cardiologists and potentially prescribed beta-blockers to treat their heart arrhythmias, while children with breathing problems may be referred to pulmonologists and those with depression to a psychiatrist.

Still, many patients like Emma go to their doctors with phantom symptoms that don’t show up on scans or blood tests.

“We’re not seeing any evidence of structural damage to the brain, for example,” said Dr. Malone. “When we do MRIs, they often come out normal.”

It’s possible that the virus lingers in some patients, said Rajeev Fernando, MD, an infectious disease specialist and a fellow at Harvard Medical School, Boston. Kids’ strong immune systems often fend off problems that can be noticed. But on the inside, dead fragments of the virus persist, floating in hidden parts of the body and activating the immune system long after the threat has passed.

The virus can be in the gut and in the brain, which may help explain why symptoms like brain fog and nausea can linger in children.

“The immune system doesn’t recognize whether fragments of the virus are dead or alive. It continues to think it’s fighting active COVID,” said Dr. Fernando.

There is little data on how long symptoms last, Dr. Fernando said, as well as how many kids get them and why some are more vulnerable than others. Some research has found that about 5%-15% of children with COVID may get long COVID, but the statistics vary globally.

“Children with long COVID have largely been ignored. And while we’re talking about it now, we’ve got some work to do,” said Dr. Fernando.

As for Emma, she recovered in January of 2021, heading back to school and her friends, although her cardiologist advised her to skip gym classes.

“For the first time in months, I was feeling like myself again,” she said.

But the coronavirus found its way to Emma again. Although she was fully vaccinated in the fall of 2021, when the Omicron variant swept the world late that year, she was infected again.

“When the wave of Omicron descended, Emma was like a sitting duck,” her mother said.

She was bedridden with a high fever and cough. The cold-like symptoms eventually went away, but the issues in her gut stuck around. Since then, Emma has had extreme nausea, losing most of the weight she had gained back.

For her part, Ms. Sherman has found solace in a group called Long COVID Kids, a nonprofit in Europe and the United States. The group is raising awareness about the condition in kids to increase funding, boost understanding, and improve treatment and outcomes.

“There’s nothing worse than watching your child suffer and not being able to do anything about it,” she said. “I tell Emma all the time: If I could just crawl in your body and take it, I would do it in a second.”

Emma is hoping for a fresh start with her family’s move in the coming weeks to Sotogrande in southern Spain.

“I miss the simplest things like going for a run, going to the fair with my friends, and just feeling well,” she said. “I have a long list of things I’ll do once this is all done.”

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

Hormone therapy did not increase mortality in postmenopausal women treated for early-stage estrogen receptor–positive breast cancer, but, in longitudinal data from Denmark, there was a recurrence risk with vaginal estrogen therapy among those treated with aromatase inhibitors.

Genitourinary syndrome of menopause (GSM) – including vaginal dryness, burning, and urinary incontinence – is common in women treated for breast cancer. Adjuvant endocrine therapy, particularly aromatase inhibitors, can aggravate these symptoms. Both local and systemic estrogen therapy are recommended for alleviating GSM symptoms in healthy women, but concerns have been raised about their use in women with breast cancer. Previous studies examining this have suggested possible risks for breast cancer recurrence, but those studies have had several limitations including small samples and short follow-up, particularly for vaginal estrogen therapy.

In the new study, from a national Danish cohort of 8,461 postmenopausal women diagnosed between 1997 and 2004 and treated for early-stage invasive estrogen receptor–positive nonmetastatic breast cancer, neither systemic menopausal hormone therapy (MHT) nor local vaginal estrogen therapy (VET) were associated with an overall increased risk for either breast cancer recurrence or mortality. However, in the subset who had received an aromatase inhibitor – with or without tamoxifen – there was a statistically significant increased risk for breast cancer recurrence, but not mortality.

The results were published in the Journal of the National Cancer Institute.

“The data are reassuring for the majority of women with no adjuvant therapy or tamoxifen. But for those using adjuvant aromatase inhibitors, there might be a small risk,” study lead author Søren Cold, MD, PhD, senior oncologist in the department of oncology at Odense (Denmark) University Hospital, Odense, said in an interview.

