Breast Cancer ICYMI

Significant weight gain after a diagnosis of breast cancer may be a bigger problem than previously thought, and clinicians need to do more to help patients manage it, say the authors of a national survey conducted in Australia.

Monkeybusinessimages/Thinkstock

“We found that two-thirds of our respondents were currently overweight or obese,” report Carolyn Ee, MBBS, PhD, of the NICM Health Research Institute, Western Sydney University, Penrith, New South Wales, and colleagues.

“Because weight gain after breast cancer may lead to poorer outcomes, efforts to prevent and manage weight gain must be prioritized and accelerated particularly in the first year after diagnosis,” they comment.

Their article was published online February 20 in BMC Cancer.

The 60-item anonymous online survey was sent to 1835 members of the Breast Cancer Network Australia Review and Survey Group.

Although the response rate for the online survey was only 15%, most women reported a “high” level of concern about weight gain – and with good reason. The results showed that 64% of women gained an average of 9 kg (20 lb), and 17% gained >20 kg (44 lb).

In the 2-year period following a breast cancer diagnosis, the rate of overweight and obesity increased from 48% to 67%. The rate of obesity alone almost doubled, from 17% to 32%.

Overweight and obesity are strongly implicated in the development of breast cancer, the authors note. Weight gain after diagnosis is associated with morbidity and all-cause mortality and may increase the risk for breast cancer recurrence by 30% to 40%.

The survey, which also collected data from 26 women who were participants in online women’s health and breast cancer support groups, did not include information on quality of life and levels of distress. “Additional research in this area appears to be warranted,” the study authors suggest.

In a press statement, Ee noted that 77% of women reported that weight gain had occurred in the 12- to 18-month period after diagnosis. This could provide a “window of opportunity” for intervention, she said.

“Timing may be the key in helping women to manage weight after a diagnosis of breast cancer,” she added. “Cancer services and general practitioners play an important role in having early conversations with women and referring them to a team of qualified healthcare professionals such as dieticians and exercise physiologists with experience in cancer.”

Coauthor John Boyages, MBBS, PhD, a radiation oncologist at the Icon Cancer Center, Sydney Adventist Hospital, Wahroonga, emphasized that all women should be prescribed exercise after being diagnosed with breast cancer. “Prescribing a healthy lifestyle is just as important as prescribing tablets,” he said.

“As doctors, we really need to actively think about weight, nutrition, and exercise and advise about possible interventions. [Among patients with breast cancer,] weight gain adds to self-esteem problems, increases the risk of heart disease and other cancers, and several reports suggest it may affect prognosis and also increases the risk of lymphedema,” he added

“More effort needs to be geared to treating the whole body, as we know obesity is a risk factor for poorer outcomes when dealing with breast cancer,” commented Stephanie Bernik, MD, chief of breast service at Mount Sinai West and associate professor of surgery at the Icahn School of Medicine at Mount Sinai in New York City. She was not involved in the study and was approached for comment.

Berwick also agreed that meeting with a nutritionist or receiving weight loss support is helpful for patients with cancer, but she added that not all cancer centers have the resources to provide these services.
 

Survey Details

Of 309 women who responded to the survey, complete data for pre- and post-diagnosis body mass index (BMI) were collected from 277 respondents, representing 15% of those surveyed.

Of these women, 254 had been diagnosed with stage I-III breast cancer; 33 had been diagnosed with ductal carcinoma in situ. The mean age of the patients was 59 years.

The results showed that for 20% of women, BMI increased from a healthy weight range at the time of diagnosis (BMI <25) to an unhealthy weight range (BMI >25). In addition, for 4.8% of patients, BMI increased from an overweight range (BMI 25 to <30) to obesity (BMI >30), and 60.7% reported an increase in BMI >1 kg/m². Conversely, only a small proportion of women lost weight – 6% experienced a decrease of more than one BMI category.

Weight gain occurred within the first 2 years of diagnosis in 87% of women and within the first 12 months in 58%. In women who gained >10 kg (22 lb), 78% said they were highly concerned about it, as did 59% of women who gained >5 kg (11 lb).

Among all age groups (35 to 74 years), 69% experienced excess weight gain that was 0.48 kg higher each year compared with age-matched control persons who had not been diagnosed with breast cancer. Over 5 years, this represented an additional weight gain of 2 kg (5 lb) among women with breast cancer.

When approached for comment, Bernick agreed with the authors that these results should be interpreted with caution.

She pointed to the self-reporting bias and the fact that only 15% of women responded to the survey. “Perhaps it was only women who had gained weight who found it worthwhile reporting their experience with weight gain after a breast cancer diagnosis,” she suggested.

Even so, there are many reasons why weight gain during treatment for breast cancer presents a problem for women in the United States as well as Australia, Bernik told Medscape Medical News.

“Women undergoing chemotherapy may not have the energy to keep up with exercise regimens and may find eating food comforting,” she pointed out. “Because chemotherapy delivery and the after effects may take up a few days out of every 2 to 3 weeks, women have less time and energy to eat correctly or exercise. Furthermore, women sometimes get steroids while receiving chemotherapy, and this is known to drive up one’s appetite.”

The authors have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Significant weight gain after a diagnosis of breast cancer may be a bigger problem than previously thought, and clinicians need to do more to help patients manage it, say the authors of a national survey conducted in Australia.

Monkeybusinessimages/Thinkstock

“We found that two-thirds of our respondents were currently overweight or obese,” report Carolyn Ee, MBBS, PhD, of the NICM Health Research Institute, Western Sydney University, Penrith, New South Wales, and colleagues.

“Because weight gain after breast cancer may lead to poorer outcomes, efforts to prevent and manage weight gain must be prioritized and accelerated particularly in the first year after diagnosis,” they comment.

Their article was published online February 20 in BMC Cancer.

The 60-item anonymous online survey was sent to 1835 members of the Breast Cancer Network Australia Review and Survey Group.

Although the response rate for the online survey was only 15%, most women reported a “high” level of concern about weight gain – and with good reason. The results showed that 64% of women gained an average of 9 kg (20 lb), and 17% gained >20 kg (44 lb).

In the 2-year period following a breast cancer diagnosis, the rate of overweight and obesity increased from 48% to 67%. The rate of obesity alone almost doubled, from 17% to 32%.

Overweight and obesity are strongly implicated in the development of breast cancer, the authors note. Weight gain after diagnosis is associated with morbidity and all-cause mortality and may increase the risk for breast cancer recurrence by 30% to 40%.

The survey, which also collected data from 26 women who were participants in online women’s health and breast cancer support groups, did not include information on quality of life and levels of distress. “Additional research in this area appears to be warranted,” the study authors suggest.

In a press statement, Ee noted that 77% of women reported that weight gain had occurred in the 12- to 18-month period after diagnosis. This could provide a “window of opportunity” for intervention, she said.

“Timing may be the key in helping women to manage weight after a diagnosis of breast cancer,” she added. “Cancer services and general practitioners play an important role in having early conversations with women and referring them to a team of qualified healthcare professionals such as dieticians and exercise physiologists with experience in cancer.”

Coauthor John Boyages, MBBS, PhD, a radiation oncologist at the Icon Cancer Center, Sydney Adventist Hospital, Wahroonga, emphasized that all women should be prescribed exercise after being diagnosed with breast cancer. “Prescribing a healthy lifestyle is just as important as prescribing tablets,” he said.

“As doctors, we really need to actively think about weight, nutrition, and exercise and advise about possible interventions. [Among patients with breast cancer,] weight gain adds to self-esteem problems, increases the risk of heart disease and other cancers, and several reports suggest it may affect prognosis and also increases the risk of lymphedema,” he added

“More effort needs to be geared to treating the whole body, as we know obesity is a risk factor for poorer outcomes when dealing with breast cancer,” commented Stephanie Bernik, MD, chief of breast service at Mount Sinai West and associate professor of surgery at the Icahn School of Medicine at Mount Sinai in New York City. She was not involved in the study and was approached for comment.

Berwick also agreed that meeting with a nutritionist or receiving weight loss support is helpful for patients with cancer, but she added that not all cancer centers have the resources to provide these services.
 

Survey Details

Of 309 women who responded to the survey, complete data for pre- and post-diagnosis body mass index (BMI) were collected from 277 respondents, representing 15% of those surveyed.

Of these women, 254 had been diagnosed with stage I-III breast cancer; 33 had been diagnosed with ductal carcinoma in situ. The mean age of the patients was 59 years.

The results showed that for 20% of women, BMI increased from a healthy weight range at the time of diagnosis (BMI <25) to an unhealthy weight range (BMI >25). In addition, for 4.8% of patients, BMI increased from an overweight range (BMI 25 to <30) to obesity (BMI >30), and 60.7% reported an increase in BMI >1 kg/m². Conversely, only a small proportion of women lost weight – 6% experienced a decrease of more than one BMI category.

Weight gain occurred within the first 2 years of diagnosis in 87% of women and within the first 12 months in 58%. In women who gained >10 kg (22 lb), 78% said they were highly concerned about it, as did 59% of women who gained >5 kg (11 lb).

Among all age groups (35 to 74 years), 69% experienced excess weight gain that was 0.48 kg higher each year compared with age-matched control persons who had not been diagnosed with breast cancer. Over 5 years, this represented an additional weight gain of 2 kg (5 lb) among women with breast cancer.

When approached for comment, Bernick agreed with the authors that these results should be interpreted with caution.

She pointed to the self-reporting bias and the fact that only 15% of women responded to the survey. “Perhaps it was only women who had gained weight who found it worthwhile reporting their experience with weight gain after a breast cancer diagnosis,” she suggested.

Even so, there are many reasons why weight gain during treatment for breast cancer presents a problem for women in the United States as well as Australia, Bernik told Medscape Medical News.

“Women undergoing chemotherapy may not have the energy to keep up with exercise regimens and may find eating food comforting,” she pointed out. “Because chemotherapy delivery and the after effects may take up a few days out of every 2 to 3 weeks, women have less time and energy to eat correctly or exercise. Furthermore, women sometimes get steroids while receiving chemotherapy, and this is known to drive up one’s appetite.”

The authors have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Significant weight gain after a diagnosis of breast cancer may be a bigger problem than previously thought, and clinicians need to do more to help patients manage it, say the authors of a national survey conducted in Australia.

Monkeybusinessimages/Thinkstock

“We found that two-thirds of our respondents were currently overweight or obese,” report Carolyn Ee, MBBS, PhD, of the NICM Health Research Institute, Western Sydney University, Penrith, New South Wales, and colleagues.

“Because weight gain after breast cancer may lead to poorer outcomes, efforts to prevent and manage weight gain must be prioritized and accelerated particularly in the first year after diagnosis,” they comment.

Their article was published online February 20 in BMC Cancer.

The 60-item anonymous online survey was sent to 1835 members of the Breast Cancer Network Australia Review and Survey Group.

Although the response rate for the online survey was only 15%, most women reported a “high” level of concern about weight gain – and with good reason. The results showed that 64% of women gained an average of 9 kg (20 lb), and 17% gained >20 kg (44 lb).

In the 2-year period following a breast cancer diagnosis, the rate of overweight and obesity increased from 48% to 67%. The rate of obesity alone almost doubled, from 17% to 32%.

Overweight and obesity are strongly implicated in the development of breast cancer, the authors note. Weight gain after diagnosis is associated with morbidity and all-cause mortality and may increase the risk for breast cancer recurrence by 30% to 40%.

The survey, which also collected data from 26 women who were participants in online women’s health and breast cancer support groups, did not include information on quality of life and levels of distress. “Additional research in this area appears to be warranted,” the study authors suggest.

In a press statement, Ee noted that 77% of women reported that weight gain had occurred in the 12- to 18-month period after diagnosis. This could provide a “window of opportunity” for intervention, she said.

“Timing may be the key in helping women to manage weight after a diagnosis of breast cancer,” she added. “Cancer services and general practitioners play an important role in having early conversations with women and referring them to a team of qualified healthcare professionals such as dieticians and exercise physiologists with experience in cancer.”

