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The robot comes to mastectomy, but cancer outcomes data not attached
The FDA warning was issued in February 2019 to both the public and physicians. The FDA cautioned that the safety and effectiveness of robotic surgical devices for mastectomy “have not been established” and robots are not approved for the prevention or treatment of breast cancer.
The agency also noted that “diminished long-term survival” was associated with robotic surgery in another women’s cancer, that of hysterectomy for cervical cancer.
The FDA also made a surprising statement. The agency typically approves the robot for surgical use based on 30-day complication rates (compared with standards of care). But it said that going forward it “anticipates” that any evaluation of new use of robots in cancer “would be supported” by cancer outcomes such as progression-free survival and overall survival, which require much longer follow-up.
In short, the FDA hinted that it would change how it regulated medical devices, or at least robots used in women’s cancers. “The FDA takes women’s health very seriously,” said the organization.
Fast forward to 2021, and there are several prospective clinical trials of robot-assisted nipple-sparing mastectomy underway in the United States, including a five-center study sponsored by Intuitive Surgical, the maker of da Vinci robots, the dominant machine on the market. There are also single-center studies at Ohio State and University of Texas Southwestern Medical Center.
However, in each case, the study design either excludes cancer outcomes or does not primarily focus on those measures.
Instead, the primary outcomes are relatively short term and include safety and efficacy measures such as en bloc (in one piece) removal of the breast tissue, conversions to open mastectomy, and the incidence of adverse events during surgery and up to 6 weeks after surgery.
Importantly, none of the studies is a randomized trial; all have single arms.
That’s not what is needed, says breast surgeon Julie A. Margenthaler, MD of Washington University in St. Louis.
“I firmly believe that robotic-assisted mastectomy should only be considered in the context of a well-designed, randomized trial evaluating patient selection, patient safety, surgical complications, and oncologic outcomes with a concomitant cost analysis,” Dr. Margenthaler wrote in an essay published last year in JAMA Surgery.
As with the FDA warning, she cites worse survival with commonly used minimally invasive radical hysterectomy for cervical cancer, saying it “is a stark reminder that the marketing of robotic surgery has its roots in cosmesis and convenience rather than oncologic outcomes.”
In addition, robotic surgery is prohibitively expensive, said Dr. Margenthaler. In fact, cost is her “main criticism regarding robotic-assisted mastectomy.” It costs an additional $6,000 for robot use per procedure, according to a study conducted at a center in Taiwan. “I simply cannot be convinced that this will ever achieve cost-effective or even cost-neutral status,” Dr. Margenthaler wrote.
Not looking at the right outcomes
“They’re not looking at the right outcomes,” said Hooman Noorchashm, MD, PhD, about the current trials in the United States. He is a former surgeon and faculty member at the University of Pennsylvania in Philadelphia, and is now a patient advocate after his wife, Amy Reed, MD, died of uterine cancer in 2017 following a laparoscopic hysterectomy performed with a power morcellator that resulted in the upstaging of an undetected gynecologic cancer.
“You have to look at oncologic outcomes and do randomized, noninferiority trials to demonstrate that those cancer outcomes are at least equivalent to standard of care,” he said in an interview.
The current U.S. trials are “totally inappropriate,” he said.
Are randomized trials forthcoming after this initial set of single-arm trials? This news organization reached out to Intuitive Surgical, maker of the market leader da Vinci robotic surgical equipment to find out.
“Any plans for use of da Vinci Xi surgical system in nipple-sparing mastectomy will be based on these [single-arm] study results as well as other data and evidence,” said a company spokesperson, who did not confirm use of a randomized trial.
What about the FDA? Will the agency change its current approach to approving robots in surgeries for women’s cancers and require – not just anticipate – cancer-related outcomes data? At press time, the FDA did not respond to a request for comment.
Not having a randomized trial with cancer outcomes in any eventual FDA review opens the door for robotic mastectomy to be cleared for use in some mastectomies with short-term, nononcologic data, said Dr. Noorchashm.
Safety concerns with robotic mastectomy
Proponents of robot-assisted nipple-sparing mastectomy, which is coupled with reconstruction to preserve the shape of both the breast and nipple-areola area, suggest that improved patient cosmesis is a significant advantage with the high-tech intervention, said Dr. Margenthaler.
That’s because most robotic mastectomies performed to date (almost exclusively in Europe and Asia) have employed a 3- to 5-cm vertical incision located behind the lateral breast fold, allowing the scar to be hidden under the patient’s arm.
But therein also lies a safety concern, she asserted.
The “oncologic integrity” of the specimen on extraction is in question in some cases, she wrote, because of “such a small opening.”
Dr. Noorchashm agreed: “It all comes down to trying to get a large specimen out of a small incision.”
Traditional open mastectomy optimally yields the en bloc removal of a tumor – in one whole piece – to avoid fragmenting the cancerous tissue and possibly leaving residual disease behind. These undesirable events are associated with a higher risk for recurrence and treatment failure, he explained.
Thus, there is a need for a randomized trial with longer-term oncologic outcomes that compares the new approach with traditional open mastectomy, argued both Dr. Margenthaler and Dr. Noorchashm.
In defense of single-arm trials
“Oncologic safety is what we are concerned about and what we would like to study,” said Ko Un (Clara) Park, MD, a breast surgeon at The Ohio State University in Columbus.
Dr. Park is leading a single-center, single-arm pilot study of robotic nipple-sparing mastectomy enrolling up to 20 women with early-stage breast cancer or inherited genetic risk factors (but no cancer diagnosis). The trial, sponsored by a Pelotonia Idea Grant and Ohio State, recently enrolled its first patient.
The study’s primary outcomes include the feasibility of removal of the breast tissue en bloc; however, none of the outcomes are classic oncologic metrics such as progression-free survival.
The en bloc removal outcome is in direct response to the FDA’s concerns about minimally invasive cancer surgeries in women, Dr. Park said in an interview. The pilot trial has an investigational device exemption (IDE) granted by the FDA.
