Susan London

VANCOUVER – A new transcranial Doppler platform that analyzes subtle changes in the cerebral blood flow waveform performed well in detecting sports-related concussion in a cohort study of 238 Los Angeles high school athletes.

The investigational headset device was able to differentiate between those with and without a recent concussion 83% of the time, investigators reported at the annual meeting of the American Academy of Neurology. In contrast, traditional transcranial Doppler analysis detected a recent concussion only 50%-60% of the time.

“Over the last few years, there has been growing evidence that cerebral hemodynamics are altered following sports-related concussion,” senior author Robert Hamilton, Ph.D., cofounder and chief science officer of Neural Analytics in Los Angeles, commented in a session and interview.

Most studies in this area have used MRI or traditional transcranial Doppler analysis, he said. However, the former is costly, time consuming, and not portable, and the latter has not proven very accurate.

As traditional Doppler analysis disregards the majority of waveform data, Dr. Hamilton and his colleagues developed an advanced platform that uses machine learning to analyze the entire shape of the cerebral blood flow velocity waveform through quantitative cerebral hemodynamics.

They compared the advanced analysis with traditional analysis among 69 high school athletes in contact sports who had sustained a concussion an average of 6 days earlier and a control group of 169 unaffected age-matched high school athletes from contact and noncontact sports.

Both groups had bilateral monitoring of blood flow in the middle cerebral artery with transcranial Doppler while they followed a standard cerebrovascular reactivity protocol that included rest and breath holding.

Results showed that for differentiating between athletes who did and did not have concussion, the advanced analysis had an area under the receiver operating characteristic curve of 83%. (Sensitivity was 72%, specificity was 82%, and overall accuracy was 80%.)

In comparison, the area under the curve was substantially lower for the traditional analysis measures: It was 55% for mean velocity (100% sensitivity, 0% specificity, 76% accuracy), 52% for the pulsatility index (86% sensitivity, 23% specificity, 61% accuracy), and 60% for the cerebrovascular reactivity index (51% sensitivity, 68% specificity, 64% accuracy).

“Unfortunately, concussion diagnostics and management today are basically subjective,” Dr. Hamilton commented. The advanced analysis may therefore improve the situation by providing objective evidence of blood flow dysfunction after injury.

The new analysis platform “is easy to use and portable, and [testing] can be done very quickly, within 5 minutes,” he noted. “The nice thing is it can be done on the sideline, in the emergency room, or in a doctor’s office.”

The investigators will next use the advanced analysis to track recovery of blood flow regulation after sports-related concussion and will compare its performance with that of additional modalities, such as MRI, according to Dr. Hamilton. Furthermore, they are testing it in various other populations: adolescents, college athletes, and members of the military.

“Ultimately, blood flow dysfunction is also important in a wide variety of conditions, such as stroke and dementia,” he pointed out. “So those are conditions that we are looking at to study this year and moving forward in the future.”

The research was supported by the National Institutes of Health and the National Science Foundation.

VANCOUVER – A new transcranial Doppler platform that analyzes subtle changes in the cerebral blood flow waveform performed well in detecting sports-related concussion in a cohort study of 238 Los Angeles high school athletes.

The investigational headset device was able to differentiate between those with and without a recent concussion 83% of the time, investigators reported at the annual meeting of the American Academy of Neurology. In contrast, traditional transcranial Doppler analysis detected a recent concussion only 50%-60% of the time.

“Over the last few years, there has been growing evidence that cerebral hemodynamics are altered following sports-related concussion,” senior author Robert Hamilton, Ph.D., cofounder and chief science officer of Neural Analytics in Los Angeles, commented in a session and interview.

Most studies in this area have used MRI or traditional transcranial Doppler analysis, he said. However, the former is costly, time consuming, and not portable, and the latter has not proven very accurate.

As traditional Doppler analysis disregards the majority of waveform data, Dr. Hamilton and his colleagues developed an advanced platform that uses machine learning to analyze the entire shape of the cerebral blood flow velocity waveform through quantitative cerebral hemodynamics.

They compared the advanced analysis with traditional analysis among 69 high school athletes in contact sports who had sustained a concussion an average of 6 days earlier and a control group of 169 unaffected age-matched high school athletes from contact and noncontact sports.

Both groups had bilateral monitoring of blood flow in the middle cerebral artery with transcranial Doppler while they followed a standard cerebrovascular reactivity protocol that included rest and breath holding.

Results showed that for differentiating between athletes who did and did not have concussion, the advanced analysis had an area under the receiver operating characteristic curve of 83%. (Sensitivity was 72%, specificity was 82%, and overall accuracy was 80%.)

In comparison, the area under the curve was substantially lower for the traditional analysis measures: It was 55% for mean velocity (100% sensitivity, 0% specificity, 76% accuracy), 52% for the pulsatility index (86% sensitivity, 23% specificity, 61% accuracy), and 60% for the cerebrovascular reactivity index (51% sensitivity, 68% specificity, 64% accuracy).

“Unfortunately, concussion diagnostics and management today are basically subjective,” Dr. Hamilton commented. The advanced analysis may therefore improve the situation by providing objective evidence of blood flow dysfunction after injury.

The new analysis platform “is easy to use and portable, and [testing] can be done very quickly, within 5 minutes,” he noted. “The nice thing is it can be done on the sideline, in the emergency room, or in a doctor’s office.”

The investigators will next use the advanced analysis to track recovery of blood flow regulation after sports-related concussion and will compare its performance with that of additional modalities, such as MRI, according to Dr. Hamilton. Furthermore, they are testing it in various other populations: adolescents, college athletes, and members of the military.

“Ultimately, blood flow dysfunction is also important in a wide variety of conditions, such as stroke and dementia,” he pointed out. “So those are conditions that we are looking at to study this year and moving forward in the future.”

The research was supported by the National Institutes of Health and the National Science Foundation.

VANCOUVER – A new transcranial Doppler platform that analyzes subtle changes in the cerebral blood flow waveform performed well in detecting sports-related concussion in a cohort study of 238 Los Angeles high school athletes.

The investigational headset device was able to differentiate between those with and without a recent concussion 83% of the time, investigators reported at the annual meeting of the American Academy of Neurology. In contrast, traditional transcranial Doppler analysis detected a recent concussion only 50%-60% of the time.

“Over the last few years, there has been growing evidence that cerebral hemodynamics are altered following sports-related concussion,” senior author Robert Hamilton, Ph.D., cofounder and chief science officer of Neural Analytics in Los Angeles, commented in a session and interview.

Most studies in this area have used MRI or traditional transcranial Doppler analysis, he said. However, the former is costly, time consuming, and not portable, and the latter has not proven very accurate.

As traditional Doppler analysis disregards the majority of waveform data, Dr. Hamilton and his colleagues developed an advanced platform that uses machine learning to analyze the entire shape of the cerebral blood flow velocity waveform through quantitative cerebral hemodynamics.

They compared the advanced analysis with traditional analysis among 69 high school athletes in contact sports who had sustained a concussion an average of 6 days earlier and a control group of 169 unaffected age-matched high school athletes from contact and noncontact sports.

Both groups had bilateral monitoring of blood flow in the middle cerebral artery with transcranial Doppler while they followed a standard cerebrovascular reactivity protocol that included rest and breath holding.

Results showed that for differentiating between athletes who did and did not have concussion, the advanced analysis had an area under the receiver operating characteristic curve of 83%. (Sensitivity was 72%, specificity was 82%, and overall accuracy was 80%.)