Moreover, Dr. Cold noted, while this study didn’t find an increased recurrence risk with MHT for women taking aromatase inhibitors, other studies have. One in particular was stopped because of harm. The reason for the difference here is likely that the previous sample was small – just 133 women.

“Our study is mainly focusing on the use of vaginal estrogen. We had so few patients using systemic menopausal hormone therapy, those data don’t mean much. ... The risk with systemic therapy has been established. The vaginal use hasn’t been thoroughly studied before,” he noted.
 

Breast cancer recurrence elevated with VET and aromatase inhibitors

The study pool was 9,710 women who underwent complete resection for estrogen-positive breast cancer and were all allocated to 5 years of adjuvant endocrine treatment or no adjuvant treatment, according to guidelines. Overall, 3,112 received no adjuvant endocrine treatment, 2,007 were treated with tamoxifen only, 403 with an aromatase inhibitor, and 2,939 with a sequence of tamoxifen and an aromatase inhibitor.

After exclusion of 1,249 who had received VET or MHT prior to breast cancer diagnosis, there were 6,391 not prescribed any estrogen hormonal treatment, 1,957 prescribed VET, and 133 prescribed MHT with or without VET.

During an estimated median 9.8 years’ follow-up, 1,333 women (16%) had a breast cancer recurrence. Of those, 111 had received VET, 16 MHT, and 1,206 neither. Compared with those receiving no hormonal treatment, the adjusted risk of recurrence was similar for the VET users (hazard ratio, 1.08; 95% confidence interval, 0.89-1.32).

However, there was an increased risk for recurrence associated with initiating VET during aromatase inhibitor treatment (HR, 1.39, 95% CI, 1.04-1.85). For women receiving MHT, the adjusted relative risk of recurrence with aromatase inhibitors wasn’t significant (HR, 1.05; 95% CI, 0.62-1.78).

Overall, compared with women who never used hormonal treatment, the absolute 10-year breast cancer recurrence risk was 19.2% for never-users of VET or MHT, 15.4% in VET users, and 17.1% in MHT users.
 

No differences found for mortality

Of the 8,461 women in the study, 40% (3,370) died during an estimated median follow-up of 15.2 years. Of those, 497 had received VET, 47 MHT, and 2,826 neither. Compared with the never-users of estrogen therapy, the adjusted HR for overall survival in VET users was 0.78 (95% CI, 0.71-0.87). The analysis stratified by adjuvant endocrine therapy didn’t show an increase in VET users by use of aromatase inhibitors (aHR, 0.94, 95% CI, 0.70-1.26). The same was found for women prescribed MHT, compared with never-users (aHR, 0.94; 95% CI, 0.70-1.26).

Never-users of VET or MHT had an absolute 10-year overall survival of 73.8% versus 79.5% and 80.5% among the women who used VET or MHT, respectively.

Asked to comment, Nanette Santoro, MD, professor and E. Stewart Taylor Chair of Obstetrics & Gynecology at the University of Colorado at Denver, Aurora, said in an interview: “It is important to look at this issue. These findings raise but don’t answer the question that vaginal estradiol may not be as safe as we hope it is for women with breast cancer using an aromatase inhibitor.”

However, she also pointed out that “the overall increase in risk is not enormous; mortality risk was not increased. Women need to consider that there may be some risk associated with this option in their decision making about taking it. Having a satisfying sex life is also important for many women! It is really compassionate use for quality of life, so there is always that unknown element of risk in the discussion. That unknown risk has to be balanced against the benefit that the estrogen provides.”

And, Dr. Santoro also noted that the use of prescription data poses limitations. “It cannot tell us what was going on in the minds of the patient and the prescriber. There may be differences in the prescriber’s impression of the patient’s risk of recurrence that influenced the decision to provide a prescription. ... Women using AIs [aromatase inhibitors] often get pretty severe vaginal dryness symptoms and may need more estrogen to be comfortable with intercourse, but we really cannot tell this from what is in this paper.”

Indeed, Dr. Cold said: “We admit it’s not a randomized study, but we’ve done what was possible to take [confounding] factors into account, including age, tumor size, nodal status, histology, and comorbidities.”

He suggested that a potential therapeutic approach to reducing the recurrence risk might be to switch VET-treated women to tamoxifen after 2-3 years of aromatase inhibitors.