Coauthor John Boyages, MBBS, PhD, a radiation oncologist at the Icon Cancer Center, Sydney Adventist Hospital, Wahroonga, emphasized that all women should be prescribed exercise after being diagnosed with breast cancer. “Prescribing a healthy lifestyle is just as important as prescribing tablets,” he said.

“As doctors, we really need to actively think about weight, nutrition, and exercise and advise about possible interventions. [Among patients with breast cancer,] weight gain adds to self-esteem problems, increases the risk of heart disease and other cancers, and several reports suggest it may affect prognosis and also increases the risk of lymphedema,” he added

“More effort needs to be geared to treating the whole body, as we know obesity is a risk factor for poorer outcomes when dealing with breast cancer,” commented Stephanie Bernik, MD, chief of breast service at Mount Sinai West and associate professor of surgery at the Icahn School of Medicine at Mount Sinai in New York City. She was not involved in the study and was approached for comment.

Berwick also agreed that meeting with a nutritionist or receiving weight loss support is helpful for patients with cancer, but she added that not all cancer centers have the resources to provide these services.
 

Survey Details

Of 309 women who responded to the survey, complete data for pre- and post-diagnosis body mass index (BMI) were collected from 277 respondents, representing 15% of those surveyed.

Of these women, 254 had been diagnosed with stage I-III breast cancer; 33 had been diagnosed with ductal carcinoma in situ. The mean age of the patients was 59 years.

The results showed that for 20% of women, BMI increased from a healthy weight range at the time of diagnosis (BMI <25) to an unhealthy weight range (BMI >25). In addition, for 4.8% of patients, BMI increased from an overweight range (BMI 25 to <30) to obesity (BMI >30), and 60.7% reported an increase in BMI >1 kg/m². Conversely, only a small proportion of women lost weight – 6% experienced a decrease of more than one BMI category.

Weight gain occurred within the first 2 years of diagnosis in 87% of women and within the first 12 months in 58%. In women who gained >10 kg (22 lb), 78% said they were highly concerned about it, as did 59% of women who gained >5 kg (11 lb).

Among all age groups (35 to 74 years), 69% experienced excess weight gain that was 0.48 kg higher each year compared with age-matched control persons who had not been diagnosed with breast cancer. Over 5 years, this represented an additional weight gain of 2 kg (5 lb) among women with breast cancer.

When approached for comment, Bernick agreed with the authors that these results should be interpreted with caution.

She pointed to the self-reporting bias and the fact that only 15% of women responded to the survey. “Perhaps it was only women who had gained weight who found it worthwhile reporting their experience with weight gain after a breast cancer diagnosis,” she suggested.

Even so, there are many reasons why weight gain during treatment for breast cancer presents a problem for women in the United States as well as Australia, Bernik told Medscape Medical News.

“Women undergoing chemotherapy may not have the energy to keep up with exercise regimens and may find eating food comforting,” she pointed out. “Because chemotherapy delivery and the after effects may take up a few days out of every 2 to 3 weeks, women have less time and energy to eat correctly or exercise. Furthermore, women sometimes get steroids while receiving chemotherapy, and this is known to drive up one’s appetite.”

The authors have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

For women with dense breasts, abbreviated magnetic resonance imaging was more effective than was digital breast tomosynthesis for detecting invasive breast cancer in a cross-sectional study of 1,444 women who underwent both procedures.

Dense breasts are a common reason for failed early diagnosis of breast cancer, wrote Christopher E. Comstock, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Digital breast tomosynthesis (DBT) and abbreviated breast magnetic resonance imaging (MRI) are becoming more popular as safe and cost-effective breast cancer screening options, but their effectiveness in women with dense breasts and average breast cancer risk has not been compared.

The researchers reviewed data from 1,444 women aged 40-75 years at 47 institutions in the United States and 1 in Germany. The women underwent both DBT and MRI. The primary endpoint was the detection of invasive cancers, of which 17 were identified at baseline screening. Abbreviated breast MRI detected all 17 cases of invasive cancer, compared with 7 detected by DBT. In addition, MRI detected six of seven women with ductal carcinoma in situ, while DBT identified two of the seven cases, according to the study, which was published in JAMA.

Overall, the invasive cancer detection rate was 11.8 per 1,000 women for MRI compared with 4.8 per 1,000 women for DBT. Sensitivity for MRI and DBT was 96% vs. 39%, and specificity was 87% vs. 97%.

The rate of recommendation for further screening was not significantly different between the procedures (8% for MRI and 10% for DBT). The most common adverse events were three cases of mild allergic reactions and two cases of anxiety.

The study findings were limited by several factors including the inability to show an association between abbreviated breast MRI and breast cancer mortality and the lack of cost-effectiveness comparisons for the two procedures. Because eligibility criteria required a prior breast mammogram to see if the breasts were dense, the study compared an incidence DBT screen to a prevalence abbreviated MRI screen, Dr. Comstock and associates noted.

However, the results show a significantly increased breast cancer detection rate with abbreviated MRI, which merits additional research to examine the relationship between screening strategies and clinical outcomes for women with dense breasts, they said.

The study was supported in part by the National Cancer Institute of the National Institutes of Health, and by Bracco Diagnostics through funding to the ECOG-ACRIN Cancer Research Group. Dr. Comstock disclosed financial relationships with Bracco Diagnostics and Bayer, and three coauthors disclosed financial relationships with other imaging companies. The remaining coauthors had no relevant financial disclosures.
 

SOURCE: Comstock CK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0572.

For women with dense breasts, abbreviated magnetic resonance imaging was more effective than was digital breast tomosynthesis for detecting invasive breast cancer in a cross-sectional study of 1,444 women who underwent both procedures.

Dense breasts are a common reason for failed early diagnosis of breast cancer, wrote Christopher E. Comstock, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Digital breast tomosynthesis (DBT) and abbreviated breast magnetic resonance imaging (MRI) are becoming more popular as safe and cost-effective breast cancer screening options, but their effectiveness in women with dense breasts and average breast cancer risk has not been compared.

The researchers reviewed data from 1,444 women aged 40-75 years at 47 institutions in the United States and 1 in Germany. The women underwent both DBT and MRI. The primary endpoint was the detection of invasive cancers, of which 17 were identified at baseline screening. Abbreviated breast MRI detected all 17 cases of invasive cancer, compared with 7 detected by DBT. In addition, MRI detected six of seven women with ductal carcinoma in situ, while DBT identified two of the seven cases, according to the study, which was published in JAMA.

Overall, the invasive cancer detection rate was 11.8 per 1,000 women for MRI compared with 4.8 per 1,000 women for DBT. Sensitivity for MRI and DBT was 96% vs. 39%, and specificity was 87% vs. 97%.

The rate of recommendation for further screening was not significantly different between the procedures (8% for MRI and 10% for DBT). The most common adverse events were three cases of mild allergic reactions and two cases of anxiety.

The study findings were limited by several factors including the inability to show an association between abbreviated breast MRI and breast cancer mortality and the lack of cost-effectiveness comparisons for the two procedures. Because eligibility criteria required a prior breast mammogram to see if the breasts were dense, the study compared an incidence DBT screen to a prevalence abbreviated MRI screen, Dr. Comstock and associates noted.

However, the results show a significantly increased breast cancer detection rate with abbreviated MRI, which merits additional research to examine the relationship between screening strategies and clinical outcomes for women with dense breasts, they said.

The study was supported in part by the National Cancer Institute of the National Institutes of Health, and by Bracco Diagnostics through funding to the ECOG-ACRIN Cancer Research Group. Dr. Comstock disclosed financial relationships with Bracco Diagnostics and Bayer, and three coauthors disclosed financial relationships with other imaging companies. The remaining coauthors had no relevant financial disclosures.
 

SOURCE: Comstock CK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0572.

For women with dense breasts, abbreviated magnetic resonance imaging was more effective than was digital breast tomosynthesis for detecting invasive breast cancer in a cross-sectional study of 1,444 women who underwent both procedures.

Dense breasts are a common reason for failed early diagnosis of breast cancer, wrote Christopher E. Comstock, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Digital breast tomosynthesis (DBT) and abbreviated breast magnetic resonance imaging (MRI) are becoming more popular as safe and cost-effective breast cancer screening options, but their effectiveness in women with dense breasts and average breast cancer risk has not been compared.

The researchers reviewed data from 1,444 women aged 40-75 years at 47 institutions in the United States and 1 in Germany. The women underwent both DBT and MRI. The primary endpoint was the detection of invasive cancers, of which 17 were identified at baseline screening. Abbreviated breast MRI detected all 17 cases of invasive cancer, compared with 7 detected by DBT. In addition, MRI detected six of seven women with ductal carcinoma in situ, while DBT identified two of the seven cases, according to the study, which was published in JAMA.

Overall, the invasive cancer detection rate was 11.8 per 1,000 women for MRI compared with 4.8 per 1,000 women for DBT. Sensitivity for MRI and DBT was 96% vs. 39%, and specificity was 87% vs. 97%.

The rate of recommendation for further screening was not significantly different between the procedures (8% for MRI and 10% for DBT). The most common adverse events were three cases of mild allergic reactions and two cases of anxiety.

The study findings were limited by several factors including the inability to show an association between abbreviated breast MRI and breast cancer mortality and the lack of cost-effectiveness comparisons for the two procedures. Because eligibility criteria required a prior breast mammogram to see if the breasts were dense, the study compared an incidence DBT screen to a prevalence abbreviated MRI screen, Dr. Comstock and associates noted.

However, the results show a significantly increased breast cancer detection rate with abbreviated MRI, which merits additional research to examine the relationship between screening strategies and clinical outcomes for women with dense breasts, they said.

The study was supported in part by the National Cancer Institute of the National Institutes of Health, and by Bracco Diagnostics through funding to the ECOG-ACRIN Cancer Research Group. Dr. Comstock disclosed financial relationships with Bracco Diagnostics and Bayer, and three coauthors disclosed financial relationships with other imaging companies. The remaining coauthors had no relevant financial disclosures.
 

SOURCE: Comstock CK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0572.

The Food and Drug Administration has approved neratinib (NERLYNX) in combination with capecitabine for use in adults with advanced or metastatic HER2-positive breast cancer who have received at least two prior anti-HER2 based regimens in the metastatic setting.

The recommended dose for neratinib in this population is 240 mg once daily with food on days 1-21 of a 21-day cycle. Neratinib should be given with capecitabine at 750 mg/m² twice daily on days 1-14 until progression or unacceptable toxicity.

The full prescribing information for neratinib is available from the FDA website.

The FDA’s new approval of neratinib is based on results from the NALA trial (NCT01808573). The trial enrolled 621 patients with metastatic HER2-positive breast cancer who had received at least two prior anti-HER2 based regimens in the metastatic setting.

The patients were randomized to neratinib plus capecitabine or lapatinib plus capecitabine and received treatment until progression or unacceptable toxicity.

The objective response rate was 32.8% in the neratinib arm and 26.7% in the lapatinib arm. The median duration of response was 8.5 months and 5.6 months, respectively.

The median progression-free survival was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (hazard ratio 0.76; P = .0059). The median overall survival was 21 months and 18.7 months, respectively (HR 0.88; P = .2086).

The most common grade 3/4 adverse events in the neratinib arm were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

jensmith@mdedge.com

The Food and Drug Administration has approved neratinib (NERLYNX) in combination with capecitabine for use in adults with advanced or metastatic HER2-positive breast cancer who have received at least two prior anti-HER2 based regimens in the metastatic setting.

The recommended dose for neratinib in this population is 240 mg once daily with food on days 1-21 of a 21-day cycle. Neratinib should be given with capecitabine at 750 mg/m² twice daily on days 1-14 until progression or unacceptable toxicity.

The full prescribing information for neratinib is available from the FDA website.

The FDA’s new approval of neratinib is based on results from the NALA trial (NCT01808573). The trial enrolled 621 patients with metastatic HER2-positive breast cancer who had received at least two prior anti-HER2 based regimens in the metastatic setting.

The patients were randomized to neratinib plus capecitabine or lapatinib plus capecitabine and received treatment until progression or unacceptable toxicity.

The objective response rate was 32.8% in the neratinib arm and 26.7% in the lapatinib arm. The median duration of response was 8.5 months and 5.6 months, respectively.