In comparison, the area under the curve was substantially lower for the traditional analysis measures: It was 55% for mean velocity (100% sensitivity, 0% specificity, 76% accuracy), 52% for the pulsatility index (86% sensitivity, 23% specificity, 61% accuracy), and 60% for the cerebrovascular reactivity index (51% sensitivity, 68% specificity, 64% accuracy).

“Unfortunately, concussion diagnostics and management today are basically subjective,” Dr. Hamilton commented. The advanced analysis may therefore improve the situation by providing objective evidence of blood flow dysfunction after injury.

The new analysis platform “is easy to use and portable, and [testing] can be done very quickly, within 5 minutes,” he noted. “The nice thing is it can be done on the sideline, in the emergency room, or in a doctor’s office.”

The investigators will next use the advanced analysis to track recovery of blood flow regulation after sports-related concussion and will compare its performance with that of additional modalities, such as MRI, according to Dr. Hamilton. Furthermore, they are testing it in various other populations: adolescents, college athletes, and members of the military.

“Ultimately, blood flow dysfunction is also important in a wide variety of conditions, such as stroke and dementia,” he pointed out. “So those are conditions that we are looking at to study this year and moving forward in the future.”

The research was supported by the National Institutes of Health and the National Science Foundation.

VANCOUVER – Many retired National Football League (NFL) players seeking care for neurocognitive symptoms have MRI evidence of traumatic brain injury, according to the largest study of this issue among living players.

Data reported at the annual meeting of the American Academy of Neurology show that 43% of a cohort of 40 symptomatic NFL retirees had abnormal results on diffusion tensor MRI and 30% had evidence of traumatic axonal injury on conventional MRI.

Susan London/Frontline Medical News

The likelihood of abnormal diffusion tensor MRI results was correlated, albeit weakly, with the length of the player’s NFL career, but not with the number of concussions sustained.

“It appears that subconcussive hits – that is, the cumulative effects and longer playing careers – place retired alumni at risk for abnormal diffusion tensor MRI,” commented lead author Dr. Francis X. Conidi, director of the Florida Center for Headache & Sports Neurology in Palm Beach and team neurologist for the Florida Panthers of the National Hockey League.

“This could be a possible link to chronic traumatic encephalopathy, as consensus is you need to have repetitive head trauma,” he proposed. “Or this could be a separate entity whereby, in NFL players, the symptoms we are seeing are actually related to the traumatic brain injury itself and [in a subset] with some genetic predisposition, they will go on to have progressive neurological decline.”

Although the cohort was quite young, only 39 years old on average, some had likely played football since youth, and that has implications for prevention, Dr. Conidi added in an interview. “One thing we need to consider is limiting the amount of contact that these people receive on a cumulative basis, starting when they are young and starting in practice, because that’s where most of the contact occurs,” he recommended.

“It is important to note that diffusion tensor imaging is not a routine part of a brain MRI study,” session moderator Dr. José E. Cavazos, professor of neurology and assistant dean at the University of Texas Health Science Center in San Antonio, said in comments provided by email. “The significant correlation between duration of years played and abnormalities in diffusion tensor imaging is of concern given the popularity of the sport.”

“The next step is to replicate the findings, but more importantly, it is to find surrogate markers for early detection for these abnormalities, aiming to intervene (sideline) those players at greater risk for developing cognitive deficits or other impairments,” he added.

In the study, the retired players had a battery of neuropsychological and imaging examinations and tests over a period of 2 days. They were classified as having abnormal diffusion tensor MRI results if they had fractional anisotropy (FA) values at least 2.5 standard deviations below those of age-matched peers in a normative database for specific regions of interest in the brain.

The players ranged in age from 27 to 56 years. On average, they had played 7 years in the NFL and sustained eight concussions during that time. Most had retired in the past 5 years.

Results showed that, overall, 43% had abnormal diffusion tensor MRI results, Dr. Conidi reported. Prevalence, however, varied according to player position: It was highest for defensive linemen (64%) and wide receivers (60%); intermediate for running backs (43%), defensive backs (33%), and offensive linemen (29%); and lowest for quarterbacks (0%) and linebackers (0%).

The number of years played was significantly correlated with abnormal results (P = .049), but the number of concussions was not.

In other findings, sizable proportions of the players had significant abnormalities in attention and concentration (43%), executive function (54%), learning and memory (46%), spatial and perceptual function (24%), and language (5%).

“These guys have played these positions probably since they were young. This isn’t just NFL. We don’t make any claims that professional football caused this,” Dr. Conidi emphasized.

As for future research, the investigators plan to undertake PET scanning to assess clinical and laboratory evidence of Alzheimer’s disease, study sleep pathology, and look for tau protein (a marker for chronic traumatic encephalopathy) in cerebrospinal fluid. Additionally, they will assess treatment outcomes.

The study is not without limitations, Dr. Conidi acknowledged. “With every study that has ever been done on these guys, it is a skewed population: They are coming to us and they are looking to be evaluated,” he elaborated. “The other issue is we don’t have a normative comparison database for the neuropsychological testing.”

Dr. Conidi disclosed that he is a consultant for the NFL, NHL, USTA, PGA, and NCAA and that he receives research support from the Seeing Stars Foundation.

VANCOUVER – Many retired National Football League (NFL) players seeking care for neurocognitive symptoms have MRI evidence of traumatic brain injury, according to the largest study of this issue among living players.

Data reported at the annual meeting of the American Academy of Neurology show that 43% of a cohort of 40 symptomatic NFL retirees had abnormal results on diffusion tensor MRI and 30% had evidence of traumatic axonal injury on conventional MRI.

Susan London/Frontline Medical News

The likelihood of abnormal diffusion tensor MRI results was correlated, albeit weakly, with the length of the player’s NFL career, but not with the number of concussions sustained.

“It appears that subconcussive hits – that is, the cumulative effects and longer playing careers – place retired alumni at risk for abnormal diffusion tensor MRI,” commented lead author Dr. Francis X. Conidi, director of the Florida Center for Headache & Sports Neurology in Palm Beach and team neurologist for the Florida Panthers of the National Hockey League.

“This could be a possible link to chronic traumatic encephalopathy, as consensus is you need to have repetitive head trauma,” he proposed. “Or this could be a separate entity whereby, in NFL players, the symptoms we are seeing are actually related to the traumatic brain injury itself and [in a subset] with some genetic predisposition, they will go on to have progressive neurological decline.”

Although the cohort was quite young, only 39 years old on average, some had likely played football since youth, and that has implications for prevention, Dr. Conidi added in an interview. “One thing we need to consider is limiting the amount of contact that these people receive on a cumulative basis, starting when they are young and starting in practice, because that’s where most of the contact occurs,” he recommended.

“It is important to note that diffusion tensor imaging is not a routine part of a brain MRI study,” session moderator Dr. José E. Cavazos, professor of neurology and assistant dean at the University of Texas Health Science Center in San Antonio, said in comments provided by email. “The significant correlation between duration of years played and abnormalities in diffusion tensor imaging is of concern given the popularity of the sport.”

“The next step is to replicate the findings, but more importantly, it is to find surrogate markers for early detection for these abnormalities, aiming to intervene (sideline) those players at greater risk for developing cognitive deficits or other impairments,” he added.

In the study, the retired players had a battery of neuropsychological and imaging examinations and tests over a period of 2 days. They were classified as having abnormal diffusion tensor MRI results if they had fractional anisotropy (FA) values at least 2.5 standard deviations below those of age-matched peers in a normative database for specific regions of interest in the brain.

