ORLANDO –A recombinant form of factor XIII was effective at preventing serious bleeding episodes in young children with factor XIII-A subunit deficiency, a rare and serious bleeding disorder.

In a small international phase III trial, there were no major bleeding episodes among six young children treated for at least 1 year with recombinant factor XIII (rFXIII; trade name Tretten), reported Susan L. Kearney, MD, of Children’s Hospitals and Clinics of Minnesota in Minneapolis.

©benjaminalbiach/ThinkStock

“Prophylaxis was effective. The annualized bleeding rate was zero and the mean trough [FXIII activity] was greater than 10%,” she said at a moderated poster session at the World Federation of Hemophilia World Congress. “We feel that recombinant factor XIII is safe and effective in pediatric subjects less than 6 years of age with congenital factor XIII-A subunit deficiency, similar to the older age cohort.”

Factor XIII-A subunit deficiency is a rare and serious heritable bleeding disorder associated with spontaneous intracranial hemorrhage and other unpredictable types of serious bleeding.

In a previous phase III trial, 77 patients, ranging in age from 7 to 60 years, received rFXIII for bleeding prophylaxis. When given monthly, the recombinant factor was effective at preventing serious bleeding in 90% of patients. The most commonly reported adverse events were headache, pain in the extremities, and injection site pain.

Based on these results, the Food and Drug Administration granted rFXIII orphan-drug designation for treatment of patients 6 and older with factor XIII-A subunit deficiency.

In the trial reported here, investigators from the United States, United Kingdom, Israel, and Denmark enrolled three boys and three girls under age 6 who had previously completed a single dose efficacy and safety study of rFXIII. The patients received intravenous rFXIII at a dose of 35 IU/kg every 28 days for a minimum of 52 weeks.

The total treatment duration ranged from 1.8 to 3.5 years, for a total of 16.6 patient years.

There were no thromboembolic events or systemic allergic reactions, the primary safety endpoint of the study. One patient experienced three incidences of atopic dermatitis, however; two serious adverse events related to head injuries from falls during play occurred in one patient, who did not experience intracranial hemorrhage.

Two adverse events were deemed to be probably or possibly related to rFXIII: a case of viral gastroenteritis affected one patient who recovered without a change in dose, and mild fluctuating lymphocytopenia seen at baseline persisted in another patient throughout the trial.

There were no inhibitory or noninhibitory antibodies to rFXIII detected in any patient during the trial, and there were no bleeding episodes requiring additional treatment. The 14 minor bleeding episodes seen in five patients did not require treatment with an FXIII-containing product, the authors noted.

“It’s a very rare disorder, but ... the phenotype is quite severe and patients are severely affected. So this product is very useful,” said Lakshmi Srivaths, MD, a pediatric hematologist at Texas Children’s Hospital in Houston. She was not involved in the study. Unlike patients with hemophilia A or B, who require frequent factor infusions, the long half-life of this product means patients need just once-a-month infusions “that change the phenotype very significantly.”

Dr. Kearney disclosed grant/research support from Novo Nordisk, which funded the study. Some coauthors reported consulting or employment with the company.

ORLANDO –A recombinant form of factor XIII was effective at preventing serious bleeding episodes in young children with factor XIII-A subunit deficiency, a rare and serious bleeding disorder.

In a small international phase III trial, there were no major bleeding episodes among six young children treated for at least 1 year with recombinant factor XIII (rFXIII; trade name Tretten), reported Susan L. Kearney, MD, of Children’s Hospitals and Clinics of Minnesota in Minneapolis.

©benjaminalbiach/ThinkStock

“Prophylaxis was effective. The annualized bleeding rate was zero and the mean trough [FXIII activity] was greater than 10%,” she said at a moderated poster session at the World Federation of Hemophilia World Congress. “We feel that recombinant factor XIII is safe and effective in pediatric subjects less than 6 years of age with congenital factor XIII-A subunit deficiency, similar to the older age cohort.”

Factor XIII-A subunit deficiency is a rare and serious heritable bleeding disorder associated with spontaneous intracranial hemorrhage and other unpredictable types of serious bleeding.

In a previous phase III trial, 77 patients, ranging in age from 7 to 60 years, received rFXIII for bleeding prophylaxis. When given monthly, the recombinant factor was effective at preventing serious bleeding in 90% of patients. The most commonly reported adverse events were headache, pain in the extremities, and injection site pain.

Based on these results, the Food and Drug Administration granted rFXIII orphan-drug designation for treatment of patients 6 and older with factor XIII-A subunit deficiency.

In the trial reported here, investigators from the United States, United Kingdom, Israel, and Denmark enrolled three boys and three girls under age 6 who had previously completed a single dose efficacy and safety study of rFXIII. The patients received intravenous rFXIII at a dose of 35 IU/kg every 28 days for a minimum of 52 weeks.

The total treatment duration ranged from 1.8 to 3.5 years, for a total of 16.6 patient years.

There were no thromboembolic events or systemic allergic reactions, the primary safety endpoint of the study. One patient experienced three incidences of atopic dermatitis, however; two serious adverse events related to head injuries from falls during play occurred in one patient, who did not experience intracranial hemorrhage.

Two adverse events were deemed to be probably or possibly related to rFXIII: a case of viral gastroenteritis affected one patient who recovered without a change in dose, and mild fluctuating lymphocytopenia seen at baseline persisted in another patient throughout the trial.

There were no inhibitory or noninhibitory antibodies to rFXIII detected in any patient during the trial, and there were no bleeding episodes requiring additional treatment. The 14 minor bleeding episodes seen in five patients did not require treatment with an FXIII-containing product, the authors noted.

“It’s a very rare disorder, but ... the phenotype is quite severe and patients are severely affected. So this product is very useful,” said Lakshmi Srivaths, MD, a pediatric hematologist at Texas Children’s Hospital in Houston. She was not involved in the study. Unlike patients with hemophilia A or B, who require frequent factor infusions, the long half-life of this product means patients need just once-a-month infusions “that change the phenotype very significantly.”

Dr. Kearney disclosed grant/research support from Novo Nordisk, which funded the study. Some coauthors reported consulting or employment with the company.

ORLANDO –A recombinant form of factor XIII was effective at preventing serious bleeding episodes in young children with factor XIII-A subunit deficiency, a rare and serious bleeding disorder.

In a small international phase III trial, there were no major bleeding episodes among six young children treated for at least 1 year with recombinant factor XIII (rFXIII; trade name Tretten), reported Susan L. Kearney, MD, of Children’s Hospitals and Clinics of Minnesota in Minneapolis.

©benjaminalbiach/ThinkStock

“Prophylaxis was effective. The annualized bleeding rate was zero and the mean trough [FXIII activity] was greater than 10%,” she said at a moderated poster session at the World Federation of Hemophilia World Congress. “We feel that recombinant factor XIII is safe and effective in pediatric subjects less than 6 years of age with congenital factor XIII-A subunit deficiency, similar to the older age cohort.”

Factor XIII-A subunit deficiency is a rare and serious heritable bleeding disorder associated with spontaneous intracranial hemorrhage and other unpredictable types of serious bleeding.

In a previous phase III trial, 77 patients, ranging in age from 7 to 60 years, received rFXIII for bleeding prophylaxis. When given monthly, the recombinant factor was effective at preventing serious bleeding in 90% of patients. The most commonly reported adverse events were headache, pain in the extremities, and injection site pain.

Based on these results, the Food and Drug Administration granted rFXIII orphan-drug designation for treatment of patients 6 and older with factor XIII-A subunit deficiency.

In the trial reported here, investigators from the United States, United Kingdom, Israel, and Denmark enrolled three boys and three girls under age 6 who had previously completed a single dose efficacy and safety study of rFXIII. The patients received intravenous rFXIII at a dose of 35 IU/kg every 28 days for a minimum of 52 weeks.

The total treatment duration ranged from 1.8 to 3.5 years, for a total of 16.6 patient years.

There were no thromboembolic events or systemic allergic reactions, the primary safety endpoint of the study. One patient experienced three incidences of atopic dermatitis, however; two serious adverse events related to head injuries from falls during play occurred in one patient, who did not experience intracranial hemorrhage.

Two adverse events were deemed to be probably or possibly related to rFXIII: a case of viral gastroenteritis affected one patient who recovered without a change in dose, and mild fluctuating lymphocytopenia seen at baseline persisted in another patient throughout the trial.

There were no inhibitory or noninhibitory antibodies to rFXIII detected in any patient during the trial, and there were no bleeding episodes requiring additional treatment. The 14 minor bleeding episodes seen in five patients did not require treatment with an FXIII-containing product, the authors noted.

“It’s a very rare disorder, but ... the phenotype is quite severe and patients are severely affected. So this product is very useful,” said Lakshmi Srivaths, MD, a pediatric hematologist at Texas Children’s Hospital in Houston. She was not involved in the study. Unlike patients with hemophilia A or B, who require frequent factor infusions, the long half-life of this product means patients need just once-a-month infusions “that change the phenotype very significantly.”

Dr. Kearney disclosed grant/research support from Novo Nordisk, which funded the study. Some coauthors reported consulting or employment with the company.

VANCOUVER—Neurologists’ best chance to reduce disability in patients with pharmacoresistant epilepsy lies in early recognition of pharmacoresistance and early referral of patients to full-service epilepsy centers, according to a lecture delivered at the 68th Annual Meeting of the American Academy of Neurology (AAN).