The median progression-free survival was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (hazard ratio 0.76; P = .0059). The median overall survival was 21 months and 18.7 months, respectively (HR 0.88; P = .2086).

The most common grade 3/4 adverse events in the neratinib arm were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

jensmith@mdedge.com

The Food and Drug Administration has approved neratinib (NERLYNX) in combination with capecitabine for use in adults with advanced or metastatic HER2-positive breast cancer who have received at least two prior anti-HER2 based regimens in the metastatic setting.

The recommended dose for neratinib in this population is 240 mg once daily with food on days 1-21 of a 21-day cycle. Neratinib should be given with capecitabine at 750 mg/m² twice daily on days 1-14 until progression or unacceptable toxicity.

The full prescribing information for neratinib is available from the FDA website.

The FDA’s new approval of neratinib is based on results from the NALA trial (NCT01808573). The trial enrolled 621 patients with metastatic HER2-positive breast cancer who had received at least two prior anti-HER2 based regimens in the metastatic setting.

The patients were randomized to neratinib plus capecitabine or lapatinib plus capecitabine and received treatment until progression or unacceptable toxicity.

The objective response rate was 32.8% in the neratinib arm and 26.7% in the lapatinib arm. The median duration of response was 8.5 months and 5.6 months, respectively.

The median progression-free survival was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (hazard ratio 0.76; P = .0059). The median overall survival was 21 months and 18.7 months, respectively (HR 0.88; P = .2086).

The most common grade 3/4 adverse events in the neratinib arm were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

jensmith@mdedge.com

The U.S. Preventive Services Task Force has deemed the current evidence “insufficient” to make a recommendation in regard to screening for cognitive impairment in adults aged 65 years or older.

“More research is needed on the effect of screening and early detection of cognitive impairment on important patient, caregiver, and societal outcomes, including decision making, advance planning, and caregiver outcomes,” wrote lead author Douglas K. Owens, MD, of Stanford (Calif.) University and fellow members of the task force. The statement was published in JAMA.

To update a 2014 recommendation from the USPSTF, which also found insufficient evidence to properly assess cognitive screening’s benefits and harms, the task force commissioned a systematic review of studies applicable to community-dwelling older adults who are not exhibiting signs or symptoms of cognitive impairment. For their statement, “cognitive impairment” is defined as mild cognitive impairment and mild to moderate dementia.

Ultimately, they determined several factors that limited the overall evidence, including the short duration of most trials and the heterogenous nature of interventions and inconsistencies in outcomes reported. Any evidence that suggested improvements was mostly applicable to patients with moderate dementia, meaning “its applicability to a screen-detected population is uncertain.”
 

Updating 2014 recommendations

Their statement was based on an evidence report, also published in JAMA, in which a team of researchers reviewed 287 studies that included more than 285,000 older adults; 92 of the studies were newly identified, while the other 195 were carried forward from the 2014 recommendation’s review. The researchers sought the answers to five key questions, carrying over the framework from the previous review.

“Despite the accumulation of new data, the conclusions for these key questions are essentially unchanged from the prior review,” wrote lead author Carrie D. Patnode, PhD, of the Kaiser Permanente Center for Health Research in Portland, Ore., and coauthors.

Of the questions – which concerned the accuracy of screening instruments; the harms of screening; the harms of interventions; and if screening or interventions improved decision making or outcomes for the patient, family/caregiver, or society – moderate evidence was found to support the accuracy of the instruments, treatment with acetylcholinesterase inhibitors and memantine for patients with moderate dementia, and psychoeducation interventions for caregivers of patients with moderate dementia. At the same time, there was moderate evidence of adverse effects from acetylcholinesterase inhibitors and memantine in patients with moderate dementia.

“I think, eventually, there will be sufficient evidence to justify screening, once we have what I call a tiered approach,” Marwan Sabbagh, MD, of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, said in an interview. “The very near future will include blood tests for Alzheimer’s, or PET scans, or genetics, or something else. Right now, the cognitive screens lack the specificity and sensitivity, and the secondary screening infrastructure that would improve the accuracy doesn’t exist yet.

“I think this is a ‘not now,’ ” he added, “but I wouldn’t say ‘not ever.’ ”

Dr. Patnode and coauthors noted specific limitations in the evidence, including a lack of studies on how screening for and treating cognitive impairment affects decision making. In addition, details like quality of life and institutionalization were inconsistently reported, and “consistent and standardized reporting of results according to meaningful thresholds of clinical significance” would have been valuable across all measures.
 

Clinical implications

The implications of this report’s conclusions are substantial, especially as the rising prevalence of mild cognitive impairment and dementia becomes a worldwide concern, wrote Ronald C. Petersen, PhD, MD, of the Mayo Clinic in Rochester, Minn., and Kristine Yaffe, MD, of the University of California, San Francisco, in an accompanying editorial.

Though the data does not explicitly support screening, Dr. Petersen and Dr. Yaffe noted that it still may have benefits. An estimated 10% of cognitive impairment is caused by at least somewhat reversible causes, and screening could also be used to improve care in medical problems that are worsened by cognitive impairment. To find the true value of these efforts, they wrote, researchers need to design and execute additional clinical trials that “answer many of the important questions surrounding screening and treatment of cognitive impairment.”

“The absence of evidence for benefit may lead to inaction,” they added, noting that clinicians screening should still consider the value of screening on a case-by-case basis in order to keep up with the impact of new disease-modifying therapies for certain neurodegenerative diseases.

All members of the USPSTF received travel reimbursement and an honorarium for participating in meetings. One member reported receiving grants and personal fees from Healthwise. The study was funded by the Department of Health & Human Services. One of the authors reported receiving grants from the National Institutes of Health and the Food and Drug Administration. Dr. Petersen and Dr. Yaffe reported consulting for, and receiving funding from, various pharmaceutical companies, foundations, and government organizations.

SOURCES: Owens DK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0435; Patnode CD et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2019.22258.

The U.S. Preventive Services Task Force has deemed the current evidence “insufficient” to make a recommendation in regard to screening for cognitive impairment in adults aged 65 years or older.

“More research is needed on the effect of screening and early detection of cognitive impairment on important patient, caregiver, and societal outcomes, including decision making, advance planning, and caregiver outcomes,” wrote lead author Douglas K. Owens, MD, of Stanford (Calif.) University and fellow members of the task force. The statement was published in JAMA.

To update a 2014 recommendation from the USPSTF, which also found insufficient evidence to properly assess cognitive screening’s benefits and harms, the task force commissioned a systematic review of studies applicable to community-dwelling older adults who are not exhibiting signs or symptoms of cognitive impairment. For their statement, “cognitive impairment” is defined as mild cognitive impairment and mild to moderate dementia.

Ultimately, they determined several factors that limited the overall evidence, including the short duration of most trials and the heterogenous nature of interventions and inconsistencies in outcomes reported. Any evidence that suggested improvements was mostly applicable to patients with moderate dementia, meaning “its applicability to a screen-detected population is uncertain.”
 

Updating 2014 recommendations

Their statement was based on an evidence report, also published in JAMA, in which a team of researchers reviewed 287 studies that included more than 285,000 older adults; 92 of the studies were newly identified, while the other 195 were carried forward from the 2014 recommendation’s review. The researchers sought the answers to five key questions, carrying over the framework from the previous review.

“Despite the accumulation of new data, the conclusions for these key questions are essentially unchanged from the prior review,” wrote lead author Carrie D. Patnode, PhD, of the Kaiser Permanente Center for Health Research in Portland, Ore., and coauthors.

Of the questions – which concerned the accuracy of screening instruments; the harms of screening; the harms of interventions; and if screening or interventions improved decision making or outcomes for the patient, family/caregiver, or society – moderate evidence was found to support the accuracy of the instruments, treatment with acetylcholinesterase inhibitors and memantine for patients with moderate dementia, and psychoeducation interventions for caregivers of patients with moderate dementia. At the same time, there was moderate evidence of adverse effects from acetylcholinesterase inhibitors and memantine in patients with moderate dementia.

“I think, eventually, there will be sufficient evidence to justify screening, once we have what I call a tiered approach,” Marwan Sabbagh, MD, of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, said in an interview. “The very near future will include blood tests for Alzheimer’s, or PET scans, or genetics, or something else. Right now, the cognitive screens lack the specificity and sensitivity, and the secondary screening infrastructure that would improve the accuracy doesn’t exist yet.

“I think this is a ‘not now,’ ” he added, “but I wouldn’t say ‘not ever.’ ”

Dr. Patnode and coauthors noted specific limitations in the evidence, including a lack of studies on how screening for and treating cognitive impairment affects decision making. In addition, details like quality of life and institutionalization were inconsistently reported, and “consistent and standardized reporting of results according to meaningful thresholds of clinical significance” would have been valuable across all measures.
 

Clinical implications

The implications of this report’s conclusions are substantial, especially as the rising prevalence of mild cognitive impairment and dementia becomes a worldwide concern, wrote Ronald C. Petersen, PhD, MD, of the Mayo Clinic in Rochester, Minn., and Kristine Yaffe, MD, of the University of California, San Francisco, in an accompanying editorial.

Though the data does not explicitly support screening, Dr. Petersen and Dr. Yaffe noted that it still may have benefits. An estimated 10% of cognitive impairment is caused by at least somewhat reversible causes, and screening could also be used to improve care in medical problems that are worsened by cognitive impairment. To find the true value of these efforts, they wrote, researchers need to design and execute additional clinical trials that “answer many of the important questions surrounding screening and treatment of cognitive impairment.”

“The absence of evidence for benefit may lead to inaction,” they added, noting that clinicians screening should still consider the value of screening on a case-by-case basis in order to keep up with the impact of new disease-modifying therapies for certain neurodegenerative diseases.

All members of the USPSTF received travel reimbursement and an honorarium for participating in meetings. One member reported receiving grants and personal fees from Healthwise. The study was funded by the Department of Health & Human Services. One of the authors reported receiving grants from the National Institutes of Health and the Food and Drug Administration. Dr. Petersen and Dr. Yaffe reported consulting for, and receiving funding from, various pharmaceutical companies, foundations, and government organizations.

SOURCES: Owens DK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0435; Patnode CD et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2019.22258.

The U.S. Preventive Services Task Force has deemed the current evidence “insufficient” to make a recommendation in regard to screening for cognitive impairment in adults aged 65 years or older.

“More research is needed on the effect of screening and early detection of cognitive impairment on important patient, caregiver, and societal outcomes, including decision making, advance planning, and caregiver outcomes,” wrote lead author Douglas K. Owens, MD, of Stanford (Calif.) University and fellow members of the task force. The statement was published in JAMA.

To update a 2014 recommendation from the USPSTF, which also found insufficient evidence to properly assess cognitive screening’s benefits and harms, the task force commissioned a systematic review of studies applicable to community-dwelling older adults who are not exhibiting signs or symptoms of cognitive impairment. For their statement, “cognitive impairment” is defined as mild cognitive impairment and mild to moderate dementia.

Ultimately, they determined several factors that limited the overall evidence, including the short duration of most trials and the heterogenous nature of interventions and inconsistencies in outcomes reported. Any evidence that suggested improvements was mostly applicable to patients with moderate dementia, meaning “its applicability to a screen-detected population is uncertain.”
 

Updating 2014 recommendations

Their statement was based on an evidence report, also published in JAMA, in which a team of researchers reviewed 287 studies that included more than 285,000 older adults; 92 of the studies were newly identified, while the other 195 were carried forward from the 2014 recommendation’s review. The researchers sought the answers to five key questions, carrying over the framework from the previous review.

“Despite the accumulation of new data, the conclusions for these key questions are essentially unchanged from the prior review,” wrote lead author Carrie D. Patnode, PhD, of the Kaiser Permanente Center for Health Research in Portland, Ore., and coauthors.

Of the questions – which concerned the accuracy of screening instruments; the harms of screening; the harms of interventions; and if screening or interventions improved decision making or outcomes for the patient, family/caregiver, or society – moderate evidence was found to support the accuracy of the instruments, treatment with acetylcholinesterase inhibitors and memantine for patients with moderate dementia, and psychoeducation interventions for caregivers of patients with moderate dementia. At the same time, there was moderate evidence of adverse effects from acetylcholinesterase inhibitors and memantine in patients with moderate dementia.