“The reason why we can’t just open a randomized controlled study (of robot versus open) and measure oncologic outcomes like recurrence-free survival is because, before we get to that point, we have to make sure” basic safety issues are addressed and established, she explained.
But Dr. Noorchashm said that argument is missing the larger, more important point: “They are still doing an oncologic procedure – you are still obliged to do noninferiority [randomized] testing with respect to cancer outcomes.”
Dr. Park sounded a different note: “We are doing it as safely as we can do it.”
Prophylactic use is also a cancer surgery
Intuitive’s five-center trial does not include en bloc removal of the breast gland as a primary outcome. Instead, the two primary outcomes are conversions to open mastectomy (efficacy measure) and the incidence of adverse events during surgery to 42 days after surgery (safety measure).
The company’s trial does not include any women with breast cancer, but is limited to women at increased risk for breast cancer and seeking prophylactic nipple-sparing mastectomy surgery.
Enrollment in the 145-patient single-arm trial began in the last few months and has a primary completion date of December 2022. It also has an IDE from the FDA.
“I do think that things like this need to be done with caution,” said Katherine Kopkash, MD, an investigator in the Intuitive trial and a breast surgeon at NorthShore University HealthSystem in Evanston, Ill., referring to the trial’s FDA exemption.
Dr. Kopkash said in an interview that the researchers in the multisite, single-arm Intuitive trial will also track oncologic outcomes, but the trial description at clinicaltrials.gov does not indicate that.
Both Dr. Kopkash and Dr. Park cited the high-profile missteps that took place in 2018 at Monmouth County Medical Center in Long Branch, N.J., during what was described as the first-ever use of robotic nipple-sparing mastectomy for invasive cancer in the United States, as reported by Medscape Medical News. However, neither the center or surgeon, Stephen Chagares, MD, requested or received an IDE from the FDA, and use of robotic mastectomy was halted after two cases.
It’s conceivable that Intuitive will seek out FDA clearance for use of its da Vinci system in robotic nipple-sparing mastectomy with data in a prophylactic setting and then expand the pool of patients, argued Dr. Noorchashm.
“Even if you introduce a new technology ... for a narrow subset of patients, the application of it eventually occurs on a ‘sliding scale,’ ” he said.
The former surgeon gave an example: The first device used in gastric bypass surgery was cleared for use in 2001 by the FDA for adults who were “severely morbidly obese.” But by the late 2000s, the operation was also being performed on people with lower body mass indexes who hadn’t exhausted traditional weight loss procedures. “It was very lucrative,” Dr. Noorchashm said about the surgery.
Surgeons only get one body
Intuitive has been hugely successful in developing and marketing its da Vinci system around the world for general and oncologic surgeries, with more than 1 million surgeries in 2018, a greater than sevenfold increase in 10 years, according to the authors of a new essay published in the June issue of the Annals of Surgery. The authors include breast surgeon Rosa F. Hwang, MD, of MD Anderson Cancer Center in Houston, who is also an investigator for the Intuitive trial.
However, robotic mastectomy is still a new surgery – only about 150 patients have been treated in the world, mostly in Italy, France, Taiwan, and Korea, the authors noted.
Despite such small numbers, “there’s a lot of interest in bringing this to the United States,” said Dr. Park.
One of the arguments in favor of robotic mastectomy for nipple-sparing procedures has nothing to do with patients. Instead, it is improved ergonomics – the robot makes a tough surgery easier on the surgeon.
Even stalwart robot critic Dr. Margenthaler conceded that this was possibly a winning feature.
“Nipple-sparing mastectomy is a very physically demanding procedure for the surgeon, resulting in higher rates of neck and back pain and fatigue compared with a standard skin-sparing approach,” she noted. She suggested, however, that practitioners of traditional mastectomy ought to first experiment with changes to patient positioning and incision placement to alleviate stress before looking to the robot for change.
When this news organization interviewed NorthShore University’s Dr. Kopkash, she had conducted four nipple-sparing mastectomies in the previous week. “It’s a difficult procedure on our bodies. I just turned 40 and I’m considered young for a surgeon. We get one body for our career and we have to figure out ways to make it work and protect it.”
Intuitive Surgical is funding the five-center clinical trial of robot-assisted nipple-sparing mastectomy, and UT Southwestern is funding its own trial. The Ohio State trial is funded by the university and a Pelotonia Idea Grant. Dr. Noorchashm and Dr. Margenthaler have no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
The FDA warning was issued in February 2019 to both the public and physicians. The FDA cautioned that the safety and effectiveness of robotic surgical devices for mastectomy “have not been established” and robots are not approved for the prevention or treatment of breast cancer.
The agency also noted that “diminished long-term survival” was associated with robotic surgery in another women’s cancer, that of hysterectomy for cervical cancer.
The FDA also made a surprising statement. The agency typically approves the robot for surgical use based on 30-day complication rates (compared with standards of care). But it said that going forward it “anticipates” that any evaluation of new use of robots in cancer “would be supported” by cancer outcomes such as progression-free survival and overall survival, which require much longer follow-up.
In short, the FDA hinted that it would change how it regulated medical devices, or at least robots used in women’s cancers. “The FDA takes women’s health very seriously,” said the organization.
Fast forward to 2021, and there are several prospective clinical trials of robot-assisted nipple-sparing mastectomy underway in the United States, including a five-center study sponsored by Intuitive Surgical, the maker of da Vinci robots, the dominant machine on the market. There are also single-center studies at Ohio State and University of Texas Southwestern Medical Center.
However, in each case, the study design either excludes cancer outcomes or does not primarily focus on those measures.
Instead, the primary outcomes are relatively short term and include safety and efficacy measures such as en bloc (in one piece) removal of the breast tissue, conversions to open mastectomy, and the incidence of adverse events during surgery and up to 6 weeks after surgery.
Importantly, none of the studies is a randomized trial; all have single arms.
That’s not what is needed, says breast surgeon Julie A. Margenthaler, MD of Washington University in St. Louis.