Fewer than 1% of patients with refractory epilepsy are referred to epilepsy centers each year, and many patients are referred too late to significantly affect disability, said Jerome Engel Jr, MD, PhD, Jonathan Sinay Distinguished Professor of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences and Director of the Seizure Disorder Center at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Misconceptions about epilepsy centers and epilepsy surgery may be partly responsible for the dearth of referrals.

“I think a major misconception—and I have to take partial blame for this because of all the talking I’ve done about surgery in the last three decades or more—is that all epilepsy centers do is surgery. I think a common attitude among referring neurologists is, ‘My patient is not a surgical candidate or doesn’t want surgery, so there’s no reason to refer him or her to an epilepsy center,’” Dr. Engel said.

Beyond performing surgery, specialized centers can recognize pseudopharmacoresistance, diagnose nonepileptic seizures, identify specific epilepsy syndromes, and provide psychosocial support. Dr. Engel noted that, given his position as the director of an epilepsy center, his message might seem self-serving and critical of his audience, but he asked neurologists to keep an open mind. “Early, effective intervention offers the best chance to prevent irreversible psychosocial problems, a lifetime of disability, and premature death,” he said.

A Serious Burden

Refractory epilepsy can lead to developmental delays and interfere with interpersonal and vocational skills. Patients may have interictal behavioral problems, most commonly depression, or neurologic impairment. “The mortality rate for uncontrolled epilepsy is five to 10 times that of the general population, not only because of sudden unexpected death in epilepsy and accidents, but also suicide,” Dr. Engel said. Although more than 20 new antiseizure drugs have been approved in the last three decades, the percentage of patients with pharmacoresistant epilepsy has not changed.

According to the International League Against Epilepsy, a patient has drug-resistant epilepsy when he or she fails two trials of appropriate antiseizure drugs, either alone or in combination, due to inefficacy and not intolerance. Of the approximately three million people with epilepsy in the United States, about one-third have pharmacoresistant epilepsy. According to the National Association of Epilepsy Centers, about 4,000 patients are referred to epilepsy centers per year, Dr. Engel said.

The publication of evidence-based recommendations for epilepsy center referrals has not had an obvious effect on clinical practice. In 2003, Dr. Engel and colleagues in the Quality Standards Subcommittee of the AAN published a practice parameter for temporal lobe resections. Based on a randomized controlled trial and 24 case series, they concluded that surgery provides greater benefit than medical treatment, with risks that are at least comparable. The trial by Wiebe et al found that, after a year, 64% of the patients who had surgery were seizure-free, compared with 8% of patients in the medical arm. An analysis of the case series, which included 1,952 patients, yielded nearly the same results. They recommended that patients with drug-resistant temporal lobe seizures be referred to an epilepsy center, and that surgical candidates undergo surgery.

The practice parameter, however, did not lead to earlier referrals for surgery evaluations at UCLA’s epilepsy center. Haneef et al found that in the four years before publication of the practice parameter, patients’ average time from diagnosis to referral was 17 years, compared with 18.6 years in the four years after publication.

More Than Surgery

Epilepsy centers can identify pseudopharmacoresistance in patients who are not compliant in taking their medication or who are prescribed the wrong drugs or dosage. Furthermore, a third of patients admitted to epilepsy centers do not have epilepsy, Dr. Engel said. Patients’ apparent pharmacoresistance may be caused by lifestyle issues, such as substance abuse or frequent sleep deprivation, or other conditions.

Many patients, even if their condition improves, continue to have seizures and disability. “Epilepsy centers have psychologists, psychiatrists, social workers, and counselors who help patients deal with problems that are caused by their seizures,” Dr. Engel said.

Other treatments that epilepsy centers provide include experimental drug trials and stimulation techniques, such as vagus nerve stimulation, trigeminal nerve stimulation, and responsive neurostimulation. In addition, epilepsy centers can identify patients who might benefit from the ketogenic diet or modified Atkins diet.

Surgical Candidates?

Various common misconceptions about contraindications for surgery also may prevent patients from being referred to specialized centers. For instance, bilateral interictal spikes are not a contraindication for surgery because in most patients with this finding, all seizures originate from one side. A normal MRI is not a contraindication for surgery because techniques such as PET-MRI fusion and magnetoencephalography can identify epileptogenic regions that do not appear on MRI. If a patient has multiple or diffuse lesions, only one of the lesions might be epileptogenic, or if a patient has a large lesion, only part of the lesion might be epileptogenic. When an abnormality is in a primary cortex, there are ways to identify cortex that cannot be removed and still obtain good results with surgery, Dr. Engel said.

In patients with existing memory deficits, surgery typically does not worsen memory and can improve it. In patients who do not have memory deficits, however, surgery of the language-dominant temporal lobe may worsen memory, and this complication may be a concern.

Chronic psychosis is not a contraindication for surgery. “If it’s postictal psychosis, it will go away after seizures stop. If it’s interictal psychosis, a patient with schizophrenia is better off without epilepsy than with epilepsy, even if they’ll still have schizophrenia,” Dr. Engel said. An IQ less than 70 was once considered a contraindication for surgery, but that is no longer necessarily the case.

Another issue that may be increasingly common is the removal of lesions at hospitals that perform few epilepsy surgeries (ie, low-volume hospitals). “The outcomes are not as good. There’s more morbidity, and there’s mortality, which we don’t see very much in the epilepsy centers,” Dr. Engel said. In addition, many lesions are incidental findings. “You really need to demonstrate when you see a lesion that that lesion is the source of the habitual seizures,” Dr. Engel said.

In an analysis of 6,200 epilepsy surgery procedures published in the August issue of Epilepsy Research, Rolston et al observed higher rates of adverse events when low- and high-volume centers were examined together, compared with high-volume centers alone.

ERSET Outcomes

Some 100,000 to 500,000 patients with epilepsy in the US are potential surgical candidates, and about 2,000 epilepsy surgeries are performed per year. Surgical outcomes have improved over the last few decades, and new surgical techniques have been developed, including laser thermal ablation, which can be performed through a small drill hole, Dr. Engel said.

To determine whether surgery soon after failure of two antiepileptic drug trials is superior to continued medical management, Dr. Engel and colleagues conducted the Early Randomized Surgical Epilepsy Trial (ERSET), which was published in JAMA in 2012. The multicenter trial was stopped early due to slow study recruitment. It included 38 participants (ages 12 and older, 18 men) who had mesial temporal lobe epilepsy and disabling seizures for no more than two consecutive years after their two failed drug trials. Only surgical candidates were randomized. In an intent-to-treat analysis, all of the patients in the medical arm continued to have seizures, while 11 patients in the surgical arm (73%) were seizure-free during year two of follow-up. In an analysis that included only patients for whom researchers had complete data, 85% of patients in the surgical group were seizure-free. Compared with the medical treatment group, patients in the surgical group had improved quality of life. Adverse events included three episodes of status epilepticus in the medical group and a transient stroke in the surgical group. Memory decline occurred in four participants after surgery, but the sample was too small to assess the effect of treatment on cognitive function.

“All people with refractory epilepsy deserve a timely consultation at an epilepsy center,” Dr. Engel said. “Many are not refractory. Many are surgical candidates. And the remainder of them deserve psychosocial support.”

—Jake Remaly

VANCOUVER—Neurologists’ best chance to reduce disability in patients with pharmacoresistant epilepsy lies in early recognition of pharmacoresistance and early referral of patients to full-service epilepsy centers, according to a lecture delivered at the 68th Annual Meeting of the American Academy of Neurology (AAN).

Fewer than 1% of patients with refractory epilepsy are referred to epilepsy centers each year, and many patients are referred too late to significantly affect disability, said Jerome Engel Jr, MD, PhD, Jonathan Sinay Distinguished Professor of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences and Director of the Seizure Disorder Center at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Misconceptions about epilepsy centers and epilepsy surgery may be partly responsible for the dearth of referrals.

“I think a major misconception—and I have to take partial blame for this because of all the talking I’ve done about surgery in the last three decades or more—is that all epilepsy centers do is surgery. I think a common attitude among referring neurologists is, ‘My patient is not a surgical candidate or doesn’t want surgery, so there’s no reason to refer him or her to an epilepsy center,’” Dr. Engel said.

Beyond performing surgery, specialized centers can recognize pseudopharmacoresistance, diagnose nonepileptic seizures, identify specific epilepsy syndromes, and provide psychosocial support. Dr. Engel noted that, given his position as the director of an epilepsy center, his message might seem self-serving and critical of his audience, but he asked neurologists to keep an open mind. “Early, effective intervention offers the best chance to prevent irreversible psychosocial problems, a lifetime of disability, and premature death,” he said.

A Serious Burden

Refractory epilepsy can lead to developmental delays and interfere with interpersonal and vocational skills. Patients may have interictal behavioral problems, most commonly depression, or neurologic impairment. “The mortality rate for uncontrolled epilepsy is five to 10 times that of the general population, not only because of sudden unexpected death in epilepsy and accidents, but also suicide,” Dr. Engel said. Although more than 20 new antiseizure drugs have been approved in the last three decades, the percentage of patients with pharmacoresistant epilepsy has not changed.