“I think, eventually, there will be sufficient evidence to justify screening, once we have what I call a tiered approach,” Marwan Sabbagh, MD, of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, said in an interview. “The very near future will include blood tests for Alzheimer’s, or PET scans, or genetics, or something else. Right now, the cognitive screens lack the specificity and sensitivity, and the secondary screening infrastructure that would improve the accuracy doesn’t exist yet.

“I think this is a ‘not now,’ ” he added, “but I wouldn’t say ‘not ever.’ ”

Dr. Patnode and coauthors noted specific limitations in the evidence, including a lack of studies on how screening for and treating cognitive impairment affects decision making. In addition, details like quality of life and institutionalization were inconsistently reported, and “consistent and standardized reporting of results according to meaningful thresholds of clinical significance” would have been valuable across all measures.
 

Clinical implications

The implications of this report’s conclusions are substantial, especially as the rising prevalence of mild cognitive impairment and dementia becomes a worldwide concern, wrote Ronald C. Petersen, PhD, MD, of the Mayo Clinic in Rochester, Minn., and Kristine Yaffe, MD, of the University of California, San Francisco, in an accompanying editorial.

Though the data does not explicitly support screening, Dr. Petersen and Dr. Yaffe noted that it still may have benefits. An estimated 10% of cognitive impairment is caused by at least somewhat reversible causes, and screening could also be used to improve care in medical problems that are worsened by cognitive impairment. To find the true value of these efforts, they wrote, researchers need to design and execute additional clinical trials that “answer many of the important questions surrounding screening and treatment of cognitive impairment.”

“The absence of evidence for benefit may lead to inaction,” they added, noting that clinicians screening should still consider the value of screening on a case-by-case basis in order to keep up with the impact of new disease-modifying therapies for certain neurodegenerative diseases.

All members of the USPSTF received travel reimbursement and an honorarium for participating in meetings. One member reported receiving grants and personal fees from Healthwise. The study was funded by the Department of Health & Human Services. One of the authors reported receiving grants from the National Institutes of Health and the Food and Drug Administration. Dr. Petersen and Dr. Yaffe reported consulting for, and receiving funding from, various pharmaceutical companies, foundations, and government organizations.

SOURCES: Owens DK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0435; Patnode CD et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2019.22258.

Cancer patients in states that opted to expand Medicaid insurance coverage under the Affordable Care Act saw a slightly better rate of early diagnosis, compared with patients in states that refused expansion, according to a new study. However, time to treatment was similar in states that opted for expansion and states that did not.

Samuel U. Takvorian, MD, of the University of Pennsylvania, Philadelphia, and colleagues reported these results in JAMA Network Open.

The researchers used the National Cancer Database to examine the changes in health insurance coverage and cancer health outcomes in nonelderly patients following implementation of the Affordable Care Act in January 2014. The investigators identified records for 925,543 patients who had new-onset breast (59%), colon (15%), or non–small cell lung (27%) cancer between 2011 and 2016. The patients’ mean age was 55 years (range, 40-64 years), 79% were women, 14% were black, and 6% were Hispanic.

The researchers looked at insurance status, cancer stage at diagnosis, and treatment initiation within 30 and 90 days of diagnosis. The cohort was equally divided between residents of Medicaid expansion states (48%) and nonexpansion states (52%).

Using a statistical technique that mimics a controlled experiment, the investigators found the percentage of uninsured patients decreased more in the expansion states (adjusted difference-in-differences, −0.7 percentage points; 95% confidence interval, −1.2 to −0.3; P = .001), compared with nonexpansion states. Expansion states also had a greater increase in early-stage cancer diagnoses (adjusted DID, 0.8; 95% CI 0.3-1.2; P = .001) and a greater decrease in advanced-stage cancer diagnoses (adjusted DID, −0.5; 95% CI, −0.9 to −0.2; P = .003).

Among the 848,329 patients who underwent cancer treatment within a year of diagnosis, the percentage initiating treatment within 30 days declined from 52.7% before to 48% after Medicaid expansion in states opting in (unadjusted DID, −4.7; percentage points, 95% CI; −5.1 to −4.5). States that did not expand their Medicaid programs, meanwhile, saw the share decline from 56.9% to 51.5% in the same time period (adjusted DID, −5.4; 95% CI, −5.6 to −5.1). There was no statistically significant difference in timely treatment associated with Medicaid expansion (adjusted DID, 0.6; 95% CI, −0.2 to 1.4; P = .14).

The researchers speculated that the lack of significant between-group differences in time to treatment, despite an improvement in early-stage diagnoses associated with Medicaid expansion, could reflect a cancer care system strained by a surge in insured patients, overall increases in cancer prevalence and complexity of care, a shortage of workers, or a mixture of factors.

In a related editorial, Sue Fu, MD, of Stanford (Calif.) University, and colleagues wrote that, while the findings of increased early diagnosis seen in the study are promising, the time to treatment results are “puzzling” and deserve further consideration.

Time to treatment is important in cancer, as longer times are associated with increased mortality, Dr. Fu and colleagues noted. Slowing times to cancer treatment is a systemic problem in the United States that has been documented since the mid-2000s. Paradoxically, expanded insurance coverage could contribute to increasing time to treatment even after timely diagnosis by adding administrative burdens leading to longer wait times. “Newly insured and underinsured individuals may be particularly vulnerable to this,” the editorialists wrote.

Dr. Takvorian and colleagues noted as weaknesses of their study its observational design, a limited range of ages and cancers included, and an inability to adjust for state-level effects.

This study was funded by the National Cancer Institute and the Agency for Health Research and Quality. The authors of the study and the editorial disclosed no relevant conflicts of interest.

SOURCES: Takvorian SU et al. JAMA Netw Open. 2020 Feb 5;3(2):e1921653; Fu S et al. JAMA Netw Open. 2020 Feb 5;3(2):e1921690.

Cancer patients in states that opted to expand Medicaid insurance coverage under the Affordable Care Act saw a slightly better rate of early diagnosis, compared with patients in states that refused expansion, according to a new study. However, time to treatment was similar in states that opted for expansion and states that did not.

Samuel U. Takvorian, MD, of the University of Pennsylvania, Philadelphia, and colleagues reported these results in JAMA Network Open.

The researchers used the National Cancer Database to examine the changes in health insurance coverage and cancer health outcomes in nonelderly patients following implementation of the Affordable Care Act in January 2014. The investigators identified records for 925,543 patients who had new-onset breast (59%), colon (15%), or non–small cell lung (27%) cancer between 2011 and 2016. The patients’ mean age was 55 years (range, 40-64 years), 79% were women, 14% were black, and 6% were Hispanic.

The researchers looked at insurance status, cancer stage at diagnosis, and treatment initiation within 30 and 90 days of diagnosis. The cohort was equally divided between residents of Medicaid expansion states (48%) and nonexpansion states (52%).

Using a statistical technique that mimics a controlled experiment, the investigators found the percentage of uninsured patients decreased more in the expansion states (adjusted difference-in-differences, −0.7 percentage points; 95% confidence interval, −1.2 to −0.3; P = .001), compared with nonexpansion states. Expansion states also had a greater increase in early-stage cancer diagnoses (adjusted DID, 0.8; 95% CI 0.3-1.2; P = .001) and a greater decrease in advanced-stage cancer diagnoses (adjusted DID, −0.5; 95% CI, −0.9 to −0.2; P = .003).

Among the 848,329 patients who underwent cancer treatment within a year of diagnosis, the percentage initiating treatment within 30 days declined from 52.7% before to 48% after Medicaid expansion in states opting in (unadjusted DID, −4.7; percentage points, 95% CI; −5.1 to −4.5). States that did not expand their Medicaid programs, meanwhile, saw the share decline from 56.9% to 51.5% in the same time period (adjusted DID, −5.4; 95% CI, −5.6 to −5.1). There was no statistically significant difference in timely treatment associated with Medicaid expansion (adjusted DID, 0.6; 95% CI, −0.2 to 1.4; P = .14).

The researchers speculated that the lack of significant between-group differences in time to treatment, despite an improvement in early-stage diagnoses associated with Medicaid expansion, could reflect a cancer care system strained by a surge in insured patients, overall increases in cancer prevalence and complexity of care, a shortage of workers, or a mixture of factors.

In a related editorial, Sue Fu, MD, of Stanford (Calif.) University, and colleagues wrote that, while the findings of increased early diagnosis seen in the study are promising, the time to treatment results are “puzzling” and deserve further consideration.

Time to treatment is important in cancer, as longer times are associated with increased mortality, Dr. Fu and colleagues noted. Slowing times to cancer treatment is a systemic problem in the United States that has been documented since the mid-2000s. Paradoxically, expanded insurance coverage could contribute to increasing time to treatment even after timely diagnosis by adding administrative burdens leading to longer wait times. “Newly insured and underinsured individuals may be particularly vulnerable to this,” the editorialists wrote.

Dr. Takvorian and colleagues noted as weaknesses of their study its observational design, a limited range of ages and cancers included, and an inability to adjust for state-level effects.

This study was funded by the National Cancer Institute and the Agency for Health Research and Quality. The authors of the study and the editorial disclosed no relevant conflicts of interest.

SOURCES: Takvorian SU et al. JAMA Netw Open. 2020 Feb 5;3(2):e1921653; Fu S et al. JAMA Netw Open. 2020 Feb 5;3(2):e1921690.

Cancer patients in states that opted to expand Medicaid insurance coverage under the Affordable Care Act saw a slightly better rate of early diagnosis, compared with patients in states that refused expansion, according to a new study. However, time to treatment was similar in states that opted for expansion and states that did not.

Samuel U. Takvorian, MD, of the University of Pennsylvania, Philadelphia, and colleagues reported these results in JAMA Network Open.

The researchers used the National Cancer Database to examine the changes in health insurance coverage and cancer health outcomes in nonelderly patients following implementation of the Affordable Care Act in January 2014. The investigators identified records for 925,543 patients who had new-onset breast (59%), colon (15%), or non–small cell lung (27%) cancer between 2011 and 2016. The patients’ mean age was 55 years (range, 40-64 years), 79% were women, 14% were black, and 6% were Hispanic.

The researchers looked at insurance status, cancer stage at diagnosis, and treatment initiation within 30 and 90 days of diagnosis. The cohort was equally divided between residents of Medicaid expansion states (48%) and nonexpansion states (52%).

Using a statistical technique that mimics a controlled experiment, the investigators found the percentage of uninsured patients decreased more in the expansion states (adjusted difference-in-differences, −0.7 percentage points; 95% confidence interval, −1.2 to −0.3; P = .001), compared with nonexpansion states. Expansion states also had a greater increase in early-stage cancer diagnoses (adjusted DID, 0.8; 95% CI 0.3-1.2; P = .001) and a greater decrease in advanced-stage cancer diagnoses (adjusted DID, −0.5; 95% CI, −0.9 to −0.2; P = .003).

Among the 848,329 patients who underwent cancer treatment within a year of diagnosis, the percentage initiating treatment within 30 days declined from 52.7% before to 48% after Medicaid expansion in states opting in (unadjusted DID, −4.7; percentage points, 95% CI; −5.1 to −4.5). States that did not expand their Medicaid programs, meanwhile, saw the share decline from 56.9% to 51.5% in the same time period (adjusted DID, −5.4; 95% CI, −5.6 to −5.1). There was no statistically significant difference in timely treatment associated with Medicaid expansion (adjusted DID, 0.6; 95% CI, −0.2 to 1.4; P = .14).

The researchers speculated that the lack of significant between-group differences in time to treatment, despite an improvement in early-stage diagnoses associated with Medicaid expansion, could reflect a cancer care system strained by a surge in insured patients, overall increases in cancer prevalence and complexity of care, a shortage of workers, or a mixture of factors.

In a related editorial, Sue Fu, MD, of Stanford (Calif.) University, and colleagues wrote that, while the findings of increased early diagnosis seen in the study are promising, the time to treatment results are “puzzling” and deserve further consideration.