“I firmly believe that robotic-assisted mastectomy should only be considered in the context of a well-designed, randomized trial evaluating patient selection, patient safety, surgical complications, and oncologic outcomes with a concomitant cost analysis,” Dr. Margenthaler wrote in an essay published last year in JAMA Surgery.
As with the FDA warning, she cites worse survival with commonly used minimally invasive radical hysterectomy for cervical cancer, saying it “is a stark reminder that the marketing of robotic surgery has its roots in cosmesis and convenience rather than oncologic outcomes.”
In addition, robotic surgery is prohibitively expensive, said Dr. Margenthaler. In fact, cost is her “main criticism regarding robotic-assisted mastectomy.” It costs an additional $6,000 for robot use per procedure, according to a study conducted at a center in Taiwan. “I simply cannot be convinced that this will ever achieve cost-effective or even cost-neutral status,” Dr. Margenthaler wrote.
Not looking at the right outcomes
“They’re not looking at the right outcomes,” said Hooman Noorchashm, MD, PhD, about the current trials in the United States. He is a former surgeon and faculty member at the University of Pennsylvania in Philadelphia, and is now a patient advocate after his wife, Amy Reed, MD, died of uterine cancer in 2017 following a laparoscopic hysterectomy performed with a power morcellator that resulted in the upstaging of an undetected gynecologic cancer.
“You have to look at oncologic outcomes and do randomized, noninferiority trials to demonstrate that those cancer outcomes are at least equivalent to standard of care,” he said in an interview.
The current U.S. trials are “totally inappropriate,” he said.
Are randomized trials forthcoming after this initial set of single-arm trials? This news organization reached out to Intuitive Surgical, maker of the market leader da Vinci robotic surgical equipment to find out.
“Any plans for use of da Vinci Xi surgical system in nipple-sparing mastectomy will be based on these [single-arm] study results as well as other data and evidence,” said a company spokesperson, who did not confirm use of a randomized trial.
What about the FDA? Will the agency change its current approach to approving robots in surgeries for women’s cancers and require – not just anticipate – cancer-related outcomes data? At press time, the FDA did not respond to a request for comment.
Not having a randomized trial with cancer outcomes in any eventual FDA review opens the door for robotic mastectomy to be cleared for use in some mastectomies with short-term, nononcologic data, said Dr. Noorchashm.
Safety concerns with robotic mastectomy
Proponents of robot-assisted nipple-sparing mastectomy, which is coupled with reconstruction to preserve the shape of both the breast and nipple-areola area, suggest that improved patient cosmesis is a significant advantage with the high-tech intervention, said Dr. Margenthaler.
That’s because most robotic mastectomies performed to date (almost exclusively in Europe and Asia) have employed a 3- to 5-cm vertical incision located behind the lateral breast fold, allowing the scar to be hidden under the patient’s arm.
But therein also lies a safety concern, she asserted.
The “oncologic integrity” of the specimen on extraction is in question in some cases, she wrote, because of “such a small opening.”
Dr. Noorchashm agreed: “It all comes down to trying to get a large specimen out of a small incision.”
Traditional open mastectomy optimally yields the en bloc removal of a tumor – in one whole piece – to avoid fragmenting the cancerous tissue and possibly leaving residual disease behind. These undesirable events are associated with a higher risk for recurrence and treatment failure, he explained.
Thus, there is a need for a randomized trial with longer-term oncologic outcomes that compares the new approach with traditional open mastectomy, argued both Dr. Margenthaler and Dr. Noorchashm.
In defense of single-arm trials
“Oncologic safety is what we are concerned about and what we would like to study,” said Ko Un (Clara) Park, MD, a breast surgeon at The Ohio State University in Columbus.
Dr. Park is leading a single-center, single-arm pilot study of robotic nipple-sparing mastectomy enrolling up to 20 women with early-stage breast cancer or inherited genetic risk factors (but no cancer diagnosis). The trial, sponsored by a Pelotonia Idea Grant and Ohio State, recently enrolled its first patient.
The study’s primary outcomes include the feasibility of removal of the breast tissue en bloc; however, none of the outcomes are classic oncologic metrics such as progression-free survival.
The en bloc removal outcome is in direct response to the FDA’s concerns about minimally invasive cancer surgeries in women, Dr. Park said in an interview. The pilot trial has an investigational device exemption (IDE) granted by the FDA.
“The reason why we can’t just open a randomized controlled study (of robot versus open) and measure oncologic outcomes like recurrence-free survival is because, before we get to that point, we have to make sure” basic safety issues are addressed and established, she explained.
But Dr. Noorchashm said that argument is missing the larger, more important point: “They are still doing an oncologic procedure – you are still obliged to do noninferiority [randomized] testing with respect to cancer outcomes.”
Dr. Park sounded a different note: “We are doing it as safely as we can do it.”
Prophylactic use is also a cancer surgery
Intuitive’s five-center trial does not include en bloc removal of the breast gland as a primary outcome. Instead, the two primary outcomes are conversions to open mastectomy (efficacy measure) and the incidence of adverse events during surgery to 42 days after surgery (safety measure).
The company’s trial does not include any women with breast cancer, but is limited to women at increased risk for breast cancer and seeking prophylactic nipple-sparing mastectomy surgery.
Enrollment in the 145-patient single-arm trial began in the last few months and has a primary completion date of December 2022. It also has an IDE from the FDA.
“I do think that things like this need to be done with caution,” said Katherine Kopkash, MD, an investigator in the Intuitive trial and a breast surgeon at NorthShore University HealthSystem in Evanston, Ill., referring to the trial’s FDA exemption.
Dr. Kopkash said in an interview that the researchers in the multisite, single-arm Intuitive trial will also track oncologic outcomes, but the trial description at clinicaltrials.gov does not indicate that.
Both Dr. Kopkash and Dr. Park cited the high-profile missteps that took place in 2018 at Monmouth County Medical Center in Long Branch, N.J., during what was described as the first-ever use of robotic nipple-sparing mastectomy for invasive cancer in the United States, as reported by Medscape Medical News. However, neither the center or surgeon, Stephen Chagares, MD, requested or received an IDE from the FDA, and use of robotic mastectomy was halted after two cases.
