A study of testicular cancer mortality finds worse outcomes among Hispanic men, but better outcomes among Black men.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

Incidence rates for testicular cancer in the United States have increased slowly in recent decades, said Anushka Ghosh, a clinical research coordinatory with Massachusetts General Hospital, Boston. Her analysis found mortality increases from 1999 to 2019 to be significantly greater among Hispanic men. The increase was 0.0019 per 100,000, compared with a 0.0003 per 100,000 decrease among non-Hispanic men (comparison P = .010).

Among Black men, testicular cancer–specific mortality rates declined by 0.0007 per 100,000, compared with a marginally significant increase of 0.0006 per 100,000 among White men (P =.049).

“Given that testicular cancer generally has a favorable prognosis, it is concerning that the mortality rate for this disease is increasing,” said Sophia C. Kamran, MD, the study’s lead author and a radiation oncologist at Massachusetts General Hospital.

Dr. Kamran urged new efforts to understand these trends and to make testicular cancer care more accessible for all patients.

Ms. Ghosh said that other researchers have identified the same disparity among Hispanic men with prostate cancer. “Even though testicular cancer is a rare, our finding warrants further investigation to find the basis of these disparities to better serve the Hispanic community.”

Other studies have shown higher likelihood of later stage diagnosis and worse survival outcomes among Black patients.

No funding sources were reported for this study.

A study of testicular cancer mortality finds worse outcomes among Hispanic men, but better outcomes among Black men.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

Incidence rates for testicular cancer in the United States have increased slowly in recent decades, said Anushka Ghosh, a clinical research coordinatory with Massachusetts General Hospital, Boston. Her analysis found mortality increases from 1999 to 2019 to be significantly greater among Hispanic men. The increase was 0.0019 per 100,000, compared with a 0.0003 per 100,000 decrease among non-Hispanic men (comparison P = .010).

Among Black men, testicular cancer–specific mortality rates declined by 0.0007 per 100,000, compared with a marginally significant increase of 0.0006 per 100,000 among White men (P =.049).

“Given that testicular cancer generally has a favorable prognosis, it is concerning that the mortality rate for this disease is increasing,” said Sophia C. Kamran, MD, the study’s lead author and a radiation oncologist at Massachusetts General Hospital.

Dr. Kamran urged new efforts to understand these trends and to make testicular cancer care more accessible for all patients.

Ms. Ghosh said that other researchers have identified the same disparity among Hispanic men with prostate cancer. “Even though testicular cancer is a rare, our finding warrants further investigation to find the basis of these disparities to better serve the Hispanic community.”

Other studies have shown higher likelihood of later stage diagnosis and worse survival outcomes among Black patients.

No funding sources were reported for this study.

A study of testicular cancer mortality finds worse outcomes among Hispanic men, but better outcomes among Black men.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

Incidence rates for testicular cancer in the United States have increased slowly in recent decades, said Anushka Ghosh, a clinical research coordinatory with Massachusetts General Hospital, Boston. Her analysis found mortality increases from 1999 to 2019 to be significantly greater among Hispanic men. The increase was 0.0019 per 100,000, compared with a 0.0003 per 100,000 decrease among non-Hispanic men (comparison P = .010).

Among Black men, testicular cancer–specific mortality rates declined by 0.0007 per 100,000, compared with a marginally significant increase of 0.0006 per 100,000 among White men (P =.049).

“Given that testicular cancer generally has a favorable prognosis, it is concerning that the mortality rate for this disease is increasing,” said Sophia C. Kamran, MD, the study’s lead author and a radiation oncologist at Massachusetts General Hospital.

Dr. Kamran urged new efforts to understand these trends and to make testicular cancer care more accessible for all patients.

Ms. Ghosh said that other researchers have identified the same disparity among Hispanic men with prostate cancer. “Even though testicular cancer is a rare, our finding warrants further investigation to find the basis of these disparities to better serve the Hispanic community.”

Other studies have shown higher likelihood of later stage diagnosis and worse survival outcomes among Black patients.

No funding sources were reported for this study.

This has been an unfortunate, but not an atypical year, for the children in Maine whose lives have intersected with the state’s Department of Health and Human Services. In 2021, 25 children died of abuse and neglect or in homes with prior involvement with the child protective system. Four cases not included in that number are currently listed as homicides. At a recent legislative hearing the grandmother of one of those victims told her story to the lawmaker.

Her grandson was removed from his mother’s custody at 3 months of age after a 2-year-old sibling overdosed on methadone. Father and grandmother became his caregivers but when the father was arrested the child was returned to the mother’s custody by a judge despite the pleas of the child’s court-appointed guardian. The child eventually returned to the care of his paternal aunt and father, but when the father was arrested again the then 3-year-old was returned to his mother. Within months he was dead with multiple fractures, including to his spine and with internal and intracranial bleeding (Overton P. Maine’s child welfare system failed a 3-year old who died, grandmother tells lawmakers. 2022 Feb 11. Portland Press Herald).

The grandmother questioned the legislators why a vulnerable child would be returned to the care of a woman with such an extensive history of involvement with the Department of Health and Human Services. While there may have been errors of judgment on the part of department staff, in large part the answer lies in the system’s emphasis on reunification. Like apple pie, motherhood, and more recently fatherhood, have been viewed as something deserving of our unquestioning efforts to preserve.

This is not a recent trend. Some of the most frustrating cases over my 40 years of practice involved the failure of the courts and in some cases social workers to place a child’s welfare in the proper perspective as court schedules and custody decisions were made. Too often the reunification of “the family” seemed to trump the needs of the child. Fortunately, I’m unaware of any of my patients who died as the result of these untimely and poorly made decisions. However, many of my patients lived in unsettled conditions never sure what the next week would bring while the system focused on giving an adult whose life was a mess one more chance to demonstrate his or her ability to parent.

Of course, there are occasions in which child protective workers have been too hasty in pulling a child from his or her parents. But, in my experience those cases pale next to the number of times in which children were exposed to home environments that threatened their psychological health and development. Yes, there are bad foster homes. Many foster homes might do a better job if they were working in a system that put a higher value on the emotional needs and safety of the children in making its custody decisions.

We have a governor here in Maine who has worked hard to do the right thing during the pandemic and has made child health a focus. However, her recent proposed appropriations bill appears to continue the focus on reunification by funneling money into programs such as family reunion training and coaching as well as a parent mentorship program. Certainly, one can’t argue that these kind of programs might be helpful to some families. On the other hand, we can’t let these programs create the impression that an intact family is our primary goal. Not every family is repairable, at least on a time schedule compatible with the emotional and health needs of the children.

I wouldn’t be surprised to learn that many of you have experienced a similar frustration when decisions based on an unrealistic goal of family reunification have put your patients at risk.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

This has been an unfortunate, but not an atypical year, for the children in Maine whose lives have intersected with the state’s Department of Health and Human Services. In 2021, 25 children died of abuse and neglect or in homes with prior involvement with the child protective system. Four cases not included in that number are currently listed as homicides. At a recent legislative hearing the grandmother of one of those victims told her story to the lawmaker.

Her grandson was removed from his mother’s custody at 3 months of age after a 2-year-old sibling overdosed on methadone. Father and grandmother became his caregivers but when the father was arrested the child was returned to the mother’s custody by a judge despite the pleas of the child’s court-appointed guardian. The child eventually returned to the care of his paternal aunt and father, but when the father was arrested again the then 3-year-old was returned to his mother. Within months he was dead with multiple fractures, including to his spine and with internal and intracranial bleeding (Overton P. Maine’s child welfare system failed a 3-year old who died, grandmother tells lawmakers. 2022 Feb 11. Portland Press Herald).

The grandmother questioned the legislators why a vulnerable child would be returned to the care of a woman with such an extensive history of involvement with the Department of Health and Human Services. While there may have been errors of judgment on the part of department staff, in large part the answer lies in the system’s emphasis on reunification. Like apple pie, motherhood, and more recently fatherhood, have been viewed as something deserving of our unquestioning efforts to preserve.

This is not a recent trend. Some of the most frustrating cases over my 40 years of practice involved the failure of the courts and in some cases social workers to place a child’s welfare in the proper perspective as court schedules and custody decisions were made. Too often the reunification of “the family” seemed to trump the needs of the child. Fortunately, I’m unaware of any of my patients who died as the result of these untimely and poorly made decisions. However, many of my patients lived in unsettled conditions never sure what the next week would bring while the system focused on giving an adult whose life was a mess one more chance to demonstrate his or her ability to parent.

Of course, there are occasions in which child protective workers have been too hasty in pulling a child from his or her parents. But, in my experience those cases pale next to the number of times in which children were exposed to home environments that threatened their psychological health and development. Yes, there are bad foster homes. Many foster homes might do a better job if they were working in a system that put a higher value on the emotional needs and safety of the children in making its custody decisions.

We have a governor here in Maine who has worked hard to do the right thing during the pandemic and has made child health a focus. However, her recent proposed appropriations bill appears to continue the focus on reunification by funneling money into programs such as family reunion training and coaching as well as a parent mentorship program. Certainly, one can’t argue that these kind of programs might be helpful to some families. On the other hand, we can’t let these programs create the impression that an intact family is our primary goal. Not every family is repairable, at least on a time schedule compatible with the emotional and health needs of the children.

I wouldn’t be surprised to learn that many of you have experienced a similar frustration when decisions based on an unrealistic goal of family reunification have put your patients at risk.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

This has been an unfortunate, but not an atypical year, for the children in Maine whose lives have intersected with the state’s Department of Health and Human Services. In 2021, 25 children died of abuse and neglect or in homes with prior involvement with the child protective system. Four cases not included in that number are currently listed as homicides. At a recent legislative hearing the grandmother of one of those victims told her story to the lawmaker.

Her grandson was removed from his mother’s custody at 3 months of age after a 2-year-old sibling overdosed on methadone. Father and grandmother became his caregivers but when the father was arrested the child was returned to the mother’s custody by a judge despite the pleas of the child’s court-appointed guardian. The child eventually returned to the care of his paternal aunt and father, but when the father was arrested again the then 3-year-old was returned to his mother. Within months he was dead with multiple fractures, including to his spine and with internal and intracranial bleeding (Overton P. Maine’s child welfare system failed a 3-year old who died, grandmother tells lawmakers. 2022 Feb 11. Portland Press Herald).

The grandmother questioned the legislators why a vulnerable child would be returned to the care of a woman with such an extensive history of involvement with the Department of Health and Human Services. While there may have been errors of judgment on the part of department staff, in large part the answer lies in the system’s emphasis on reunification. Like apple pie, motherhood, and more recently fatherhood, have been viewed as something deserving of our unquestioning efforts to preserve.

This is not a recent trend. Some of the most frustrating cases over my 40 years of practice involved the failure of the courts and in some cases social workers to place a child’s welfare in the proper perspective as court schedules and custody decisions were made. Too often the reunification of “the family” seemed to trump the needs of the child. Fortunately, I’m unaware of any of my patients who died as the result of these untimely and poorly made decisions. However, many of my patients lived in unsettled conditions never sure what the next week would bring while the system focused on giving an adult whose life was a mess one more chance to demonstrate his or her ability to parent.

Of course, there are occasions in which child protective workers have been too hasty in pulling a child from his or her parents. But, in my experience those cases pale next to the number of times in which children were exposed to home environments that threatened their psychological health and development. Yes, there are bad foster homes. Many foster homes might do a better job if they were working in a system that put a higher value on the emotional needs and safety of the children in making its custody decisions.

We have a governor here in Maine who has worked hard to do the right thing during the pandemic and has made child health a focus. However, her recent proposed appropriations bill appears to continue the focus on reunification by funneling money into programs such as family reunion training and coaching as well as a parent mentorship program. Certainly, one can’t argue that these kind of programs might be helpful to some families. On the other hand, we can’t let these programs create the impression that an intact family is our primary goal. Not every family is repairable, at least on a time schedule compatible with the emotional and health needs of the children.

I wouldn’t be surprised to learn that many of you have experienced a similar frustration when decisions based on an unrealistic goal of family reunification have put your patients at risk.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Long-term results from the Dutch PREOPANC randomized, controlled trial confirm that neoadjuvant chemoradiotherapy conveys a survival advantage to patients with resectable and borderline resectable pancreatic cancer.

Neoadjuvant therapy remains controversial in this patient population, which makes up 15% of pancreatic cancer cases. Historically, these patients have been treated with surgery followed by adjuvant chemotherapy, but only about half of patients ever receive adjuvant chemotherapy due to early recurrence, surgical complication, or worsening disease. Neoadjuvant chemoradiotherapy is thought to increase the fraction of patients who receive chemotherapy. Improved exposure to chemotherapy could increase survival, and may also increase the rate of microscopically margin-negative resections.

Neoadjuvant chemoradiotherapy has become increasingly common, but the practice is based on retrospective analysis and small, phase II trials.

“This phase III, randomized trial demonstrates a long-term survival benefit with neoadjuvant treatment compared with upfront surgery in patients with resectable and borderline resectable pancreatic cancer,” the researchers wrote in the study, published online Jan. 27 in the Journal of Clinical Oncology. “The effect of neoadjuvant chemoradiotherapy was consistent across subgroups, including resectable and borderline resectable disease,” they added.

The new data represent long-term follow-up of 246 patients who had been randomized to neoadjuvant chemoradiotherapy or upfront surgery. Short-term data, published in 2020, showed trends toward improved survival but no statistically significant difference at a median of 27 months of follow-up. In the update, after a median follow-up of 59 months, patients in the neoadjuvant chemoradiotherapy group had better overall survival (hazard ratio [HR], 0.73; P = .025) and the 5-year overall survival was higher in the neoadjuvant chemoradiotherapy group (20.5%; 95% confidence interval [CI], 14.2%-29.8%) than the upfront surgery group (6.5%; 95% CI, 3.1%-13.7%).

Subgroup analyses found a survival advantage for upfront chemoradiotherapy among patients with borderline resectable tumors (HR, 0.67; P = .045), and a trend toward improved survival among patients with resectable tumors (HR, 0.79; P = .23). There was a trend toward more serious adverse events in the upfront chemoradiotherapy group (52% versus 41%; P = .096). There was no difference in major surgical complications or postoperative mortality.