The players ranged in age from 27 to 56 years. On average, they had played 7 years in the NFL and sustained eight concussions during that time. Most had retired in the past 5 years.

Results showed that, overall, 43% had abnormal diffusion tensor MRI results, Dr. Conidi reported. Prevalence, however, varied according to player position: It was highest for defensive linemen (64%) and wide receivers (60%); intermediate for running backs (43%), defensive backs (33%), and offensive linemen (29%); and lowest for quarterbacks (0%) and linebackers (0%).

The number of years played was significantly correlated with abnormal results (P = .049), but the number of concussions was not.

In other findings, sizable proportions of the players had significant abnormalities in attention and concentration (43%), executive function (54%), learning and memory (46%), spatial and perceptual function (24%), and language (5%).

“These guys have played these positions probably since they were young. This isn’t just NFL. We don’t make any claims that professional football caused this,” Dr. Conidi emphasized.

As for future research, the investigators plan to undertake PET scanning to assess clinical and laboratory evidence of Alzheimer’s disease, study sleep pathology, and look for tau protein (a marker for chronic traumatic encephalopathy) in cerebrospinal fluid. Additionally, they will assess treatment outcomes.

The study is not without limitations, Dr. Conidi acknowledged. “With every study that has ever been done on these guys, it is a skewed population: They are coming to us and they are looking to be evaluated,” he elaborated. “The other issue is we don’t have a normative comparison database for the neuropsychological testing.”

Dr. Conidi disclosed that he is a consultant for the NFL, NHL, USTA, PGA, and NCAA and that he receives research support from the Seeing Stars Foundation.

VANCOUVER – Many retired National Football League (NFL) players seeking care for neurocognitive symptoms have MRI evidence of traumatic brain injury, according to the largest study of this issue among living players.

Data reported at the annual meeting of the American Academy of Neurology show that 43% of a cohort of 40 symptomatic NFL retirees had abnormal results on diffusion tensor MRI and 30% had evidence of traumatic axonal injury on conventional MRI.

Susan London/Frontline Medical News

The likelihood of abnormal diffusion tensor MRI results was correlated, albeit weakly, with the length of the player’s NFL career, but not with the number of concussions sustained.

“It appears that subconcussive hits – that is, the cumulative effects and longer playing careers – place retired alumni at risk for abnormal diffusion tensor MRI,” commented lead author Dr. Francis X. Conidi, director of the Florida Center for Headache & Sports Neurology in Palm Beach and team neurologist for the Florida Panthers of the National Hockey League.

“This could be a possible link to chronic traumatic encephalopathy, as consensus is you need to have repetitive head trauma,” he proposed. “Or this could be a separate entity whereby, in NFL players, the symptoms we are seeing are actually related to the traumatic brain injury itself and [in a subset] with some genetic predisposition, they will go on to have progressive neurological decline.”

Although the cohort was quite young, only 39 years old on average, some had likely played football since youth, and that has implications for prevention, Dr. Conidi added in an interview. “One thing we need to consider is limiting the amount of contact that these people receive on a cumulative basis, starting when they are young and starting in practice, because that’s where most of the contact occurs,” he recommended.

“It is important to note that diffusion tensor imaging is not a routine part of a brain MRI study,” session moderator Dr. José E. Cavazos, professor of neurology and assistant dean at the University of Texas Health Science Center in San Antonio, said in comments provided by email. “The significant correlation between duration of years played and abnormalities in diffusion tensor imaging is of concern given the popularity of the sport.”

“The next step is to replicate the findings, but more importantly, it is to find surrogate markers for early detection for these abnormalities, aiming to intervene (sideline) those players at greater risk for developing cognitive deficits or other impairments,” he added.

In the study, the retired players had a battery of neuropsychological and imaging examinations and tests over a period of 2 days. They were classified as having abnormal diffusion tensor MRI results if they had fractional anisotropy (FA) values at least 2.5 standard deviations below those of age-matched peers in a normative database for specific regions of interest in the brain.

The players ranged in age from 27 to 56 years. On average, they had played 7 years in the NFL and sustained eight concussions during that time. Most had retired in the past 5 years.

Results showed that, overall, 43% had abnormal diffusion tensor MRI results, Dr. Conidi reported. Prevalence, however, varied according to player position: It was highest for defensive linemen (64%) and wide receivers (60%); intermediate for running backs (43%), defensive backs (33%), and offensive linemen (29%); and lowest for quarterbacks (0%) and linebackers (0%).

The number of years played was significantly correlated with abnormal results (P = .049), but the number of concussions was not.

In other findings, sizable proportions of the players had significant abnormalities in attention and concentration (43%), executive function (54%), learning and memory (46%), spatial and perceptual function (24%), and language (5%).

“These guys have played these positions probably since they were young. This isn’t just NFL. We don’t make any claims that professional football caused this,” Dr. Conidi emphasized.

As for future research, the investigators plan to undertake PET scanning to assess clinical and laboratory evidence of Alzheimer’s disease, study sleep pathology, and look for tau protein (a marker for chronic traumatic encephalopathy) in cerebrospinal fluid. Additionally, they will assess treatment outcomes.

The study is not without limitations, Dr. Conidi acknowledged. “With every study that has ever been done on these guys, it is a skewed population: They are coming to us and they are looking to be evaluated,” he elaborated. “The other issue is we don’t have a normative comparison database for the neuropsychological testing.”

Dr. Conidi disclosed that he is a consultant for the NFL, NHL, USTA, PGA, and NCAA and that he receives research support from the Seeing Stars Foundation.

VANCOUVER – Once-daily eslicarbazepine may offer a more convenient option for controlling newly diagnosed partial-onset seizures, suggest findings of a phase III trial reported at the annual meeting of the American Academy of Neurology.

The study of 815 adult patients found that 71.1% of those treated with once-daily eslicarbazepine as monotherapy were seizure free for at least 6 months, compared with 75.6% of those treated with twice-daily controlled-release carbamazepine as monotherapy. The difference fell within the predefined margin for noninferiority.

Additionally, the safety profile of eslicarbazepine was at least as good as that of carbamazepine, and there were no new or unexpected adverse events, relative to those seen in trials in which the former has been used as adjunctive therapy.

“Eslicarbazepine has the same efficacy, has a little bit better safety, and it can be taken once a day,” coauthor Dr. Pedro André Kowacs commented in an interview. “I have been working with it for 12 years. It’s a very, very good drug.”

“There are few antiepileptic drugs that can be taken once a day,” he added. “We know that a more simple schedule enhances adherence of the patient, compliance of the patient to therapy.”

Also, patients can choose when to take eslicarbazepine, according to Dr. Kowacs, who is a neurologist at the Instituto de Neurologia de Curitiba in Brazil. “You can take it in the morning or you can take it at night. It doesn’t matter,” he elaborated. “This is in contrast to, say, phenobarbital. If you take it in the morning, perhaps you are going to sleep all day long. And if you take three tabs of Dilantin (phenytoin), probably you get a little bit dizzy.”

In the trial, patients were randomized evenly to once-daily eslicarbazepine (brand name Aptiom) or twice-daily controlled-release carbamazepine (brand name Tegretol XR), each as monotherapy. Eslicarbazepine is currently approved by the U.S. Food and Drug Administration for the treatment of partial-onset seizures as monotherapy or adjunctive therapy.