It’s conceivable that Intuitive will seek out FDA clearance for use of its da Vinci system in robotic nipple-sparing mastectomy with data in a prophylactic setting and then expand the pool of patients, argued Dr. Noorchashm.
“Even if you introduce a new technology ... for a narrow subset of patients, the application of it eventually occurs on a ‘sliding scale,’ ” he said.
The former surgeon gave an example: The first device used in gastric bypass surgery was cleared for use in 2001 by the FDA for adults who were “severely morbidly obese.” But by the late 2000s, the operation was also being performed on people with lower body mass indexes who hadn’t exhausted traditional weight loss procedures. “It was very lucrative,” Dr. Noorchashm said about the surgery.
Surgeons only get one body
Intuitive has been hugely successful in developing and marketing its da Vinci system around the world for general and oncologic surgeries, with more than 1 million surgeries in 2018, a greater than sevenfold increase in 10 years, according to the authors of a new essay published in the June issue of the Annals of Surgery. The authors include breast surgeon Rosa F. Hwang, MD, of MD Anderson Cancer Center in Houston, who is also an investigator for the Intuitive trial.
However, robotic mastectomy is still a new surgery – only about 150 patients have been treated in the world, mostly in Italy, France, Taiwan, and Korea, the authors noted.
Despite such small numbers, “there’s a lot of interest in bringing this to the United States,” said Dr. Park.
One of the arguments in favor of robotic mastectomy for nipple-sparing procedures has nothing to do with patients. Instead, it is improved ergonomics – the robot makes a tough surgery easier on the surgeon.
Even stalwart robot critic Dr. Margenthaler conceded that this was possibly a winning feature.
“Nipple-sparing mastectomy is a very physically demanding procedure for the surgeon, resulting in higher rates of neck and back pain and fatigue compared with a standard skin-sparing approach,” she noted. She suggested, however, that practitioners of traditional mastectomy ought to first experiment with changes to patient positioning and incision placement to alleviate stress before looking to the robot for change.
When this news organization interviewed NorthShore University’s Dr. Kopkash, she had conducted four nipple-sparing mastectomies in the previous week. “It’s a difficult procedure on our bodies. I just turned 40 and I’m considered young for a surgeon. We get one body for our career and we have to figure out ways to make it work and protect it.”
Intuitive Surgical is funding the five-center clinical trial of robot-assisted nipple-sparing mastectomy, and UT Southwestern is funding its own trial. The Ohio State trial is funded by the university and a Pelotonia Idea Grant. Dr. Noorchashm and Dr. Margenthaler have no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
The FDA warning was issued in February 2019 to both the public and physicians. The FDA cautioned that the safety and effectiveness of robotic surgical devices for mastectomy “have not been established” and robots are not approved for the prevention or treatment of breast cancer.
The agency also noted that “diminished long-term survival” was associated with robotic surgery in another women’s cancer, that of hysterectomy for cervical cancer.
The FDA also made a surprising statement. The agency typically approves the robot for surgical use based on 30-day complication rates (compared with standards of care). But it said that going forward it “anticipates” that any evaluation of new use of robots in cancer “would be supported” by cancer outcomes such as progression-free survival and overall survival, which require much longer follow-up.
In short, the FDA hinted that it would change how it regulated medical devices, or at least robots used in women’s cancers. “The FDA takes women’s health very seriously,” said the organization.
Fast forward to 2021, and there are several prospective clinical trials of robot-assisted nipple-sparing mastectomy underway in the United States, including a five-center study sponsored by Intuitive Surgical, the maker of da Vinci robots, the dominant machine on the market. There are also single-center studies at Ohio State and University of Texas Southwestern Medical Center.
However, in each case, the study design either excludes cancer outcomes or does not primarily focus on those measures.
Instead, the primary outcomes are relatively short term and include safety and efficacy measures such as en bloc (in one piece) removal of the breast tissue, conversions to open mastectomy, and the incidence of adverse events during surgery and up to 6 weeks after surgery.
Importantly, none of the studies is a randomized trial; all have single arms.
That’s not what is needed, says breast surgeon Julie A. Margenthaler, MD of Washington University in St. Louis.
“I firmly believe that robotic-assisted mastectomy should only be considered in the context of a well-designed, randomized trial evaluating patient selection, patient safety, surgical complications, and oncologic outcomes with a concomitant cost analysis,” Dr. Margenthaler wrote in an essay published last year in JAMA Surgery.
As with the FDA warning, she cites worse survival with commonly used minimally invasive radical hysterectomy for cervical cancer, saying it “is a stark reminder that the marketing of robotic surgery has its roots in cosmesis and convenience rather than oncologic outcomes.”
In addition, robotic surgery is prohibitively expensive, said Dr. Margenthaler. In fact, cost is her “main criticism regarding robotic-assisted mastectomy.” It costs an additional $6,000 for robot use per procedure, according to a study conducted at a center in Taiwan. “I simply cannot be convinced that this will ever achieve cost-effective or even cost-neutral status,” Dr. Margenthaler wrote.
Not looking at the right outcomes
“They’re not looking at the right outcomes,” said Hooman Noorchashm, MD, PhD, about the current trials in the United States. He is a former surgeon and faculty member at the University of Pennsylvania in Philadelphia, and is now a patient advocate after his wife, Amy Reed, MD, died of uterine cancer in 2017 following a laparoscopic hysterectomy performed with a power morcellator that resulted in the upstaging of an undetected gynecologic cancer.
“You have to look at oncologic outcomes and do randomized, noninferiority trials to demonstrate that those cancer outcomes are at least equivalent to standard of care,” he said in an interview.
The current U.S. trials are “totally inappropriate,” he said.
Are randomized trials forthcoming after this initial set of single-arm trials? This news organization reached out to Intuitive Surgical, maker of the market leader da Vinci robotic surgical equipment to find out.
“Any plans for use of da Vinci Xi surgical system in nipple-sparing mastectomy will be based on these [single-arm] study results as well as other data and evidence,” said a company spokesperson, who did not confirm use of a randomized trial.