The study found high progression rates within the first year in both the neoadjuvant chemoradiotherapy group and the upfront surgery group. “Apparently, our neoadjuvant schedule was not able to prevent many of these early progressions, and more effective schedules are warranted,” the authors wrote.

The survival outcomes were lower than those found in adjuvant trials, likely because of differences in patient populations. Adjuvant studies generally recruit patients who have recovered well from resection and have no early signs of recurrence, and therefore have a more favorable prognosis.

The long-term results from PREOPANC are in agreement with four previous studies that compared neoadjuvant chemoradiotherapy to upfront surgery.

A limitation of the study was that gemcitabine monotherapy was used in the adjuvant setting, and this regimen is now considered out of date.

The study was funded by the Dutch Cancer Foundation.

Long-term results from the Dutch PREOPANC randomized, controlled trial confirm that neoadjuvant chemoradiotherapy conveys a survival advantage to patients with resectable and borderline resectable pancreatic cancer.

Neoadjuvant therapy remains controversial in this patient population, which makes up 15% of pancreatic cancer cases. Historically, these patients have been treated with surgery followed by adjuvant chemotherapy, but only about half of patients ever receive adjuvant chemotherapy due to early recurrence, surgical complication, or worsening disease. Neoadjuvant chemoradiotherapy is thought to increase the fraction of patients who receive chemotherapy. Improved exposure to chemotherapy could increase survival, and may also increase the rate of microscopically margin-negative resections.

Neoadjuvant chemoradiotherapy has become increasingly common, but the practice is based on retrospective analysis and small, phase II trials.

“This phase III, randomized trial demonstrates a long-term survival benefit with neoadjuvant treatment compared with upfront surgery in patients with resectable and borderline resectable pancreatic cancer,” the researchers wrote in the study, published online Jan. 27 in the Journal of Clinical Oncology. “The effect of neoadjuvant chemoradiotherapy was consistent across subgroups, including resectable and borderline resectable disease,” they added.

The new data represent long-term follow-up of 246 patients who had been randomized to neoadjuvant chemoradiotherapy or upfront surgery. Short-term data, published in 2020, showed trends toward improved survival but no statistically significant difference at a median of 27 months of follow-up. In the update, after a median follow-up of 59 months, patients in the neoadjuvant chemoradiotherapy group had better overall survival (hazard ratio [HR], 0.73; P = .025) and the 5-year overall survival was higher in the neoadjuvant chemoradiotherapy group (20.5%; 95% confidence interval [CI], 14.2%-29.8%) than the upfront surgery group (6.5%; 95% CI, 3.1%-13.7%).

Subgroup analyses found a survival advantage for upfront chemoradiotherapy among patients with borderline resectable tumors (HR, 0.67; P = .045), and a trend toward improved survival among patients with resectable tumors (HR, 0.79; P = .23). There was a trend toward more serious adverse events in the upfront chemoradiotherapy group (52% versus 41%; P = .096). There was no difference in major surgical complications or postoperative mortality.

The study found high progression rates within the first year in both the neoadjuvant chemoradiotherapy group and the upfront surgery group. “Apparently, our neoadjuvant schedule was not able to prevent many of these early progressions, and more effective schedules are warranted,” the authors wrote.

The survival outcomes were lower than those found in adjuvant trials, likely because of differences in patient populations. Adjuvant studies generally recruit patients who have recovered well from resection and have no early signs of recurrence, and therefore have a more favorable prognosis.

The long-term results from PREOPANC are in agreement with four previous studies that compared neoadjuvant chemoradiotherapy to upfront surgery.

A limitation of the study was that gemcitabine monotherapy was used in the adjuvant setting, and this regimen is now considered out of date.

The study was funded by the Dutch Cancer Foundation.

Long-term results from the Dutch PREOPANC randomized, controlled trial confirm that neoadjuvant chemoradiotherapy conveys a survival advantage to patients with resectable and borderline resectable pancreatic cancer.

Neoadjuvant therapy remains controversial in this patient population, which makes up 15% of pancreatic cancer cases. Historically, these patients have been treated with surgery followed by adjuvant chemotherapy, but only about half of patients ever receive adjuvant chemotherapy due to early recurrence, surgical complication, or worsening disease. Neoadjuvant chemoradiotherapy is thought to increase the fraction of patients who receive chemotherapy. Improved exposure to chemotherapy could increase survival, and may also increase the rate of microscopically margin-negative resections.

Neoadjuvant chemoradiotherapy has become increasingly common, but the practice is based on retrospective analysis and small, phase II trials.

“This phase III, randomized trial demonstrates a long-term survival benefit with neoadjuvant treatment compared with upfront surgery in patients with resectable and borderline resectable pancreatic cancer,” the researchers wrote in the study, published online Jan. 27 in the Journal of Clinical Oncology. “The effect of neoadjuvant chemoradiotherapy was consistent across subgroups, including resectable and borderline resectable disease,” they added.

The new data represent long-term follow-up of 246 patients who had been randomized to neoadjuvant chemoradiotherapy or upfront surgery. Short-term data, published in 2020, showed trends toward improved survival but no statistically significant difference at a median of 27 months of follow-up. In the update, after a median follow-up of 59 months, patients in the neoadjuvant chemoradiotherapy group had better overall survival (hazard ratio [HR], 0.73; P = .025) and the 5-year overall survival was higher in the neoadjuvant chemoradiotherapy group (20.5%; 95% confidence interval [CI], 14.2%-29.8%) than the upfront surgery group (6.5%; 95% CI, 3.1%-13.7%).

Subgroup analyses found a survival advantage for upfront chemoradiotherapy among patients with borderline resectable tumors (HR, 0.67; P = .045), and a trend toward improved survival among patients with resectable tumors (HR, 0.79; P = .23). There was a trend toward more serious adverse events in the upfront chemoradiotherapy group (52% versus 41%; P = .096). There was no difference in major surgical complications or postoperative mortality.

The study found high progression rates within the first year in both the neoadjuvant chemoradiotherapy group and the upfront surgery group. “Apparently, our neoadjuvant schedule was not able to prevent many of these early progressions, and more effective schedules are warranted,” the authors wrote.

The survival outcomes were lower than those found in adjuvant trials, likely because of differences in patient populations. Adjuvant studies generally recruit patients who have recovered well from resection and have no early signs of recurrence, and therefore have a more favorable prognosis.

The long-term results from PREOPANC are in agreement with four previous studies that compared neoadjuvant chemoradiotherapy to upfront surgery.

A limitation of the study was that gemcitabine monotherapy was used in the adjuvant setting, and this regimen is now considered out of date.

The study was funded by the Dutch Cancer Foundation.

Mr. Jones has had multiple sclerosis (MS) since 2008. Initially it was pretty active, though I was able to bring it under control with drug A. He didn’t like the side effects, or the shots, but at that time options for MS treatment were kind of limited.

When the oral agents came out he switched to drug B. He still had some side effects on it, which he didn’t like, but his insurance didn’t cover the other oral agent that was available. So he soldiered on.

Then, in late 2019, he had an episode of optic neuritis, and a repeat MRI showed that in the last 2 years he’d had an uptick in demyelinating plaques. So, in early 2020, he switched to drug C.

Drug C has, to date, been pretty good. He’s had no side effects or relapses, and a recent brain MRI was stable.

Of course, drug C ain’t cheap. Its price isn’t even listed on ePocrates or GoodRx. So my staff and I have to do all kinds of paperwork and hoop-jumping to get it covered each year.

So in late 2021 we started the annual process, which doesn’t happen overnight. We finally received notice he’d been approved – until March 1, 2022. Only 3 months.

Given the alacrity with which these companies seem to work, we began the new authorization paperwork almost as soon as we got the last one in mid-January. This time we didn’t hear back, and every time we called they told us the application was “under review.” In the meantime, Mr. Jones’ supply of pills, which are pretty critical to his health and well-being, was gradually decreasing.

Recently, out of the blue, a 1-month supply of drug C showed up in his mailbox, along with a bill for $3,000. Mr. Jones is a career waiter at a local restaurant, and had no way to pay for this. So my staff went to work on the phones, and after a few hours got it in writing that it was being covered as a bridging supply under the manufacturer’s assistance program. Okay. That crises was averted. (I have no idea if the insurance really pays $3,000/month. Like buying a car, there can be a big difference between a drug’s asking price and what’s really paid for it).

The next morning, however, we got a note from his insurance company saying the medical reviewer had decided he didn’t need drug C, and wanted him to go back to drug B. After all, it was cheaper. I called the reviewer and argued with him. I told him he’d clinically worsened on drug B, not to mention the side effects. The reviewer said I should have mentioned that in my notes. I pointed out that it was in my notes, which had been sent along with the forms I’d filled out. He didn’t answer that, just said he’d have them fax me an appeal form.

The appeal form showed up about an hour later, so I took some time out of my weekend to fill it out. Then I faxed it back, along with (as they requested) chart notes and MRI reports dating back to 2008. Which was a lot.

So now we’ll see what happens.

Do other countries have this sort of thing? Or is this a product of the bizarre patchwork that makes up the American health care system? Different insurance companies, different subplans, and regional sub-subplans, and so on, each with a different set of rules, forms, and obstacle courses to navigate.

For all their glitzy TV commercials showing smiling, happy, multigenerational families, all looking to be in glowing health from the medical care they’re receiving, they seem to be pretty determined to keep Mr. Jones from receiving a drug that’s allowing him to continue working as a waiter 50-60 hours per week. Without it, he’d likely be unable to work and, at some point, would have to file for disability. Probably would eventually need increasingly high-cost items, going to a cane, then a walker, then a wheelchair, then a power wheelchair. ER visits, things that. In the long run, those would cost a helluva lot more than drug C.

Of course, that may be part of their game, too. Maybe they figure he’ll end up dropping off their insurance as he worsens, and then their shareholders don’t have to pay for his bad luck. I hope I’m wrong in thinking that, but such is the nature of business. And health insurance is a HUGE business.

So now I’ve faxed in the appeal forms, and can move on, for the time being, to the needs of other patients (not to mention spending time with my family). But Mr. Jones’ pill supply will run out on April 1, 2022, and I still have no idea what will happen then.

Neither does he. And for him, that’s pretty scary.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Mr. Jones has had multiple sclerosis (MS) since 2008. Initially it was pretty active, though I was able to bring it under control with drug A. He didn’t like the side effects, or the shots, but at that time options for MS treatment were kind of limited.

When the oral agents came out he switched to drug B. He still had some side effects on it, which he didn’t like, but his insurance didn’t cover the other oral agent that was available. So he soldiered on.

Then, in late 2019, he had an episode of optic neuritis, and a repeat MRI showed that in the last 2 years he’d had an uptick in demyelinating plaques. So, in early 2020, he switched to drug C.

Drug C has, to date, been pretty good. He’s had no side effects or relapses, and a recent brain MRI was stable.

Of course, drug C ain’t cheap. Its price isn’t even listed on ePocrates or GoodRx. So my staff and I have to do all kinds of paperwork and hoop-jumping to get it covered each year.

So in late 2021 we started the annual process, which doesn’t happen overnight. We finally received notice he’d been approved – until March 1, 2022. Only 3 months.

Given the alacrity with which these companies seem to work, we began the new authorization paperwork almost as soon as we got the last one in mid-January. This time we didn’t hear back, and every time we called they told us the application was “under review.” In the meantime, Mr. Jones’ supply of pills, which are pretty critical to his health and well-being, was gradually decreasing.

Recently, out of the blue, a 1-month supply of drug C showed up in his mailbox, along with a bill for $3,000. Mr. Jones is a career waiter at a local restaurant, and had no way to pay for this. So my staff went to work on the phones, and after a few hours got it in writing that it was being covered as a bridging supply under the manufacturer’s assistance program. Okay. That crises was averted. (I have no idea if the insurance really pays $3,000/month. Like buying a car, there can be a big difference between a drug’s asking price and what’s really paid for it).

The next morning, however, we got a note from his insurance company saying the medical reviewer had decided he didn’t need drug C, and wanted him to go back to drug B. After all, it was cheaper. I called the reviewer and argued with him. I told him he’d clinically worsened on drug B, not to mention the side effects. The reviewer said I should have mentioned that in my notes. I pointed out that it was in my notes, which had been sent along with the forms I’d filled out. He didn’t answer that, just said he’d have them fax me an appeal form.

The appeal form showed up about an hour later, so I took some time out of my weekend to fill it out. Then I faxed it back, along with (as they requested) chart notes and MRI reports dating back to 2008. Which was a lot.

So now we’ll see what happens.

Do other countries have this sort of thing? Or is this a product of the bizarre patchwork that makes up the American health care system? Different insurance companies, different subplans, and regional sub-subplans, and so on, each with a different set of rules, forms, and obstacle courses to navigate.

For all their glitzy TV commercials showing smiling, happy, multigenerational families, all looking to be in glowing health from the medical care they’re receiving, they seem to be pretty determined to keep Mr. Jones from receiving a drug that’s allowing him to continue working as a waiter 50-60 hours per week. Without it, he’d likely be unable to work and, at some point, would have to file for disability. Probably would eventually need increasingly high-cost items, going to a cane, then a walker, then a wheelchair, then a power wheelchair. ER visits, things that. In the long run, those would cost a helluva lot more than drug C.

Of course, that may be part of their game, too. Maybe they figure he’ll end up dropping off their insurance as he worsens, and then their shareholders don’t have to pay for his bad luck. I hope I’m wrong in thinking that, but such is the nature of business. And health insurance is a HUGE business.

So now I’ve faxed in the appeal forms, and can move on, for the time being, to the needs of other patients (not to mention spending time with my family). But Mr. Jones’ pill supply will run out on April 1, 2022, and I still have no idea what will happen then.

Neither does he. And for him, that’s pretty scary.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Mr. Jones has had multiple sclerosis (MS) since 2008. Initially it was pretty active, though I was able to bring it under control with drug A. He didn’t like the side effects, or the shots, but at that time options for MS treatment were kind of limited.