In both groups, the patients were treated according to a three-step dose-level design, with upward titration of dose if they experienced seizures. However, the majority in each group – 67.6% for eslicarbazepine and 76.9% for carbamazepine – remained at the lowest-dose level studied (800 mg once daily and 200 mg twice daily, respectively).

The primary endpoint was the proportion of patients in the per-protocol population who were seizure free for the entire 26-week evaluation period at the last received dose level.

Overall, that proportion was 71.1% in the eslicarbazepine group and 75.6% in the carbamazepine group, Dr. Kowacs reported in an Emerging Science session. The absolute difference of –4.28% and the lower bound of the 95% confidence interval of –10.30% fell within the predefined noninferiority margin of –12%.

The 1-year rate of freedom from seizures was 64.7% in the eslicarbazepine group and 70.3% in the carbamazepine group. The absolute difference of –5.46% and the lower bound of the 95% confidence interval of –11.88% again fell within the noninferiority margin.

Patients in the eslicarbazepine tended to have a lower rate of treatment-emergent adverse events possibly related to the drug, compared with counterparts in the carbamazepine group (41.1% vs. 49.5%). The most common were dizziness and headache.

“The [gamma glutamyl transferase level] was increased in more patients taking carbamazepine,” Dr. Kowacs noted, with a rate of 12.4% versus 2.7% with eslicarbazepine. “Hyponatremia occurred in both groups, but no patient was symptomatic.”

There were two deaths each in the eslicarbazepine group (from glioblastoma and cardiac arrest) and the carbamazepine group (from suicide and lung cancer).

Dr. Kowacs disclosed that he has received personal compensation for activities with Bial, Abbott Laboratories, GlaxoSmithKline, and Cyberonics. The trial was sponsored by Bial-Portela & Cª SA.

VANCOUVER – Once-daily eslicarbazepine may offer a more convenient option for controlling newly diagnosed partial-onset seizures, suggest findings of a phase III trial reported at the annual meeting of the American Academy of Neurology.

The study of 815 adult patients found that 71.1% of those treated with once-daily eslicarbazepine as monotherapy were seizure free for at least 6 months, compared with 75.6% of those treated with twice-daily controlled-release carbamazepine as monotherapy. The difference fell within the predefined margin for noninferiority.

Additionally, the safety profile of eslicarbazepine was at least as good as that of carbamazepine, and there were no new or unexpected adverse events, relative to those seen in trials in which the former has been used as adjunctive therapy.

“Eslicarbazepine has the same efficacy, has a little bit better safety, and it can be taken once a day,” coauthor Dr. Pedro André Kowacs commented in an interview. “I have been working with it for 12 years. It’s a very, very good drug.”

“There are few antiepileptic drugs that can be taken once a day,” he added. “We know that a more simple schedule enhances adherence of the patient, compliance of the patient to therapy.”

Also, patients can choose when to take eslicarbazepine, according to Dr. Kowacs, who is a neurologist at the Instituto de Neurologia de Curitiba in Brazil. “You can take it in the morning or you can take it at night. It doesn’t matter,” he elaborated. “This is in contrast to, say, phenobarbital. If you take it in the morning, perhaps you are going to sleep all day long. And if you take three tabs of Dilantin (phenytoin), probably you get a little bit dizzy.”

In the trial, patients were randomized evenly to once-daily eslicarbazepine (brand name Aptiom) or twice-daily controlled-release carbamazepine (brand name Tegretol XR), each as monotherapy. Eslicarbazepine is currently approved by the U.S. Food and Drug Administration for the treatment of partial-onset seizures as monotherapy or adjunctive therapy.

In both groups, the patients were treated according to a three-step dose-level design, with upward titration of dose if they experienced seizures. However, the majority in each group – 67.6% for eslicarbazepine and 76.9% for carbamazepine – remained at the lowest-dose level studied (800 mg once daily and 200 mg twice daily, respectively).

The primary endpoint was the proportion of patients in the per-protocol population who were seizure free for the entire 26-week evaluation period at the last received dose level.

Overall, that proportion was 71.1% in the eslicarbazepine group and 75.6% in the carbamazepine group, Dr. Kowacs reported in an Emerging Science session. The absolute difference of –4.28% and the lower bound of the 95% confidence interval of –10.30% fell within the predefined noninferiority margin of –12%.

The 1-year rate of freedom from seizures was 64.7% in the eslicarbazepine group and 70.3% in the carbamazepine group. The absolute difference of –5.46% and the lower bound of the 95% confidence interval of –11.88% again fell within the noninferiority margin.

Patients in the eslicarbazepine tended to have a lower rate of treatment-emergent adverse events possibly related to the drug, compared with counterparts in the carbamazepine group (41.1% vs. 49.5%). The most common were dizziness and headache.

“The [gamma glutamyl transferase level] was increased in more patients taking carbamazepine,” Dr. Kowacs noted, with a rate of 12.4% versus 2.7% with eslicarbazepine. “Hyponatremia occurred in both groups, but no patient was symptomatic.”

There were two deaths each in the eslicarbazepine group (from glioblastoma and cardiac arrest) and the carbamazepine group (from suicide and lung cancer).

Dr. Kowacs disclosed that he has received personal compensation for activities with Bial, Abbott Laboratories, GlaxoSmithKline, and Cyberonics. The trial was sponsored by Bial-Portela & Cª SA.

VANCOUVER – Once-daily eslicarbazepine may offer a more convenient option for controlling newly diagnosed partial-onset seizures, suggest findings of a phase III trial reported at the annual meeting of the American Academy of Neurology.

The study of 815 adult patients found that 71.1% of those treated with once-daily eslicarbazepine as monotherapy were seizure free for at least 6 months, compared with 75.6% of those treated with twice-daily controlled-release carbamazepine as monotherapy. The difference fell within the predefined margin for noninferiority.

Additionally, the safety profile of eslicarbazepine was at least as good as that of carbamazepine, and there were no new or unexpected adverse events, relative to those seen in trials in which the former has been used as adjunctive therapy.

“Eslicarbazepine has the same efficacy, has a little bit better safety, and it can be taken once a day,” coauthor Dr. Pedro André Kowacs commented in an interview. “I have been working with it for 12 years. It’s a very, very good drug.”

“There are few antiepileptic drugs that can be taken once a day,” he added. “We know that a more simple schedule enhances adherence of the patient, compliance of the patient to therapy.”

Also, patients can choose when to take eslicarbazepine, according to Dr. Kowacs, who is a neurologist at the Instituto de Neurologia de Curitiba in Brazil. “You can take it in the morning or you can take it at night. It doesn’t matter,” he elaborated. “This is in contrast to, say, phenobarbital. If you take it in the morning, perhaps you are going to sleep all day long. And if you take three tabs of Dilantin (phenytoin), probably you get a little bit dizzy.”

In the trial, patients were randomized evenly to once-daily eslicarbazepine (brand name Aptiom) or twice-daily controlled-release carbamazepine (brand name Tegretol XR), each as monotherapy. Eslicarbazepine is currently approved by the U.S. Food and Drug Administration for the treatment of partial-onset seizures as monotherapy or adjunctive therapy.

In both groups, the patients were treated according to a three-step dose-level design, with upward titration of dose if they experienced seizures. However, the majority in each group – 67.6% for eslicarbazepine and 76.9% for carbamazepine – remained at the lowest-dose level studied (800 mg once daily and 200 mg twice daily, respectively).