What about the FDA? Will the agency change its current approach to approving robots in surgeries for women’s cancers and require – not just anticipate – cancer-related outcomes data? At press time, the FDA did not respond to a request for comment.
Not having a randomized trial with cancer outcomes in any eventual FDA review opens the door for robotic mastectomy to be cleared for use in some mastectomies with short-term, nononcologic data, said Dr. Noorchashm.
Safety concerns with robotic mastectomy
Proponents of robot-assisted nipple-sparing mastectomy, which is coupled with reconstruction to preserve the shape of both the breast and nipple-areola area, suggest that improved patient cosmesis is a significant advantage with the high-tech intervention, said Dr. Margenthaler.
That’s because most robotic mastectomies performed to date (almost exclusively in Europe and Asia) have employed a 3- to 5-cm vertical incision located behind the lateral breast fold, allowing the scar to be hidden under the patient’s arm.
But therein also lies a safety concern, she asserted.
The “oncologic integrity” of the specimen on extraction is in question in some cases, she wrote, because of “such a small opening.”
Dr. Noorchashm agreed: “It all comes down to trying to get a large specimen out of a small incision.”
Traditional open mastectomy optimally yields the en bloc removal of a tumor – in one whole piece – to avoid fragmenting the cancerous tissue and possibly leaving residual disease behind. These undesirable events are associated with a higher risk for recurrence and treatment failure, he explained.
Thus, there is a need for a randomized trial with longer-term oncologic outcomes that compares the new approach with traditional open mastectomy, argued both Dr. Margenthaler and Dr. Noorchashm.
In defense of single-arm trials
“Oncologic safety is what we are concerned about and what we would like to study,” said Ko Un (Clara) Park, MD, a breast surgeon at The Ohio State University in Columbus.
Dr. Park is leading a single-center, single-arm pilot study of robotic nipple-sparing mastectomy enrolling up to 20 women with early-stage breast cancer or inherited genetic risk factors (but no cancer diagnosis). The trial, sponsored by a Pelotonia Idea Grant and Ohio State, recently enrolled its first patient.
The study’s primary outcomes include the feasibility of removal of the breast tissue en bloc; however, none of the outcomes are classic oncologic metrics such as progression-free survival.
The en bloc removal outcome is in direct response to the FDA’s concerns about minimally invasive cancer surgeries in women, Dr. Park said in an interview. The pilot trial has an investigational device exemption (IDE) granted by the FDA.
“The reason why we can’t just open a randomized controlled study (of robot versus open) and measure oncologic outcomes like recurrence-free survival is because, before we get to that point, we have to make sure” basic safety issues are addressed and established, she explained.
But Dr. Noorchashm said that argument is missing the larger, more important point: “They are still doing an oncologic procedure – you are still obliged to do noninferiority [randomized] testing with respect to cancer outcomes.”
Dr. Park sounded a different note: “We are doing it as safely as we can do it.”
Prophylactic use is also a cancer surgery
Intuitive’s five-center trial does not include en bloc removal of the breast gland as a primary outcome. Instead, the two primary outcomes are conversions to open mastectomy (efficacy measure) and the incidence of adverse events during surgery to 42 days after surgery (safety measure).
The company’s trial does not include any women with breast cancer, but is limited to women at increased risk for breast cancer and seeking prophylactic nipple-sparing mastectomy surgery.
Enrollment in the 145-patient single-arm trial began in the last few months and has a primary completion date of December 2022. It also has an IDE from the FDA.
“I do think that things like this need to be done with caution,” said Katherine Kopkash, MD, an investigator in the Intuitive trial and a breast surgeon at NorthShore University HealthSystem in Evanston, Ill., referring to the trial’s FDA exemption.
Dr. Kopkash said in an interview that the researchers in the multisite, single-arm Intuitive trial will also track oncologic outcomes, but the trial description at clinicaltrials.gov does not indicate that.
Both Dr. Kopkash and Dr. Park cited the high-profile missteps that took place in 2018 at Monmouth County Medical Center in Long Branch, N.J., during what was described as the first-ever use of robotic nipple-sparing mastectomy for invasive cancer in the United States, as reported by Medscape Medical News. However, neither the center or surgeon, Stephen Chagares, MD, requested or received an IDE from the FDA, and use of robotic mastectomy was halted after two cases.
It’s conceivable that Intuitive will seek out FDA clearance for use of its da Vinci system in robotic nipple-sparing mastectomy with data in a prophylactic setting and then expand the pool of patients, argued Dr. Noorchashm.
“Even if you introduce a new technology ... for a narrow subset of patients, the application of it eventually occurs on a ‘sliding scale,’ ” he said.
The former surgeon gave an example: The first device used in gastric bypass surgery was cleared for use in 2001 by the FDA for adults who were “severely morbidly obese.” But by the late 2000s, the operation was also being performed on people with lower body mass indexes who hadn’t exhausted traditional weight loss procedures. “It was very lucrative,” Dr. Noorchashm said about the surgery.
Surgeons only get one body
Intuitive has been hugely successful in developing and marketing its da Vinci system around the world for general and oncologic surgeries, with more than 1 million surgeries in 2018, a greater than sevenfold increase in 10 years, according to the authors of a new essay published in the June issue of the Annals of Surgery. The authors include breast surgeon Rosa F. Hwang, MD, of MD Anderson Cancer Center in Houston, who is also an investigator for the Intuitive trial.
However, robotic mastectomy is still a new surgery – only about 150 patients have been treated in the world, mostly in Italy, France, Taiwan, and Korea, the authors noted.
Despite such small numbers, “there’s a lot of interest in bringing this to the United States,” said Dr. Park.
One of the arguments in favor of robotic mastectomy for nipple-sparing procedures has nothing to do with patients. Instead, it is improved ergonomics – the robot makes a tough surgery easier on the surgeon.
Even stalwart robot critic Dr. Margenthaler conceded that this was possibly a winning feature.