When the oral agents came out he switched to drug B. He still had some side effects on it, which he didn’t like, but his insurance didn’t cover the other oral agent that was available. So he soldiered on.

Then, in late 2019, he had an episode of optic neuritis, and a repeat MRI showed that in the last 2 years he’d had an uptick in demyelinating plaques. So, in early 2020, he switched to drug C.

Drug C has, to date, been pretty good. He’s had no side effects or relapses, and a recent brain MRI was stable.

Of course, drug C ain’t cheap. Its price isn’t even listed on ePocrates or GoodRx. So my staff and I have to do all kinds of paperwork and hoop-jumping to get it covered each year.

So in late 2021 we started the annual process, which doesn’t happen overnight. We finally received notice he’d been approved – until March 1, 2022. Only 3 months.

Given the alacrity with which these companies seem to work, we began the new authorization paperwork almost as soon as we got the last one in mid-January. This time we didn’t hear back, and every time we called they told us the application was “under review.” In the meantime, Mr. Jones’ supply of pills, which are pretty critical to his health and well-being, was gradually decreasing.

Recently, out of the blue, a 1-month supply of drug C showed up in his mailbox, along with a bill for $3,000. Mr. Jones is a career waiter at a local restaurant, and had no way to pay for this. So my staff went to work on the phones, and after a few hours got it in writing that it was being covered as a bridging supply under the manufacturer’s assistance program. Okay. That crises was averted. (I have no idea if the insurance really pays $3,000/month. Like buying a car, there can be a big difference between a drug’s asking price and what’s really paid for it).

The next morning, however, we got a note from his insurance company saying the medical reviewer had decided he didn’t need drug C, and wanted him to go back to drug B. After all, it was cheaper. I called the reviewer and argued with him. I told him he’d clinically worsened on drug B, not to mention the side effects. The reviewer said I should have mentioned that in my notes. I pointed out that it was in my notes, which had been sent along with the forms I’d filled out. He didn’t answer that, just said he’d have them fax me an appeal form.

The appeal form showed up about an hour later, so I took some time out of my weekend to fill it out. Then I faxed it back, along with (as they requested) chart notes and MRI reports dating back to 2008. Which was a lot.

So now we’ll see what happens.

Do other countries have this sort of thing? Or is this a product of the bizarre patchwork that makes up the American health care system? Different insurance companies, different subplans, and regional sub-subplans, and so on, each with a different set of rules, forms, and obstacle courses to navigate.

For all their glitzy TV commercials showing smiling, happy, multigenerational families, all looking to be in glowing health from the medical care they’re receiving, they seem to be pretty determined to keep Mr. Jones from receiving a drug that’s allowing him to continue working as a waiter 50-60 hours per week. Without it, he’d likely be unable to work and, at some point, would have to file for disability. Probably would eventually need increasingly high-cost items, going to a cane, then a walker, then a wheelchair, then a power wheelchair. ER visits, things that. In the long run, those would cost a helluva lot more than drug C.

Of course, that may be part of their game, too. Maybe they figure he’ll end up dropping off their insurance as he worsens, and then their shareholders don’t have to pay for his bad luck. I hope I’m wrong in thinking that, but such is the nature of business. And health insurance is a HUGE business.

So now I’ve faxed in the appeal forms, and can move on, for the time being, to the needs of other patients (not to mention spending time with my family). But Mr. Jones’ pill supply will run out on April 1, 2022, and I still have no idea what will happen then.

Neither does he. And for him, that’s pretty scary.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Computed tomographic angiography (CTA) appears preferable to standard cath-based angiography for the initial evaluation of most stable, intermediate-risk patients with angina-like symptoms, researchers say, based on their study conducted at centers across Europe.

Clinical outcomes over several years in the randomized trial – called DISCHARGE, with an enrollment of more than 3,500 – were statistically similar whether the patients were assigned to CTA or invasive coronary angiography (ICA) as their initial evaluation. Symptoms and quality-of-life measures were also similar.

But the patients assigned to the initial-CTA strategy, of whom fewer than a fourth went on to cardiac cath, showed far fewer procedure-related complications and less often went to coronary revascularization during the median follow-up of 3.5 years, the group reported March 4 in the New England Journal of Medicine.

Based on the findings, CTA “is a safe alternative to cardiac catheterization for patients with suspected CAD [coronary artery disease] that will likely change clinical practice worldwide by replacing invasive testing in patients with stable chest pain who can be expected to benefit” those with an intermediate pretest probability for obstructive disease, principal investigator Marc Dewey, MD, Charité – Universitätsmedizin Berlin, told this news organization.

None of the patient subgroups explored in the trial showed a significant clinical benefit from one strategy over the other, Dr. Dewey commented in an email.

The trial’s results don’t apply to patients unlike those entered, and in particular, he said, “ICA should remain the first test option in patients with high clinical pretest probability of obstructive CAD.”

Dr. Dewey is senior author on the study’s publication, which was timed to coincide with his presentation of the results at ECR 2022 Overture, an all-virtual scientific session of the European Congress of Radiology.

“This is the definitive study,” Matthew Budoff, MD, Lundquist Institute at Harbor-UCLA, Torrance, California, said in an interview. It suggests in a large population that the initial CTA strategy “is as good and maybe safer” in stable patients at intermediate risk compared with initial ICA. “I would say close to 75% or 80% of the patients that we see would fall into that range of risk” and be suitable for the testing algorithm used in the study, said Dr. Budoff, who was not part of the trial.

Invasive angiography would generally still be the initial approach for patients at greater than intermediate risk, such as those with breakthrough angina or electrocardiographic changes, he said. “I still think there’s a huge role for invasive angiography. It’s just a bit smaller now than it used to be for the lower-risk patient.”  

The DISCHARGE trial, agreed cardiothoracic radiology specialist Rozemarijn Vliegenthart, MD, PhD, University of Groningen, the Netherlands, “shows that in patients with intermediate pretest probability, CTA should be used as a gatekeeper before invasive coronary angiography, instead of directly referring for invasive coronary angiography.”

It shows that “a CT-first approach” is both safe and clinically effective and even a trend suggesting better clinical outcomes, compared with ICA. And it demonstrates that “still, many diagnostic invasive coronary angiographies are performed unnecessarily,” Dr. Vliegenthart said as the invited discussant following Dr. Dewey’s presentation.

DISCOVER is only the latest in a series of major studies to explore how CTA best fits in with ICA, stress imaging, and other tests for evaluating patients with chest pain. For example, “the PROMISE trial and the SCOT-HEART trial found that CT was as good as or even better than functional testing. DISCHARGE, I think, confirms the safety of the CT strategy” and reaffirms that it is “at least as good” as an ICA-first approach, cardiologist Klaus F. Kofoed, MD, PhD, DMSc, Rigshospitalet University of Copenhagen, said when co-presenting the trial’s results with Dr. Dewey.

“We can now say CT may be suitable in intermediate-risk patients referred for ICA, particularly those with a clinical constellation suggesting a higher event risk, with abnormal or inconclusive functional test results, or with persistent symptoms despite medical treatment,” said Dr. Kofoed, who is on the DISCOVER steering committee.

The trial’s 3,561 patients with stable chest pain – at 26 experienced centers in 16 countries – were randomly assigned to undergo CTA or ICA as their initial diagnostic imaging approach. Entry required them to be at intermediate risk, defined as an estimated 10% to 60% probability of having obstructive CAD. Of note, women made up about 56% of both groups.

Imaging was positive for obstructive disease in 26% of the 1,808 patients in the CTA group and in the same proportion of the 1,753 who were assigned to ICA. Nonobstructive CAD was identified in 36% and 22%, respectively.

Importantly, 404 (22.3%) patients in the CTA group then underwent ICA, which identified obstructive CAD in 293 (72.5%).

With a complete follow-up in about 99% of patients, the report notes, the rate of the primary endpoint of major adverse cardiac events, or MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was 2.1% in the CTA group and in 3.0% in the ICA group. The adjusted hazard ratio of 0.70 (95% confidence interval, 0.46-1.07; P = .10) fell short of significance.

The corresponding HR for an “expanded primary outcome” that also included transient ischemic attack or major procedure-related complications was 0.60 (95% CI, 0.42-0.85) in favor of the CTA group.

As a “pragmatic trial,” DISCHARGE relied on clinically identified events for the endpoint assessments and did not require, for example, laboratory biomarker or neurologic imaging for confirmation, the report notes.

Major procedure-related complications during the initial management phase occurred in 0.5% of the CTA group, and 1.9% of those assigned to initial ICA (HR, 0.26; 95% CI, 0.13-0.55).

Coronary revascularization was less common in the CTA group during the trial’s follow-up, 14.2% versus 18.0% for those assigned to ICA (HR, 0.76; 95% CI, 0.65-0.90).

But the prevalences of angina during the final 4 weeks of follow-up, the group reported, were statistically similar at 8.8% and 7.5% for patients assigned to CTA and ICA, respectively.

The trial showed “no material difference” between the initial CTA versus ICA strategies for its MACE primary endpoint, observed Joseph Loscalzo, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass., in an accompanying editorial.

“This result is probably a consequence of the lack of effect of revascularization on cardiovascular events among most patients with stable angina and the limited number of those with high-risk anatomy who would benefit from revascularization in the trial,” he writes.

That CTA was performed “significantly earlier than angiography, 3 days versus 12 days after enrollment,” may have led to earlier coronary revascularization in that group, and therefore is “a better outcome in patients whose anatomy would benefit from it.”

Dr. Loscalzo questioned several aspects of the trial design, which, for example, led to a more than 35% prevalence of patients with nonanginal chest pain among those randomized. Different criteria for classifying patients as “intermediate risk” might also have contributed to the fairly low prevalence of patients in either group ultimately identified with obstructive CAD, he proposes. That low prevalence “suggests that the overall trial population had a low risk of obstructive CAD rather than an intermediate risk.”

DISCHARGE was supported by grants from the European Union Seventh Framework Program, the Berlin Institute of Health, Rigshospitalet of the University of Copenhagen, the British Heart Foundation, and the German Research Foundation. Disclosures for the authors and editorialist are available at NEJM.org. Dr. Budoff has disclosed receiving grant support from General Electric. Dr. Vliegenthart discloses receiving grants from Siemens Healthineers and honorarium for speaking from Siemens Healthineers and Bayer.

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

Computed tomographic angiography (CTA) appears preferable to standard cath-based angiography for the initial evaluation of most stable, intermediate-risk patients with angina-like symptoms, researchers say, based on their study conducted at centers across Europe.

Clinical outcomes over several years in the randomized trial – called DISCHARGE, with an enrollment of more than 3,500 – were statistically similar whether the patients were assigned to CTA or invasive coronary angiography (ICA) as their initial evaluation. Symptoms and quality-of-life measures were also similar.

But the patients assigned to the initial-CTA strategy, of whom fewer than a fourth went on to cardiac cath, showed far fewer procedure-related complications and less often went to coronary revascularization during the median follow-up of 3.5 years, the group reported March 4 in the New England Journal of Medicine.

Based on the findings, CTA “is a safe alternative to cardiac catheterization for patients with suspected CAD [coronary artery disease] that will likely change clinical practice worldwide by replacing invasive testing in patients with stable chest pain who can be expected to benefit” those with an intermediate pretest probability for obstructive disease, principal investigator Marc Dewey, MD, Charité – Universitätsmedizin Berlin, told this news organization.

None of the patient subgroups explored in the trial showed a significant clinical benefit from one strategy over the other, Dr. Dewey commented in an email.

The trial’s results don’t apply to patients unlike those entered, and in particular, he said, “ICA should remain the first test option in patients with high clinical pretest probability of obstructive CAD.”

Dr. Dewey is senior author on the study’s publication, which was timed to coincide with his presentation of the results at ECR 2022 Overture, an all-virtual scientific session of the European Congress of Radiology.

“This is the definitive study,” Matthew Budoff, MD, Lundquist Institute at Harbor-UCLA, Torrance, California, said in an interview. It suggests in a large population that the initial CTA strategy “is as good and maybe safer” in stable patients at intermediate risk compared with initial ICA. “I would say close to 75% or 80% of the patients that we see would fall into that range of risk” and be suitable for the testing algorithm used in the study, said Dr. Budoff, who was not part of the trial.

Invasive angiography would generally still be the initial approach for patients at greater than intermediate risk, such as those with breakthrough angina or electrocardiographic changes, he said. “I still think there’s a huge role for invasive angiography. It’s just a bit smaller now than it used to be for the lower-risk patient.”  

The DISCHARGE trial, agreed cardiothoracic radiology specialist Rozemarijn Vliegenthart, MD, PhD, University of Groningen, the Netherlands, “shows that in patients with intermediate pretest probability, CTA should be used as a gatekeeper before invasive coronary angiography, instead of directly referring for invasive coronary angiography.”

It shows that “a CT-first approach” is both safe and clinically effective and even a trend suggesting better clinical outcomes, compared with ICA. And it demonstrates that “still, many diagnostic invasive coronary angiographies are performed unnecessarily,” Dr. Vliegenthart said as the invited discussant following Dr. Dewey’s presentation.

DISCOVER is only the latest in a series of major studies to explore how CTA best fits in with ICA, stress imaging, and other tests for evaluating patients with chest pain. For example, “the PROMISE trial and the SCOT-HEART trial found that CT was as good as or even better than functional testing. DISCHARGE, I think, confirms the safety of the CT strategy” and reaffirms that it is “at least as good” as an ICA-first approach, cardiologist Klaus F. Kofoed, MD, PhD, DMSc, Rigshospitalet University of Copenhagen, said when co-presenting the trial’s results with Dr. Dewey.

“We can now say CT may be suitable in intermediate-risk patients referred for ICA, particularly those with a clinical constellation suggesting a higher event risk, with abnormal or inconclusive functional test results, or with persistent symptoms despite medical treatment,” said Dr. Kofoed, who is on the DISCOVER steering committee.

The trial’s 3,561 patients with stable chest pain – at 26 experienced centers in 16 countries – were randomly assigned to undergo CTA or ICA as their initial diagnostic imaging approach. Entry required them to be at intermediate risk, defined as an estimated 10% to 60% probability of having obstructive CAD. Of note, women made up about 56% of both groups.