The primary endpoint was the proportion of patients in the per-protocol population who were seizure free for the entire 26-week evaluation period at the last received dose level.

Overall, that proportion was 71.1% in the eslicarbazepine group and 75.6% in the carbamazepine group, Dr. Kowacs reported in an Emerging Science session. The absolute difference of –4.28% and the lower bound of the 95% confidence interval of –10.30% fell within the predefined noninferiority margin of –12%.

The 1-year rate of freedom from seizures was 64.7% in the eslicarbazepine group and 70.3% in the carbamazepine group. The absolute difference of –5.46% and the lower bound of the 95% confidence interval of –11.88% again fell within the noninferiority margin.

Patients in the eslicarbazepine tended to have a lower rate of treatment-emergent adverse events possibly related to the drug, compared with counterparts in the carbamazepine group (41.1% vs. 49.5%). The most common were dizziness and headache.

“The [gamma glutamyl transferase level] was increased in more patients taking carbamazepine,” Dr. Kowacs noted, with a rate of 12.4% versus 2.7% with eslicarbazepine. “Hyponatremia occurred in both groups, but no patient was symptomatic.”

There were two deaths each in the eslicarbazepine group (from glioblastoma and cardiac arrest) and the carbamazepine group (from suicide and lung cancer).

Dr. Kowacs disclosed that he has received personal compensation for activities with Bial, Abbott Laboratories, GlaxoSmithKline, and Cyberonics. The trial was sponsored by Bial-Portela & Cª SA.

VANCOUVER – Certain patient and disease characteristics may help guide decisions about starting and stopping therapy in progressive multiple sclerosis, according to a pair of longitudinal cohort studies reported at the annual meeting of the American Academy of Neurology.

In a cohort of patients transitioning from relapsing-remitting to progressive multiple sclerosis (MS), the age at onset of progression predicted the likelihood of subsequent relapses. The absolute lifetime risk ranged from 18% for patients younger than 35 years at the time to just 5% for those aged 55 years or older at the time.

And in a cohort of patients with secondary progressive MS, the annual rate of clinical relapse fell in the third year after immunomodulator discontinuation. Overall, 35% had a clinical relapse or radiologic disease activity. Patients had a lower risk of this outcome if they had greater disability at the time of discontinuation or if they had not had any radiologic disease activity in the antecedent years.

“These studies address a very important question, because not many people talk about stopping drugs,” commented session comoderator Helen Tremlett, Ph.D., of the division of neurology at the University of British Columbia, Vancouver, and the Canada Research Chair in Neuroepidemiology and Multiple Sclerosis. “I would like to see some of these findings validated in other cohorts. But I did like the questions they are asking.”

Age, risk of postprogression relapse

The first study focused on ongoing relapses in patients transitioning to progressive MS. “We have recently shown that these relapses indeed matter. People who continue to relapse after progressive MS onset develop a need for a cane 2 years earlier than those who don’t” continue to have relapses, explained senior author Dr. Orhun H. Kantarci of the department of neurology at the Mayo Clinic in Rochester, Minn. Therefore, continuation or initiation of disease-modifying drugs (DMDs) during this period of overlap may be beneficial.

Courtesy Mayo Clinic

He and his colleagues followed 946 patients with MS from a clinic- and population-based cohort, assessing the age at various disease landmarks.

Results showed the mean age at first relapse was 33 years, the mean age at the onset of progressive MS was 45 years, and the mean age at last relapse (whether it occurred before or after the onset of progressive disease) was 43 years.

The 95% overlap age range for age at first relapse and age at onset of progressive MS was 27-46 years, Dr. Kantarci reported. Therefore, DMDs would be expected to have a some impact during those years.

Further analyses showed that if the age of progressive MS onset was before 35 years, 35-44 years, 45-54 years, and 55 years or older, the absolute lifetime risk of relapse after progressive MS onset was 18%, 17%, 13%, and 5%, respectively. The corresponding last predicted relapse for these groups was before age 50, age 60, age 70, and age 70.

Taken together, the data suggest that in patients transitioning to progressive MS, initiation or continuation of a DMD is most likely to be beneficial if the patient is younger than 35, with some benefit, albeit less, up to the age of 54, according to Dr. Kantarci.

“But above 55, if a person has never been on a DMD, it is unlikely to be recommended, because I don’t expect it to do anything from the data we have,” he said. Furthermore, “DMD stopping can be offered to these patients. If a person is on a DMD and they are asking, ‘Can I stop it? I have been stable,’ and they are above age 55, it can be considered.”

The investigators are performing additional analyses of the data to assess the impact of DMDs on disease course, including the influence of initial and maintenance treatment choices, and factors that prompt physicians to switch treatments.

“What we haven’t done and will not be possible with this data ... the most interesting question is the impact of subclinical MRI disease, which is a different question,” Dr. Kantarci concluded. “And ultimately, we will have to have an actual stopping experiment and [assess] outcomes, which is an ongoing major planned effort.”

Outcomes after stopping immunomodulators

The second study assessed clinical and radiologic outcomes after discontinuation of immunomodulatory therapy in patients with secondary progressive MS.

“We have more and more patients [with secondary progressive disease] treated for several years, yet the natural history of the disease is less and less relapse, and progression of disability,” commented first author Dr. Julien Bonenfant, a neurologist at the Rennes University Hospital in France. Thus, the benefit of continuing treatment is unclear, especially given its cost and side effects.

He and his colleagues studied 106 consecutive patients with secondary progressive MS who had been on immunomodulators for at least 6 months, were taken off the immunomodulators, and were followed for a mean of 5 years.

Results showed that 16% of the patients had a clinical relapse after discontinuation, nearly all within the first 3 years. The annualized rate of clinical relapse actually fell from 0.13 in the 3 years before discontinuation to 0.07 in the 3 years afterward.

Overall, 35% of patients had either a clinical relapse and/or new contrast enhancement on MRI. Again, most of these events occurred within the first 3 years of discontinuation.

Patients had a lower risk of this outcome after treatment discontinuation if they had an Expanded Disability Status Scale (EDSS) score of 6 or greater at the time of discontinuation (hazard ratio, 0.4) and if they had not had any gadolinium enhancement on MRI in the 3 years before treatment discontinuation (HR, 0.4).

“Disease activity remained low after treatment withdrawal. We found no rebound of relapse rate in our population,” Dr. Bonenfant summarized. “There was no consequence on the slope of disability progression,” nor on the finding of enhancement on MRI alone.

Thirty patients were restarted on immunomodulators, about half of them solely because of MRI findings, he noted. This raises “the controversial question, is it relevant or not to resume treatment in these patients?”

“This study suggests that immunomodulatory treatment withdrawal seems reasonable for patients with advanced secondary progressive MS, especially with an EDSS of 6 or greater and no focal inflammatory disease [clinical or radiologic] at least in the past 3 years,” Dr. Bonenfant maintained. “It shows the importance of MRI monitoring to define the patients who are still in a focal immunoreactive state.”

“The results are far from being definitive, and further prospective studies are needed to provide evidence-based recommendations for clinical practice,” he concluded.

Dr. Kantarci disclosed that he has given scientific presentations at meetings supported by Novartis Pharmaceuticals and has presented as an invited speaker for Biogen but has received no personal compensation from either company. Dr. Bonenfant disclosed that he had no relevant conflicts of interest.

VANCOUVER – Certain patient and disease characteristics may help guide decisions about starting and stopping therapy in progressive multiple sclerosis, according to a pair of longitudinal cohort studies reported at the annual meeting of the American Academy of Neurology.