“Nipple-sparing mastectomy is a very physically demanding procedure for the surgeon, resulting in higher rates of neck and back pain and fatigue compared with a standard skin-sparing approach,” she noted. She suggested, however, that practitioners of traditional mastectomy ought to first experiment with changes to patient positioning and incision placement to alleviate stress before looking to the robot for change.
When this news organization interviewed NorthShore University’s Dr. Kopkash, she had conducted four nipple-sparing mastectomies in the previous week. “It’s a difficult procedure on our bodies. I just turned 40 and I’m considered young for a surgeon. We get one body for our career and we have to figure out ways to make it work and protect it.”
Intuitive Surgical is funding the five-center clinical trial of robot-assisted nipple-sparing mastectomy, and UT Southwestern is funding its own trial. The Ohio State trial is funded by the university and a Pelotonia Idea Grant. Dr. Noorchashm and Dr. Margenthaler have no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
Occipital nerve stimulation offers relief for patients with intractable chronic cluster headache
Occipital nerve stimulation may help safely prevent attacks of medically intractable chronic cluster headache, according to a new study.
Medically intractable chronic cluster headaches are unilateral headaches that cause excruciating pain during attacks, which may happen as frequently as eight times per day. They are refractory to, or intolerant of, preventive medications typically used in chronic cluster headaches.
“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting medically intractable chronic cluster headache, both at high and low intensity,” Leopoldine A. Wilbrink, MD, of Leiden (the Netherlands) University Medical Centre, and coauthors wrote in their paper.
The findings were published online.
The multicenter, randomized, double-blind, phase 3 clinical trial was carried out at seven hospitals in the Netherlands, Belgium, Germany, and Hungary. A total of 150 patients with suspected medically intractable chronic cluster headache were enrolled between October 2010 and December 2017, and observed for 12 weeks at baseline. Of those initially enrolled, 131 patients with at least four medically intractable chronic cluster headache attacks per week and a history of nonresponsiveness to at least three standard preventive medications were randomly allocated to one of two groups: Sixty-five patients received 24 weeks of ONS at high intensity (100% intensity, or the intensity 10% below the threshold of discomfort as reported by the patient) while 66 received low-intensity (30%) ONS. At 25-48 weeks, the patients received open-label ONS.
Safe and well tolerated
“Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy,” wrote Dr. Wilbrink and colleagues.
From baseline to weeks 21-24, the median weekly mean attack frequencies decreased to 7.38 (95% confidence interval [CI]: 2.5-18.5, P < .0001). A median decrease in 5.21 attacks per week (–11.18 to –0.19, P < .0001) was observed.
The 100% ONS group saw a decrease in mean attack frequency from 17.58 at baseline (range, 9.83-29.33) to 9.5 (3-21.25) at 21-24 weeks with a median change of –4.08 (–11.92 to –0.25). In the 30% ONS group, the mean attack frequency decreased from 15 (9.25 to 22.33) to 6.75 (1.5-16.5) with a median change of –6.5 (–10.83 to –0.08).
At weeks 21-24, the difference in median weekly mean attack frequency between the groups was –2.42 (–5.17 to 3.33).
The authors stated that, in both groups, ONS was “safe and well tolerated.” A total of 129 adverse events were reported in the 100% ONS group and 95 in the 30% ONS group, of which 17 and 9 were considered serious, respectively. The serious adverse events required a short hospital stay to resolve minor hardware issues. The adverse events most frequently observed were local pain, impaired wound healing, neck stiffness, and hardware damage.
Low intensity stimulation may be best
“The main limitation of the study comes from the difficulty in defining the electrical dose, which was not constant across patients within each group, but individually adjusted depending on the perception of the ONS-induced paraesthesia,” Denys Fontaine, MD, and Michel Lanteri-Minet, MD, both from Université Cote D’Azur in France, wrote in an accompanying editorial.
Given that the primary outcome did not differ significantly between the treatment groups, the editorialists stated that “the lowest stimulation intensity that induces paraesthesia is sufficient to obtain an effect in the patients who respond. Increasing the electrical dose or intensity does not seem to bring better efficacy and might even induce discomfort (painful paraesthesia or shock-like sensations) that might substantially reduce the tolerance of this approach.”
While the trial did not provide convincing evidence of high intensity ONS in medically intractable chronic cluster headache, the editorialists are otherwise optimistic about the findings: “… considering the significant difference between baseline and the end of the randomised stimulation phase in both groups (about half of the patients showed a 50% decrease in attack frequency), the findings of this study support the favourable results of previous real-world studies, and indicate that a substantial proportion of patients with intractable chronic cluster headache, although not all, could have their condition substantially improved by ONS.” Dr. Fontaine and Dr. Lanteri-Minet added that they hope that “these data will help health authorities to recognise the efficacy of ONS and consider its approval for use in patients with intractable chronic cluster headache.”
Priorities for future research in this area should “focus on optimising stimulation protocols and disentangling the underlying mechanism of action,” Dr. Wilbrink and colleagues wrote.
The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium, the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement program for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to Dr. Ferrari.
Occipital nerve stimulation may help safely prevent attacks of medically intractable chronic cluster headache, according to a new study.
Medically intractable chronic cluster headaches are unilateral headaches that cause excruciating pain during attacks, which may happen as frequently as eight times per day. They are refractory to, or intolerant of, preventive medications typically used in chronic cluster headaches.
“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting medically intractable chronic cluster headache, both at high and low intensity,” Leopoldine A. Wilbrink, MD, of Leiden (the Netherlands) University Medical Centre, and coauthors wrote in their paper.
The findings were published online.
The multicenter, randomized, double-blind, phase 3 clinical trial was carried out at seven hospitals in the Netherlands, Belgium, Germany, and Hungary. A total of 150 patients with suspected medically intractable chronic cluster headache were enrolled between October 2010 and December 2017, and observed for 12 weeks at baseline. Of those initially enrolled, 131 patients with at least four medically intractable chronic cluster headache attacks per week and a history of nonresponsiveness to at least three standard preventive medications were randomly allocated to one of two groups: Sixty-five patients received 24 weeks of ONS at high intensity (100% intensity, or the intensity 10% below the threshold of discomfort as reported by the patient) while 66 received low-intensity (30%) ONS. At 25-48 weeks, the patients received open-label ONS.