Time to treatment is important in cancer, as longer times are associated with increased mortality, Dr. Fu and colleagues noted. Slowing times to cancer treatment is a systemic problem in the United States that has been documented since the mid-2000s. Paradoxically, expanded insurance coverage could contribute to increasing time to treatment even after timely diagnosis by adding administrative burdens leading to longer wait times. “Newly insured and underinsured individuals may be particularly vulnerable to this,” the editorialists wrote.

Dr. Takvorian and colleagues noted as weaknesses of their study its observational design, a limited range of ages and cancers included, and an inability to adjust for state-level effects.

This study was funded by the National Cancer Institute and the Agency for Health Research and Quality. The authors of the study and the editorial disclosed no relevant conflicts of interest.

SOURCES: Takvorian SU et al. JAMA Netw Open. 2020 Feb 5;3(2):e1921653; Fu S et al. JAMA Netw Open. 2020 Feb 5;3(2):e1921690.

The topoisomerase I (TOP1) inhibitor irinotecan could be effective in treating triple-negative breast cancer (TNBC), according to results from a preclinical study published in Science Translational Medicine.

Florence Coussy, MD, PhD, of Institut Curie, Paris, and colleagues evaluated the antitumor activity of the Food and Drug Administration–approved TOP1 inhibitor irinotecan in 40 patient-derived xenografts (PDXs) of TNBC.

Other treatments, such as noncamptothecin TOP1 inhibitors (indotecan and indimitecan) and irinotecan plus VE-822 (an ataxia telangiectasia and Rad3-related protein [ATR] inhibitor), were also evaluated in the PDX models.

Tumor samples were collected from patients with primary breast cancer at the time of surgery (55%), residual breast cancer after neoadjuvant treatment (40%), or axillary lymph node metastases (5%). The patients had a mean age of 56 years (range, 29-89 years).

The researchers assessed BRCAness using the homologous recombination deficiency–large-scale state transition assay. Additional potential markers of response, including expression of retinoblastoma transcriptional corepressor 1 (RB1) and Schlafen family member 11 (SLFN11), were detected on transcriptomic analysis and validated using immunohistochemistry analyses.

The researchers found that 37.5% (n = 15) of TNBC PDX models achieved a partial or complete response to irinotecan therapy, while 22.5% (n = 9) of models had stable disease. BRCAness, RB1 loss, and high SLFN11 expression were deemed potential markers of response to irinotecan and other clinical TOP1 inhibitors.

The researchers then evaluated 250 breast cancer patients treated with anthracycline-based chemotherapy and found that lower expression of SLFN11 was associated with worse survival.

“We also [found] that, in the absence of SLFN11, response to irinotecan can be increased by adding an ATR inhibitor and that the clinical TOP1 inhibitors are highly efficient in BRCA1-mutant and BRCAness-positive TNBC PDXs,” the researchers reported.

They acknowledged that a key limitation of this study was the absence of tumor samples from patients who had received a TOP1 inhibitor.

“Overall, our findings are in line with the notion that concomitant defects in DNA repair and checkpoints render cancer cells highly vulnerable to TOP1 inhibitors,” the researchers concluded.

The study was funded by the National Cancer Institute, PIC3i NCI-Curie, and Site de Recherche Intégrée sur le Cancer. One author is an inventor of indotecan and indimitecan. Two authors are coinventors of the method used to detect inactivation of the homologous recombination pathway, which is licensed to Myriad Genetics.

SOURCE: Coussy F et al. Sci Transl Med. 2020 Feb 19. doi: 10.1126/scitranslmed.aax2625.

The topoisomerase I (TOP1) inhibitor irinotecan could be effective in treating triple-negative breast cancer (TNBC), according to results from a preclinical study published in Science Translational Medicine.

Florence Coussy, MD, PhD, of Institut Curie, Paris, and colleagues evaluated the antitumor activity of the Food and Drug Administration–approved TOP1 inhibitor irinotecan in 40 patient-derived xenografts (PDXs) of TNBC.

Other treatments, such as noncamptothecin TOP1 inhibitors (indotecan and indimitecan) and irinotecan plus VE-822 (an ataxia telangiectasia and Rad3-related protein [ATR] inhibitor), were also evaluated in the PDX models.

Tumor samples were collected from patients with primary breast cancer at the time of surgery (55%), residual breast cancer after neoadjuvant treatment (40%), or axillary lymph node metastases (5%). The patients had a mean age of 56 years (range, 29-89 years).

The researchers assessed BRCAness using the homologous recombination deficiency–large-scale state transition assay. Additional potential markers of response, including expression of retinoblastoma transcriptional corepressor 1 (RB1) and Schlafen family member 11 (SLFN11), were detected on transcriptomic analysis and validated using immunohistochemistry analyses.

The researchers found that 37.5% (n = 15) of TNBC PDX models achieved a partial or complete response to irinotecan therapy, while 22.5% (n = 9) of models had stable disease. BRCAness, RB1 loss, and high SLFN11 expression were deemed potential markers of response to irinotecan and other clinical TOP1 inhibitors.

The researchers then evaluated 250 breast cancer patients treated with anthracycline-based chemotherapy and found that lower expression of SLFN11 was associated with worse survival.

“We also [found] that, in the absence of SLFN11, response to irinotecan can be increased by adding an ATR inhibitor and that the clinical TOP1 inhibitors are highly efficient in BRCA1-mutant and BRCAness-positive TNBC PDXs,” the researchers reported.

They acknowledged that a key limitation of this study was the absence of tumor samples from patients who had received a TOP1 inhibitor.

“Overall, our findings are in line with the notion that concomitant defects in DNA repair and checkpoints render cancer cells highly vulnerable to TOP1 inhibitors,” the researchers concluded.

The study was funded by the National Cancer Institute, PIC3i NCI-Curie, and Site de Recherche Intégrée sur le Cancer. One author is an inventor of indotecan and indimitecan. Two authors are coinventors of the method used to detect inactivation of the homologous recombination pathway, which is licensed to Myriad Genetics.

SOURCE: Coussy F et al. Sci Transl Med. 2020 Feb 19. doi: 10.1126/scitranslmed.aax2625.

The topoisomerase I (TOP1) inhibitor irinotecan could be effective in treating triple-negative breast cancer (TNBC), according to results from a preclinical study published in Science Translational Medicine.

Florence Coussy, MD, PhD, of Institut Curie, Paris, and colleagues evaluated the antitumor activity of the Food and Drug Administration–approved TOP1 inhibitor irinotecan in 40 patient-derived xenografts (PDXs) of TNBC.

Other treatments, such as noncamptothecin TOP1 inhibitors (indotecan and indimitecan) and irinotecan plus VE-822 (an ataxia telangiectasia and Rad3-related protein [ATR] inhibitor), were also evaluated in the PDX models.

Tumor samples were collected from patients with primary breast cancer at the time of surgery (55%), residual breast cancer after neoadjuvant treatment (40%), or axillary lymph node metastases (5%). The patients had a mean age of 56 years (range, 29-89 years).

The researchers assessed BRCAness using the homologous recombination deficiency–large-scale state transition assay. Additional potential markers of response, including expression of retinoblastoma transcriptional corepressor 1 (RB1) and Schlafen family member 11 (SLFN11), were detected on transcriptomic analysis and validated using immunohistochemistry analyses.

The researchers found that 37.5% (n = 15) of TNBC PDX models achieved a partial or complete response to irinotecan therapy, while 22.5% (n = 9) of models had stable disease. BRCAness, RB1 loss, and high SLFN11 expression were deemed potential markers of response to irinotecan and other clinical TOP1 inhibitors.

The researchers then evaluated 250 breast cancer patients treated with anthracycline-based chemotherapy and found that lower expression of SLFN11 was associated with worse survival.

“We also [found] that, in the absence of SLFN11, response to irinotecan can be increased by adding an ATR inhibitor and that the clinical TOP1 inhibitors are highly efficient in BRCA1-mutant and BRCAness-positive TNBC PDXs,” the researchers reported.

They acknowledged that a key limitation of this study was the absence of tumor samples from patients who had received a TOP1 inhibitor.

“Overall, our findings are in line with the notion that concomitant defects in DNA repair and checkpoints render cancer cells highly vulnerable to TOP1 inhibitors,” the researchers concluded.

The study was funded by the National Cancer Institute, PIC3i NCI-Curie, and Site de Recherche Intégrée sur le Cancer. One author is an inventor of indotecan and indimitecan. Two authors are coinventors of the method used to detect inactivation of the homologous recombination pathway, which is licensed to Myriad Genetics.

SOURCE: Coussy F et al. Sci Transl Med. 2020 Feb 19. doi: 10.1126/scitranslmed.aax2625.

Higher out-of-pocket costs for prescription drugs are associated with poorer adherence across common neurologic conditions, a new study has found, suggesting that physicians should take patient costs into consideration when choosing which drugs to prescribe.

For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.

The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.

Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.

Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.

Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.

“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.

Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.

The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.

SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.

Higher out-of-pocket costs for prescription drugs are associated with poorer adherence across common neurologic conditions, a new study has found, suggesting that physicians should take patient costs into consideration when choosing which drugs to prescribe.

For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.

The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.

Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.

Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.

Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.

“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.

Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.

The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.

SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.

Higher out-of-pocket costs for prescription drugs are associated with poorer adherence across common neurologic conditions, a new study has found, suggesting that physicians should take patient costs into consideration when choosing which drugs to prescribe.

For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.

The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.

Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.

Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.

Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.

“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.

Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.

The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.

SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.

The first trial of robot-assisted, high-precision supermicrosurgery in humans has shown that the technique was safe for treating breast cancer–related lymphedema.

Although results were preliminary – only 20 patients participated, and a single highly skilled surgeon performed the supermicrosurgery – additional trials are underway to test the new robotic technique at other centers.

The pilot study was published online Feb. 11 in Nature Communications.

The new device, known as MUSA, was supplied by MicroSure.

MUSA allowed surgeons to connect tiny vessels, as small as 0.3-0.8 mm across, a technique referred to as supermicrosurgery. This technique can be used to connect blocked lymph vessels to veins, which can reestablish flow of lymphatic fluid and decrease arm swelling in women with breast cancer–related lymphedema, the researchers explain.

Only a few highly skilled surgeons worldwide can conduct supermicrosurgery using current surgical techniques, the authors comment.

“The success of supermicrosurgery is limited by the precision and stability of the surgeon’s hands. Robot-assisted supermicrosurgery has the potential to overcome this obstacle because more refined and subtle movements can be performed. Before now, no robots were able to perform this type of surgery,” coauthor Rutger M. Schols, MD, PhD, of Maastricht (the Netherlands) University Medical Center, said in an interview.

Robot-assisted surgery is not new – the Da Vinci system was the first robotic surgery device to be approved by the Food and Drug Administration. It was approved in 2000. However, Da Vinci was developed for minimally invasive surgery and is not precise enough for supermicrosurgery. And despite its $2 million price tag, Da Vinci has yet to show that it performs better than traditional surgery.

Designed specifically for supermicrosurgery

The MUSA robot was designed by surgeons at the Maastricht University Medical Center, engineers at the Eindhoven University of Technology, and the medical technology company Microsure specifically for reconstructive supermicrosurgery; all are located in the Netherlands. Two of the authors of the article hold positions and are shareholders in the company.

Surgeons activate MUSA using foot pedals and operate forceps-like joysticks to control high-precision surgical instruments that filter out hand tremors and scale down motions. For example, moving the joystick 1 cm causes the robot to move 0.10 mm. MUSA also works with standard microscopes found in most operating rooms.

To test MUSA, Dr. Schols and colleagues conducted a prospective, randomized trial that included 20 women with breast cancer–related lymphedema. The team randomly assigned eight women to undergo supermicrosurgery with MUSA and 12 women to undergo manual supermicrosurgery performed by a single surgeon. Two microsurgeons who were blinded to treatment groups evaluated the quality of the surgery using standardized scoring methods.

The results, which were adjusted for baseline factors, showed no significant differences in upper-limb lymphedema between the two groups 1 and 3 months after surgery, nor were there significant differences between the two groups in quality of life.