Imaging was positive for obstructive disease in 26% of the 1,808 patients in the CTA group and in the same proportion of the 1,753 who were assigned to ICA. Nonobstructive CAD was identified in 36% and 22%, respectively.

Importantly, 404 (22.3%) patients in the CTA group then underwent ICA, which identified obstructive CAD in 293 (72.5%).

With a complete follow-up in about 99% of patients, the report notes, the rate of the primary endpoint of major adverse cardiac events, or MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was 2.1% in the CTA group and in 3.0% in the ICA group. The adjusted hazard ratio of 0.70 (95% confidence interval, 0.46-1.07; P = .10) fell short of significance.

The corresponding HR for an “expanded primary outcome” that also included transient ischemic attack or major procedure-related complications was 0.60 (95% CI, 0.42-0.85) in favor of the CTA group.

As a “pragmatic trial,” DISCHARGE relied on clinically identified events for the endpoint assessments and did not require, for example, laboratory biomarker or neurologic imaging for confirmation, the report notes.

Major procedure-related complications during the initial management phase occurred in 0.5% of the CTA group, and 1.9% of those assigned to initial ICA (HR, 0.26; 95% CI, 0.13-0.55).

Coronary revascularization was less common in the CTA group during the trial’s follow-up, 14.2% versus 18.0% for those assigned to ICA (HR, 0.76; 95% CI, 0.65-0.90).

But the prevalences of angina during the final 4 weeks of follow-up, the group reported, were statistically similar at 8.8% and 7.5% for patients assigned to CTA and ICA, respectively.

The trial showed “no material difference” between the initial CTA versus ICA strategies for its MACE primary endpoint, observed Joseph Loscalzo, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass., in an accompanying editorial.

“This result is probably a consequence of the lack of effect of revascularization on cardiovascular events among most patients with stable angina and the limited number of those with high-risk anatomy who would benefit from revascularization in the trial,” he writes.

That CTA was performed “significantly earlier than angiography, 3 days versus 12 days after enrollment,” may have led to earlier coronary revascularization in that group, and therefore is “a better outcome in patients whose anatomy would benefit from it.”

Dr. Loscalzo questioned several aspects of the trial design, which, for example, led to a more than 35% prevalence of patients with nonanginal chest pain among those randomized. Different criteria for classifying patients as “intermediate risk” might also have contributed to the fairly low prevalence of patients in either group ultimately identified with obstructive CAD, he proposes. That low prevalence “suggests that the overall trial population had a low risk of obstructive CAD rather than an intermediate risk.”

DISCHARGE was supported by grants from the European Union Seventh Framework Program, the Berlin Institute of Health, Rigshospitalet of the University of Copenhagen, the British Heart Foundation, and the German Research Foundation. Disclosures for the authors and editorialist are available at NEJM.org. Dr. Budoff has disclosed receiving grant support from General Electric. Dr. Vliegenthart discloses receiving grants from Siemens Healthineers and honorarium for speaking from Siemens Healthineers and Bayer.

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

Computed tomographic angiography (CTA) appears preferable to standard cath-based angiography for the initial evaluation of most stable, intermediate-risk patients with angina-like symptoms, researchers say, based on their study conducted at centers across Europe.

Clinical outcomes over several years in the randomized trial – called DISCHARGE, with an enrollment of more than 3,500 – were statistically similar whether the patients were assigned to CTA or invasive coronary angiography (ICA) as their initial evaluation. Symptoms and quality-of-life measures were also similar.

But the patients assigned to the initial-CTA strategy, of whom fewer than a fourth went on to cardiac cath, showed far fewer procedure-related complications and less often went to coronary revascularization during the median follow-up of 3.5 years, the group reported March 4 in the New England Journal of Medicine.

Based on the findings, CTA “is a safe alternative to cardiac catheterization for patients with suspected CAD [coronary artery disease] that will likely change clinical practice worldwide by replacing invasive testing in patients with stable chest pain who can be expected to benefit” those with an intermediate pretest probability for obstructive disease, principal investigator Marc Dewey, MD, Charité – Universitätsmedizin Berlin, told this news organization.

None of the patient subgroups explored in the trial showed a significant clinical benefit from one strategy over the other, Dr. Dewey commented in an email.

The trial’s results don’t apply to patients unlike those entered, and in particular, he said, “ICA should remain the first test option in patients with high clinical pretest probability of obstructive CAD.”

Dr. Dewey is senior author on the study’s publication, which was timed to coincide with his presentation of the results at ECR 2022 Overture, an all-virtual scientific session of the European Congress of Radiology.

“This is the definitive study,” Matthew Budoff, MD, Lundquist Institute at Harbor-UCLA, Torrance, California, said in an interview. It suggests in a large population that the initial CTA strategy “is as good and maybe safer” in stable patients at intermediate risk compared with initial ICA. “I would say close to 75% or 80% of the patients that we see would fall into that range of risk” and be suitable for the testing algorithm used in the study, said Dr. Budoff, who was not part of the trial.

Invasive angiography would generally still be the initial approach for patients at greater than intermediate risk, such as those with breakthrough angina or electrocardiographic changes, he said. “I still think there’s a huge role for invasive angiography. It’s just a bit smaller now than it used to be for the lower-risk patient.”  

The DISCHARGE trial, agreed cardiothoracic radiology specialist Rozemarijn Vliegenthart, MD, PhD, University of Groningen, the Netherlands, “shows that in patients with intermediate pretest probability, CTA should be used as a gatekeeper before invasive coronary angiography, instead of directly referring for invasive coronary angiography.”

It shows that “a CT-first approach” is both safe and clinically effective and even a trend suggesting better clinical outcomes, compared with ICA. And it demonstrates that “still, many diagnostic invasive coronary angiographies are performed unnecessarily,” Dr. Vliegenthart said as the invited discussant following Dr. Dewey’s presentation.

DISCOVER is only the latest in a series of major studies to explore how CTA best fits in with ICA, stress imaging, and other tests for evaluating patients with chest pain. For example, “the PROMISE trial and the SCOT-HEART trial found that CT was as good as or even better than functional testing. DISCHARGE, I think, confirms the safety of the CT strategy” and reaffirms that it is “at least as good” as an ICA-first approach, cardiologist Klaus F. Kofoed, MD, PhD, DMSc, Rigshospitalet University of Copenhagen, said when co-presenting the trial’s results with Dr. Dewey.

“We can now say CT may be suitable in intermediate-risk patients referred for ICA, particularly those with a clinical constellation suggesting a higher event risk, with abnormal or inconclusive functional test results, or with persistent symptoms despite medical treatment,” said Dr. Kofoed, who is on the DISCOVER steering committee.

The trial’s 3,561 patients with stable chest pain – at 26 experienced centers in 16 countries – were randomly assigned to undergo CTA or ICA as their initial diagnostic imaging approach. Entry required them to be at intermediate risk, defined as an estimated 10% to 60% probability of having obstructive CAD. Of note, women made up about 56% of both groups.

Imaging was positive for obstructive disease in 26% of the 1,808 patients in the CTA group and in the same proportion of the 1,753 who were assigned to ICA. Nonobstructive CAD was identified in 36% and 22%, respectively.

Importantly, 404 (22.3%) patients in the CTA group then underwent ICA, which identified obstructive CAD in 293 (72.5%).

With a complete follow-up in about 99% of patients, the report notes, the rate of the primary endpoint of major adverse cardiac events, or MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was 2.1% in the CTA group and in 3.0% in the ICA group. The adjusted hazard ratio of 0.70 (95% confidence interval, 0.46-1.07; P = .10) fell short of significance.

The corresponding HR for an “expanded primary outcome” that also included transient ischemic attack or major procedure-related complications was 0.60 (95% CI, 0.42-0.85) in favor of the CTA group.

As a “pragmatic trial,” DISCHARGE relied on clinically identified events for the endpoint assessments and did not require, for example, laboratory biomarker or neurologic imaging for confirmation, the report notes.

Major procedure-related complications during the initial management phase occurred in 0.5% of the CTA group, and 1.9% of those assigned to initial ICA (HR, 0.26; 95% CI, 0.13-0.55).

Coronary revascularization was less common in the CTA group during the trial’s follow-up, 14.2% versus 18.0% for those assigned to ICA (HR, 0.76; 95% CI, 0.65-0.90).

But the prevalences of angina during the final 4 weeks of follow-up, the group reported, were statistically similar at 8.8% and 7.5% for patients assigned to CTA and ICA, respectively.

The trial showed “no material difference” between the initial CTA versus ICA strategies for its MACE primary endpoint, observed Joseph Loscalzo, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass., in an accompanying editorial.

“This result is probably a consequence of the lack of effect of revascularization on cardiovascular events among most patients with stable angina and the limited number of those with high-risk anatomy who would benefit from revascularization in the trial,” he writes.

That CTA was performed “significantly earlier than angiography, 3 days versus 12 days after enrollment,” may have led to earlier coronary revascularization in that group, and therefore is “a better outcome in patients whose anatomy would benefit from it.”

Dr. Loscalzo questioned several aspects of the trial design, which, for example, led to a more than 35% prevalence of patients with nonanginal chest pain among those randomized. Different criteria for classifying patients as “intermediate risk” might also have contributed to the fairly low prevalence of patients in either group ultimately identified with obstructive CAD, he proposes. That low prevalence “suggests that the overall trial population had a low risk of obstructive CAD rather than an intermediate risk.”

DISCHARGE was supported by grants from the European Union Seventh Framework Program, the Berlin Institute of Health, Rigshospitalet of the University of Copenhagen, the British Heart Foundation, and the German Research Foundation. Disclosures for the authors and editorialist are available at NEJM.org. Dr. Budoff has disclosed receiving grant support from General Electric. Dr. Vliegenthart discloses receiving grants from Siemens Healthineers and honorarium for speaking from Siemens Healthineers and Bayer.

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

New cases of COVID-19 in children continued their descent toward normalcy, falling below 100,000 in a week for the first time since early August 2021, according to the American Academy of Pediatrics and the Children’s Hospital Association.

The sixth consecutive week of declines saw just under 69,000 U.S. children test positive for COVID-19 from Feb. 25 to March 3, a drop of almost 46% from the previous week and 94% since the Omicron-fueled peak of 1.15 million during the week of Jan. 14-20, the AAP and CHA said in their weekly COVID report. The total number of child cases is 12.7 million since the pandemic began, with children representing 19% of all cases.

New admissions also stayed on a downward path, as the rate dropped to 0.24 per 100,000 children aged 0-17 years on March 5, a decline of nearly 81% since hitting 1.25 per 100,000 on Jan. 15. The latest 7-day average for daily admissions, 178 per day from Feb. 27 to March 5, was 29% lower than the previous week and almost 81% lower than the peak of 914 per day for Jan. 10-16, the Centers for Disease Control and Prevention reported.

The story is the same for emergency department visits with diagnosed COVID-19, which are reported as a percentage of all ED visits. On March 4, the 7-day average for children aged 0-11 years was 0.8%, compared with a high of 13.9% in mid-January, while 12- to 15-year-olds had dropped from 12.4% to 0.5% and 16- to 17-year-olds went from 12.6% down to 0.5%, the CDC said on its COVID Data Tracker.

Florida’s surgeon general says no to the vaccine

Vaccination, in the meantime, is struggling to maintain a foothold against the current of declining cases. Florida Surgeon General Joseph Ladapo said that “the Florida Department of Health is going to be the first state to officially recommend against the COVID-19 vaccines for healthy children,” NBC News reported March 7. With such a move, “Florida would become the first state to break from the CDC on vaccines for children,” CNN said in its report.

Vaccinations among children aged 5-11 years, which hit 1.6 million in 1 week shortly after emergency use was authorized in early November, declined quickly shorty thereafter and only rose slightly during the Omicron surge. Since mid-January, the number of children receiving an initial dose has declined for seven consecutive weeks and is now lower than ever, based on CDC data compiled by the AAP.

Just over one-third of children aged 5-11 have gotten at least one dose of COVID-19 vaccine, while 26.4% are fully vaccinated. Among children aged 12-17, just over two-thirds (67.8%) have received at least one dose, 57.8% have completed the vaccine regimen, and 21.9% have gotten a booster, the CDC reported.

As of March 2, “about 8.4 million children 12-17 have yet to receive their initial COVID-19 vaccine dose,” the AAP said. About 64,000 children aged 12-17 had received their first dose in the previous week, the group noted, which was the second-lowest weekly total since the vaccine was approved for children aged 12-15 in May of 2021.

New cases of COVID-19 in children continued their descent toward normalcy, falling below 100,000 in a week for the first time since early August 2021, according to the American Academy of Pediatrics and the Children’s Hospital Association.

The sixth consecutive week of declines saw just under 69,000 U.S. children test positive for COVID-19 from Feb. 25 to March 3, a drop of almost 46% from the previous week and 94% since the Omicron-fueled peak of 1.15 million during the week of Jan. 14-20, the AAP and CHA said in their weekly COVID report. The total number of child cases is 12.7 million since the pandemic began, with children representing 19% of all cases.

New admissions also stayed on a downward path, as the rate dropped to 0.24 per 100,000 children aged 0-17 years on March 5, a decline of nearly 81% since hitting 1.25 per 100,000 on Jan. 15. The latest 7-day average for daily admissions, 178 per day from Feb. 27 to March 5, was 29% lower than the previous week and almost 81% lower than the peak of 914 per day for Jan. 10-16, the Centers for Disease Control and Prevention reported.

The story is the same for emergency department visits with diagnosed COVID-19, which are reported as a percentage of all ED visits. On March 4, the 7-day average for children aged 0-11 years was 0.8%, compared with a high of 13.9% in mid-January, while 12- to 15-year-olds had dropped from 12.4% to 0.5% and 16- to 17-year-olds went from 12.6% down to 0.5%, the CDC said on its COVID Data Tracker.