Safe and well tolerated
“Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy,” wrote Dr. Wilbrink and colleagues.
From baseline to weeks 21-24, the median weekly mean attack frequencies decreased to 7.38 (95% confidence interval [CI]: 2.5-18.5, P < .0001). A median decrease in 5.21 attacks per week (–11.18 to –0.19, P < .0001) was observed.
The 100% ONS group saw a decrease in mean attack frequency from 17.58 at baseline (range, 9.83-29.33) to 9.5 (3-21.25) at 21-24 weeks with a median change of –4.08 (–11.92 to –0.25). In the 30% ONS group, the mean attack frequency decreased from 15 (9.25 to 22.33) to 6.75 (1.5-16.5) with a median change of –6.5 (–10.83 to –0.08).
At weeks 21-24, the difference in median weekly mean attack frequency between the groups was –2.42 (–5.17 to 3.33).
The authors stated that, in both groups, ONS was “safe and well tolerated.” A total of 129 adverse events were reported in the 100% ONS group and 95 in the 30% ONS group, of which 17 and 9 were considered serious, respectively. The serious adverse events required a short hospital stay to resolve minor hardware issues. The adverse events most frequently observed were local pain, impaired wound healing, neck stiffness, and hardware damage.
Low intensity stimulation may be best
“The main limitation of the study comes from the difficulty in defining the electrical dose, which was not constant across patients within each group, but individually adjusted depending on the perception of the ONS-induced paraesthesia,” Denys Fontaine, MD, and Michel Lanteri-Minet, MD, both from Université Cote D’Azur in France, wrote in an accompanying editorial.
Given that the primary outcome did not differ significantly between the treatment groups, the editorialists stated that “the lowest stimulation intensity that induces paraesthesia is sufficient to obtain an effect in the patients who respond. Increasing the electrical dose or intensity does not seem to bring better efficacy and might even induce discomfort (painful paraesthesia or shock-like sensations) that might substantially reduce the tolerance of this approach.”
While the trial did not provide convincing evidence of high intensity ONS in medically intractable chronic cluster headache, the editorialists are otherwise optimistic about the findings: “… considering the significant difference between baseline and the end of the randomised stimulation phase in both groups (about half of the patients showed a 50% decrease in attack frequency), the findings of this study support the favourable results of previous real-world studies, and indicate that a substantial proportion of patients with intractable chronic cluster headache, although not all, could have their condition substantially improved by ONS.” Dr. Fontaine and Dr. Lanteri-Minet added that they hope that “these data will help health authorities to recognise the efficacy of ONS and consider its approval for use in patients with intractable chronic cluster headache.”
Priorities for future research in this area should “focus on optimising stimulation protocols and disentangling the underlying mechanism of action,” Dr. Wilbrink and colleagues wrote.
The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium, the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement program for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to Dr. Ferrari.
Occipital nerve stimulation may help safely prevent attacks of medically intractable chronic cluster headache, according to a new study.
Medically intractable chronic cluster headaches are unilateral headaches that cause excruciating pain during attacks, which may happen as frequently as eight times per day. They are refractory to, or intolerant of, preventive medications typically used in chronic cluster headaches.
“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting medically intractable chronic cluster headache, both at high and low intensity,” Leopoldine A. Wilbrink, MD, of Leiden (the Netherlands) University Medical Centre, and coauthors wrote in their paper.
The findings were published online.
The multicenter, randomized, double-blind, phase 3 clinical trial was carried out at seven hospitals in the Netherlands, Belgium, Germany, and Hungary. A total of 150 patients with suspected medically intractable chronic cluster headache were enrolled between October 2010 and December 2017, and observed for 12 weeks at baseline. Of those initially enrolled, 131 patients with at least four medically intractable chronic cluster headache attacks per week and a history of nonresponsiveness to at least three standard preventive medications were randomly allocated to one of two groups: Sixty-five patients received 24 weeks of ONS at high intensity (100% intensity, or the intensity 10% below the threshold of discomfort as reported by the patient) while 66 received low-intensity (30%) ONS. At 25-48 weeks, the patients received open-label ONS.
Safe and well tolerated
“Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy,” wrote Dr. Wilbrink and colleagues.
From baseline to weeks 21-24, the median weekly mean attack frequencies decreased to 7.38 (95% confidence interval [CI]: 2.5-18.5, P < .0001). A median decrease in 5.21 attacks per week (–11.18 to –0.19, P < .0001) was observed.
The 100% ONS group saw a decrease in mean attack frequency from 17.58 at baseline (range, 9.83-29.33) to 9.5 (3-21.25) at 21-24 weeks with a median change of –4.08 (–11.92 to –0.25). In the 30% ONS group, the mean attack frequency decreased from 15 (9.25 to 22.33) to 6.75 (1.5-16.5) with a median change of –6.5 (–10.83 to –0.08).
At weeks 21-24, the difference in median weekly mean attack frequency between the groups was –2.42 (–5.17 to 3.33).
The authors stated that, in both groups, ONS was “safe and well tolerated.” A total of 129 adverse events were reported in the 100% ONS group and 95 in the 30% ONS group, of which 17 and 9 were considered serious, respectively. The serious adverse events required a short hospital stay to resolve minor hardware issues. The adverse events most frequently observed were local pain, impaired wound healing, neck stiffness, and hardware damage.
Low intensity stimulation may be best
“The main limitation of the study comes from the difficulty in defining the electrical dose, which was not constant across patients within each group, but individually adjusted depending on the perception of the ONS-induced paraesthesia,” Denys Fontaine, MD, and Michel Lanteri-Minet, MD, both from Université Cote D’Azur in France, wrote in an accompanying editorial.
Given that the primary outcome did not differ significantly between the treatment groups, the editorialists stated that “the lowest stimulation intensity that induces paraesthesia is sufficient to obtain an effect in the patients who respond. Increasing the electrical dose or intensity does not seem to bring better efficacy and might even induce discomfort (painful paraesthesia or shock-like sensations) that might substantially reduce the tolerance of this approach.”