According to the International League Against Epilepsy, a patient has drug-resistant epilepsy when he or she fails two trials of appropriate antiseizure drugs, either alone or in combination, due to inefficacy and not intolerance. Of the approximately three million people with epilepsy in the United States, about one-third have pharmacoresistant epilepsy. According to the National Association of Epilepsy Centers, about 4,000 patients are referred to epilepsy centers per year, Dr. Engel said.

The publication of evidence-based recommendations for epilepsy center referrals has not had an obvious effect on clinical practice. In 2003, Dr. Engel and colleagues in the Quality Standards Subcommittee of the AAN published a practice parameter for temporal lobe resections. Based on a randomized controlled trial and 24 case series, they concluded that surgery provides greater benefit than medical treatment, with risks that are at least comparable. The trial by Wiebe et al found that, after a year, 64% of the patients who had surgery were seizure-free, compared with 8% of patients in the medical arm. An analysis of the case series, which included 1,952 patients, yielded nearly the same results. They recommended that patients with drug-resistant temporal lobe seizures be referred to an epilepsy center, and that surgical candidates undergo surgery.

The practice parameter, however, did not lead to earlier referrals for surgery evaluations at UCLA’s epilepsy center. Haneef et al found that in the four years before publication of the practice parameter, patients’ average time from diagnosis to referral was 17 years, compared with 18.6 years in the four years after publication.

More Than Surgery

Epilepsy centers can identify pseudopharmacoresistance in patients who are not compliant in taking their medication or who are prescribed the wrong drugs or dosage. Furthermore, a third of patients admitted to epilepsy centers do not have epilepsy, Dr. Engel said. Patients’ apparent pharmacoresistance may be caused by lifestyle issues, such as substance abuse or frequent sleep deprivation, or other conditions.

Many patients, even if their condition improves, continue to have seizures and disability. “Epilepsy centers have psychologists, psychiatrists, social workers, and counselors who help patients deal with problems that are caused by their seizures,” Dr. Engel said.

Other treatments that epilepsy centers provide include experimental drug trials and stimulation techniques, such as vagus nerve stimulation, trigeminal nerve stimulation, and responsive neurostimulation. In addition, epilepsy centers can identify patients who might benefit from the ketogenic diet or modified Atkins diet.

Surgical Candidates?

Various common misconceptions about contraindications for surgery also may prevent patients from being referred to specialized centers. For instance, bilateral interictal spikes are not a contraindication for surgery because in most patients with this finding, all seizures originate from one side. A normal MRI is not a contraindication for surgery because techniques such as PET-MRI fusion and magnetoencephalography can identify epileptogenic regions that do not appear on MRI. If a patient has multiple or diffuse lesions, only one of the lesions might be epileptogenic, or if a patient has a large lesion, only part of the lesion might be epileptogenic. When an abnormality is in a primary cortex, there are ways to identify cortex that cannot be removed and still obtain good results with surgery, Dr. Engel said.

In patients with existing memory deficits, surgery typically does not worsen memory and can improve it. In patients who do not have memory deficits, however, surgery of the language-dominant temporal lobe may worsen memory, and this complication may be a concern.

Chronic psychosis is not a contraindication for surgery. “If it’s postictal psychosis, it will go away after seizures stop. If it’s interictal psychosis, a patient with schizophrenia is better off without epilepsy than with epilepsy, even if they’ll still have schizophrenia,” Dr. Engel said. An IQ less than 70 was once considered a contraindication for surgery, but that is no longer necessarily the case.

Another issue that may be increasingly common is the removal of lesions at hospitals that perform few epilepsy surgeries (ie, low-volume hospitals). “The outcomes are not as good. There’s more morbidity, and there’s mortality, which we don’t see very much in the epilepsy centers,” Dr. Engel said. In addition, many lesions are incidental findings. “You really need to demonstrate when you see a lesion that that lesion is the source of the habitual seizures,” Dr. Engel said.

In an analysis of 6,200 epilepsy surgery procedures published in the August issue of Epilepsy Research, Rolston et al observed higher rates of adverse events when low- and high-volume centers were examined together, compared with high-volume centers alone.

ERSET Outcomes

Some 100,000 to 500,000 patients with epilepsy in the US are potential surgical candidates, and about 2,000 epilepsy surgeries are performed per year. Surgical outcomes have improved over the last few decades, and new surgical techniques have been developed, including laser thermal ablation, which can be performed through a small drill hole, Dr. Engel said.

To determine whether surgery soon after failure of two antiepileptic drug trials is superior to continued medical management, Dr. Engel and colleagues conducted the Early Randomized Surgical Epilepsy Trial (ERSET), which was published in JAMA in 2012. The multicenter trial was stopped early due to slow study recruitment. It included 38 participants (ages 12 and older, 18 men) who had mesial temporal lobe epilepsy and disabling seizures for no more than two consecutive years after their two failed drug trials. Only surgical candidates were randomized. In an intent-to-treat analysis, all of the patients in the medical arm continued to have seizures, while 11 patients in the surgical arm (73%) were seizure-free during year two of follow-up. In an analysis that included only patients for whom researchers had complete data, 85% of patients in the surgical group were seizure-free. Compared with the medical treatment group, patients in the surgical group had improved quality of life. Adverse events included three episodes of status epilepticus in the medical group and a transient stroke in the surgical group. Memory decline occurred in four participants after surgery, but the sample was too small to assess the effect of treatment on cognitive function.

“All people with refractory epilepsy deserve a timely consultation at an epilepsy center,” Dr. Engel said. “Many are not refractory. Many are surgical candidates. And the remainder of them deserve psychosocial support.”

—Jake Remaly

VANCOUVER—Neurologists’ best chance to reduce disability in patients with pharmacoresistant epilepsy lies in early recognition of pharmacoresistance and early referral of patients to full-service epilepsy centers, according to a lecture delivered at the 68th Annual Meeting of the American Academy of Neurology (AAN).

Fewer than 1% of patients with refractory epilepsy are referred to epilepsy centers each year, and many patients are referred too late to significantly affect disability, said Jerome Engel Jr, MD, PhD, Jonathan Sinay Distinguished Professor of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences and Director of the Seizure Disorder Center at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Misconceptions about epilepsy centers and epilepsy surgery may be partly responsible for the dearth of referrals.

“I think a major misconception—and I have to take partial blame for this because of all the talking I’ve done about surgery in the last three decades or more—is that all epilepsy centers do is surgery. I think a common attitude among referring neurologists is, ‘My patient is not a surgical candidate or doesn’t want surgery, so there’s no reason to refer him or her to an epilepsy center,’” Dr. Engel said.

Beyond performing surgery, specialized centers can recognize pseudopharmacoresistance, diagnose nonepileptic seizures, identify specific epilepsy syndromes, and provide psychosocial support. Dr. Engel noted that, given his position as the director of an epilepsy center, his message might seem self-serving and critical of his audience, but he asked neurologists to keep an open mind. “Early, effective intervention offers the best chance to prevent irreversible psychosocial problems, a lifetime of disability, and premature death,” he said.

A Serious Burden

Refractory epilepsy can lead to developmental delays and interfere with interpersonal and vocational skills. Patients may have interictal behavioral problems, most commonly depression, or neurologic impairment. “The mortality rate for uncontrolled epilepsy is five to 10 times that of the general population, not only because of sudden unexpected death in epilepsy and accidents, but also suicide,” Dr. Engel said. Although more than 20 new antiseizure drugs have been approved in the last three decades, the percentage of patients with pharmacoresistant epilepsy has not changed.

According to the International League Against Epilepsy, a patient has drug-resistant epilepsy when he or she fails two trials of appropriate antiseizure drugs, either alone or in combination, due to inefficacy and not intolerance. Of the approximately three million people with epilepsy in the United States, about one-third have pharmacoresistant epilepsy. According to the National Association of Epilepsy Centers, about 4,000 patients are referred to epilepsy centers per year, Dr. Engel said.

The publication of evidence-based recommendations for epilepsy center referrals has not had an obvious effect on clinical practice. In 2003, Dr. Engel and colleagues in the Quality Standards Subcommittee of the AAN published a practice parameter for temporal lobe resections. Based on a randomized controlled trial and 24 case series, they concluded that surgery provides greater benefit than medical treatment, with risks that are at least comparable. The trial by Wiebe et al found that, after a year, 64% of the patients who had surgery were seizure-free, compared with 8% of patients in the medical arm. An analysis of the case series, which included 1,952 patients, yielded nearly the same results. They recommended that patients with drug-resistant temporal lobe seizures be referred to an epilepsy center, and that surgical candidates undergo surgery.

The practice parameter, however, did not lead to earlier referrals for surgery evaluations at UCLA’s epilepsy center. Haneef et al found that in the four years before publication of the practice parameter, patients’ average time from diagnosis to referral was 17 years, compared with 18.6 years in the four years after publication.

More Than Surgery

Epilepsy centers can identify pseudopharmacoresistance in patients who are not compliant in taking their medication or who are prescribed the wrong drugs or dosage. Furthermore, a third of patients admitted to epilepsy centers do not have epilepsy, Dr. Engel said. Patients’ apparent pharmacoresistance may be caused by lifestyle issues, such as substance abuse or frequent sleep deprivation, or other conditions.

Many patients, even if their condition improves, continue to have seizures and disability. “Epilepsy centers have psychologists, psychiatrists, social workers, and counselors who help patients deal with problems that are caused by their seizures,” Dr. Engel said.