In a cohort of patients transitioning from relapsing-remitting to progressive multiple sclerosis (MS), the age at onset of progression predicted the likelihood of subsequent relapses. The absolute lifetime risk ranged from 18% for patients younger than 35 years at the time to just 5% for those aged 55 years or older at the time.

And in a cohort of patients with secondary progressive MS, the annual rate of clinical relapse fell in the third year after immunomodulator discontinuation. Overall, 35% had a clinical relapse or radiologic disease activity. Patients had a lower risk of this outcome if they had greater disability at the time of discontinuation or if they had not had any radiologic disease activity in the antecedent years.

“These studies address a very important question, because not many people talk about stopping drugs,” commented session comoderator Helen Tremlett, Ph.D., of the division of neurology at the University of British Columbia, Vancouver, and the Canada Research Chair in Neuroepidemiology and Multiple Sclerosis. “I would like to see some of these findings validated in other cohorts. But I did like the questions they are asking.”

Age, risk of postprogression relapse

The first study focused on ongoing relapses in patients transitioning to progressive MS. “We have recently shown that these relapses indeed matter. People who continue to relapse after progressive MS onset develop a need for a cane 2 years earlier than those who don’t” continue to have relapses, explained senior author Dr. Orhun H. Kantarci of the department of neurology at the Mayo Clinic in Rochester, Minn. Therefore, continuation or initiation of disease-modifying drugs (DMDs) during this period of overlap may be beneficial.

Courtesy Mayo Clinic

He and his colleagues followed 946 patients with MS from a clinic- and population-based cohort, assessing the age at various disease landmarks.

Results showed the mean age at first relapse was 33 years, the mean age at the onset of progressive MS was 45 years, and the mean age at last relapse (whether it occurred before or after the onset of progressive disease) was 43 years.

The 95% overlap age range for age at first relapse and age at onset of progressive MS was 27-46 years, Dr. Kantarci reported. Therefore, DMDs would be expected to have a some impact during those years.

Further analyses showed that if the age of progressive MS onset was before 35 years, 35-44 years, 45-54 years, and 55 years or older, the absolute lifetime risk of relapse after progressive MS onset was 18%, 17%, 13%, and 5%, respectively. The corresponding last predicted relapse for these groups was before age 50, age 60, age 70, and age 70.

Taken together, the data suggest that in patients transitioning to progressive MS, initiation or continuation of a DMD is most likely to be beneficial if the patient is younger than 35, with some benefit, albeit less, up to the age of 54, according to Dr. Kantarci.

“But above 55, if a person has never been on a DMD, it is unlikely to be recommended, because I don’t expect it to do anything from the data we have,” he said. Furthermore, “DMD stopping can be offered to these patients. If a person is on a DMD and they are asking, ‘Can I stop it? I have been stable,’ and they are above age 55, it can be considered.”

The investigators are performing additional analyses of the data to assess the impact of DMDs on disease course, including the influence of initial and maintenance treatment choices, and factors that prompt physicians to switch treatments.

“What we haven’t done and will not be possible with this data ... the most interesting question is the impact of subclinical MRI disease, which is a different question,” Dr. Kantarci concluded. “And ultimately, we will have to have an actual stopping experiment and [assess] outcomes, which is an ongoing major planned effort.”

Outcomes after stopping immunomodulators

The second study assessed clinical and radiologic outcomes after discontinuation of immunomodulatory therapy in patients with secondary progressive MS.

“We have more and more patients [with secondary progressive disease] treated for several years, yet the natural history of the disease is less and less relapse, and progression of disability,” commented first author Dr. Julien Bonenfant, a neurologist at the Rennes University Hospital in France. Thus, the benefit of continuing treatment is unclear, especially given its cost and side effects.

He and his colleagues studied 106 consecutive patients with secondary progressive MS who had been on immunomodulators for at least 6 months, were taken off the immunomodulators, and were followed for a mean of 5 years.

Results showed that 16% of the patients had a clinical relapse after discontinuation, nearly all within the first 3 years. The annualized rate of clinical relapse actually fell from 0.13 in the 3 years before discontinuation to 0.07 in the 3 years afterward.

Overall, 35% of patients had either a clinical relapse and/or new contrast enhancement on MRI. Again, most of these events occurred within the first 3 years of discontinuation.

Patients had a lower risk of this outcome after treatment discontinuation if they had an Expanded Disability Status Scale (EDSS) score of 6 or greater at the time of discontinuation (hazard ratio, 0.4) and if they had not had any gadolinium enhancement on MRI in the 3 years before treatment discontinuation (HR, 0.4).

“Disease activity remained low after treatment withdrawal. We found no rebound of relapse rate in our population,” Dr. Bonenfant summarized. “There was no consequence on the slope of disability progression,” nor on the finding of enhancement on MRI alone.

Thirty patients were restarted on immunomodulators, about half of them solely because of MRI findings, he noted. This raises “the controversial question, is it relevant or not to resume treatment in these patients?”

“This study suggests that immunomodulatory treatment withdrawal seems reasonable for patients with advanced secondary progressive MS, especially with an EDSS of 6 or greater and no focal inflammatory disease [clinical or radiologic] at least in the past 3 years,” Dr. Bonenfant maintained. “It shows the importance of MRI monitoring to define the patients who are still in a focal immunoreactive state.”

“The results are far from being definitive, and further prospective studies are needed to provide evidence-based recommendations for clinical practice,” he concluded.

Dr. Kantarci disclosed that he has given scientific presentations at meetings supported by Novartis Pharmaceuticals and has presented as an invited speaker for Biogen but has received no personal compensation from either company. Dr. Bonenfant disclosed that he had no relevant conflicts of interest.

VANCOUVER – Certain patient and disease characteristics may help guide decisions about starting and stopping therapy in progressive multiple sclerosis, according to a pair of longitudinal cohort studies reported at the annual meeting of the American Academy of Neurology.

In a cohort of patients transitioning from relapsing-remitting to progressive multiple sclerosis (MS), the age at onset of progression predicted the likelihood of subsequent relapses. The absolute lifetime risk ranged from 18% for patients younger than 35 years at the time to just 5% for those aged 55 years or older at the time.

And in a cohort of patients with secondary progressive MS, the annual rate of clinical relapse fell in the third year after immunomodulator discontinuation. Overall, 35% had a clinical relapse or radiologic disease activity. Patients had a lower risk of this outcome if they had greater disability at the time of discontinuation or if they had not had any radiologic disease activity in the antecedent years.

“These studies address a very important question, because not many people talk about stopping drugs,” commented session comoderator Helen Tremlett, Ph.D., of the division of neurology at the University of British Columbia, Vancouver, and the Canada Research Chair in Neuroepidemiology and Multiple Sclerosis. “I would like to see some of these findings validated in other cohorts. But I did like the questions they are asking.”

Age, risk of postprogression relapse

The first study focused on ongoing relapses in patients transitioning to progressive MS. “We have recently shown that these relapses indeed matter. People who continue to relapse after progressive MS onset develop a need for a cane 2 years earlier than those who don’t” continue to have relapses, explained senior author Dr. Orhun H. Kantarci of the department of neurology at the Mayo Clinic in Rochester, Minn. Therefore, continuation or initiation of disease-modifying drugs (DMDs) during this period of overlap may be beneficial.