A slightly higher percentage of women in the MUSA group were able to discontinue daily use of a compressive garment to treat arm swelling at 3 months, compared with the group that underwent manual supermicrosurgery (87.5% vs. 83.3%). Participants reported no serious adverse events.

For the group that underwent manual surgery, the quality of anastomosis was significantly better, compared with the MUSA group. Surgical competency also was significantly higher in the group that underwent manual surgery.

The MUSA group experienced a longer total surgery time (mean, 115 min), compared with the group that underwent manual surgery (mean, 81 min). But the authors note that duration of surgery declined steeply over time for the MUSA group, suggesting a learning curve in using the robot.

The researchers caution that the study may have been too small to detect significant differences between groups. Larger studies are needed to test MUSA with other surgeons operating in other centers, the authors note.

“With respect to treatment of breast cancer–related lymphedema, we are continuing trials with more patients, more surgeons, and more centers,” Dr. Schols said in an interview.

“We expect that other centers – both national and international – are willing to test the MUSA,” he added.

Dr. Schols and several coauthors have disclosed no relevant financial relationships. Two coauthors are shareholders and hold positions at MicroSure.
 

This article first appeared on Medscape.com.

The first trial of robot-assisted, high-precision supermicrosurgery in humans has shown that the technique was safe for treating breast cancer–related lymphedema.

Although results were preliminary – only 20 patients participated, and a single highly skilled surgeon performed the supermicrosurgery – additional trials are underway to test the new robotic technique at other centers.

The pilot study was published online Feb. 11 in Nature Communications.

The new device, known as MUSA, was supplied by MicroSure.

MUSA allowed surgeons to connect tiny vessels, as small as 0.3-0.8 mm across, a technique referred to as supermicrosurgery. This technique can be used to connect blocked lymph vessels to veins, which can reestablish flow of lymphatic fluid and decrease arm swelling in women with breast cancer–related lymphedema, the researchers explain.

Only a few highly skilled surgeons worldwide can conduct supermicrosurgery using current surgical techniques, the authors comment.

“The success of supermicrosurgery is limited by the precision and stability of the surgeon’s hands. Robot-assisted supermicrosurgery has the potential to overcome this obstacle because more refined and subtle movements can be performed. Before now, no robots were able to perform this type of surgery,” coauthor Rutger M. Schols, MD, PhD, of Maastricht (the Netherlands) University Medical Center, said in an interview.

Robot-assisted surgery is not new – the Da Vinci system was the first robotic surgery device to be approved by the Food and Drug Administration. It was approved in 2000. However, Da Vinci was developed for minimally invasive surgery and is not precise enough for supermicrosurgery. And despite its $2 million price tag, Da Vinci has yet to show that it performs better than traditional surgery.

Designed specifically for supermicrosurgery

The MUSA robot was designed by surgeons at the Maastricht University Medical Center, engineers at the Eindhoven University of Technology, and the medical technology company Microsure specifically for reconstructive supermicrosurgery; all are located in the Netherlands. Two of the authors of the article hold positions and are shareholders in the company.

Surgeons activate MUSA using foot pedals and operate forceps-like joysticks to control high-precision surgical instruments that filter out hand tremors and scale down motions. For example, moving the joystick 1 cm causes the robot to move 0.10 mm. MUSA also works with standard microscopes found in most operating rooms.

To test MUSA, Dr. Schols and colleagues conducted a prospective, randomized trial that included 20 women with breast cancer–related lymphedema. The team randomly assigned eight women to undergo supermicrosurgery with MUSA and 12 women to undergo manual supermicrosurgery performed by a single surgeon. Two microsurgeons who were blinded to treatment groups evaluated the quality of the surgery using standardized scoring methods.

The results, which were adjusted for baseline factors, showed no significant differences in upper-limb lymphedema between the two groups 1 and 3 months after surgery, nor were there significant differences between the two groups in quality of life.

A slightly higher percentage of women in the MUSA group were able to discontinue daily use of a compressive garment to treat arm swelling at 3 months, compared with the group that underwent manual supermicrosurgery (87.5% vs. 83.3%). Participants reported no serious adverse events.

For the group that underwent manual surgery, the quality of anastomosis was significantly better, compared with the MUSA group. Surgical competency also was significantly higher in the group that underwent manual surgery.

The MUSA group experienced a longer total surgery time (mean, 115 min), compared with the group that underwent manual surgery (mean, 81 min). But the authors note that duration of surgery declined steeply over time for the MUSA group, suggesting a learning curve in using the robot.

The researchers caution that the study may have been too small to detect significant differences between groups. Larger studies are needed to test MUSA with other surgeons operating in other centers, the authors note.

“With respect to treatment of breast cancer–related lymphedema, we are continuing trials with more patients, more surgeons, and more centers,” Dr. Schols said in an interview.

“We expect that other centers – both national and international – are willing to test the MUSA,” he added.

Dr. Schols and several coauthors have disclosed no relevant financial relationships. Two coauthors are shareholders and hold positions at MicroSure.
 

This article first appeared on Medscape.com.

The first trial of robot-assisted, high-precision supermicrosurgery in humans has shown that the technique was safe for treating breast cancer–related lymphedema.

Although results were preliminary – only 20 patients participated, and a single highly skilled surgeon performed the supermicrosurgery – additional trials are underway to test the new robotic technique at other centers.

The pilot study was published online Feb. 11 in Nature Communications.

The new device, known as MUSA, was supplied by MicroSure.

MUSA allowed surgeons to connect tiny vessels, as small as 0.3-0.8 mm across, a technique referred to as supermicrosurgery. This technique can be used to connect blocked lymph vessels to veins, which can reestablish flow of lymphatic fluid and decrease arm swelling in women with breast cancer–related lymphedema, the researchers explain.

Only a few highly skilled surgeons worldwide can conduct supermicrosurgery using current surgical techniques, the authors comment.

“The success of supermicrosurgery is limited by the precision and stability of the surgeon’s hands. Robot-assisted supermicrosurgery has the potential to overcome this obstacle because more refined and subtle movements can be performed. Before now, no robots were able to perform this type of surgery,” coauthor Rutger M. Schols, MD, PhD, of Maastricht (the Netherlands) University Medical Center, said in an interview.

Robot-assisted surgery is not new – the Da Vinci system was the first robotic surgery device to be approved by the Food and Drug Administration. It was approved in 2000. However, Da Vinci was developed for minimally invasive surgery and is not precise enough for supermicrosurgery. And despite its $2 million price tag, Da Vinci has yet to show that it performs better than traditional surgery.

Designed specifically for supermicrosurgery

The MUSA robot was designed by surgeons at the Maastricht University Medical Center, engineers at the Eindhoven University of Technology, and the medical technology company Microsure specifically for reconstructive supermicrosurgery; all are located in the Netherlands. Two of the authors of the article hold positions and are shareholders in the company.

Surgeons activate MUSA using foot pedals and operate forceps-like joysticks to control high-precision surgical instruments that filter out hand tremors and scale down motions. For example, moving the joystick 1 cm causes the robot to move 0.10 mm. MUSA also works with standard microscopes found in most operating rooms.

To test MUSA, Dr. Schols and colleagues conducted a prospective, randomized trial that included 20 women with breast cancer–related lymphedema. The team randomly assigned eight women to undergo supermicrosurgery with MUSA and 12 women to undergo manual supermicrosurgery performed by a single surgeon. Two microsurgeons who were blinded to treatment groups evaluated the quality of the surgery using standardized scoring methods.

The results, which were adjusted for baseline factors, showed no significant differences in upper-limb lymphedema between the two groups 1 and 3 months after surgery, nor were there significant differences between the two groups in quality of life.

A slightly higher percentage of women in the MUSA group were able to discontinue daily use of a compressive garment to treat arm swelling at 3 months, compared with the group that underwent manual supermicrosurgery (87.5% vs. 83.3%). Participants reported no serious adverse events.

For the group that underwent manual surgery, the quality of anastomosis was significantly better, compared with the MUSA group. Surgical competency also was significantly higher in the group that underwent manual surgery.

The MUSA group experienced a longer total surgery time (mean, 115 min), compared with the group that underwent manual surgery (mean, 81 min). But the authors note that duration of surgery declined steeply over time for the MUSA group, suggesting a learning curve in using the robot.

The researchers caution that the study may have been too small to detect significant differences between groups. Larger studies are needed to test MUSA with other surgeons operating in other centers, the authors note.

“With respect to treatment of breast cancer–related lymphedema, we are continuing trials with more patients, more surgeons, and more centers,” Dr. Schols said in an interview.

“We expect that other centers – both national and international – are willing to test the MUSA,” he added.

Dr. Schols and several coauthors have disclosed no relevant financial relationships. Two coauthors are shareholders and hold positions at MicroSure.
 

This article first appeared on Medscape.com.

The complement C5 inhibitor zilucoplan significantly improved muscle weakness and daily functioning in patients with moderate to severe generalized myasthenia gravis (gMG), according to investigators who conducted a phase 2, randomized, placebo-controlled study of the agent.

The clinical effect of the self-administered macrocyclic peptide inhibitor was “similar,” the investigators wrote, to what was seen in studies of the intravenously administered complement inhibitor eculizumab, which is approved by the Food and Drug Administration for treatment of gMG.

While eculizumab studies were restricted to patients with refractory gMG, the investigators wrote that their study of zilucoplan included a broader population, including patients who had not failed prior therapies, who were earlier in their disease course, and who had a history of thymoma.

“This observation is important because in gMG, disease severity frequently peaks within the first few years after diagnosis, before all treatment options have been exhausted, and before patients may be formally declared treatment refractory,” wrote James F. Howard Jr, MD, of the University of North Carolina in Chapel Hill, and coauthors.

Complement inhibition is a “targeted approach” that addresses the primary mechanism of tissue damage in gMG, the investigators wrote.

That stands in contrast to conventional gMG treatments including pyridostigmine, corticosteroids, and other immunosuppressants. “These treatments lack strong evidence from clinical trials to support their efficacy, are often poorly tolerated, and can be associated with considerable long-term toxicities,” Dr. Howard and colleagues wrote in their report, which was published in JAMA Neurology.

A total of 44 adult patients with gMG were randomized to receive daily zilucoplan 0.1 mg/kg, 0.3 mg/kg, or placebo for 12 weeks in this 25-center North American study. All patients had acetylcholine receptor autoantibody–positive disease and a Quantitative Myasthenia Gravis (QMG) score of 12 or higher. The QMG score ranges from 0, indicating no muscle weakness, to 39, or severe weakness.

Per the study protocol, patients had to keep taking their current gMG medication without changing the dose.

Change in QMG score from baseline to 12 weeks, the primary efficacy endpoint of the study, showed a significant and clinically meaningful difference favoring zilucoplan 0.3 mg/kg over placebo, according to the investigators.

The mean change was –6.0 points for zilucoplan 0.3 mg/kg and –3.2 for placebo (P = .05), according to their report, which indicated a rapid onset of action apparent 1 week after starting treatment.

Zilucoplan 0.1 mg/kg also yielded a significant and clinically meaningful improvement versus placebo, but its magnitude was smaller and took 4 weeks to become apparent.

Treatment with zilucoplan also significantly improved MG Activities of Daily Living scores versus placebo, a key secondary endpoint of the trial, according to the researchers.

Treatment-emergent adverse events, which included local injection-site reactions, were mild and judged to be unrelated to the study treatment, according to the report.

Ra Pharmaceuticals funded the study. Dr. Howard reported disclosures related to Ra Pharmaceuticals, Alexion Pharmaceuticals, argenx, Viela Bio, and others.

SOURCE: Howard Jr JF et al. JAMA Neurol. 2020 Feb 17. doi: 10.1001/jamaneurol.2019.5125.

The complement C5 inhibitor zilucoplan significantly improved muscle weakness and daily functioning in patients with moderate to severe generalized myasthenia gravis (gMG), according to investigators who conducted a phase 2, randomized, placebo-controlled study of the agent.

The clinical effect of the self-administered macrocyclic peptide inhibitor was “similar,” the investigators wrote, to what was seen in studies of the intravenously administered complement inhibitor eculizumab, which is approved by the Food and Drug Administration for treatment of gMG.