Other treatments that epilepsy centers provide include experimental drug trials and stimulation techniques, such as vagus nerve stimulation, trigeminal nerve stimulation, and responsive neurostimulation. In addition, epilepsy centers can identify patients who might benefit from the ketogenic diet or modified Atkins diet.

Surgical Candidates?

Various common misconceptions about contraindications for surgery also may prevent patients from being referred to specialized centers. For instance, bilateral interictal spikes are not a contraindication for surgery because in most patients with this finding, all seizures originate from one side. A normal MRI is not a contraindication for surgery because techniques such as PET-MRI fusion and magnetoencephalography can identify epileptogenic regions that do not appear on MRI. If a patient has multiple or diffuse lesions, only one of the lesions might be epileptogenic, or if a patient has a large lesion, only part of the lesion might be epileptogenic. When an abnormality is in a primary cortex, there are ways to identify cortex that cannot be removed and still obtain good results with surgery, Dr. Engel said.

In patients with existing memory deficits, surgery typically does not worsen memory and can improve it. In patients who do not have memory deficits, however, surgery of the language-dominant temporal lobe may worsen memory, and this complication may be a concern.

Chronic psychosis is not a contraindication for surgery. “If it’s postictal psychosis, it will go away after seizures stop. If it’s interictal psychosis, a patient with schizophrenia is better off without epilepsy than with epilepsy, even if they’ll still have schizophrenia,” Dr. Engel said. An IQ less than 70 was once considered a contraindication for surgery, but that is no longer necessarily the case.

Another issue that may be increasingly common is the removal of lesions at hospitals that perform few epilepsy surgeries (ie, low-volume hospitals). “The outcomes are not as good. There’s more morbidity, and there’s mortality, which we don’t see very much in the epilepsy centers,” Dr. Engel said. In addition, many lesions are incidental findings. “You really need to demonstrate when you see a lesion that that lesion is the source of the habitual seizures,” Dr. Engel said.

In an analysis of 6,200 epilepsy surgery procedures published in the August issue of Epilepsy Research, Rolston et al observed higher rates of adverse events when low- and high-volume centers were examined together, compared with high-volume centers alone.

ERSET Outcomes

Some 100,000 to 500,000 patients with epilepsy in the US are potential surgical candidates, and about 2,000 epilepsy surgeries are performed per year. Surgical outcomes have improved over the last few decades, and new surgical techniques have been developed, including laser thermal ablation, which can be performed through a small drill hole, Dr. Engel said.

To determine whether surgery soon after failure of two antiepileptic drug trials is superior to continued medical management, Dr. Engel and colleagues conducted the Early Randomized Surgical Epilepsy Trial (ERSET), which was published in JAMA in 2012. The multicenter trial was stopped early due to slow study recruitment. It included 38 participants (ages 12 and older, 18 men) who had mesial temporal lobe epilepsy and disabling seizures for no more than two consecutive years after their two failed drug trials. Only surgical candidates were randomized. In an intent-to-treat analysis, all of the patients in the medical arm continued to have seizures, while 11 patients in the surgical arm (73%) were seizure-free during year two of follow-up. In an analysis that included only patients for whom researchers had complete data, 85% of patients in the surgical group were seizure-free. Compared with the medical treatment group, patients in the surgical group had improved quality of life. Adverse events included three episodes of status epilepticus in the medical group and a transient stroke in the surgical group. Memory decline occurred in four participants after surgery, but the sample was too small to assess the effect of treatment on cognitive function.

“All people with refractory epilepsy deserve a timely consultation at an epilepsy center,” Dr. Engel said. “Many are not refractory. Many are surgical candidates. And the remainder of them deserve psychosocial support.”

—Jake Remaly

The Centers for Medicare & Medicaid Services in April announced its newest initiative, Comprehensive Primary Care Plus, to target primary care practices of varying capabilities to participate in an innovative payment model designed to support the delivery of comprehensive primary care that rewards value and quality.

“Strengthening primary care is critical to an effective health care system,” said Patrick Conway, MD, CMS deputy administrator and chief medical officer. “By supporting primary care doctors and clinicians to spend time with patients, serve patients’ needs outside of the office visit, and better coordinate care with specialists, we can continue to build a health care system that results in healthier people and smarter spending of our health care dollars.”

As readers of this column know, these are also the engines of accountable care organization success. So, if you and your patient-centered medical home are not in a Medicare ACO, this gets you going on high-value activities – and pays you monthly to do it.

The rub is that once you are in the Medicare Shared Savings Program, you can’t continue with this initiative. But, it’s a great “on ramp” to prep you for ACO success. You get monthly payments instead of waiting 18 months for shared savings that you may or may not get under the Medicare Shared Savings Program.

CPC+ is an advanced primary medical home model, created from lessons learned in the Comprehensive Primary Care Initiative and the Multi-Payer Advanced Primary Care Practice Demonstration. Similar to these programs, multi-payer engagement is an essential component of the model.

In the CPC+ model, the CMS intends to nationally solicit a variety of payers committed to strengthening primary care in up to 20 regions and accept up to 5,000 practices to participate in those regions. The CPC+ program is further evidence that primary care should not only be a fundamental component to moving our health care system to one that awards clinicians based on the quality, not quantity, of care they give patients, but that payment redesign must provide flexibility to accommodate the diverse needs of primary care practices.

What to know about payment

To provide this flexibility and to attract practices of varying capabilities and levels of experience, the CPC+ program offers two tracks with different payment options, which include a monthly care management fee, comprehensive primary care payments, and performance-based incentive payments.

In track 1, the CMS will pay practices a risk-adjusted prospective monthly care management fee ($15 per beneficiary per month [PBPM] average across four risk tiers), in addition to the fee-for-service payments under the Medicare Physician Fee Schedule for activities.

In track 2, the Medicare monthly care management fees will average $28 PBPM across five risk tiers, which includes a $100 care management fee to support care for patients with the most complex needs. Instead of full Medicare fee-for-service payments for evaluation and management services, track 2 practices will receive a hybrid of reduced Medicare fee-for-service payments and up-front comprehensive primary care payments for those services.

In addition, the CMS is providing incentive payments at $2.50 PBPM for track 1 and $4 PBPM for track 2, based on practice performance on utilization metrics and quality, measured at the practice level. While these payments are prepaid at the beginning of a performance year, they are subject to recoupment if the practice does not meet thresholds for quality and utilization performance.

What to know about participation

To participate, your practice must be located within 1 of the 20 regional geographic areas selected by the CMS and must serve not only Medicare beneficiaries, but patients covered by one or more additional participating payers.

You may apply for either track 1 or track 2, but participation for the entire 5-year period will be within a single track.

All practices will be expected to deliver a set of five comprehensive primary care functions and have certified electronic health record technology capabilities. Track 2 practices will be expected to focus on a core set of advance capabilities for health information technology and must submit a letter of support from their health IT vendors. The CMS may require a track 2 applicant to participate in track 1.

Participating in the CPC+ program limits your ability to fully participate in or utilize other CMS initiatives, models, or demonstrations, however – including the Medicare Shared Savings Program and Next Generation ACO, or bill for the chronic care management fee. This is a big trade-off for practices well down the value transformation path, but an opportunity for those getting started.

Although the shift to payment for improved population health can herald the golden age of primary care, you cannot default on this opportunity through inaction. It is urgent that you choose a path to value-care delivery. CPC+ provides the ability for greater cash flow and flexibility for primary care practices to deliver high-quality, whole-person patient-centered care.

Mr. Bobbitt is head of the health law group at the Smith Anderson law firm in Raleigh, N.C. He is president of Value Health Partners, LLC, a health care strategic consulting company. He has years of experience assisting physicians to form integrated delivery systems and prepare for the value-based compensation era. Mr. Parker is a member of the health law group at Smith Anderson and works with Mr. Bobbitt to guide physicians regarding preparing for value-based care. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author at [email protected] or 919-821-6612.

The Centers for Medicare & Medicaid Services in April announced its newest initiative, Comprehensive Primary Care Plus, to target primary care practices of varying capabilities to participate in an innovative payment model designed to support the delivery of comprehensive primary care that rewards value and quality.

“Strengthening primary care is critical to an effective health care system,” said Patrick Conway, MD, CMS deputy administrator and chief medical officer. “By supporting primary care doctors and clinicians to spend time with patients, serve patients’ needs outside of the office visit, and better coordinate care with specialists, we can continue to build a health care system that results in healthier people and smarter spending of our health care dollars.”

As readers of this column know, these are also the engines of accountable care organization success. So, if you and your patient-centered medical home are not in a Medicare ACO, this gets you going on high-value activities – and pays you monthly to do it.

The rub is that once you are in the Medicare Shared Savings Program, you can’t continue with this initiative. But, it’s a great “on ramp” to prep you for ACO success. You get monthly payments instead of waiting 18 months for shared savings that you may or may not get under the Medicare Shared Savings Program.

CPC+ is an advanced primary medical home model, created from lessons learned in the Comprehensive Primary Care Initiative and the Multi-Payer Advanced Primary Care Practice Demonstration. Similar to these programs, multi-payer engagement is an essential component of the model.