This work was supported by Breast Friends, a part of the Danish Cancer Society. Dr. Cold received support from Breast Friends for the current study. Some of the other coauthors have pharmaceutical company disclosures. Dr. Santoro is a member of the scientific advisory boards for Astellas, Menogenix, Que Oncology, and Amazon Ember, and is a consultant for Ansh Labs.

Hormone therapy did not increase mortality in postmenopausal women treated for early-stage estrogen receptor–positive breast cancer, but, in longitudinal data from Denmark, there was a recurrence risk with vaginal estrogen therapy among those treated with aromatase inhibitors.

Genitourinary syndrome of menopause (GSM) – including vaginal dryness, burning, and urinary incontinence – is common in women treated for breast cancer. Adjuvant endocrine therapy, particularly aromatase inhibitors, can aggravate these symptoms. Both local and systemic estrogen therapy are recommended for alleviating GSM symptoms in healthy women, but concerns have been raised about their use in women with breast cancer. Previous studies examining this have suggested possible risks for breast cancer recurrence, but those studies have had several limitations including small samples and short follow-up, particularly for vaginal estrogen therapy.

In the new study, from a national Danish cohort of 8,461 postmenopausal women diagnosed between 1997 and 2004 and treated for early-stage invasive estrogen receptor–positive nonmetastatic breast cancer, neither systemic menopausal hormone therapy (MHT) nor local vaginal estrogen therapy (VET) were associated with an overall increased risk for either breast cancer recurrence or mortality. However, in the subset who had received an aromatase inhibitor – with or without tamoxifen – there was a statistically significant increased risk for breast cancer recurrence, but not mortality.

The results were published in the Journal of the National Cancer Institute.

“The data are reassuring for the majority of women with no adjuvant therapy or tamoxifen. But for those using adjuvant aromatase inhibitors, there might be a small risk,” study lead author Søren Cold, MD, PhD, senior oncologist in the department of oncology at Odense (Denmark) University Hospital, Odense, said in an interview.

Moreover, Dr. Cold noted, while this study didn’t find an increased recurrence risk with MHT for women taking aromatase inhibitors, other studies have. One in particular was stopped because of harm. The reason for the difference here is likely that the previous sample was small – just 133 women.

“Our study is mainly focusing on the use of vaginal estrogen. We had so few patients using systemic menopausal hormone therapy, those data don’t mean much. ... The risk with systemic therapy has been established. The vaginal use hasn’t been thoroughly studied before,” he noted.
 

Breast cancer recurrence elevated with VET and aromatase inhibitors

The study pool was 9,710 women who underwent complete resection for estrogen-positive breast cancer and were all allocated to 5 years of adjuvant endocrine treatment or no adjuvant treatment, according to guidelines. Overall, 3,112 received no adjuvant endocrine treatment, 2,007 were treated with tamoxifen only, 403 with an aromatase inhibitor, and 2,939 with a sequence of tamoxifen and an aromatase inhibitor.

After exclusion of 1,249 who had received VET or MHT prior to breast cancer diagnosis, there were 6,391 not prescribed any estrogen hormonal treatment, 1,957 prescribed VET, and 133 prescribed MHT with or without VET.

During an estimated median 9.8 years’ follow-up, 1,333 women (16%) had a breast cancer recurrence. Of those, 111 had received VET, 16 MHT, and 1,206 neither. Compared with those receiving no hormonal treatment, the adjusted risk of recurrence was similar for the VET users (hazard ratio, 1.08; 95% confidence interval, 0.89-1.32).

However, there was an increased risk for recurrence associated with initiating VET during aromatase inhibitor treatment (HR, 1.39, 95% CI, 1.04-1.85). For women receiving MHT, the adjusted relative risk of recurrence with aromatase inhibitors wasn’t significant (HR, 1.05; 95% CI, 0.62-1.78).

Overall, compared with women who never used hormonal treatment, the absolute 10-year breast cancer recurrence risk was 19.2% for never-users of VET or MHT, 15.4% in VET users, and 17.1% in MHT users.
 

No differences found for mortality

Of the 8,461 women in the study, 40% (3,370) died during an estimated median follow-up of 15.2 years. Of those, 497 had received VET, 47 MHT, and 2,826 neither. Compared with the never-users of estrogen therapy, the adjusted HR for overall survival in VET users was 0.78 (95% CI, 0.71-0.87). The analysis stratified by adjuvant endocrine therapy didn’t show an increase in VET users by use of aromatase inhibitors (aHR, 0.94, 95% CI, 0.70-1.26). The same was found for women prescribed MHT, compared with never-users (aHR, 0.94; 95% CI, 0.70-1.26).