Florida’s surgeon general says no to the vaccine

Vaccination, in the meantime, is struggling to maintain a foothold against the current of declining cases. Florida Surgeon General Joseph Ladapo said that “the Florida Department of Health is going to be the first state to officially recommend against the COVID-19 vaccines for healthy children,” NBC News reported March 7. With such a move, “Florida would become the first state to break from the CDC on vaccines for children,” CNN said in its report.

Vaccinations among children aged 5-11 years, which hit 1.6 million in 1 week shortly after emergency use was authorized in early November, declined quickly shorty thereafter and only rose slightly during the Omicron surge. Since mid-January, the number of children receiving an initial dose has declined for seven consecutive weeks and is now lower than ever, based on CDC data compiled by the AAP.

Just over one-third of children aged 5-11 have gotten at least one dose of COVID-19 vaccine, while 26.4% are fully vaccinated. Among children aged 12-17, just over two-thirds (67.8%) have received at least one dose, 57.8% have completed the vaccine regimen, and 21.9% have gotten a booster, the CDC reported.

As of March 2, “about 8.4 million children 12-17 have yet to receive their initial COVID-19 vaccine dose,” the AAP said. About 64,000 children aged 12-17 had received their first dose in the previous week, the group noted, which was the second-lowest weekly total since the vaccine was approved for children aged 12-15 in May of 2021.

New cases of COVID-19 in children continued their descent toward normalcy, falling below 100,000 in a week for the first time since early August 2021, according to the American Academy of Pediatrics and the Children’s Hospital Association.

The sixth consecutive week of declines saw just under 69,000 U.S. children test positive for COVID-19 from Feb. 25 to March 3, a drop of almost 46% from the previous week and 94% since the Omicron-fueled peak of 1.15 million during the week of Jan. 14-20, the AAP and CHA said in their weekly COVID report. The total number of child cases is 12.7 million since the pandemic began, with children representing 19% of all cases.

New admissions also stayed on a downward path, as the rate dropped to 0.24 per 100,000 children aged 0-17 years on March 5, a decline of nearly 81% since hitting 1.25 per 100,000 on Jan. 15. The latest 7-day average for daily admissions, 178 per day from Feb. 27 to March 5, was 29% lower than the previous week and almost 81% lower than the peak of 914 per day for Jan. 10-16, the Centers for Disease Control and Prevention reported.

The story is the same for emergency department visits with diagnosed COVID-19, which are reported as a percentage of all ED visits. On March 4, the 7-day average for children aged 0-11 years was 0.8%, compared with a high of 13.9% in mid-January, while 12- to 15-year-olds had dropped from 12.4% to 0.5% and 16- to 17-year-olds went from 12.6% down to 0.5%, the CDC said on its COVID Data Tracker.

Florida’s surgeon general says no to the vaccine

Vaccination, in the meantime, is struggling to maintain a foothold against the current of declining cases. Florida Surgeon General Joseph Ladapo said that “the Florida Department of Health is going to be the first state to officially recommend against the COVID-19 vaccines for healthy children,” NBC News reported March 7. With such a move, “Florida would become the first state to break from the CDC on vaccines for children,” CNN said in its report.

Vaccinations among children aged 5-11 years, which hit 1.6 million in 1 week shortly after emergency use was authorized in early November, declined quickly shorty thereafter and only rose slightly during the Omicron surge. Since mid-January, the number of children receiving an initial dose has declined for seven consecutive weeks and is now lower than ever, based on CDC data compiled by the AAP.

Just over one-third of children aged 5-11 have gotten at least one dose of COVID-19 vaccine, while 26.4% are fully vaccinated. Among children aged 12-17, just over two-thirds (67.8%) have received at least one dose, 57.8% have completed the vaccine regimen, and 21.9% have gotten a booster, the CDC reported.

As of March 2, “about 8.4 million children 12-17 have yet to receive their initial COVID-19 vaccine dose,” the AAP said. About 64,000 children aged 12-17 had received their first dose in the previous week, the group noted, which was the second-lowest weekly total since the vaccine was approved for children aged 12-15 in May of 2021.

Sotorasib, an approved treatment for lung cancer, has demonstrated clinically meaningful anticancer activity and tolerability in patients with heavily pretreated KRASG12C-mutated advanced pancreatic cancer.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

“This is clinically meaningful for patients because there is not an established standard therapy for these patients once they get to a third line of treatment,” said the study’s author John H Strickler, MD, of Duke University Medical Center, Durham, N.C.

The study, called CodeBreaK100, is an open-label global phase 1 and 2 trial. It consists of the largest dataset evaluating efficacy and safety of a KRASG12C inhibitor in patients with stage 4 pancreatic cancer.

Survival with Food and Drug Administration–approved second-line therapy in pancreatic ductal adenocarcinoma is 6 months with a 16% response rate. No therapies have demonstrated survival benefit after progression on first- and second-line chemotherapy. Among the 90% of pancreatic ductal adenocarcinoma tumors which harbor a KRAS mutation, 1%-2% are p.G12ac mutations. There are currently no approved treatments for KRASG12C-mutated PDAC.

The study included 38 patients (median age, 65.5 years; 76.3% male) with locally advanced or metastatic pancreatic malignancies who received oral sotorasib (960 mg once daily).

The patients in the trial received one or more prior systemic therapies (79% received two; range, one to eight) or were intolerant or ineligible for available therapies. The primary endpoint was complete plus partial response by blinded independent central review (RECIST 1.1).

Confirmed objective response were reported in 8 patients (21.1%; 95% confidence interval, 9.55%-37.22%) with disease control in 32 (84.2%; 95% CI, 68.75%-93.98%). The median duration of response was 5.7 months. After a median follow-up of 16.8 months, median progression-free survival was 4.0 months (95% CI, 2.8-5.6), and median overall survival was 6.9 months (95% CI, 5.0-9.1).

Once-daily sotorasib was well tolerated. The only treatment-related adverse events above grade 2 were six (15.8%) grade 3 events, with diarrhea in two and fatigue in two (each 5.3%), and single occurrences (2.6%) of abdominal pain, ALT/AST increase, pleural effusion and pulmonary embolism. Three adverse events were serious (7.9%), and no adverse events led to sotorasib discontinuation or were fatal.

Dr. Strickler described the case of a 64-year-old female with stage IV pancreatic cancer at diagnosis, who had baseline metastatic lesions in the liver, lymph nodes, lung and peritoneum. She received prior FOLFIRINOX first line until disease progression. With once-daily sotorasib, time to treatment response was 1.3 month, duration of response was 5.8 months, progression-free survival and overall were 7.1 months each.

Pointing to the centrally confirmed objective response rate of 21.1% and the disease control rate of 84.2%, Dr. Strickler observed in an interview that the CodeBreaK100 data support further exploration of sotorasib in this population with high unmet medical need and that based on these data, the CodeBreaK 100 clinical trial will be expanded to enroll more patients with pancreatic cancer and other tumor types.

The study was funded by Amgen.

Sotorasib, an approved treatment for lung cancer, has demonstrated clinically meaningful anticancer activity and tolerability in patients with heavily pretreated KRASG12C-mutated advanced pancreatic cancer.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

“This is clinically meaningful for patients because there is not an established standard therapy for these patients once they get to a third line of treatment,” said the study’s author John H Strickler, MD, of Duke University Medical Center, Durham, N.C.

The study, called CodeBreaK100, is an open-label global phase 1 and 2 trial. It consists of the largest dataset evaluating efficacy and safety of a KRASG12C inhibitor in patients with stage 4 pancreatic cancer.

Survival with Food and Drug Administration–approved second-line therapy in pancreatic ductal adenocarcinoma is 6 months with a 16% response rate. No therapies have demonstrated survival benefit after progression on first- and second-line chemotherapy. Among the 90% of pancreatic ductal adenocarcinoma tumors which harbor a KRAS mutation, 1%-2% are p.G12ac mutations. There are currently no approved treatments for KRASG12C-mutated PDAC.

The study included 38 patients (median age, 65.5 years; 76.3% male) with locally advanced or metastatic pancreatic malignancies who received oral sotorasib (960 mg once daily).

The patients in the trial received one or more prior systemic therapies (79% received two; range, one to eight) or were intolerant or ineligible for available therapies. The primary endpoint was complete plus partial response by blinded independent central review (RECIST 1.1).

Confirmed objective response were reported in 8 patients (21.1%; 95% confidence interval, 9.55%-37.22%) with disease control in 32 (84.2%; 95% CI, 68.75%-93.98%). The median duration of response was 5.7 months. After a median follow-up of 16.8 months, median progression-free survival was 4.0 months (95% CI, 2.8-5.6), and median overall survival was 6.9 months (95% CI, 5.0-9.1).

Once-daily sotorasib was well tolerated. The only treatment-related adverse events above grade 2 were six (15.8%) grade 3 events, with diarrhea in two and fatigue in two (each 5.3%), and single occurrences (2.6%) of abdominal pain, ALT/AST increase, pleural effusion and pulmonary embolism. Three adverse events were serious (7.9%), and no adverse events led to sotorasib discontinuation or were fatal.

Dr. Strickler described the case of a 64-year-old female with stage IV pancreatic cancer at diagnosis, who had baseline metastatic lesions in the liver, lymph nodes, lung and peritoneum. She received prior FOLFIRINOX first line until disease progression. With once-daily sotorasib, time to treatment response was 1.3 month, duration of response was 5.8 months, progression-free survival and overall were 7.1 months each.

Pointing to the centrally confirmed objective response rate of 21.1% and the disease control rate of 84.2%, Dr. Strickler observed in an interview that the CodeBreaK100 data support further exploration of sotorasib in this population with high unmet medical need and that based on these data, the CodeBreaK 100 clinical trial will be expanded to enroll more patients with pancreatic cancer and other tumor types.

The study was funded by Amgen.

Sotorasib, an approved treatment for lung cancer, has demonstrated clinically meaningful anticancer activity and tolerability in patients with heavily pretreated KRASG12C-mutated advanced pancreatic cancer.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

“This is clinically meaningful for patients because there is not an established standard therapy for these patients once they get to a third line of treatment,” said the study’s author John H Strickler, MD, of Duke University Medical Center, Durham, N.C.

The study, called CodeBreaK100, is an open-label global phase 1 and 2 trial. It consists of the largest dataset evaluating efficacy and safety of a KRASG12C inhibitor in patients with stage 4 pancreatic cancer.

Survival with Food and Drug Administration–approved second-line therapy in pancreatic ductal adenocarcinoma is 6 months with a 16% response rate. No therapies have demonstrated survival benefit after progression on first- and second-line chemotherapy. Among the 90% of pancreatic ductal adenocarcinoma tumors which harbor a KRAS mutation, 1%-2% are p.G12ac mutations. There are currently no approved treatments for KRASG12C-mutated PDAC.

The study included 38 patients (median age, 65.5 years; 76.3% male) with locally advanced or metastatic pancreatic malignancies who received oral sotorasib (960 mg once daily).

The patients in the trial received one or more prior systemic therapies (79% received two; range, one to eight) or were intolerant or ineligible for available therapies. The primary endpoint was complete plus partial response by blinded independent central review (RECIST 1.1).

Confirmed objective response were reported in 8 patients (21.1%; 95% confidence interval, 9.55%-37.22%) with disease control in 32 (84.2%; 95% CI, 68.75%-93.98%). The median duration of response was 5.7 months. After a median follow-up of 16.8 months, median progression-free survival was 4.0 months (95% CI, 2.8-5.6), and median overall survival was 6.9 months (95% CI, 5.0-9.1).

Once-daily sotorasib was well tolerated. The only treatment-related adverse events above grade 2 were six (15.8%) grade 3 events, with diarrhea in two and fatigue in two (each 5.3%), and single occurrences (2.6%) of abdominal pain, ALT/AST increase, pleural effusion and pulmonary embolism. Three adverse events were serious (7.9%), and no adverse events led to sotorasib discontinuation or were fatal.

Dr. Strickler described the case of a 64-year-old female with stage IV pancreatic cancer at diagnosis, who had baseline metastatic lesions in the liver, lymph nodes, lung and peritoneum. She received prior FOLFIRINOX first line until disease progression. With once-daily sotorasib, time to treatment response was 1.3 month, duration of response was 5.8 months, progression-free survival and overall were 7.1 months each.

Pointing to the centrally confirmed objective response rate of 21.1% and the disease control rate of 84.2%, Dr. Strickler observed in an interview that the CodeBreaK100 data support further exploration of sotorasib in this population with high unmet medical need and that based on these data, the CodeBreaK 100 clinical trial will be expanded to enroll more patients with pancreatic cancer and other tumor types.

The study was funded by Amgen.

A large-scale meta-analysis has verified that the gut microbiome does influence patients’s response to immune checkpoint inhibitor (ICI) therapy in advanced melanoma, but the relationship appears to be more complex than previously thought.

Overall, researchers identified a panel of species, including Roseburia spp. and Akkermansia muciniphila, associated with responses to ICI therapy. However, no single species was a “fully consistent biomarker” across the studies, the authors explain.

This “machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts,” Karla A. Lee, PhD, a clinical research fellow at King’s College London, and colleagues report. The results suggest that “the microbiome is predictive of response in some, but not all, cohorts.”

The findings were published online Feb. 28 in Nature Medicine.

Despite recent advances in targeted therapies for melanoma, less than half of the those who receive a single-agent ICI respond, and those who receive combination ICI therapy often suffer from severe drug toxicity problems. That is why finding patients more likely to respond to a single-agent ICI has become a priority.

Previous studies have identified the gut microbiome as “a potential biomarker of response, as well as a therapeutic target” in melanoma and other malignancies, but “little consensus exists on which microbiome characteristics are associated with treatment responses in the human setting,” the authors explain.

To further clarify the microbiome–immunotherapy relationship, the researchers performed metagenomic sequencing of stool samples collected from 165 ICI-naive patients with unresectable stage III or IV cutaneous melanoma from 5 observational cohorts in the Netherlands, United Kingdom, and Spain. These data were integrated with 147 samples from publicly available datasets.

First, the authors highlighted the variability in findings across these observational studies. For instance, they analyzed stool samples from one UK-based observational study of patients with melanoma (PRIMM-UK) and found a small but statistically significant difference in the microbiome composition of immunotherapy responders versus nonresponders (P = .05) but did not find such an association in a parallel study in the Netherlands (PRIMM-NL, P = .61).