In the CPC+ model, the CMS intends to nationally solicit a variety of payers committed to strengthening primary care in up to 20 regions and accept up to 5,000 practices to participate in those regions. The CPC+ program is further evidence that primary care should not only be a fundamental component to moving our health care system to one that awards clinicians based on the quality, not quantity, of care they give patients, but that payment redesign must provide flexibility to accommodate the diverse needs of primary care practices.

What to know about payment

To provide this flexibility and to attract practices of varying capabilities and levels of experience, the CPC+ program offers two tracks with different payment options, which include a monthly care management fee, comprehensive primary care payments, and performance-based incentive payments.

In track 1, the CMS will pay practices a risk-adjusted prospective monthly care management fee ($15 per beneficiary per month [PBPM] average across four risk tiers), in addition to the fee-for-service payments under the Medicare Physician Fee Schedule for activities.

In track 2, the Medicare monthly care management fees will average $28 PBPM across five risk tiers, which includes a $100 care management fee to support care for patients with the most complex needs. Instead of full Medicare fee-for-service payments for evaluation and management services, track 2 practices will receive a hybrid of reduced Medicare fee-for-service payments and up-front comprehensive primary care payments for those services.

In addition, the CMS is providing incentive payments at $2.50 PBPM for track 1 and $4 PBPM for track 2, based on practice performance on utilization metrics and quality, measured at the practice level. While these payments are prepaid at the beginning of a performance year, they are subject to recoupment if the practice does not meet thresholds for quality and utilization performance.

What to know about participation

To participate, your practice must be located within 1 of the 20 regional geographic areas selected by the CMS and must serve not only Medicare beneficiaries, but patients covered by one or more additional participating payers.

You may apply for either track 1 or track 2, but participation for the entire 5-year period will be within a single track.

All practices will be expected to deliver a set of five comprehensive primary care functions and have certified electronic health record technology capabilities. Track 2 practices will be expected to focus on a core set of advance capabilities for health information technology and must submit a letter of support from their health IT vendors. The CMS may require a track 2 applicant to participate in track 1.

Participating in the CPC+ program limits your ability to fully participate in or utilize other CMS initiatives, models, or demonstrations, however – including the Medicare Shared Savings Program and Next Generation ACO, or bill for the chronic care management fee. This is a big trade-off for practices well down the value transformation path, but an opportunity for those getting started.

Although the shift to payment for improved population health can herald the golden age of primary care, you cannot default on this opportunity through inaction. It is urgent that you choose a path to value-care delivery. CPC+ provides the ability for greater cash flow and flexibility for primary care practices to deliver high-quality, whole-person patient-centered care.

Mr. Bobbitt is head of the health law group at the Smith Anderson law firm in Raleigh, N.C. He is president of Value Health Partners, LLC, a health care strategic consulting company. He has years of experience assisting physicians to form integrated delivery systems and prepare for the value-based compensation era. Mr. Parker is a member of the health law group at Smith Anderson and works with Mr. Bobbitt to guide physicians regarding preparing for value-based care. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author at [email protected] or 919-821-6612.

The Centers for Medicare & Medicaid Services in April announced its newest initiative, Comprehensive Primary Care Plus, to target primary care practices of varying capabilities to participate in an innovative payment model designed to support the delivery of comprehensive primary care that rewards value and quality.

“Strengthening primary care is critical to an effective health care system,” said Patrick Conway, MD, CMS deputy administrator and chief medical officer. “By supporting primary care doctors and clinicians to spend time with patients, serve patients’ needs outside of the office visit, and better coordinate care with specialists, we can continue to build a health care system that results in healthier people and smarter spending of our health care dollars.”

As readers of this column know, these are also the engines of accountable care organization success. So, if you and your patient-centered medical home are not in a Medicare ACO, this gets you going on high-value activities – and pays you monthly to do it.

The rub is that once you are in the Medicare Shared Savings Program, you can’t continue with this initiative. But, it’s a great “on ramp” to prep you for ACO success. You get monthly payments instead of waiting 18 months for shared savings that you may or may not get under the Medicare Shared Savings Program.

CPC+ is an advanced primary medical home model, created from lessons learned in the Comprehensive Primary Care Initiative and the Multi-Payer Advanced Primary Care Practice Demonstration. Similar to these programs, multi-payer engagement is an essential component of the model.

In the CPC+ model, the CMS intends to nationally solicit a variety of payers committed to strengthening primary care in up to 20 regions and accept up to 5,000 practices to participate in those regions. The CPC+ program is further evidence that primary care should not only be a fundamental component to moving our health care system to one that awards clinicians based on the quality, not quantity, of care they give patients, but that payment redesign must provide flexibility to accommodate the diverse needs of primary care practices.

What to know about payment

To provide this flexibility and to attract practices of varying capabilities and levels of experience, the CPC+ program offers two tracks with different payment options, which include a monthly care management fee, comprehensive primary care payments, and performance-based incentive payments.

In track 1, the CMS will pay practices a risk-adjusted prospective monthly care management fee ($15 per beneficiary per month [PBPM] average across four risk tiers), in addition to the fee-for-service payments under the Medicare Physician Fee Schedule for activities.

In track 2, the Medicare monthly care management fees will average $28 PBPM across five risk tiers, which includes a $100 care management fee to support care for patients with the most complex needs. Instead of full Medicare fee-for-service payments for evaluation and management services, track 2 practices will receive a hybrid of reduced Medicare fee-for-service payments and up-front comprehensive primary care payments for those services.

In addition, the CMS is providing incentive payments at $2.50 PBPM for track 1 and $4 PBPM for track 2, based on practice performance on utilization metrics and quality, measured at the practice level. While these payments are prepaid at the beginning of a performance year, they are subject to recoupment if the practice does not meet thresholds for quality and utilization performance.

What to know about participation

To participate, your practice must be located within 1 of the 20 regional geographic areas selected by the CMS and must serve not only Medicare beneficiaries, but patients covered by one or more additional participating payers.

You may apply for either track 1 or track 2, but participation for the entire 5-year period will be within a single track.

All practices will be expected to deliver a set of five comprehensive primary care functions and have certified electronic health record technology capabilities. Track 2 practices will be expected to focus on a core set of advance capabilities for health information technology and must submit a letter of support from their health IT vendors. The CMS may require a track 2 applicant to participate in track 1.

Participating in the CPC+ program limits your ability to fully participate in or utilize other CMS initiatives, models, or demonstrations, however – including the Medicare Shared Savings Program and Next Generation ACO, or bill for the chronic care management fee. This is a big trade-off for practices well down the value transformation path, but an opportunity for those getting started.

Although the shift to payment for improved population health can herald the golden age of primary care, you cannot default on this opportunity through inaction. It is urgent that you choose a path to value-care delivery. CPC+ provides the ability for greater cash flow and flexibility for primary care practices to deliver high-quality, whole-person patient-centered care.

Mr. Bobbitt is head of the health law group at the Smith Anderson law firm in Raleigh, N.C. He is president of Value Health Partners, LLC, a health care strategic consulting company. He has years of experience assisting physicians to form integrated delivery systems and prepare for the value-based compensation era. Mr. Parker is a member of the health law group at Smith Anderson and works with Mr. Bobbitt to guide physicians regarding preparing for value-based care. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author at [email protected] or 919-821-6612.

For patients with extensive-stage small-cell lung cancer, adding the anti–CTLA-4 antibody ipilimumab (Yervoy) to etoposide and platinum did not improve overall survival, compared with administering etoposide and platinum alone, investigators reported in the Journal of Clinical Oncology.

“Although exploratory in nature, chemotherapy plus ipilimumab did not demonstrate significant improvement in other endpoints, and no subgroups demonstrated greater benefit versus chemotherapy alone,” added Martin Reck, MD, of LungenClinic Grosshansdorf (Germany), and his associates.

The randomized phase III study enrolled 1,132 chemotherapy-naive patients who were randomly assigned to either chemotherapy plus ipilimumab (etoposide plus investigator’s choice of cisplatin or carboplatin during cycles one to four, and ipilimumab during cycles three to six) or to chemotherapy plus placebo (etoposide plus investigator’s choice of cisplatin or carboplatin during cycles one to four, and placebo during cycles three to six). Patients with a complete or partial response during induction could undergo prophylactic cranial irradiation before starting maintenance ipilimumab (10 mg/kg) or placebo administered every 12 weeks, the investigators reported (J Clin Oncol. 2016 July 26. doi:10.1200/JCO.2016.67.6601).

Among 954 patients who received at least one dose of study therapy, the primary endpoint, median overall survival, was 11.0 months for the ipilimumab-chemotherapy arm and 10.9 months for the placebo arm (hazard ratio, 0.9; 95% confidence interval, 0.8-1.1; P = .4). “Across most prespecified patient subgroups, hazard ratios for overall survival [also] did not seem to favor one treatment arm,” the researchers wrote.

Ipilimumab also failed to achieve a meaningful increase in median progression-free survival, compared with placebo (4.6 months and 4.4 months, respectively). There was only one complete response in the ipilimumab-chemotherapy group and none in the chemotherapy-placebo group. A total of 62% of patients achieved a partial response in each group, and the median duration of response was 4 months in the ipilimumab-chemotherapy group (95% CI, 3.3-4.2 months) versus 3.5 months (95% CI, 3.3-4.1 months) in the chemotherapy-placebo group.