While eculizumab studies were restricted to patients with refractory gMG, the investigators wrote that their study of zilucoplan included a broader population, including patients who had not failed prior therapies, who were earlier in their disease course, and who had a history of thymoma.

“This observation is important because in gMG, disease severity frequently peaks within the first few years after diagnosis, before all treatment options have been exhausted, and before patients may be formally declared treatment refractory,” wrote James F. Howard Jr, MD, of the University of North Carolina in Chapel Hill, and coauthors.

Complement inhibition is a “targeted approach” that addresses the primary mechanism of tissue damage in gMG, the investigators wrote.

That stands in contrast to conventional gMG treatments including pyridostigmine, corticosteroids, and other immunosuppressants. “These treatments lack strong evidence from clinical trials to support their efficacy, are often poorly tolerated, and can be associated with considerable long-term toxicities,” Dr. Howard and colleagues wrote in their report, which was published in JAMA Neurology.

A total of 44 adult patients with gMG were randomized to receive daily zilucoplan 0.1 mg/kg, 0.3 mg/kg, or placebo for 12 weeks in this 25-center North American study. All patients had acetylcholine receptor autoantibody–positive disease and a Quantitative Myasthenia Gravis (QMG) score of 12 or higher. The QMG score ranges from 0, indicating no muscle weakness, to 39, or severe weakness.

Per the study protocol, patients had to keep taking their current gMG medication without changing the dose.

Change in QMG score from baseline to 12 weeks, the primary efficacy endpoint of the study, showed a significant and clinically meaningful difference favoring zilucoplan 0.3 mg/kg over placebo, according to the investigators.

The mean change was –6.0 points for zilucoplan 0.3 mg/kg and –3.2 for placebo (P = .05), according to their report, which indicated a rapid onset of action apparent 1 week after starting treatment.

Zilucoplan 0.1 mg/kg also yielded a significant and clinically meaningful improvement versus placebo, but its magnitude was smaller and took 4 weeks to become apparent.

Treatment with zilucoplan also significantly improved MG Activities of Daily Living scores versus placebo, a key secondary endpoint of the trial, according to the researchers.

Treatment-emergent adverse events, which included local injection-site reactions, were mild and judged to be unrelated to the study treatment, according to the report.

Ra Pharmaceuticals funded the study. Dr. Howard reported disclosures related to Ra Pharmaceuticals, Alexion Pharmaceuticals, argenx, Viela Bio, and others.

SOURCE: Howard Jr JF et al. JAMA Neurol. 2020 Feb 17. doi: 10.1001/jamaneurol.2019.5125.

The complement C5 inhibitor zilucoplan significantly improved muscle weakness and daily functioning in patients with moderate to severe generalized myasthenia gravis (gMG), according to investigators who conducted a phase 2, randomized, placebo-controlled study of the agent.

The clinical effect of the self-administered macrocyclic peptide inhibitor was “similar,” the investigators wrote, to what was seen in studies of the intravenously administered complement inhibitor eculizumab, which is approved by the Food and Drug Administration for treatment of gMG.

While eculizumab studies were restricted to patients with refractory gMG, the investigators wrote that their study of zilucoplan included a broader population, including patients who had not failed prior therapies, who were earlier in their disease course, and who had a history of thymoma.

“This observation is important because in gMG, disease severity frequently peaks within the first few years after diagnosis, before all treatment options have been exhausted, and before patients may be formally declared treatment refractory,” wrote James F. Howard Jr, MD, of the University of North Carolina in Chapel Hill, and coauthors.

Complement inhibition is a “targeted approach” that addresses the primary mechanism of tissue damage in gMG, the investigators wrote.

That stands in contrast to conventional gMG treatments including pyridostigmine, corticosteroids, and other immunosuppressants. “These treatments lack strong evidence from clinical trials to support their efficacy, are often poorly tolerated, and can be associated with considerable long-term toxicities,” Dr. Howard and colleagues wrote in their report, which was published in JAMA Neurology.

A total of 44 adult patients with gMG were randomized to receive daily zilucoplan 0.1 mg/kg, 0.3 mg/kg, or placebo for 12 weeks in this 25-center North American study. All patients had acetylcholine receptor autoantibody–positive disease and a Quantitative Myasthenia Gravis (QMG) score of 12 or higher. The QMG score ranges from 0, indicating no muscle weakness, to 39, or severe weakness.

Per the study protocol, patients had to keep taking their current gMG medication without changing the dose.

Change in QMG score from baseline to 12 weeks, the primary efficacy endpoint of the study, showed a significant and clinically meaningful difference favoring zilucoplan 0.3 mg/kg over placebo, according to the investigators.

The mean change was –6.0 points for zilucoplan 0.3 mg/kg and –3.2 for placebo (P = .05), according to their report, which indicated a rapid onset of action apparent 1 week after starting treatment.

Zilucoplan 0.1 mg/kg also yielded a significant and clinically meaningful improvement versus placebo, but its magnitude was smaller and took 4 weeks to become apparent.

Treatment with zilucoplan also significantly improved MG Activities of Daily Living scores versus placebo, a key secondary endpoint of the trial, according to the researchers.

Treatment-emergent adverse events, which included local injection-site reactions, were mild and judged to be unrelated to the study treatment, according to the report.

Ra Pharmaceuticals funded the study. Dr. Howard reported disclosures related to Ra Pharmaceuticals, Alexion Pharmaceuticals, argenx, Viela Bio, and others.

SOURCE: Howard Jr JF et al. JAMA Neurol. 2020 Feb 17. doi: 10.1001/jamaneurol.2019.5125.

No antiepileptic drug (AED) is independently associated with cognitive dysfunction, according to research published online ahead of print Feb. 3 in Neurology. Optimizing AED therapy to reduce or prevent seizures is thus unlikely to affect cognition, according to the investigators.

Patients who take AEDs commonly report cognitive problems, but investigations into the cognitive effects of AEDs have yielded inconsistent results. “We were also interested in this association, as we often treat complex patients taking multiple or high-dose AEDs, and our patients often report cognitive dysfunction,” said Emma Foster, MBBS, an epilepsy fellow at Alfred Health and the Royal Melbourne Hospital in Victoria, Australia. “We were particularly interested to examine how much AEDs affect cognition relative to other factors. We commonly see patients in our tertiary epilepsy care unit who have had severe epilepsy for a long time or who have psychiatric disorders, and these factors may also contribute to cognitive dysfunction.”
 

Researchers analyzed patients admitted for video EEG monitoring

For their study, Dr. Foster and colleagues prospectively enrolled patients admitted to the Royal Melbourne Hospital’s video EEG monitoring unit between January 2009 and December 2016. Patients were included in the study if they were age 18 years or older, had been admitted for diagnostic or surgical evaluation, and had complete data for the relevant variables. Patients were prescribed AED monotherapy or polytherapy.

The researchers based epilepsy diagnoses on the 2014 International League Against Epilepsy criteria. Diagnoses of psychogenic nonepileptic seizures (PNES) were based on a consensus of epileptologists at weekly multidisciplinary clinical meetings, which was supported by evaluation of all available data. Some patients received a diagnosis of comorbid epilepsy and PNES. If data were insufficient to support a diagnosis of epilepsy or PNES, the admission was considered nondiagnostic.

All participants underwent neuropsychologic and neuropsychiatric screening. Researchers assessed patients’ objective, global cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), a validated instrument. Patients responded to the Quality of Life in Epilepsy inventory (QOLIE-89) to provide a measure of subjective cognitive function. They also responded to the Hospital Anxiety and Depression Scale (HADS) to screen for mood disorders.

Dr. Foster and colleagues measured seizure frequency through patient self-report. Patients averaged their seizure frequency during the 12-month period before admission to the video EEG unit. They categorized it according to a 12-point system in which 0 denotes patients who are seizure-free and not taking AEDs and 12 denotes patients in status epilepticus. Patients with PNES used the same scale to report event frequency, although the system was not designed for this purpose.
 

Almost half of patients were prescribed polypharmacy

The researchers included 331 patients in their analysis. The population’s mean age was 39.3 years, and about 62% of patients were female. Approximately 47% of patients had epilepsy, 25.7% had PNES, 6.6% had comorbid epilepsy and PNES, and 20.5% had a nondiagnostic outcome. Among patients with epilepsy, most (54.5%) had temporal lobe epilepsy, followed by extratemporal focal epilepsy (32.1%) and generalized epilepsy (13.5%). The mean number of AEDs prescribed on admission was 1.6, and mean seizure or event frequency score was 7.2, which indicated 1-3 seizures per month. Mean HADS depression score was within the normal range (5.7), and mean HADS anxiety score was in the borderline range (8.2).

Approximately 45% of patients were prescribed AED polypharmacy on admission, 25.1% were prescribed AED monotherapy, and 29.9% were prescribed no AED. Levetiracetam, valproate, and carbamazepine were the most frequently prescribed AEDs. Most patients with epilepsy (73.1%) were on polypharmacy, compared with 17.6% of patients with PNES, 63.6% of patients with epilepsy and PNES, and 8.8% of nondiagnostic patients.

Older age and greater seizure frequency predicted impaired objective cognitive function. Comorbid epilepsy and PNES appeared to predict impaired objective cognitive function as well, but the data were inconclusive. No AED was a significant predictor of objective cognitive function. Higher depression and anxiety scores and greater seizure frequency predicted impaired subjective cognitive function. No AED predicted subjective cognitive function.
 

Future studies could address particular cognitive domains

Previous studies have suggested that treatment with topiramate predicts objective or subjective cognitive function, but Dr. Foster and colleagues did not observe this result. The current findings suggest that topiramate may have a less significant effect on cognition than the literature suggests, they wrote. In addition, more evidence is needed to fully understand the effects of clobazam, valproate, phenytoin, and gabapentin because the analysis was underpowered for these drugs.

Although NUCOG assesses global cognitive function reliably, its ability to measure particular cognitive subdomains is limited. “We aim to conduct future research investigating the complex associations between different cognitive functions, including processing speed, and specific AEDs in this heterogeneous population,” said Dr. Foster.

Despite the study’s large sample size, the researchers could not explore potential interactions between various predictor variables. “Epilepsy may interact with the aging process or with other medical conditions associated with aging, such as hypertension and diabetes, and this may increase the risk of cognitive decline,” said Dr. Foster. “Older age may also be associated with reduced capacity to metabolize drugs, increased sensitivity to the cognitive and neurological effects of drugs, less cognitive reserve, and increased likelihood of taking multiple medications, which, along with AEDs, may exert a cognitive effect.”

The current findings may reduce concerns about the effects of AEDs on cognitive function and encourage neurologists to pursue the proper dosing for optimal seizure control, wrote the authors. “However, it is possible that some individuals may be more susceptible than others to AED-related cognitive dysfunction,” said Dr. Foster. “We do not have a robust way to predict who these patients will be, and it is still good practice to make patients aware that some people experience adverse cognitive effects from AEDs. However, it needs to be emphasized that it is unlikely to be the sole reason for their cognitive impairment. Other issues, such as poor seizure control or unrecognized or undertreated mood disorders, are even more important factors for impaired cognition.”

Patients who report cognitive problems should be screened for mood disorders, Dr. Foster continued. “It would also be important to consider whether the patients’ cognitive complaints arise from subtle clinical or subclinical seizure activity and subsequent postictal periods. To investigate this [question] further, clinicians may arrange for prolonged EEG monitoring. This [monitoring] could be done in an ambulatory setting or during an inpatient admission.”

The study was conducted without external funding. Dr. Foster and other investigators reported research funding from professional associations and pharmaceutical companies that was unrelated to the study.

egreb@mdedge.com

SOURCE: Foster E et al. Neurology. 2020 Feb 3. doi: 10.1212/WNL.0000000000009061.

No antiepileptic drug (AED) is independently associated with cognitive dysfunction, according to research published online ahead of print Feb. 3 in Neurology. Optimizing AED therapy to reduce or prevent seizures is thus unlikely to affect cognition, according to the investigators.