The investigators also explored biomarkers of response across different cohorts and found several standouts. In trials using ORR as an endpoint, two uncultivated Roseburia species (CAG:182 and CAG:471) were associated with responses to ICIs. For patients with available PFS data, Phascolarctobacterium succinatutens and Lactobacillus vaginalis were “enriched in responders” across 7 datasets and significant in 3 of the 8 meta-analysis approaches. A muciniphila and Dorea formicigenerans were also associated with ORR and PFS at 12 months in several meta-analyses.

However, “no single bacterium was a fully consistent biomarker of response across all datasets,” the authors wrote.

Still, the findings could have important implications for the more than 50% of patients with advanced melanoma who don’t respond to single-agent ICI therapy.

“Our study shows that studying the microbiome is important to improve and personalize immunotherapy treatments for melanoma,” study coauthor Nicola Segata, PhD, principal investigator in the Laboratory of Computational Metagenomics, University of Trento, Italy, said in a press release. “However, it also suggests that because of the person-to-person variability of the gut microbiome, even larger studies must be carried out to understand the specific gut microbial features that are more likely to lead to a positive response to immunotherapy.”

Coauthor Tim Spector, PhD, head of the Department of Twin Research & Genetic Epidemiology at King’s College London, added that “the ultimate goal is to identify which specific features of the microbiome are directly influencing the clinical benefits of immunotherapy to exploit these features in new personalized approaches to support cancer immunotherapy.”

In the meantime, he said, “this study highlights the potential impact of good diet and gut health on chances of survival in patients undergoing immunotherapy.”

This study was coordinated by King’s College London, CIBIO Department of the University of Trento and European Institute of Oncology in Italy, and the University of Groningen in the Netherlands, and was funded by the Seerave Foundation. Dr. Lee, Dr. Segata, and Dr. Spector have disclosed no relevant financial relationships.

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

A large-scale meta-analysis has verified that the gut microbiome does influence patients’s response to immune checkpoint inhibitor (ICI) therapy in advanced melanoma, but the relationship appears to be more complex than previously thought.

Overall, researchers identified a panel of species, including Roseburia spp. and Akkermansia muciniphila, associated with responses to ICI therapy. However, no single species was a “fully consistent biomarker” across the studies, the authors explain.

This “machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts,” Karla A. Lee, PhD, a clinical research fellow at King’s College London, and colleagues report. The results suggest that “the microbiome is predictive of response in some, but not all, cohorts.”

The findings were published online Feb. 28 in Nature Medicine.

Despite recent advances in targeted therapies for melanoma, less than half of the those who receive a single-agent ICI respond, and those who receive combination ICI therapy often suffer from severe drug toxicity problems. That is why finding patients more likely to respond to a single-agent ICI has become a priority.

Previous studies have identified the gut microbiome as “a potential biomarker of response, as well as a therapeutic target” in melanoma and other malignancies, but “little consensus exists on which microbiome characteristics are associated with treatment responses in the human setting,” the authors explain.

To further clarify the microbiome–immunotherapy relationship, the researchers performed metagenomic sequencing of stool samples collected from 165 ICI-naive patients with unresectable stage III or IV cutaneous melanoma from 5 observational cohorts in the Netherlands, United Kingdom, and Spain. These data were integrated with 147 samples from publicly available datasets.

First, the authors highlighted the variability in findings across these observational studies. For instance, they analyzed stool samples from one UK-based observational study of patients with melanoma (PRIMM-UK) and found a small but statistically significant difference in the microbiome composition of immunotherapy responders versus nonresponders (P = .05) but did not find such an association in a parallel study in the Netherlands (PRIMM-NL, P = .61).

The investigators also explored biomarkers of response across different cohorts and found several standouts. In trials using ORR as an endpoint, two uncultivated Roseburia species (CAG:182 and CAG:471) were associated with responses to ICIs. For patients with available PFS data, Phascolarctobacterium succinatutens and Lactobacillus vaginalis were “enriched in responders” across 7 datasets and significant in 3 of the 8 meta-analysis approaches. A muciniphila and Dorea formicigenerans were also associated with ORR and PFS at 12 months in several meta-analyses.

However, “no single bacterium was a fully consistent biomarker of response across all datasets,” the authors wrote.

Still, the findings could have important implications for the more than 50% of patients with advanced melanoma who don’t respond to single-agent ICI therapy.

“Our study shows that studying the microbiome is important to improve and personalize immunotherapy treatments for melanoma,” study coauthor Nicola Segata, PhD, principal investigator in the Laboratory of Computational Metagenomics, University of Trento, Italy, said in a press release. “However, it also suggests that because of the person-to-person variability of the gut microbiome, even larger studies must be carried out to understand the specific gut microbial features that are more likely to lead to a positive response to immunotherapy.”

Coauthor Tim Spector, PhD, head of the Department of Twin Research & Genetic Epidemiology at King’s College London, added that “the ultimate goal is to identify which specific features of the microbiome are directly influencing the clinical benefits of immunotherapy to exploit these features in new personalized approaches to support cancer immunotherapy.”

In the meantime, he said, “this study highlights the potential impact of good diet and gut health on chances of survival in patients undergoing immunotherapy.”

This study was coordinated by King’s College London, CIBIO Department of the University of Trento and European Institute of Oncology in Italy, and the University of Groningen in the Netherlands, and was funded by the Seerave Foundation. Dr. Lee, Dr. Segata, and Dr. Spector have disclosed no relevant financial relationships.

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

A large-scale meta-analysis has verified that the gut microbiome does influence patients’s response to immune checkpoint inhibitor (ICI) therapy in advanced melanoma, but the relationship appears to be more complex than previously thought.

Overall, researchers identified a panel of species, including Roseburia spp. and Akkermansia muciniphila, associated with responses to ICI therapy. However, no single species was a “fully consistent biomarker” across the studies, the authors explain.

This “machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts,” Karla A. Lee, PhD, a clinical research fellow at King’s College London, and colleagues report. The results suggest that “the microbiome is predictive of response in some, but not all, cohorts.”

The findings were published online Feb. 28 in Nature Medicine.

Despite recent advances in targeted therapies for melanoma, less than half of the those who receive a single-agent ICI respond, and those who receive combination ICI therapy often suffer from severe drug toxicity problems. That is why finding patients more likely to respond to a single-agent ICI has become a priority.

Previous studies have identified the gut microbiome as “a potential biomarker of response, as well as a therapeutic target” in melanoma and other malignancies, but “little consensus exists on which microbiome characteristics are associated with treatment responses in the human setting,” the authors explain.

To further clarify the microbiome–immunotherapy relationship, the researchers performed metagenomic sequencing of stool samples collected from 165 ICI-naive patients with unresectable stage III or IV cutaneous melanoma from 5 observational cohorts in the Netherlands, United Kingdom, and Spain. These data were integrated with 147 samples from publicly available datasets.

First, the authors highlighted the variability in findings across these observational studies. For instance, they analyzed stool samples from one UK-based observational study of patients with melanoma (PRIMM-UK) and found a small but statistically significant difference in the microbiome composition of immunotherapy responders versus nonresponders (P = .05) but did not find such an association in a parallel study in the Netherlands (PRIMM-NL, P = .61).

The investigators also explored biomarkers of response across different cohorts and found several standouts. In trials using ORR as an endpoint, two uncultivated Roseburia species (CAG:182 and CAG:471) were associated with responses to ICIs. For patients with available PFS data, Phascolarctobacterium succinatutens and Lactobacillus vaginalis were “enriched in responders” across 7 datasets and significant in 3 of the 8 meta-analysis approaches. A muciniphila and Dorea formicigenerans were also associated with ORR and PFS at 12 months in several meta-analyses.

However, “no single bacterium was a fully consistent biomarker of response across all datasets,” the authors wrote.

Still, the findings could have important implications for the more than 50% of patients with advanced melanoma who don’t respond to single-agent ICI therapy.

“Our study shows that studying the microbiome is important to improve and personalize immunotherapy treatments for melanoma,” study coauthor Nicola Segata, PhD, principal investigator in the Laboratory of Computational Metagenomics, University of Trento, Italy, said in a press release. “However, it also suggests that because of the person-to-person variability of the gut microbiome, even larger studies must be carried out to understand the specific gut microbial features that are more likely to lead to a positive response to immunotherapy.”

Coauthor Tim Spector, PhD, head of the Department of Twin Research & Genetic Epidemiology at King’s College London, added that “the ultimate goal is to identify which specific features of the microbiome are directly influencing the clinical benefits of immunotherapy to exploit these features in new personalized approaches to support cancer immunotherapy.”

In the meantime, he said, “this study highlights the potential impact of good diet and gut health on chances of survival in patients undergoing immunotherapy.”

This study was coordinated by King’s College London, CIBIO Department of the University of Trento and European Institute of Oncology in Italy, and the University of Groningen in the Netherlands, and was funded by the Seerave Foundation. Dr. Lee, Dr. Segata, and Dr. Spector have disclosed no relevant financial relationships.

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

A new study has found that methotrexate plus leflunomide outperforms methotrexate alone as a treatment option for patients with psoriatic arthritis (PsA).

“We believe that prescribing this combination in routine practice is viable when combined with shared decision-making and strict monitoring of side effects,” write Michelle L.M. Mulder, MD, of the department of rheumatology at Sint Maartenskliniek in Nijmegen, the Netherlands, and her coauthors. Their findings were published in The Lancet Rheumatology.

The latest treatment guidelines from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the European Alliance of Associations for Rheumatology recommend conventional synthetic disease-modifying antirheumatic drugs for patients with active PsA, but Dr. Mulder and her colleagues note a distinct lack of information on their effectiveness, especially this particular combination.

To assess the efficacy and safety of methotrexate plus leflunomide, they launched a single-center, double-blind, randomized trial that included 78 Dutch patients with PsA. The majority of the participants in this trial – dubbed COMPLETE-PsA – were men (64%), and the median age of the patients was 55 years. All had active disease at baseline; the median swollen joint count (SJC) and tender joint count were 4.0 in both groups.

Participants were assigned to receive either methotrexate plus leflunomide (n = 39) or methotrexate plus placebo (n = 39). After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1; standard deviation, 1.4 vs. 3.7; SD, 1.3; treatment difference, –0.6; 90% confidence interval, –1.0 to –0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than did the monotherapy group (34%; P = .019).

Other notable differences after 16 weeks included improvements in SJC for 66 joints (–3.0 in the combination therapy group vs. –2.0 in the monotherapy group) and significantly better skin and nail measures – such as active psoriasis and change in body surface area – in the methotrexate plus leflunomide group.

When asked who should be prescribed the combination therapy and who should be prescribed methotrexate going forward, Dr. Mulder told this news organization, “At the moment, we have insufficient knowledge on who will benefit most or who will develop clinically relevant side effects. It seems warranted to discuss with every patient which approach they would prefer. This could be a step-down or -up approach.

“We hope to be able to better predict treatment response and side effects in the future via post hoc analysis of our study and via extensive flow-cytometric phenotyping of immune blood cells taken at baseline,” she added.

Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events were more common in the methotrexate plus leflunomide group. No participants died, and all patients with adverse events recovered completely.

“It appears good practice to do blood draws for laboratory tests on liver enzymes at least monthly for the first 4 months and every 4 months after that once stable dosing is achieved, as well as have a telephone consultation after 6-8 weeks to talk about possible side effects a patient might experience and change or add therapy if necessary,” Dr. Mulder added.

Study turns perception of combination therapy into reality

It had already been perceived by rheumatologists that methotrexate plus leflunomide was an effective combo for PsA, and this study reinforces those beliefs, Clementina López-Medina, MD, PhD, and colleagues from the University of Cordoba (Spain), write in an accompanying editorial.

They highlight this study’s notable strengths, one of which was defining “active disease” as two or more swollen joints, which opened the study up to a larger patient population. The editorialists also underline the confirmation that leflunomide plus methotrexate reduces both joint symptoms and skin involvement in this subset of patients, which had also been found in a previous study.

“Leflunomide is usually considered as a second-line option after methotrexate is unsuccessful,” they note, “despite the fact that methotrexate did not show superiority over placebo in previous trials.”

The editorialists were not surprised that the combination therapy was more toxic than the monotherapy. Rheumatologists could use these data to individualize treatment accordingly, they write, while keeping an eye on “gastrointestinal disturbances.”

Overall, Dr. López-Medina and colleagues say that the study results should “be considered not only in daily clinical practice but also in the development of future recommendations.”

Leflunomide: Forgotten no longer, at least for PsA

“I think we probably underutilize leflunomide,” Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy at the University of California, San Diego, told this news organization. “Sometimes medicines get ‘old,’ for lack of a better term, and fall a little bit of out of favor, sometimes unnecessarily. Leflunomide falls into that category. Because it’s older, it doesn’t get as much buzz as what’s new and shiny.

“I was not surprised by the results on the joints,” he said, “because we know from previous studies that leflunomide works in that regard. What did surprise me is that the skin got better, especially with the combination.”

Regarding the side effects for the combination therapy, he commended the authors for limiting potential uncertainty by using such a high dose of methotrexate.

“By going with a dose of 25 mg [per week], no one can say, ‘They pulled their punches and methotrexate monotherapy would’ve been just as good if it was given at a higher dose,’ “ he said. “And they also used leflunomide at a high dose. It makes you wonder: Could you use lower doses, and do lower doses mean fewer lab test abnormalities? This positive study does lend itself to some other permutations in terms of study design.

“Even though this was a small study,” he added, “it brings us right back to: We should really consider leflunomide in the treatment of PsA.”

The authors acknowledge their study’s limitations, including the fact that it was conducted in a single country and the absence of a nontreatment placebo group. They also note the higher percentage of women in the methotrexate plus leflunomide group, “which might have lowered the treatment response and increased the adverse event rate, resulting in bias.”

The study was funded by a Regional Junior Researcher Grant from Sint Maartenskliniek. The authors reported numerous potential conflicts of interest, including receiving payment, research grants, and consulting and speaker fees from various pharmaceutical companies.