Courtesy Mayo Clinic

He and his colleagues followed 946 patients with MS from a clinic- and population-based cohort, assessing the age at various disease landmarks.

Results showed the mean age at first relapse was 33 years, the mean age at the onset of progressive MS was 45 years, and the mean age at last relapse (whether it occurred before or after the onset of progressive disease) was 43 years.

The 95% overlap age range for age at first relapse and age at onset of progressive MS was 27-46 years, Dr. Kantarci reported. Therefore, DMDs would be expected to have a some impact during those years.

Further analyses showed that if the age of progressive MS onset was before 35 years, 35-44 years, 45-54 years, and 55 years or older, the absolute lifetime risk of relapse after progressive MS onset was 18%, 17%, 13%, and 5%, respectively. The corresponding last predicted relapse for these groups was before age 50, age 60, age 70, and age 70.

Taken together, the data suggest that in patients transitioning to progressive MS, initiation or continuation of a DMD is most likely to be beneficial if the patient is younger than 35, with some benefit, albeit less, up to the age of 54, according to Dr. Kantarci.

“But above 55, if a person has never been on a DMD, it is unlikely to be recommended, because I don’t expect it to do anything from the data we have,” he said. Furthermore, “DMD stopping can be offered to these patients. If a person is on a DMD and they are asking, ‘Can I stop it? I have been stable,’ and they are above age 55, it can be considered.”

The investigators are performing additional analyses of the data to assess the impact of DMDs on disease course, including the influence of initial and maintenance treatment choices, and factors that prompt physicians to switch treatments.

“What we haven’t done and will not be possible with this data ... the most interesting question is the impact of subclinical MRI disease, which is a different question,” Dr. Kantarci concluded. “And ultimately, we will have to have an actual stopping experiment and [assess] outcomes, which is an ongoing major planned effort.”

Outcomes after stopping immunomodulators

The second study assessed clinical and radiologic outcomes after discontinuation of immunomodulatory therapy in patients with secondary progressive MS.

“We have more and more patients [with secondary progressive disease] treated for several years, yet the natural history of the disease is less and less relapse, and progression of disability,” commented first author Dr. Julien Bonenfant, a neurologist at the Rennes University Hospital in France. Thus, the benefit of continuing treatment is unclear, especially given its cost and side effects.

He and his colleagues studied 106 consecutive patients with secondary progressive MS who had been on immunomodulators for at least 6 months, were taken off the immunomodulators, and were followed for a mean of 5 years.

Results showed that 16% of the patients had a clinical relapse after discontinuation, nearly all within the first 3 years. The annualized rate of clinical relapse actually fell from 0.13 in the 3 years before discontinuation to 0.07 in the 3 years afterward.

Overall, 35% of patients had either a clinical relapse and/or new contrast enhancement on MRI. Again, most of these events occurred within the first 3 years of discontinuation.

Patients had a lower risk of this outcome after treatment discontinuation if they had an Expanded Disability Status Scale (EDSS) score of 6 or greater at the time of discontinuation (hazard ratio, 0.4) and if they had not had any gadolinium enhancement on MRI in the 3 years before treatment discontinuation (HR, 0.4).

“Disease activity remained low after treatment withdrawal. We found no rebound of relapse rate in our population,” Dr. Bonenfant summarized. “There was no consequence on the slope of disability progression,” nor on the finding of enhancement on MRI alone.

Thirty patients were restarted on immunomodulators, about half of them solely because of MRI findings, he noted. This raises “the controversial question, is it relevant or not to resume treatment in these patients?”

“This study suggests that immunomodulatory treatment withdrawal seems reasonable for patients with advanced secondary progressive MS, especially with an EDSS of 6 or greater and no focal inflammatory disease [clinical or radiologic] at least in the past 3 years,” Dr. Bonenfant maintained. “It shows the importance of MRI monitoring to define the patients who are still in a focal immunoreactive state.”

“The results are far from being definitive, and further prospective studies are needed to provide evidence-based recommendations for clinical practice,” he concluded.

Dr. Kantarci disclosed that he has given scientific presentations at meetings supported by Novartis Pharmaceuticals and has presented as an invited speaker for Biogen but has received no personal compensation from either company. Dr. Bonenfant disclosed that he had no relevant conflicts of interest.

Oncologists should take an individualized approach when making decisions about adjuvant endocrine therapies for premenopausal hormone receptor–positive, HER2-negative early breast cancer, suggests an analysis of a pair of randomized phase III trials published online in the Journal of Clinical Oncology.

Investigators led by Meredith M. Regan, Sc.D., of Dana-Farber Cancer Institute in Boston, analyzed data from the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials of adjuvant endocrine therapies, comprising a total of nearly 5,000 women.

Results suggested that the absolute improvement in the 5-year breast cancer–free interval rate with exemestane plus ovarian function suppression (OFS) versus tamoxifen with or without OFS ranged from less than 1% in women with a lowest recurrence risk based on clinicopathologic factors to 10%-15% in women with a highest risk.

“TEXT and SOFT demonstrated that premenopausal women with hormone receptor–positive disease benefit, on average, from exemestane plus OFS versus tamoxifen with or without OFS. However, individualized treatment decisions should weigh the benefits against the adverse effects and costs of these therapy options,” the investigators wrote.

“In the absence of predictive biomarkers, consideration of a patient’s prognosis, as illustrated by STEPP [Subpopulation Treatment Effect Pattern Plot] analysis of a composite measure of recurrence risk in the TEXT and SOFT populations, is integral to this decision making,” they added.

In the SOFT trial, women were randomized to 5 years of tamoxifen alone (as an active comparator), tamoxifen plus OFS, or exemestane (Aromasin) plus OFS. In the TEXT trial, women were randomized to 5 years of exemestane plus OFS or of tamoxifen plus OFS.

Dr. Regan and colleagues based their analyses on a total of 4,891 women. They assessed each patient’s composite recurrence risk from a Cox model that included a set of conventional clinicopathologic factors: age, nodal status, tumor size and grade, and estrogen receptor, progesterone receptor, and Ki-67 expression levels. And they used STEPP methodology to assess the impact of endocrine therapy across groups having different risk.

The median duration of follow-up was 5.6 years in the SOFT trial and 6 years in the TEXT trial. Results showed that the 5-year breast cancer–free interval rate was 90.8% for the study cohort as a whole. But it ranged considerably from 98.6% for patients with composite risk in the lowest quartile to 77.5% for patients with composite risk in the highest quartiles, the investigators reported (J Clin Oncol. 2016. doi: 10.1200/JCO.2015.64.3171).

In the SOFT population, patients who remained premenopausal after neoadjuvant or adjuvant chemotherapy had an absolute improvement of 5% or more in the 5-year breast cancer–free interval rate with exemestane plus OFS, compared with tamoxifen plus OFS or tamoxifen alone. The difference was 10%-15% for the subset at intermediate to high risk for recurrence.

In addition, a benefit of tamoxifen plus OFS over tamoxifen alone was evident in patients having the highest composite risk.

Among patients who were not given chemotherapy, who on average had the lowest composite recurrence risk, the 5-year breast cancer–free interval rate was excellent regardless of the endocrine therapy received.

In the TEXT trial population, the benefit of exemestane plus OFS over tamoxifen plus OFS in 5-year breast cancer–free interval rate ranged from 5% to 15%. Again, the patients who were not given chemotherapy, who had the lowest composite recurrence risk, fared well regardless of which endocrine therapy they received.