Never-users of VET or MHT had an absolute 10-year overall survival of 73.8% versus 79.5% and 80.5% among the women who used VET or MHT, respectively.

Asked to comment, Nanette Santoro, MD, professor and E. Stewart Taylor Chair of Obstetrics & Gynecology at the University of Colorado at Denver, Aurora, said in an interview: “It is important to look at this issue. These findings raise but don’t answer the question that vaginal estradiol may not be as safe as we hope it is for women with breast cancer using an aromatase inhibitor.”

However, she also pointed out that “the overall increase in risk is not enormous; mortality risk was not increased. Women need to consider that there may be some risk associated with this option in their decision making about taking it. Having a satisfying sex life is also important for many women! It is really compassionate use for quality of life, so there is always that unknown element of risk in the discussion. That unknown risk has to be balanced against the benefit that the estrogen provides.”

And, Dr. Santoro also noted that the use of prescription data poses limitations. “It cannot tell us what was going on in the minds of the patient and the prescriber. There may be differences in the prescriber’s impression of the patient’s risk of recurrence that influenced the decision to provide a prescription. ... Women using AIs [aromatase inhibitors] often get pretty severe vaginal dryness symptoms and may need more estrogen to be comfortable with intercourse, but we really cannot tell this from what is in this paper.”

Indeed, Dr. Cold said: “We admit it’s not a randomized study, but we’ve done what was possible to take [confounding] factors into account, including age, tumor size, nodal status, histology, and comorbidities.”

He suggested that a potential therapeutic approach to reducing the recurrence risk might be to switch VET-treated women to tamoxifen after 2-3 years of aromatase inhibitors.

This work was supported by Breast Friends, a part of the Danish Cancer Society. Dr. Cold received support from Breast Friends for the current study. Some of the other coauthors have pharmaceutical company disclosures. Dr. Santoro is a member of the scientific advisory boards for Astellas, Menogenix, Que Oncology, and Amazon Ember, and is a consultant for Ansh Labs.

Hormone therapy did not increase mortality in postmenopausal women treated for early-stage estrogen receptor–positive breast cancer, but, in longitudinal data from Denmark, there was a recurrence risk with vaginal estrogen therapy among those treated with aromatase inhibitors.

Genitourinary syndrome of menopause (GSM) – including vaginal dryness, burning, and urinary incontinence – is common in women treated for breast cancer. Adjuvant endocrine therapy, particularly aromatase inhibitors, can aggravate these symptoms. Both local and systemic estrogen therapy are recommended for alleviating GSM symptoms in healthy women, but concerns have been raised about their use in women with breast cancer. Previous studies examining this have suggested possible risks for breast cancer recurrence, but those studies have had several limitations including small samples and short follow-up, particularly for vaginal estrogen therapy.

In the new study, from a national Danish cohort of 8,461 postmenopausal women diagnosed between 1997 and 2004 and treated for early-stage invasive estrogen receptor–positive nonmetastatic breast cancer, neither systemic menopausal hormone therapy (MHT) nor local vaginal estrogen therapy (VET) were associated with an overall increased risk for either breast cancer recurrence or mortality. However, in the subset who had received an aromatase inhibitor – with or without tamoxifen – there was a statistically significant increased risk for breast cancer recurrence, but not mortality.

The results were published in the Journal of the National Cancer Institute.

“The data are reassuring for the majority of women with no adjuvant therapy or tamoxifen. But for those using adjuvant aromatase inhibitors, there might be a small risk,” study lead author Søren Cold, MD, PhD, senior oncologist in the department of oncology at Odense (Denmark) University Hospital, Odense, said in an interview.

Moreover, Dr. Cold noted, while this study didn’t find an increased recurrence risk with MHT for women taking aromatase inhibitors, other studies have. One in particular was stopped because of harm. The reason for the difference here is likely that the previous sample was small – just 133 women.

“Our study is mainly focusing on the use of vaginal estrogen. We had so few patients using systemic menopausal hormone therapy, those data don’t mean much. ... The risk with systemic therapy has been established. The vaginal use hasn’t been thoroughly studied before,” he noted.
 