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

A new study has found that methotrexate plus leflunomide outperforms methotrexate alone as a treatment option for patients with psoriatic arthritis (PsA).

“We believe that prescribing this combination in routine practice is viable when combined with shared decision-making and strict monitoring of side effects,” write Michelle L.M. Mulder, MD, of the department of rheumatology at Sint Maartenskliniek in Nijmegen, the Netherlands, and her coauthors. Their findings were published in The Lancet Rheumatology.

The latest treatment guidelines from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the European Alliance of Associations for Rheumatology recommend conventional synthetic disease-modifying antirheumatic drugs for patients with active PsA, but Dr. Mulder and her colleagues note a distinct lack of information on their effectiveness, especially this particular combination.

To assess the efficacy and safety of methotrexate plus leflunomide, they launched a single-center, double-blind, randomized trial that included 78 Dutch patients with PsA. The majority of the participants in this trial – dubbed COMPLETE-PsA – were men (64%), and the median age of the patients was 55 years. All had active disease at baseline; the median swollen joint count (SJC) and tender joint count were 4.0 in both groups.

Participants were assigned to receive either methotrexate plus leflunomide (n = 39) or methotrexate plus placebo (n = 39). After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1; standard deviation, 1.4 vs. 3.7; SD, 1.3; treatment difference, –0.6; 90% confidence interval, –1.0 to –0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than did the monotherapy group (34%; P = .019).

Other notable differences after 16 weeks included improvements in SJC for 66 joints (–3.0 in the combination therapy group vs. –2.0 in the monotherapy group) and significantly better skin and nail measures – such as active psoriasis and change in body surface area – in the methotrexate plus leflunomide group.

When asked who should be prescribed the combination therapy and who should be prescribed methotrexate going forward, Dr. Mulder told this news organization, “At the moment, we have insufficient knowledge on who will benefit most or who will develop clinically relevant side effects. It seems warranted to discuss with every patient which approach they would prefer. This could be a step-down or -up approach.

“We hope to be able to better predict treatment response and side effects in the future via post hoc analysis of our study and via extensive flow-cytometric phenotyping of immune blood cells taken at baseline,” she added.

Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events were more common in the methotrexate plus leflunomide group. No participants died, and all patients with adverse events recovered completely.

“It appears good practice to do blood draws for laboratory tests on liver enzymes at least monthly for the first 4 months and every 4 months after that once stable dosing is achieved, as well as have a telephone consultation after 6-8 weeks to talk about possible side effects a patient might experience and change or add therapy if necessary,” Dr. Mulder added.

Study turns perception of combination therapy into reality

It had already been perceived by rheumatologists that methotrexate plus leflunomide was an effective combo for PsA, and this study reinforces those beliefs, Clementina López-Medina, MD, PhD, and colleagues from the University of Cordoba (Spain), write in an accompanying editorial.

They highlight this study’s notable strengths, one of which was defining “active disease” as two or more swollen joints, which opened the study up to a larger patient population. The editorialists also underline the confirmation that leflunomide plus methotrexate reduces both joint symptoms and skin involvement in this subset of patients, which had also been found in a previous study.

“Leflunomide is usually considered as a second-line option after methotrexate is unsuccessful,” they note, “despite the fact that methotrexate did not show superiority over placebo in previous trials.”

The editorialists were not surprised that the combination therapy was more toxic than the monotherapy. Rheumatologists could use these data to individualize treatment accordingly, they write, while keeping an eye on “gastrointestinal disturbances.”

Overall, Dr. López-Medina and colleagues say that the study results should “be considered not only in daily clinical practice but also in the development of future recommendations.”

Leflunomide: Forgotten no longer, at least for PsA

“I think we probably underutilize leflunomide,” Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy at the University of California, San Diego, told this news organization. “Sometimes medicines get ‘old,’ for lack of a better term, and fall a little bit of out of favor, sometimes unnecessarily. Leflunomide falls into that category. Because it’s older, it doesn’t get as much buzz as what’s new and shiny.

“I was not surprised by the results on the joints,” he said, “because we know from previous studies that leflunomide works in that regard. What did surprise me is that the skin got better, especially with the combination.”

Regarding the side effects for the combination therapy, he commended the authors for limiting potential uncertainty by using such a high dose of methotrexate.

“By going with a dose of 25 mg [per week], no one can say, ‘They pulled their punches and methotrexate monotherapy would’ve been just as good if it was given at a higher dose,’ “ he said. “And they also used leflunomide at a high dose. It makes you wonder: Could you use lower doses, and do lower doses mean fewer lab test abnormalities? This positive study does lend itself to some other permutations in terms of study design.

“Even though this was a small study,” he added, “it brings us right back to: We should really consider leflunomide in the treatment of PsA.”

The authors acknowledge their study’s limitations, including the fact that it was conducted in a single country and the absence of a nontreatment placebo group. They also note the higher percentage of women in the methotrexate plus leflunomide group, “which might have lowered the treatment response and increased the adverse event rate, resulting in bias.”

The study was funded by a Regional Junior Researcher Grant from Sint Maartenskliniek. The authors reported numerous potential conflicts of interest, including receiving payment, research grants, and consulting and speaker fees from various pharmaceutical companies.

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

A new study has found that methotrexate plus leflunomide outperforms methotrexate alone as a treatment option for patients with psoriatic arthritis (PsA).

“We believe that prescribing this combination in routine practice is viable when combined with shared decision-making and strict monitoring of side effects,” write Michelle L.M. Mulder, MD, of the department of rheumatology at Sint Maartenskliniek in Nijmegen, the Netherlands, and her coauthors. Their findings were published in The Lancet Rheumatology.

The latest treatment guidelines from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the European Alliance of Associations for Rheumatology recommend conventional synthetic disease-modifying antirheumatic drugs for patients with active PsA, but Dr. Mulder and her colleagues note a distinct lack of information on their effectiveness, especially this particular combination.

To assess the efficacy and safety of methotrexate plus leflunomide, they launched a single-center, double-blind, randomized trial that included 78 Dutch patients with PsA. The majority of the participants in this trial – dubbed COMPLETE-PsA – were men (64%), and the median age of the patients was 55 years. All had active disease at baseline; the median swollen joint count (SJC) and tender joint count were 4.0 in both groups.

Participants were assigned to receive either methotrexate plus leflunomide (n = 39) or methotrexate plus placebo (n = 39). After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1; standard deviation, 1.4 vs. 3.7; SD, 1.3; treatment difference, –0.6; 90% confidence interval, –1.0 to –0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than did the monotherapy group (34%; P = .019).

Other notable differences after 16 weeks included improvements in SJC for 66 joints (–3.0 in the combination therapy group vs. –2.0 in the monotherapy group) and significantly better skin and nail measures – such as active psoriasis and change in body surface area – in the methotrexate plus leflunomide group.

When asked who should be prescribed the combination therapy and who should be prescribed methotrexate going forward, Dr. Mulder told this news organization, “At the moment, we have insufficient knowledge on who will benefit most or who will develop clinically relevant side effects. It seems warranted to discuss with every patient which approach they would prefer. This could be a step-down or -up approach.

“We hope to be able to better predict treatment response and side effects in the future via post hoc analysis of our study and via extensive flow-cytometric phenotyping of immune blood cells taken at baseline,” she added.

Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events were more common in the methotrexate plus leflunomide group. No participants died, and all patients with adverse events recovered completely.

“It appears good practice to do blood draws for laboratory tests on liver enzymes at least monthly for the first 4 months and every 4 months after that once stable dosing is achieved, as well as have a telephone consultation after 6-8 weeks to talk about possible side effects a patient might experience and change or add therapy if necessary,” Dr. Mulder added.

Study turns perception of combination therapy into reality

It had already been perceived by rheumatologists that methotrexate plus leflunomide was an effective combo for PsA, and this study reinforces those beliefs, Clementina López-Medina, MD, PhD, and colleagues from the University of Cordoba (Spain), write in an accompanying editorial.

They highlight this study’s notable strengths, one of which was defining “active disease” as two or more swollen joints, which opened the study up to a larger patient population. The editorialists also underline the confirmation that leflunomide plus methotrexate reduces both joint symptoms and skin involvement in this subset of patients, which had also been found in a previous study.

“Leflunomide is usually considered as a second-line option after methotrexate is unsuccessful,” they note, “despite the fact that methotrexate did not show superiority over placebo in previous trials.”

The editorialists were not surprised that the combination therapy was more toxic than the monotherapy. Rheumatologists could use these data to individualize treatment accordingly, they write, while keeping an eye on “gastrointestinal disturbances.”

Overall, Dr. López-Medina and colleagues say that the study results should “be considered not only in daily clinical practice but also in the development of future recommendations.”

Leflunomide: Forgotten no longer, at least for PsA

“I think we probably underutilize leflunomide,” Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy at the University of California, San Diego, told this news organization. “Sometimes medicines get ‘old,’ for lack of a better term, and fall a little bit of out of favor, sometimes unnecessarily. Leflunomide falls into that category. Because it’s older, it doesn’t get as much buzz as what’s new and shiny.

“I was not surprised by the results on the joints,” he said, “because we know from previous studies that leflunomide works in that regard. What did surprise me is that the skin got better, especially with the combination.”

Regarding the side effects for the combination therapy, he commended the authors for limiting potential uncertainty by using such a high dose of methotrexate.

“By going with a dose of 25 mg [per week], no one can say, ‘They pulled their punches and methotrexate monotherapy would’ve been just as good if it was given at a higher dose,’ “ he said. “And they also used leflunomide at a high dose. It makes you wonder: Could you use lower doses, and do lower doses mean fewer lab test abnormalities? This positive study does lend itself to some other permutations in terms of study design.

“Even though this was a small study,” he added, “it brings us right back to: We should really consider leflunomide in the treatment of PsA.”

The authors acknowledge their study’s limitations, including the fact that it was conducted in a single country and the absence of a nontreatment placebo group. They also note the higher percentage of women in the methotrexate plus leflunomide group, “which might have lowered the treatment response and increased the adverse event rate, resulting in bias.”

The study was funded by a Regional Junior Researcher Grant from Sint Maartenskliniek. The authors reported numerous potential conflicts of interest, including receiving payment, research grants, and consulting and speaker fees from various pharmaceutical companies.

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

Should patients with metastatic colorectal cancer (CRC) who respond to first-line treatment receive maintenance therapy, or are they better off on active surveillance?

In a recent trial designed to explore this question, British investigators made a strong case for active surveillance over maintenance therapy.

The researchers found that patients with metastatic CRC randomized to maintenance therapy with oral capecitabine (Xeloda) showed improved progression-free survival (PFS), compared with those being actively monitored – 3.88 versus 1.87 months.

But that benefit came at a cost. Patients on capecitabine experienced much worse toxicity and showed no overall survival benefit – 14.8 months in the capecitabine arm versus 15.2 in the surveillance arm.

The FOCUS4-N trial supports “the use of treatment breaks as safe management alternatives for patients” after induction, lead author Richard Adams, MD, an oncology professor at Cardiff University, Wales, and colleagues conclude in a study published in the Journal of Clinical Oncology.

Current treatment standards either require or recommend that patients with metastatic CRC receive maintenance therapy after induction chemotherapy, at least until they progress or experience excessive toxicity.

Although maintenance strategies have typically demonstrated a PFS benefit, that advantage may come at “the expense of ongoing ... toxicity.”

Dr. Adams and colleagues wanted to explore how patients would fare on an oral maintenance therapy with capecitabine, compared with active surveillance.

In the trial, researchers randomly assigned 254 patients who had responded to first-line therapy or had stable disease to either capecitabine (n = 127) or active monitoring (n = 127). Subjects were treated at 88 hospitals in the United Kingdom from 2014-2020. Most patients had widespread synchronous metastatic disease. About half had unresected primary tumors, and the majority had received doublet chemotherapy induction, which was irinotecan-based in 57%.

The authors found that patients receiving capecitabine maintenance therapy showed significant improvements in PFS (hazard ratio, 0.40; P < .0001), but also encountered considerably more toxicity than the surveillance group – including grade 2 or higher fatigue (25% vs. 12%), diarrhea (23% vs. 13%), and hand-foot skin reactions (26% vs. 3%).

Perhaps most notably, the treatment group did not experience an overall survival benefit (HR, 0.93; 95% confidence interval, 0.69-1.27; P = .66).

Overall, the authors noted, the main advantage of active maintenance was to delay the return of aggressive chemotherapy combinations for a few months.  

With previous trials reporting pretty much the same findings, there is now “overwhelming level-one evidence” that surveillance is an “appropriate” option with “less time on therapy, lower toxicity, and in a number of studies, better quality of life,” which are all important factors for patients, according to Dr. Adams and colleagues in a follow-up letter.   
 

A viable option

The current study pushes back on existing standards, which support maintenance therapy and can prevent patients from being offered active surveillance.

According to Dr. Adams and colleagues, “FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for [metastatic] CRC.”

In addition, the FOCUS4-N trial suggests that oral capecitabine alone – instead of alongside intravenous bevacizumab (Avastin) every 3 weeks – is probably adequate for mCRC maintenance.

“It has been shown that single-agent bevacizumab is both ineffective and highly uneconomic” in the mCRC maintenance setting, “suggesting that it may be the capecitabine element of the combination that” provides the PFS benefit, the team noted.

An editorial accompanying the study also concluded that “treatment holidays are an equally viable and more cost-effective alternative” to maintenance and one of special interest to patients looking for a break after intensive induction.

“For patients, caregivers, and oncologists alike who are hesitant to ... stop therapy completely, it is important to note that” at least in trials, patients under surveillance “continue to be vigilantly monitored, including imaging every 8-12 weeks and symptom assessment every few weeks,” Pashtoon Murtaza Kasi, MD, medical oncologist at Weill Cornell Medicine/NewYork-Presbyterian, Manhattan, said in his editorial. 

Interestingly, Dr. Kasi pointed out, the trial found no difference in quality-of-life scores between the study arms in the FOCUS4-N trial.

The two groups scored similarly on mobility, self-care, usual activities, anxiety, and depression, and patients in the capecitabine group reported slightly less pain and discomfort, which may have occurred because of delayed disease progression.