There were no new or unexpected safety signals, but ipilimumab was associated with higher rates of overall and severe-grade diarrhea, colitis, and rash. The five treatment-related deaths in the ipilimumab-chemotherapy group included two from colitis, two from sepsis, and one from liver toxicity. “In the chemotherapy plus placebo arm, there were two treatment-related deaths, one resulting from sepsis and one from bone marrow suppression,” the researchers wrote. Treatment-related discontinuations also were more common with ipilimumab plus chemotherapy (18%) than with chemotherapy plus placebo (2%).

“To date, PD-1 inhibitors, alone or in combination with CTLA-4 inhibitors, show the most promise in small-cell lung cancer,” the investigators said. Multiple trials are exploring the use of these agents as maintenance therapy or in second-line settings, they added.

Bristol-Myers Squibb makes ipilimumab, funded the study, and helped collect and analyze the data. Dr. Reck disclosed financial ties to Bristol-Myers Squibb, Hoffmann-La Roche, Eli Lilly, Merck Sharp & Dohme, and several other pharmaceutical companies.

[email protected]

For patients with extensive-stage small-cell lung cancer, adding the anti–CTLA-4 antibody ipilimumab (Yervoy) to etoposide and platinum did not improve overall survival, compared with administering etoposide and platinum alone, investigators reported in the Journal of Clinical Oncology.

“Although exploratory in nature, chemotherapy plus ipilimumab did not demonstrate significant improvement in other endpoints, and no subgroups demonstrated greater benefit versus chemotherapy alone,” added Martin Reck, MD, of LungenClinic Grosshansdorf (Germany), and his associates.

The randomized phase III study enrolled 1,132 chemotherapy-naive patients who were randomly assigned to either chemotherapy plus ipilimumab (etoposide plus investigator’s choice of cisplatin or carboplatin during cycles one to four, and ipilimumab during cycles three to six) or to chemotherapy plus placebo (etoposide plus investigator’s choice of cisplatin or carboplatin during cycles one to four, and placebo during cycles three to six). Patients with a complete or partial response during induction could undergo prophylactic cranial irradiation before starting maintenance ipilimumab (10 mg/kg) or placebo administered every 12 weeks, the investigators reported (J Clin Oncol. 2016 July 26. doi:10.1200/JCO.2016.67.6601).

Among 954 patients who received at least one dose of study therapy, the primary endpoint, median overall survival, was 11.0 months for the ipilimumab-chemotherapy arm and 10.9 months for the placebo arm (hazard ratio, 0.9; 95% confidence interval, 0.8-1.1; P = .4). “Across most prespecified patient subgroups, hazard ratios for overall survival [also] did not seem to favor one treatment arm,” the researchers wrote.

Ipilimumab also failed to achieve a meaningful increase in median progression-free survival, compared with placebo (4.6 months and 4.4 months, respectively). There was only one complete response in the ipilimumab-chemotherapy group and none in the chemotherapy-placebo group. A total of 62% of patients achieved a partial response in each group, and the median duration of response was 4 months in the ipilimumab-chemotherapy group (95% CI, 3.3-4.2 months) versus 3.5 months (95% CI, 3.3-4.1 months) in the chemotherapy-placebo group.

There were no new or unexpected safety signals, but ipilimumab was associated with higher rates of overall and severe-grade diarrhea, colitis, and rash. The five treatment-related deaths in the ipilimumab-chemotherapy group included two from colitis, two from sepsis, and one from liver toxicity. “In the chemotherapy plus placebo arm, there were two treatment-related deaths, one resulting from sepsis and one from bone marrow suppression,” the researchers wrote. Treatment-related discontinuations also were more common with ipilimumab plus chemotherapy (18%) than with chemotherapy plus placebo (2%).

“To date, PD-1 inhibitors, alone or in combination with CTLA-4 inhibitors, show the most promise in small-cell lung cancer,” the investigators said. Multiple trials are exploring the use of these agents as maintenance therapy or in second-line settings, they added.

Bristol-Myers Squibb makes ipilimumab, funded the study, and helped collect and analyze the data. Dr. Reck disclosed financial ties to Bristol-Myers Squibb, Hoffmann-La Roche, Eli Lilly, Merck Sharp & Dohme, and several other pharmaceutical companies.

[email protected]

For patients with extensive-stage small-cell lung cancer, adding the anti–CTLA-4 antibody ipilimumab (Yervoy) to etoposide and platinum did not improve overall survival, compared with administering etoposide and platinum alone, investigators reported in the Journal of Clinical Oncology.

“Although exploratory in nature, chemotherapy plus ipilimumab did not demonstrate significant improvement in other endpoints, and no subgroups demonstrated greater benefit versus chemotherapy alone,” added Martin Reck, MD, of LungenClinic Grosshansdorf (Germany), and his associates.

The randomized phase III study enrolled 1,132 chemotherapy-naive patients who were randomly assigned to either chemotherapy plus ipilimumab (etoposide plus investigator’s choice of cisplatin or carboplatin during cycles one to four, and ipilimumab during cycles three to six) or to chemotherapy plus placebo (etoposide plus investigator’s choice of cisplatin or carboplatin during cycles one to four, and placebo during cycles three to six). Patients with a complete or partial response during induction could undergo prophylactic cranial irradiation before starting maintenance ipilimumab (10 mg/kg) or placebo administered every 12 weeks, the investigators reported (J Clin Oncol. 2016 July 26. doi:10.1200/JCO.2016.67.6601).

Among 954 patients who received at least one dose of study therapy, the primary endpoint, median overall survival, was 11.0 months for the ipilimumab-chemotherapy arm and 10.9 months for the placebo arm (hazard ratio, 0.9; 95% confidence interval, 0.8-1.1; P = .4). “Across most prespecified patient subgroups, hazard ratios for overall survival [also] did not seem to favor one treatment arm,” the researchers wrote.

Ipilimumab also failed to achieve a meaningful increase in median progression-free survival, compared with placebo (4.6 months and 4.4 months, respectively). There was only one complete response in the ipilimumab-chemotherapy group and none in the chemotherapy-placebo group. A total of 62% of patients achieved a partial response in each group, and the median duration of response was 4 months in the ipilimumab-chemotherapy group (95% CI, 3.3-4.2 months) versus 3.5 months (95% CI, 3.3-4.1 months) in the chemotherapy-placebo group.

There were no new or unexpected safety signals, but ipilimumab was associated with higher rates of overall and severe-grade diarrhea, colitis, and rash. The five treatment-related deaths in the ipilimumab-chemotherapy group included two from colitis, two from sepsis, and one from liver toxicity. “In the chemotherapy plus placebo arm, there were two treatment-related deaths, one resulting from sepsis and one from bone marrow suppression,” the researchers wrote. Treatment-related discontinuations also were more common with ipilimumab plus chemotherapy (18%) than with chemotherapy plus placebo (2%).

“To date, PD-1 inhibitors, alone or in combination with CTLA-4 inhibitors, show the most promise in small-cell lung cancer,” the investigators said. Multiple trials are exploring the use of these agents as maintenance therapy or in second-line settings, they added.

Bristol-Myers Squibb makes ipilimumab, funded the study, and helped collect and analyze the data. Dr. Reck disclosed financial ties to Bristol-Myers Squibb, Hoffmann-La Roche, Eli Lilly, Merck Sharp & Dohme, and several other pharmaceutical companies.

[email protected]

DENVER – U.S. rheumatologists plan to develop new criteria to define minimal disease activity in patients with axial spondyloarthritis to better gauge in routine clinical practice how well these patients respond to treatment.

A score on the Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 1.3 is the most commonly used measure today of minimal disease activity, but the ASDAS isn’t suitable for point-of-care assessment in routine practice because of the need for a C-reactive protein level or erythrocyte sedimentation rate.

Mitchel L. Zoler/Frontline Medical News

“In the clinic, ASDAS is very difficult or next to impossible to do” because it needs CRP or ESR, which are “never available at the point of care,” Atul A. Deodhar, MD, said in an interview at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN). Another limitation of ASDAS is that it focuses exclusively on musculoskeletal measures and does not take into account extra-articular manifestations of axial spondyloarthritis such as those in the eye, gastrointestinal tract, or skin.

“We would like a clinical measurement that might tell us that a patient is appropriately treated and at minimal disease activity,” said Dr. Deodhar, professor of medicine and medical director of the rheumatology clinics at Oregon Health & Science University in Portland.

As outgoing chair of SPARTAN, Dr. Deodhar introduced a proposal that SPARTAN develop new minimal disease activity criteria for patients with axial spondyloarthritis, presenting the rationale for this project at the meeting along with the incoming chair Lianne S. Gensler, MD.

“We want a way to measure disease activity at a stage that is not full remission but with enough of a reduction in disease activity to make a difference,” said Dr. Gensler, director of the Ankylosing Spondylitis Clinic at the University of California, San Francisco. Another frequently used gauge of minimal disease activity in axial spondyloarthritis, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), is flawed by being totally based on subjective measurements without input from the attending rheumatologist, Dr. Gensler said.

The SPARTAN leadership will try to partner in this effort with the OMERACT (Outcome Measures in Rheumatology) program, the Assessment of Spondyloarthritis International Society (ASAS), or both, but if necessary SPARTAN will develop new minimal disease activity criteria on its own, Dr. Deodhar said.

Dr. Deodhar has received research support from 10 drug companies. Dr. Gensler has been a consultant to or has received research support from AbbVie, Amgen, Janssen, Novartis, and UCB.