Breast cancer recurrence elevated with VET and aromatase inhibitors

The study pool was 9,710 women who underwent complete resection for estrogen-positive breast cancer and were all allocated to 5 years of adjuvant endocrine treatment or no adjuvant treatment, according to guidelines. Overall, 3,112 received no adjuvant endocrine treatment, 2,007 were treated with tamoxifen only, 403 with an aromatase inhibitor, and 2,939 with a sequence of tamoxifen and an aromatase inhibitor.

After exclusion of 1,249 who had received VET or MHT prior to breast cancer diagnosis, there were 6,391 not prescribed any estrogen hormonal treatment, 1,957 prescribed VET, and 133 prescribed MHT with or without VET.

During an estimated median 9.8 years’ follow-up, 1,333 women (16%) had a breast cancer recurrence. Of those, 111 had received VET, 16 MHT, and 1,206 neither. Compared with those receiving no hormonal treatment, the adjusted risk of recurrence was similar for the VET users (hazard ratio, 1.08; 95% confidence interval, 0.89-1.32).

However, there was an increased risk for recurrence associated with initiating VET during aromatase inhibitor treatment (HR, 1.39, 95% CI, 1.04-1.85). For women receiving MHT, the adjusted relative risk of recurrence with aromatase inhibitors wasn’t significant (HR, 1.05; 95% CI, 0.62-1.78).

Overall, compared with women who never used hormonal treatment, the absolute 10-year breast cancer recurrence risk was 19.2% for never-users of VET or MHT, 15.4% in VET users, and 17.1% in MHT users.
 

No differences found for mortality

Of the 8,461 women in the study, 40% (3,370) died during an estimated median follow-up of 15.2 years. Of those, 497 had received VET, 47 MHT, and 2,826 neither. Compared with the never-users of estrogen therapy, the adjusted HR for overall survival in VET users was 0.78 (95% CI, 0.71-0.87). The analysis stratified by adjuvant endocrine therapy didn’t show an increase in VET users by use of aromatase inhibitors (aHR, 0.94, 95% CI, 0.70-1.26). The same was found for women prescribed MHT, compared with never-users (aHR, 0.94; 95% CI, 0.70-1.26).

Never-users of VET or MHT had an absolute 10-year overall survival of 73.8% versus 79.5% and 80.5% among the women who used VET or MHT, respectively.

Asked to comment, Nanette Santoro, MD, professor and E. Stewart Taylor Chair of Obstetrics & Gynecology at the University of Colorado at Denver, Aurora, said in an interview: “It is important to look at this issue. These findings raise but don’t answer the question that vaginal estradiol may not be as safe as we hope it is for women with breast cancer using an aromatase inhibitor.”

However, she also pointed out that “the overall increase in risk is not enormous; mortality risk was not increased. Women need to consider that there may be some risk associated with this option in their decision making about taking it. Having a satisfying sex life is also important for many women! It is really compassionate use for quality of life, so there is always that unknown element of risk in the discussion. That unknown risk has to be balanced against the benefit that the estrogen provides.”

And, Dr. Santoro also noted that the use of prescription data poses limitations. “It cannot tell us what was going on in the minds of the patient and the prescriber. There may be differences in the prescriber’s impression of the patient’s risk of recurrence that influenced the decision to provide a prescription. ... Women using AIs [aromatase inhibitors] often get pretty severe vaginal dryness symptoms and may need more estrogen to be comfortable with intercourse, but we really cannot tell this from what is in this paper.”

Indeed, Dr. Cold said: “We admit it’s not a randomized study, but we’ve done what was possible to take [confounding] factors into account, including age, tumor size, nodal status, histology, and comorbidities.”

He suggested that a potential therapeutic approach to reducing the recurrence risk might be to switch VET-treated women to tamoxifen after 2-3 years of aromatase inhibitors.

This work was supported by Breast Friends, a part of the Danish Cancer Society. Dr. Cold received support from Breast Friends for the current study. Some of the other coauthors have pharmaceutical company disclosures. Dr. Santoro is a member of the scientific advisory boards for Astellas, Menogenix, Que Oncology, and Amazon Ember, and is a consultant for Ansh Labs.