“Although it is somewhat reassuring that maintenance approaches do not adversely affect overall quality of life and functioning, it does not mean that these regimens are free from side effects,” Dr. Kasi writes, adding that it’s possible the surveys missed the impacts of increased toxicity with maintenance therapy.
 

Caveats to the study

A letter published in the Journal of Clinical Oncology raises questions about the generalizability of the FOCUS4-N results.

In the letter, Annika Kurreck, MD, and colleagues from Charity-University Medicine Berlin, Germany, highlighted that the trial only included patients without actionable biomarkers, which likely meant the study population had particularly aggressive disease. This possibility is supported by the “dramatically short” PFS reported in FOCUS4-N compared with prior maintenance versus surveillance investigations.

In addition, the letter writers caution that the study was underpowered to detect an overall survival benefit.

“Therefore, it might be hypothesized that FOCUS4-N comprised a cohort of patients with a rather aggressive tumor biology and/or high tumor load, leading to a quick failure of any de-escalation treatment strategy,” Dr. Kurreck and colleagues write.

In a response letter, Dr. Adams and his team countered that there’s no consistent evidence from past trials suggesting that patients with poorer prognostic features are unfit for surveillance. “We believe that it is a common misrepresentation of the evidence that all patients with worse prognostic features need to be maintained on active but toxic combination therapies for longer,” they said.

Instead of a blanket approach, maintenance versus surveillance should be “an assessment guided by the clinician listening to and guiding the patient rather than a molecular or biologically measurable parameter,” they write.

Dr. Adams and colleagues agreed that identifying subgroups of patients who are more likely to benefit from maintenance versus surveillance is required research, which “we plan to undertake.”

The work was funded by Cancer Research UK and the National Institute for Health Research. Many of the investigators had industry ties, including Dr. Adams, who reported various relationships with and payments from Merck, Amgen, and others. Dr. Kasi also had ties to several companies, including Bristol Myers Squibb, Lilly, and AstraZeneca. Dr. Kurreck and the other letter writers had numerous company ties as well, including relationships and payments from Roche, the maker of bevacizumab.

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

Should patients with metastatic colorectal cancer (CRC) who respond to first-line treatment receive maintenance therapy, or are they better off on active surveillance?

In a recent trial designed to explore this question, British investigators made a strong case for active surveillance over maintenance therapy.

The researchers found that patients with metastatic CRC randomized to maintenance therapy with oral capecitabine (Xeloda) showed improved progression-free survival (PFS), compared with those being actively monitored – 3.88 versus 1.87 months.

But that benefit came at a cost. Patients on capecitabine experienced much worse toxicity and showed no overall survival benefit – 14.8 months in the capecitabine arm versus 15.2 in the surveillance arm.

The FOCUS4-N trial supports “the use of treatment breaks as safe management alternatives for patients” after induction, lead author Richard Adams, MD, an oncology professor at Cardiff University, Wales, and colleagues conclude in a study published in the Journal of Clinical Oncology.

Current treatment standards either require or recommend that patients with metastatic CRC receive maintenance therapy after induction chemotherapy, at least until they progress or experience excessive toxicity.

Although maintenance strategies have typically demonstrated a PFS benefit, that advantage may come at “the expense of ongoing ... toxicity.”

Dr. Adams and colleagues wanted to explore how patients would fare on an oral maintenance therapy with capecitabine, compared with active surveillance.

In the trial, researchers randomly assigned 254 patients who had responded to first-line therapy or had stable disease to either capecitabine (n = 127) or active monitoring (n = 127). Subjects were treated at 88 hospitals in the United Kingdom from 2014-2020. Most patients had widespread synchronous metastatic disease. About half had unresected primary tumors, and the majority had received doublet chemotherapy induction, which was irinotecan-based in 57%.

The authors found that patients receiving capecitabine maintenance therapy showed significant improvements in PFS (hazard ratio, 0.40; P < .0001), but also encountered considerably more toxicity than the surveillance group – including grade 2 or higher fatigue (25% vs. 12%), diarrhea (23% vs. 13%), and hand-foot skin reactions (26% vs. 3%).

Perhaps most notably, the treatment group did not experience an overall survival benefit (HR, 0.93; 95% confidence interval, 0.69-1.27; P = .66).

Overall, the authors noted, the main advantage of active maintenance was to delay the return of aggressive chemotherapy combinations for a few months.  

With previous trials reporting pretty much the same findings, there is now “overwhelming level-one evidence” that surveillance is an “appropriate” option with “less time on therapy, lower toxicity, and in a number of studies, better quality of life,” which are all important factors for patients, according to Dr. Adams and colleagues in a follow-up letter.   
 

A viable option

The current study pushes back on existing standards, which support maintenance therapy and can prevent patients from being offered active surveillance.

According to Dr. Adams and colleagues, “FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for [metastatic] CRC.”

In addition, the FOCUS4-N trial suggests that oral capecitabine alone – instead of alongside intravenous bevacizumab (Avastin) every 3 weeks – is probably adequate for mCRC maintenance.

“It has been shown that single-agent bevacizumab is both ineffective and highly uneconomic” in the mCRC maintenance setting, “suggesting that it may be the capecitabine element of the combination that” provides the PFS benefit, the team noted.

An editorial accompanying the study also concluded that “treatment holidays are an equally viable and more cost-effective alternative” to maintenance and one of special interest to patients looking for a break after intensive induction.

“For patients, caregivers, and oncologists alike who are hesitant to ... stop therapy completely, it is important to note that” at least in trials, patients under surveillance “continue to be vigilantly monitored, including imaging every 8-12 weeks and symptom assessment every few weeks,” Pashtoon Murtaza Kasi, MD, medical oncologist at Weill Cornell Medicine/NewYork-Presbyterian, Manhattan, said in his editorial. 

Interestingly, Dr. Kasi pointed out, the trial found no difference in quality-of-life scores between the study arms in the FOCUS4-N trial.

The two groups scored similarly on mobility, self-care, usual activities, anxiety, and depression, and patients in the capecitabine group reported slightly less pain and discomfort, which may have occurred because of delayed disease progression.

“Although it is somewhat reassuring that maintenance approaches do not adversely affect overall quality of life and functioning, it does not mean that these regimens are free from side effects,” Dr. Kasi writes, adding that it’s possible the surveys missed the impacts of increased toxicity with maintenance therapy.
 

Caveats to the study

A letter published in the Journal of Clinical Oncology raises questions about the generalizability of the FOCUS4-N results.

In the letter, Annika Kurreck, MD, and colleagues from Charity-University Medicine Berlin, Germany, highlighted that the trial only included patients without actionable biomarkers, which likely meant the study population had particularly aggressive disease. This possibility is supported by the “dramatically short” PFS reported in FOCUS4-N compared with prior maintenance versus surveillance investigations.

In addition, the letter writers caution that the study was underpowered to detect an overall survival benefit.

“Therefore, it might be hypothesized that FOCUS4-N comprised a cohort of patients with a rather aggressive tumor biology and/or high tumor load, leading to a quick failure of any de-escalation treatment strategy,” Dr. Kurreck and colleagues write.

In a response letter, Dr. Adams and his team countered that there’s no consistent evidence from past trials suggesting that patients with poorer prognostic features are unfit for surveillance. “We believe that it is a common misrepresentation of the evidence that all patients with worse prognostic features need to be maintained on active but toxic combination therapies for longer,” they said.

Instead of a blanket approach, maintenance versus surveillance should be “an assessment guided by the clinician listening to and guiding the patient rather than a molecular or biologically measurable parameter,” they write.

Dr. Adams and colleagues agreed that identifying subgroups of patients who are more likely to benefit from maintenance versus surveillance is required research, which “we plan to undertake.”

The work was funded by Cancer Research UK and the National Institute for Health Research. Many of the investigators had industry ties, including Dr. Adams, who reported various relationships with and payments from Merck, Amgen, and others. Dr. Kasi also had ties to several companies, including Bristol Myers Squibb, Lilly, and AstraZeneca. Dr. Kurreck and the other letter writers had numerous company ties as well, including relationships and payments from Roche, the maker of bevacizumab.

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

Should patients with metastatic colorectal cancer (CRC) who respond to first-line treatment receive maintenance therapy, or are they better off on active surveillance?

In a recent trial designed to explore this question, British investigators made a strong case for active surveillance over maintenance therapy.

The researchers found that patients with metastatic CRC randomized to maintenance therapy with oral capecitabine (Xeloda) showed improved progression-free survival (PFS), compared with those being actively monitored – 3.88 versus 1.87 months.

But that benefit came at a cost. Patients on capecitabine experienced much worse toxicity and showed no overall survival benefit – 14.8 months in the capecitabine arm versus 15.2 in the surveillance arm.

The FOCUS4-N trial supports “the use of treatment breaks as safe management alternatives for patients” after induction, lead author Richard Adams, MD, an oncology professor at Cardiff University, Wales, and colleagues conclude in a study published in the Journal of Clinical Oncology.

Current treatment standards either require or recommend that patients with metastatic CRC receive maintenance therapy after induction chemotherapy, at least until they progress or experience excessive toxicity.

Although maintenance strategies have typically demonstrated a PFS benefit, that advantage may come at “the expense of ongoing ... toxicity.”

Dr. Adams and colleagues wanted to explore how patients would fare on an oral maintenance therapy with capecitabine, compared with active surveillance.

In the trial, researchers randomly assigned 254 patients who had responded to first-line therapy or had stable disease to either capecitabine (n = 127) or active monitoring (n = 127). Subjects were treated at 88 hospitals in the United Kingdom from 2014-2020. Most patients had widespread synchronous metastatic disease. About half had unresected primary tumors, and the majority had received doublet chemotherapy induction, which was irinotecan-based in 57%.

The authors found that patients receiving capecitabine maintenance therapy showed significant improvements in PFS (hazard ratio, 0.40; P < .0001), but also encountered considerably more toxicity than the surveillance group – including grade 2 or higher fatigue (25% vs. 12%), diarrhea (23% vs. 13%), and hand-foot skin reactions (26% vs. 3%).

Perhaps most notably, the treatment group did not experience an overall survival benefit (HR, 0.93; 95% confidence interval, 0.69-1.27; P = .66).

Overall, the authors noted, the main advantage of active maintenance was to delay the return of aggressive chemotherapy combinations for a few months.  

With previous trials reporting pretty much the same findings, there is now “overwhelming level-one evidence” that surveillance is an “appropriate” option with “less time on therapy, lower toxicity, and in a number of studies, better quality of life,” which are all important factors for patients, according to Dr. Adams and colleagues in a follow-up letter.   
 

A viable option

The current study pushes back on existing standards, which support maintenance therapy and can prevent patients from being offered active surveillance.

According to Dr. Adams and colleagues, “FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for [metastatic] CRC.”

In addition, the FOCUS4-N trial suggests that oral capecitabine alone – instead of alongside intravenous bevacizumab (Avastin) every 3 weeks – is probably adequate for mCRC maintenance.

“It has been shown that single-agent bevacizumab is both ineffective and highly uneconomic” in the mCRC maintenance setting, “suggesting that it may be the capecitabine element of the combination that” provides the PFS benefit, the team noted.

An editorial accompanying the study also concluded that “treatment holidays are an equally viable and more cost-effective alternative” to maintenance and one of special interest to patients looking for a break after intensive induction.

“For patients, caregivers, and oncologists alike who are hesitant to ... stop therapy completely, it is important to note that” at least in trials, patients under surveillance “continue to be vigilantly monitored, including imaging every 8-12 weeks and symptom assessment every few weeks,” Pashtoon Murtaza Kasi, MD, medical oncologist at Weill Cornell Medicine/NewYork-Presbyterian, Manhattan, said in his editorial. 

Interestingly, Dr. Kasi pointed out, the trial found no difference in quality-of-life scores between the study arms in the FOCUS4-N trial.

The two groups scored similarly on mobility, self-care, usual activities, anxiety, and depression, and patients in the capecitabine group reported slightly less pain and discomfort, which may have occurred because of delayed disease progression.

“Although it is somewhat reassuring that maintenance approaches do not adversely affect overall quality of life and functioning, it does not mean that these regimens are free from side effects,” Dr. Kasi writes, adding that it’s possible the surveys missed the impacts of increased toxicity with maintenance therapy.
 

Caveats to the study

A letter published in the Journal of Clinical Oncology raises questions about the generalizability of the FOCUS4-N results.

In the letter, Annika Kurreck, MD, and colleagues from Charity-University Medicine Berlin, Germany, highlighted that the trial only included patients without actionable biomarkers, which likely meant the study population had particularly aggressive disease. This possibility is supported by the “dramatically short” PFS reported in FOCUS4-N compared with prior maintenance versus surveillance investigations.

In addition, the letter writers caution that the study was underpowered to detect an overall survival benefit.

“Therefore, it might be hypothesized that FOCUS4-N comprised a cohort of patients with a rather aggressive tumor biology and/or high tumor load, leading to a quick failure of any de-escalation treatment strategy,” Dr. Kurreck and colleagues write.

In a response letter, Dr. Adams and his team countered that there’s no consistent evidence from past trials suggesting that patients with poorer prognostic features are unfit for surveillance. “We believe that it is a common misrepresentation of the evidence that all patients with worse prognostic features need to be maintained on active but toxic combination therapies for longer,” they said.

Instead of a blanket approach, maintenance versus surveillance should be “an assessment guided by the clinician listening to and guiding the patient rather than a molecular or biologically measurable parameter,” they write.

Dr. Adams and colleagues agreed that identifying subgroups of patients who are more likely to benefit from maintenance versus surveillance is required research, which “we plan to undertake.”

The work was funded by Cancer Research UK and the National Institute for Health Research. Many of the investigators had industry ties, including Dr. Adams, who reported various relationships with and payments from Merck, Amgen, and others. Dr. Kasi also had ties to several companies, including Bristol Myers Squibb, Lilly, and AstraZeneca. Dr. Kurreck and the other letter writers had numerous company ties as well, including relationships and payments from Roche, the maker of bevacizumab.

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