These findings should help guide clinical decisions in premenopausal women with hormone receptor–positive, HER2-negative breast cancer, both at the extremes of risk and in the scenario of intermediate risk, where factors such as patient preference, tolerance, and cost play a greater role, according to the investigators.

“Further follow-up of TEXT and SOFT patients is essential to guide patient care,” they concluded.

Oncologists should take an individualized approach when making decisions about adjuvant endocrine therapies for premenopausal hormone receptor–positive, HER2-negative early breast cancer, suggests an analysis of a pair of randomized phase III trials published online in the Journal of Clinical Oncology.

Investigators led by Meredith M. Regan, Sc.D., of Dana-Farber Cancer Institute in Boston, analyzed data from the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials of adjuvant endocrine therapies, comprising a total of nearly 5,000 women.

Results suggested that the absolute improvement in the 5-year breast cancer–free interval rate with exemestane plus ovarian function suppression (OFS) versus tamoxifen with or without OFS ranged from less than 1% in women with a lowest recurrence risk based on clinicopathologic factors to 10%-15% in women with a highest risk.

“TEXT and SOFT demonstrated that premenopausal women with hormone receptor–positive disease benefit, on average, from exemestane plus OFS versus tamoxifen with or without OFS. However, individualized treatment decisions should weigh the benefits against the adverse effects and costs of these therapy options,” the investigators wrote.

“In the absence of predictive biomarkers, consideration of a patient’s prognosis, as illustrated by STEPP [Subpopulation Treatment Effect Pattern Plot] analysis of a composite measure of recurrence risk in the TEXT and SOFT populations, is integral to this decision making,” they added.

In the SOFT trial, women were randomized to 5 years of tamoxifen alone (as an active comparator), tamoxifen plus OFS, or exemestane (Aromasin) plus OFS. In the TEXT trial, women were randomized to 5 years of exemestane plus OFS or of tamoxifen plus OFS.

Dr. Regan and colleagues based their analyses on a total of 4,891 women. They assessed each patient’s composite recurrence risk from a Cox model that included a set of conventional clinicopathologic factors: age, nodal status, tumor size and grade, and estrogen receptor, progesterone receptor, and Ki-67 expression levels. And they used STEPP methodology to assess the impact of endocrine therapy across groups having different risk.

The median duration of follow-up was 5.6 years in the SOFT trial and 6 years in the TEXT trial. Results showed that the 5-year breast cancer–free interval rate was 90.8% for the study cohort as a whole. But it ranged considerably from 98.6% for patients with composite risk in the lowest quartile to 77.5% for patients with composite risk in the highest quartiles, the investigators reported (J Clin Oncol. 2016. doi: 10.1200/JCO.2015.64.3171).

In the SOFT population, patients who remained premenopausal after neoadjuvant or adjuvant chemotherapy had an absolute improvement of 5% or more in the 5-year breast cancer–free interval rate with exemestane plus OFS, compared with tamoxifen plus OFS or tamoxifen alone. The difference was 10%-15% for the subset at intermediate to high risk for recurrence.

In addition, a benefit of tamoxifen plus OFS over tamoxifen alone was evident in patients having the highest composite risk.

Among patients who were not given chemotherapy, who on average had the lowest composite recurrence risk, the 5-year breast cancer–free interval rate was excellent regardless of the endocrine therapy received.

In the TEXT trial population, the benefit of exemestane plus OFS over tamoxifen plus OFS in 5-year breast cancer–free interval rate ranged from 5% to 15%. Again, the patients who were not given chemotherapy, who had the lowest composite recurrence risk, fared well regardless of which endocrine therapy they received.

These findings should help guide clinical decisions in premenopausal women with hormone receptor–positive, HER2-negative breast cancer, both at the extremes of risk and in the scenario of intermediate risk, where factors such as patient preference, tolerance, and cost play a greater role, according to the investigators.

“Further follow-up of TEXT and SOFT patients is essential to guide patient care,” they concluded.

Oncologists should take an individualized approach when making decisions about adjuvant endocrine therapies for premenopausal hormone receptor–positive, HER2-negative early breast cancer, suggests an analysis of a pair of randomized phase III trials published online in the Journal of Clinical Oncology.

Investigators led by Meredith M. Regan, Sc.D., of Dana-Farber Cancer Institute in Boston, analyzed data from the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials of adjuvant endocrine therapies, comprising a total of nearly 5,000 women.

Results suggested that the absolute improvement in the 5-year breast cancer–free interval rate with exemestane plus ovarian function suppression (OFS) versus tamoxifen with or without OFS ranged from less than 1% in women with a lowest recurrence risk based on clinicopathologic factors to 10%-15% in women with a highest risk.

“TEXT and SOFT demonstrated that premenopausal women with hormone receptor–positive disease benefit, on average, from exemestane plus OFS versus tamoxifen with or without OFS. However, individualized treatment decisions should weigh the benefits against the adverse effects and costs of these therapy options,” the investigators wrote.

“In the absence of predictive biomarkers, consideration of a patient’s prognosis, as illustrated by STEPP [Subpopulation Treatment Effect Pattern Plot] analysis of a composite measure of recurrence risk in the TEXT and SOFT populations, is integral to this decision making,” they added.

In the SOFT trial, women were randomized to 5 years of tamoxifen alone (as an active comparator), tamoxifen plus OFS, or exemestane (Aromasin) plus OFS. In the TEXT trial, women were randomized to 5 years of exemestane plus OFS or of tamoxifen plus OFS.

Dr. Regan and colleagues based their analyses on a total of 4,891 women. They assessed each patient’s composite recurrence risk from a Cox model that included a set of conventional clinicopathologic factors: age, nodal status, tumor size and grade, and estrogen receptor, progesterone receptor, and Ki-67 expression levels. And they used STEPP methodology to assess the impact of endocrine therapy across groups having different risk.

The median duration of follow-up was 5.6 years in the SOFT trial and 6 years in the TEXT trial. Results showed that the 5-year breast cancer–free interval rate was 90.8% for the study cohort as a whole. But it ranged considerably from 98.6% for patients with composite risk in the lowest quartile to 77.5% for patients with composite risk in the highest quartiles, the investigators reported (J Clin Oncol. 2016. doi: 10.1200/JCO.2015.64.3171).

In the SOFT population, patients who remained premenopausal after neoadjuvant or adjuvant chemotherapy had an absolute improvement of 5% or more in the 5-year breast cancer–free interval rate with exemestane plus OFS, compared with tamoxifen plus OFS or tamoxifen alone. The difference was 10%-15% for the subset at intermediate to high risk for recurrence.

In addition, a benefit of tamoxifen plus OFS over tamoxifen alone was evident in patients having the highest composite risk.

Among patients who were not given chemotherapy, who on average had the lowest composite recurrence risk, the 5-year breast cancer–free interval rate was excellent regardless of the endocrine therapy received.

In the TEXT trial population, the benefit of exemestane plus OFS over tamoxifen plus OFS in 5-year breast cancer–free interval rate ranged from 5% to 15%. Again, the patients who were not given chemotherapy, who had the lowest composite recurrence risk, fared well regardless of which endocrine therapy they received.

These findings should help guide clinical decisions in premenopausal women with hormone receptor–positive, HER2-negative breast cancer, both at the extremes of risk and in the scenario of intermediate risk, where factors such as patient preference, tolerance, and cost play a greater role, according to the investigators.

“Further follow-up of TEXT and SOFT patients is essential to guide patient care,” they concluded.