[email protected]

On Twitter @mitchelzoler

DENVER – U.S. rheumatologists plan to develop new criteria to define minimal disease activity in patients with axial spondyloarthritis to better gauge in routine clinical practice how well these patients respond to treatment.

A score on the Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 1.3 is the most commonly used measure today of minimal disease activity, but the ASDAS isn’t suitable for point-of-care assessment in routine practice because of the need for a C-reactive protein level or erythrocyte sedimentation rate.

Mitchel L. Zoler/Frontline Medical News

“In the clinic, ASDAS is very difficult or next to impossible to do” because it needs CRP or ESR, which are “never available at the point of care,” Atul A. Deodhar, MD, said in an interview at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN). Another limitation of ASDAS is that it focuses exclusively on musculoskeletal measures and does not take into account extra-articular manifestations of axial spondyloarthritis such as those in the eye, gastrointestinal tract, or skin.

“We would like a clinical measurement that might tell us that a patient is appropriately treated and at minimal disease activity,” said Dr. Deodhar, professor of medicine and medical director of the rheumatology clinics at Oregon Health & Science University in Portland.

As outgoing chair of SPARTAN, Dr. Deodhar introduced a proposal that SPARTAN develop new minimal disease activity criteria for patients with axial spondyloarthritis, presenting the rationale for this project at the meeting along with the incoming chair Lianne S. Gensler, MD.

“We want a way to measure disease activity at a stage that is not full remission but with enough of a reduction in disease activity to make a difference,” said Dr. Gensler, director of the Ankylosing Spondylitis Clinic at the University of California, San Francisco. Another frequently used gauge of minimal disease activity in axial spondyloarthritis, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), is flawed by being totally based on subjective measurements without input from the attending rheumatologist, Dr. Gensler said.

The SPARTAN leadership will try to partner in this effort with the OMERACT (Outcome Measures in Rheumatology) program, the Assessment of Spondyloarthritis International Society (ASAS), or both, but if necessary SPARTAN will develop new minimal disease activity criteria on its own, Dr. Deodhar said.

Dr. Deodhar has received research support from 10 drug companies. Dr. Gensler has been a consultant to or has received research support from AbbVie, Amgen, Janssen, Novartis, and UCB.

[email protected]

On Twitter @mitchelzoler

DENVER – U.S. rheumatologists plan to develop new criteria to define minimal disease activity in patients with axial spondyloarthritis to better gauge in routine clinical practice how well these patients respond to treatment.

A score on the Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 1.3 is the most commonly used measure today of minimal disease activity, but the ASDAS isn’t suitable for point-of-care assessment in routine practice because of the need for a C-reactive protein level or erythrocyte sedimentation rate.

Mitchel L. Zoler/Frontline Medical News

“In the clinic, ASDAS is very difficult or next to impossible to do” because it needs CRP or ESR, which are “never available at the point of care,” Atul A. Deodhar, MD, said in an interview at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN). Another limitation of ASDAS is that it focuses exclusively on musculoskeletal measures and does not take into account extra-articular manifestations of axial spondyloarthritis such as those in the eye, gastrointestinal tract, or skin.

“We would like a clinical measurement that might tell us that a patient is appropriately treated and at minimal disease activity,” said Dr. Deodhar, professor of medicine and medical director of the rheumatology clinics at Oregon Health & Science University in Portland.

As outgoing chair of SPARTAN, Dr. Deodhar introduced a proposal that SPARTAN develop new minimal disease activity criteria for patients with axial spondyloarthritis, presenting the rationale for this project at the meeting along with the incoming chair Lianne S. Gensler, MD.

“We want a way to measure disease activity at a stage that is not full remission but with enough of a reduction in disease activity to make a difference,” said Dr. Gensler, director of the Ankylosing Spondylitis Clinic at the University of California, San Francisco. Another frequently used gauge of minimal disease activity in axial spondyloarthritis, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), is flawed by being totally based on subjective measurements without input from the attending rheumatologist, Dr. Gensler said.

The SPARTAN leadership will try to partner in this effort with the OMERACT (Outcome Measures in Rheumatology) program, the Assessment of Spondyloarthritis International Society (ASAS), or both, but if necessary SPARTAN will develop new minimal disease activity criteria on its own, Dr. Deodhar said.

Dr. Deodhar has received research support from 10 drug companies. Dr. Gensler has been a consultant to or has received research support from AbbVie, Amgen, Janssen, Novartis, and UCB.

[email protected]

On Twitter @mitchelzoler

SAN DIEGO—Migraine with aura is associated with increased risk of venous thromboembolism, but migraine without aura is not, according to research presented at the 58th Annual Scientific Meeting of the American Headache Society. The investigators plan to identify the mechanism of the increased risk, which they hypothesize could involve hormones, genes, or prothrombotic states.

Many previous studies have focused on the associations between migraine and atherothrombosis, migraine and stroke, and migraine and myocardial infarction. Results generally have indicated that gender and migraine status (ie, migraine with or without aura) modify the risk of these outcomes. Fewer studies have examined the relationship between migraine and venous thromboembolism, however. Most of the published studies of this topic have focused on specific subgroups of patients and lacked data on the general population of migraineurs.

Kuan-Po Peng, MD, a neurologist at Taipei Veterans Hospital in Taiwan, and colleagues sought to evaluate the risk of venous thromboembolism in the general migraine population and to identify the subgroup of patients at greatest risk. They collected data from the Taiwan National Health Insurance Research Database, which includes information for nearly 750,000 patients with migraine. To increase diagnostic accuracy, the researchers identified patients with neurologist-diagnosed migraine. They also used a diagnosis code plus a composite of anticoagulation prescriptions to identify patients with venous thromboembolism.

Kuan-Po Peng, MD

Dr. Peng and colleagues identified a cohort of migraineurs and a cohort of patients without headache. Each cohort included 102,159 patients, and both were matched by sex and propensity score. The researchers followed both cohorts for approximately four years and observed cases of venous thromboembolism. They used Cox proportional hazards regression analyses to calculate adjusted hazard ratios (aHRs) for the two study arms.

In all, 226 migraineurs and 203 patients without headache had venous thromboembolism. “To our surprise, we found that, overall, the risk of venous thromboembolism is not increased in the migraine population,” said Dr. Peng. The aHR of venous thromboembolism was 1.12 among migraineurs. Subgroup analysis by migraine subtype indicated an elevated risk of venous thromboembolism in patients with migraine with aura (aHR, 2.42), but not in patients with migraine without aura (aHR, 0.81). When the investigators analyzed the data by gender, they found a higher risk of venous thromboembolism among female migraineurs with aura, compared with their male counterparts (aHR, 2.81 vs 1.81).

Dr. Peng’s group conducted sensitivity analyses, excluding anticoagulant use, contraceptive use, major surgery, pregnancy, and other risk factors for venous thromboembolism. In these analyses, the risk of venous thromboembolism was similar to that in the primary analysis.

“We are interested in the mechanism behind this specific association,” said Dr. Peng. “There might be a role for estrogen because … all the patients at higher risk are female, and estrogen is a known risk factor for venous thromboembolism.” The investigators, however, saw no difference in the association between migraine with aura and venous thromboembolism when comparing women younger than 50 (an age used to mark the beginning of menopause) and those older than 50. The low number of cases of venous thromboembolism, and consequent lack of power, may explain this result, said Dr. Peng.

—Erik Greb

SAN DIEGO—Migraine with aura is associated with increased risk of venous thromboembolism, but migraine without aura is not, according to research presented at the 58th Annual Scientific Meeting of the American Headache Society. The investigators plan to identify the mechanism of the increased risk, which they hypothesize could involve hormones, genes, or prothrombotic states.

Many previous studies have focused on the associations between migraine and atherothrombosis, migraine and stroke, and migraine and myocardial infarction. Results generally have indicated that gender and migraine status (ie, migraine with or without aura) modify the risk of these outcomes. Fewer studies have examined the relationship between migraine and venous thromboembolism, however. Most of the published studies of this topic have focused on specific subgroups of patients and lacked data on the general population of migraineurs.

Kuan-Po Peng, MD, a neurologist at Taipei Veterans Hospital in Taiwan, and colleagues sought to evaluate the risk of venous thromboembolism in the general migraine population and to identify the subgroup of patients at greatest risk. They collected data from the Taiwan National Health Insurance Research Database, which includes information for nearly 750,000 patients with migraine. To increase diagnostic accuracy, the researchers identified patients with neurologist-diagnosed migraine. They also used a diagnosis code plus a composite of anticoagulation prescriptions to identify patients with venous thromboembolism.

Kuan-Po Peng, MD

Dr. Peng and colleagues identified a cohort of migraineurs and a cohort of patients without headache. Each cohort included 102,159 patients, and both were matched by sex and propensity score. The researchers followed both cohorts for approximately four years and observed cases of venous thromboembolism. They used Cox proportional hazards regression analyses to calculate adjusted hazard ratios (aHRs) for the two study arms.

In all, 226 migraineurs and 203 patients without headache had venous thromboembolism. “To our surprise, we found that, overall, the risk of venous thromboembolism is not increased in the migraine population,” said Dr. Peng. The aHR of venous thromboembolism was 1.12 among migraineurs. Subgroup analysis by migraine subtype indicated an elevated risk of venous thromboembolism in patients with migraine with aura (aHR, 2.42), but not in patients with migraine without aura (aHR, 0.81). When the investigators analyzed the data by gender, they found a higher risk of venous thromboembolism among female migraineurs with aura, compared with their male counterparts (aHR, 2.81 vs 1.81).