Patients who take AEDs commonly report cognitive problems, but investigations into the cognitive effects of AEDs have yielded inconsistent results. “We were also interested in this association, as we often treat complex patients taking multiple or high-dose AEDs, and our patients often report cognitive dysfunction,” said Emma Foster, MBBS, an epilepsy fellow at Alfred Health and the Royal Melbourne Hospital in Victoria, Australia. “We were particularly interested to examine how much AEDs affect cognition relative to other factors. We commonly see patients in our tertiary epilepsy care unit who have had severe epilepsy for a long time or who have psychiatric disorders, and these factors may also contribute to cognitive dysfunction.”
 

Researchers analyzed patients admitted for video EEG monitoring

For their study, Dr. Foster and colleagues prospectively enrolled patients admitted to the Royal Melbourne Hospital’s video EEG monitoring unit between January 2009 and December 2016. Patients were included in the study if they were age 18 years or older, had been admitted for diagnostic or surgical evaluation, and had complete data for the relevant variables. Patients were prescribed AED monotherapy or polytherapy.

The researchers based epilepsy diagnoses on the 2014 International League Against Epilepsy criteria. Diagnoses of psychogenic nonepileptic seizures (PNES) were based on a consensus of epileptologists at weekly multidisciplinary clinical meetings, which was supported by evaluation of all available data. Some patients received a diagnosis of comorbid epilepsy and PNES. If data were insufficient to support a diagnosis of epilepsy or PNES, the admission was considered nondiagnostic.

All participants underwent neuropsychologic and neuropsychiatric screening. Researchers assessed patients’ objective, global cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), a validated instrument. Patients responded to the Quality of Life in Epilepsy inventory (QOLIE-89) to provide a measure of subjective cognitive function. They also responded to the Hospital Anxiety and Depression Scale (HADS) to screen for mood disorders.

Dr. Foster and colleagues measured seizure frequency through patient self-report. Patients averaged their seizure frequency during the 12-month period before admission to the video EEG unit. They categorized it according to a 12-point system in which 0 denotes patients who are seizure-free and not taking AEDs and 12 denotes patients in status epilepticus. Patients with PNES used the same scale to report event frequency, although the system was not designed for this purpose.
 

Almost half of patients were prescribed polypharmacy

The researchers included 331 patients in their analysis. The population’s mean age was 39.3 years, and about 62% of patients were female. Approximately 47% of patients had epilepsy, 25.7% had PNES, 6.6% had comorbid epilepsy and PNES, and 20.5% had a nondiagnostic outcome. Among patients with epilepsy, most (54.5%) had temporal lobe epilepsy, followed by extratemporal focal epilepsy (32.1%) and generalized epilepsy (13.5%). The mean number of AEDs prescribed on admission was 1.6, and mean seizure or event frequency score was 7.2, which indicated 1-3 seizures per month. Mean HADS depression score was within the normal range (5.7), and mean HADS anxiety score was in the borderline range (8.2).

Approximately 45% of patients were prescribed AED polypharmacy on admission, 25.1% were prescribed AED monotherapy, and 29.9% were prescribed no AED. Levetiracetam, valproate, and carbamazepine were the most frequently prescribed AEDs. Most patients with epilepsy (73.1%) were on polypharmacy, compared with 17.6% of patients with PNES, 63.6% of patients with epilepsy and PNES, and 8.8% of nondiagnostic patients.

Older age and greater seizure frequency predicted impaired objective cognitive function. Comorbid epilepsy and PNES appeared to predict impaired objective cognitive function as well, but the data were inconclusive. No AED was a significant predictor of objective cognitive function. Higher depression and anxiety scores and greater seizure frequency predicted impaired subjective cognitive function. No AED predicted subjective cognitive function.
 

Future studies could address particular cognitive domains

Previous studies have suggested that treatment with topiramate predicts objective or subjective cognitive function, but Dr. Foster and colleagues did not observe this result. The current findings suggest that topiramate may have a less significant effect on cognition than the literature suggests, they wrote. In addition, more evidence is needed to fully understand the effects of clobazam, valproate, phenytoin, and gabapentin because the analysis was underpowered for these drugs.

Although NUCOG assesses global cognitive function reliably, its ability to measure particular cognitive subdomains is limited. “We aim to conduct future research investigating the complex associations between different cognitive functions, including processing speed, and specific AEDs in this heterogeneous population,” said Dr. Foster.

Despite the study’s large sample size, the researchers could not explore potential interactions between various predictor variables. “Epilepsy may interact with the aging process or with other medical conditions associated with aging, such as hypertension and diabetes, and this may increase the risk of cognitive decline,” said Dr. Foster. “Older age may also be associated with reduced capacity to metabolize drugs, increased sensitivity to the cognitive and neurological effects of drugs, less cognitive reserve, and increased likelihood of taking multiple medications, which, along with AEDs, may exert a cognitive effect.”

The current findings may reduce concerns about the effects of AEDs on cognitive function and encourage neurologists to pursue the proper dosing for optimal seizure control, wrote the authors. “However, it is possible that some individuals may be more susceptible than others to AED-related cognitive dysfunction,” said Dr. Foster. “We do not have a robust way to predict who these patients will be, and it is still good practice to make patients aware that some people experience adverse cognitive effects from AEDs. However, it needs to be emphasized that it is unlikely to be the sole reason for their cognitive impairment. Other issues, such as poor seizure control or unrecognized or undertreated mood disorders, are even more important factors for impaired cognition.”

Patients who report cognitive problems should be screened for mood disorders, Dr. Foster continued. “It would also be important to consider whether the patients’ cognitive complaints arise from subtle clinical or subclinical seizure activity and subsequent postictal periods. To investigate this [question] further, clinicians may arrange for prolonged EEG monitoring. This [monitoring] could be done in an ambulatory setting or during an inpatient admission.”

The study was conducted without external funding. Dr. Foster and other investigators reported research funding from professional associations and pharmaceutical companies that was unrelated to the study.

egreb@mdedge.com

SOURCE: Foster E et al. Neurology. 2020 Feb 3. doi: 10.1212/WNL.0000000000009061.

No antiepileptic drug (AED) is independently associated with cognitive dysfunction, according to research published online ahead of print Feb. 3 in Neurology. Optimizing AED therapy to reduce or prevent seizures is thus unlikely to affect cognition, according to the investigators.

Patients who take AEDs commonly report cognitive problems, but investigations into the cognitive effects of AEDs have yielded inconsistent results. “We were also interested in this association, as we often treat complex patients taking multiple or high-dose AEDs, and our patients often report cognitive dysfunction,” said Emma Foster, MBBS, an epilepsy fellow at Alfred Health and the Royal Melbourne Hospital in Victoria, Australia. “We were particularly interested to examine how much AEDs affect cognition relative to other factors. We commonly see patients in our tertiary epilepsy care unit who have had severe epilepsy for a long time or who have psychiatric disorders, and these factors may also contribute to cognitive dysfunction.”
 

Researchers analyzed patients admitted for video EEG monitoring

For their study, Dr. Foster and colleagues prospectively enrolled patients admitted to the Royal Melbourne Hospital’s video EEG monitoring unit between January 2009 and December 2016. Patients were included in the study if they were age 18 years or older, had been admitted for diagnostic or surgical evaluation, and had complete data for the relevant variables. Patients were prescribed AED monotherapy or polytherapy.

The researchers based epilepsy diagnoses on the 2014 International League Against Epilepsy criteria. Diagnoses of psychogenic nonepileptic seizures (PNES) were based on a consensus of epileptologists at weekly multidisciplinary clinical meetings, which was supported by evaluation of all available data. Some patients received a diagnosis of comorbid epilepsy and PNES. If data were insufficient to support a diagnosis of epilepsy or PNES, the admission was considered nondiagnostic.

All participants underwent neuropsychologic and neuropsychiatric screening. Researchers assessed patients’ objective, global cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), a validated instrument. Patients responded to the Quality of Life in Epilepsy inventory (QOLIE-89) to provide a measure of subjective cognitive function. They also responded to the Hospital Anxiety and Depression Scale (HADS) to screen for mood disorders.

Dr. Foster and colleagues measured seizure frequency through patient self-report. Patients averaged their seizure frequency during the 12-month period before admission to the video EEG unit. They categorized it according to a 12-point system in which 0 denotes patients who are seizure-free and not taking AEDs and 12 denotes patients in status epilepticus. Patients with PNES used the same scale to report event frequency, although the system was not designed for this purpose.
 

Almost half of patients were prescribed polypharmacy

The researchers included 331 patients in their analysis. The population’s mean age was 39.3 years, and about 62% of patients were female. Approximately 47% of patients had epilepsy, 25.7% had PNES, 6.6% had comorbid epilepsy and PNES, and 20.5% had a nondiagnostic outcome. Among patients with epilepsy, most (54.5%) had temporal lobe epilepsy, followed by extratemporal focal epilepsy (32.1%) and generalized epilepsy (13.5%). The mean number of AEDs prescribed on admission was 1.6, and mean seizure or event frequency score was 7.2, which indicated 1-3 seizures per month. Mean HADS depression score was within the normal range (5.7), and mean HADS anxiety score was in the borderline range (8.2).

Approximately 45% of patients were prescribed AED polypharmacy on admission, 25.1% were prescribed AED monotherapy, and 29.9% were prescribed no AED. Levetiracetam, valproate, and carbamazepine were the most frequently prescribed AEDs. Most patients with epilepsy (73.1%) were on polypharmacy, compared with 17.6% of patients with PNES, 63.6% of patients with epilepsy and PNES, and 8.8% of nondiagnostic patients.

Older age and greater seizure frequency predicted impaired objective cognitive function. Comorbid epilepsy and PNES appeared to predict impaired objective cognitive function as well, but the data were inconclusive. No AED was a significant predictor of objective cognitive function. Higher depression and anxiety scores and greater seizure frequency predicted impaired subjective cognitive function. No AED predicted subjective cognitive function.
 

Future studies could address particular cognitive domains

Previous studies have suggested that treatment with topiramate predicts objective or subjective cognitive function, but Dr. Foster and colleagues did not observe this result. The current findings suggest that topiramate may have a less significant effect on cognition than the literature suggests, they wrote. In addition, more evidence is needed to fully understand the effects of clobazam, valproate, phenytoin, and gabapentin because the analysis was underpowered for these drugs.

Although NUCOG assesses global cognitive function reliably, its ability to measure particular cognitive subdomains is limited. “We aim to conduct future research investigating the complex associations between different cognitive functions, including processing speed, and specific AEDs in this heterogeneous population,” said Dr. Foster.

Despite the study’s large sample size, the researchers could not explore potential interactions between various predictor variables. “Epilepsy may interact with the aging process or with other medical conditions associated with aging, such as hypertension and diabetes, and this may increase the risk of cognitive decline,” said Dr. Foster. “Older age may also be associated with reduced capacity to metabolize drugs, increased sensitivity to the cognitive and neurological effects of drugs, less cognitive reserve, and increased likelihood of taking multiple medications, which, along with AEDs, may exert a cognitive effect.”

The current findings may reduce concerns about the effects of AEDs on cognitive function and encourage neurologists to pursue the proper dosing for optimal seizure control, wrote the authors. “However, it is possible that some individuals may be more susceptible than others to AED-related cognitive dysfunction,” said Dr. Foster. “We do not have a robust way to predict who these patients will be, and it is still good practice to make patients aware that some people experience adverse cognitive effects from AEDs. However, it needs to be emphasized that it is unlikely to be the sole reason for their cognitive impairment. Other issues, such as poor seizure control or unrecognized or undertreated mood disorders, are even more important factors for impaired cognition.”

Patients who report cognitive problems should be screened for mood disorders, Dr. Foster continued. “It would also be important to consider whether the patients’ cognitive complaints arise from subtle clinical or subclinical seizure activity and subsequent postictal periods. To investigate this [question] further, clinicians may arrange for prolonged EEG monitoring. This [monitoring] could be done in an ambulatory setting or during an inpatient admission.”

The study was conducted without external funding. Dr. Foster and other investigators reported research funding from professional associations and pharmaceutical companies that was unrelated to the study.

egreb@mdedge.com

SOURCE: Foster E et al. Neurology. 2020 Feb 3. doi: 10.1212/WNL.0000000000009061.