Dr. Peng’s group conducted sensitivity analyses, excluding anticoagulant use, contraceptive use, major surgery, pregnancy, and other risk factors for venous thromboembolism. In these analyses, the risk of venous thromboembolism was similar to that in the primary analysis.

“We are interested in the mechanism behind this specific association,” said Dr. Peng. “There might be a role for estrogen because … all the patients at higher risk are female, and estrogen is a known risk factor for venous thromboembolism.” The investigators, however, saw no difference in the association between migraine with aura and venous thromboembolism when comparing women younger than 50 (an age used to mark the beginning of menopause) and those older than 50. The low number of cases of venous thromboembolism, and consequent lack of power, may explain this result, said Dr. Peng.

—Erik Greb

SAN DIEGO—Migraine with aura is associated with increased risk of venous thromboembolism, but migraine without aura is not, according to research presented at the 58th Annual Scientific Meeting of the American Headache Society. The investigators plan to identify the mechanism of the increased risk, which they hypothesize could involve hormones, genes, or prothrombotic states.

Many previous studies have focused on the associations between migraine and atherothrombosis, migraine and stroke, and migraine and myocardial infarction. Results generally have indicated that gender and migraine status (ie, migraine with or without aura) modify the risk of these outcomes. Fewer studies have examined the relationship between migraine and venous thromboembolism, however. Most of the published studies of this topic have focused on specific subgroups of patients and lacked data on the general population of migraineurs.

Kuan-Po Peng, MD, a neurologist at Taipei Veterans Hospital in Taiwan, and colleagues sought to evaluate the risk of venous thromboembolism in the general migraine population and to identify the subgroup of patients at greatest risk. They collected data from the Taiwan National Health Insurance Research Database, which includes information for nearly 750,000 patients with migraine. To increase diagnostic accuracy, the researchers identified patients with neurologist-diagnosed migraine. They also used a diagnosis code plus a composite of anticoagulation prescriptions to identify patients with venous thromboembolism.

Kuan-Po Peng, MD

Dr. Peng and colleagues identified a cohort of migraineurs and a cohort of patients without headache. Each cohort included 102,159 patients, and both were matched by sex and propensity score. The researchers followed both cohorts for approximately four years and observed cases of venous thromboembolism. They used Cox proportional hazards regression analyses to calculate adjusted hazard ratios (aHRs) for the two study arms.

In all, 226 migraineurs and 203 patients without headache had venous thromboembolism. “To our surprise, we found that, overall, the risk of venous thromboembolism is not increased in the migraine population,” said Dr. Peng. The aHR of venous thromboembolism was 1.12 among migraineurs. Subgroup analysis by migraine subtype indicated an elevated risk of venous thromboembolism in patients with migraine with aura (aHR, 2.42), but not in patients with migraine without aura (aHR, 0.81). When the investigators analyzed the data by gender, they found a higher risk of venous thromboembolism among female migraineurs with aura, compared with their male counterparts (aHR, 2.81 vs 1.81).

Dr. Peng’s group conducted sensitivity analyses, excluding anticoagulant use, contraceptive use, major surgery, pregnancy, and other risk factors for venous thromboembolism. In these analyses, the risk of venous thromboembolism was similar to that in the primary analysis.

“We are interested in the mechanism behind this specific association,” said Dr. Peng. “There might be a role for estrogen because … all the patients at higher risk are female, and estrogen is a known risk factor for venous thromboembolism.” The investigators, however, saw no difference in the association between migraine with aura and venous thromboembolism when comparing women younger than 50 (an age used to mark the beginning of menopause) and those older than 50. The low number of cases of venous thromboembolism, and consequent lack of power, may explain this result, said Dr. Peng.

—Erik Greb

Protective treatment with the GnRH agonist triptorelin failed to prevent chemotherapy-induced premature ovarian failure in young women with lymphoma, according to a report published in the Journal of Clinical Oncology.

This type of protective therapy has been used for at least 20 years but is still controversial. Some clinical practice guidelines endorse the practice, but others do not. The evidence is both sparse and ambiguous, said Isabelle Demeestere, MD, of the research laboratory on human reproduction, Université Libre de Bruxelles (Belgium), and her associates.

In what they described as “the first randomized clinical trial providing accurate information on ovarian function and fertility after a median of 5 years of follow-up,” the investigators assessed 67 young women (median age, 26 years) treated for Hodgkin’s or non-Hodgkin’s lymphoma at 15 cancer centers in France, Belgium, and Italy. These patients had been randomly assigned to receive chemotherapy plus triptorelin (32 women) or chemotherapy plus placebo injections (35 women) at baseline.

Premature ovarian failure, as measured by elevated FSH levels, occurred in six of the GnRH group and eight of the control group, a nonsignificant difference. Moreover, the rate of recovery of ovarian function, as measured by at least one FSH level of 15 IU/L or less, was the same between the two study groups. And 17 women (53%) in the GnRH group eventually achieved pregnancy, which is not significantly different from the 43% pregnancy rate in the control group (15 of 35 women).

Five women – two in the GnRH group and three in the control group – achieved pregnancy during long-term follow-up, even though they had been classified as having premature ovarian failure. This “confirms the possibility of incidental ovarian cycle recovery, leading to fertility restoration several years after treatment in this young population,” Dr. Demeestere and her associates wrote (J Clin Oncol. 2016. [doi:10.1200/JCO.2015.65.884]).

The study findings “suggest caution” regarding guidelines that recommend using GnRH agonists to preserve fertility in young women undergoing chemotherapy, they added.

Protective treatment with the GnRH agonist triptorelin failed to prevent chemotherapy-induced premature ovarian failure in young women with lymphoma, according to a report published in the Journal of Clinical Oncology.

This type of protective therapy has been used for at least 20 years but is still controversial. Some clinical practice guidelines endorse the practice, but others do not. The evidence is both sparse and ambiguous, said Isabelle Demeestere, MD, of the research laboratory on human reproduction, Université Libre de Bruxelles (Belgium), and her associates.

In what they described as “the first randomized clinical trial providing accurate information on ovarian function and fertility after a median of 5 years of follow-up,” the investigators assessed 67 young women (median age, 26 years) treated for Hodgkin’s or non-Hodgkin’s lymphoma at 15 cancer centers in France, Belgium, and Italy. These patients had been randomly assigned to receive chemotherapy plus triptorelin (32 women) or chemotherapy plus placebo injections (35 women) at baseline.

Premature ovarian failure, as measured by elevated FSH levels, occurred in six of the GnRH group and eight of the control group, a nonsignificant difference. Moreover, the rate of recovery of ovarian function, as measured by at least one FSH level of 15 IU/L or less, was the same between the two study groups. And 17 women (53%) in the GnRH group eventually achieved pregnancy, which is not significantly different from the 43% pregnancy rate in the control group (15 of 35 women).

Five women – two in the GnRH group and three in the control group – achieved pregnancy during long-term follow-up, even though they had been classified as having premature ovarian failure. This “confirms the possibility of incidental ovarian cycle recovery, leading to fertility restoration several years after treatment in this young population,” Dr. Demeestere and her associates wrote (J Clin Oncol. 2016. [doi:10.1200/JCO.2015.65.884]).

The study findings “suggest caution” regarding guidelines that recommend using GnRH agonists to preserve fertility in young women undergoing chemotherapy, they added.

Protective treatment with the GnRH agonist triptorelin failed to prevent chemotherapy-induced premature ovarian failure in young women with lymphoma, according to a report published in the Journal of Clinical Oncology.

This type of protective therapy has been used for at least 20 years but is still controversial. Some clinical practice guidelines endorse the practice, but others do not. The evidence is both sparse and ambiguous, said Isabelle Demeestere, MD, of the research laboratory on human reproduction, Université Libre de Bruxelles (Belgium), and her associates.

In what they described as “the first randomized clinical trial providing accurate information on ovarian function and fertility after a median of 5 years of follow-up,” the investigators assessed 67 young women (median age, 26 years) treated for Hodgkin’s or non-Hodgkin’s lymphoma at 15 cancer centers in France, Belgium, and Italy. These patients had been randomly assigned to receive chemotherapy plus triptorelin (32 women) or chemotherapy plus placebo injections (35 women) at baseline.

Premature ovarian failure, as measured by elevated FSH levels, occurred in six of the GnRH group and eight of the control group, a nonsignificant difference. Moreover, the rate of recovery of ovarian function, as measured by at least one FSH level of 15 IU/L or less, was the same between the two study groups. And 17 women (53%) in the GnRH group eventually achieved pregnancy, which is not significantly different from the 43% pregnancy rate in the control group (15 of 35 women).

Five women – two in the GnRH group and three in the control group – achieved pregnancy during long-term follow-up, even though they had been classified as having premature ovarian failure. This “confirms the possibility of incidental ovarian cycle recovery, leading to fertility restoration several years after treatment in this young population,” Dr. Demeestere and her associates wrote (J Clin Oncol. 2016. [doi:10.1200/JCO.2015.65.884]).

The study findings “suggest caution” regarding guidelines that recommend using GnRH agonists to preserve fertility in young women undergoing chemotherapy, they added.