While the trial did not provide convincing evidence of high intensity ONS in medically intractable chronic cluster headache, the editorialists are otherwise optimistic about the findings: “… considering the significant difference between baseline and the end of the randomised stimulation phase in both groups (about half of the patients showed a 50% decrease in attack frequency), the findings of this study support the favourable results of previous real-world studies, and indicate that a substantial proportion of patients with intractable chronic cluster headache, although not all, could have their condition substantially improved by ONS.” Dr. Fontaine and Dr. Lanteri-Minet added that they hope that “these data will help health authorities to recognise the efficacy of ONS and consider its approval for use in patients with intractable chronic cluster headache.”
Priorities for future research in this area should “focus on optimising stimulation protocols and disentangling the underlying mechanism of action,” Dr. Wilbrink and colleagues wrote.
The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium, the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement program for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to Dr. Ferrari.
FROM LANCET NEUROLOGY
Novel gene therapy ‘reprograms’ cells to reverse neurologic deficits in children with rare disease
An experimental gene therapy produced marked clinical improvement in children with aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder that affects the synthesis of key neurotransmitters to cause severe developmental and motor disability.
In an article published July 12, 2021, in Nature Communications, a group of researchers based at the University of California, San Francisco, and Ohio State University, Columbus, described results from seven children ages 4-9 with AADC deficiency who underwent a novel form of surgery to deliver a viral vector expressing the human AADC gene to the midbrain.
Previous trials of this gene therapy in children with AADC deficiency targeted a different region of the brain, the putamen, with only slight clinical improvement. Here, investigators chose two midbrain regions – the substantia nigra pars compacta and the ventral tegmental area – in the hope of restoring healthy AADC enzyme activity in those neurons.
The study’s corresponding author, Krystof Bankiewicz, MD, PhD, professor and vice chair of research at Ohio State University, director of the Brain Health and Performance Center at Ohio State University, and professor emeritus and vice chair for research at UCSF, said in an interview that the brain regions chosen for this trial resulted from years of efforts to identify an ideal target in this disease.
“This particular vector undergoes axonal transport,” he said. “If you inject it into specific regions of the brain it will be transported into the terminals [of the nerve fibers]. And by looking at the imaging of these patients, we found that they still have the wiring in the brain that’s so critical. So we decided to aim at a much more difficult target, going directly to the source of the problem, which is the substantia nigra and the ventral tegmental area. This targets two critical pathways in the brain: one that drives motor responses and another that controls emotions.”
‘Surprising’ improvement seen
The children in the study – four girls and three boys – underwent surgery from 2016 to the end of 2018, and were divided into two dose cohorts, with one receiving three times the amount of vector as the other. Both groups, however, saw similar levels of improvement.
All but one child saw complete resolution of a hallmark symptom of the disease – oculogyric crises, or prolonged spasms of muscles controlling eye movement – within 3 months of surgery. Of the children followed at least 18 months, six attained head control within a year, two became able to eat and drink by mouth, and four gained the ability to sit up unaided in that time. At 18 months one child had learned to speak 50 words using an augmentative communication device.
One child died unexpectedly 7 months after the procedure, Dr. Bankiewicz said in an interview. This death appeared to be caused by cardiac complications of his disease, Dr. Bankiewicz said, which are common in AADC deficiency.
While the investigators are now looking at delivering the AADC gene therapy in younger children – who were excluded from this trial because of safety concerns surrounding the complex procedure – investigators were surprised by the level of improvement seen in older children.
“We initially didn’t believe – at least not all of us – that we could actually make an impact in the older patients, and that is not the case,” said Dr. Bankiewicz, who has since used the same gene therapy on a compassionate-use basis in Europe and seen durable clinical improvement in patients as old as 26. “The fact that we saw a response in that patient tells us something about how incredibly plastic the brain is.”
While the new study does not detail improvements in the children’s social and emotional well-being, Dr. Bankiewicz said these, too, were pronounced. “Kids fall into oculogyric crises in stress-inducing situation. They might be in a stroller being taken for a walk, and something in the environment would stress them. Sometimes they had to be kept in a dark room isolated from stress.” Following the gene therapy, “they’re laughing, they’re social, they can interact with their environment. It’s really touching to see them able to develop a bond now with their caregivers.”
Implication for other disorders
Dr. Bankiewicz and colleagues have previously used the same gene to boost AADC activity in patients with Parkinson’s disease. The group is also in trials to deliver a neuroprotective gene to the brains of people with early-stage Alzheimer’s disease, and a gene-silencing therapy in patients with Huntington’s disease. They will also continue recruiting pediatric patients for trials of the AADC gene therapy.
“We have been developing a method for safely treating younger children, so now we will go to 3 years old and maybe even below,” Dr. Bankiewicz said. “Earlier is probably better, but for technical and safety considerations we needed to be conservative first. It is hugely stressful to go into very sick patients with that type of therapy in that part of the brain. We had to get it right the first time, and it looks like we did.”
The study was funded by the National Institutes of Health, the AADC Research Trust, the Pediatric Neurotransmitter Disease Association, and Ohio State University, with materials and technical support donated by ClearPoint Neuro. Several coauthors disclosed financial relationships with producers of diagnostic tests or biotechnology firms. Dr. Bankiewicz is a founder and shareholder of Brain Neurotherapy Bio, a company that develops gene therapies for Parkinson’s and other diseases.
An experimental gene therapy produced marked clinical improvement in children with aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder that affects the synthesis of key neurotransmitters to cause severe developmental and motor disability.
In an article published July 12, 2021, in Nature Communications, a group of researchers based at the University of California, San Francisco, and Ohio State University, Columbus, described results from seven children ages 4-9 with AADC deficiency who underwent a novel form of surgery to deliver a viral vector expressing the human AADC gene to the midbrain.
Previous trials of this gene therapy in children with AADC deficiency targeted a different region of the brain, the putamen, with only slight clinical improvement. Here, investigators chose two midbrain regions – the substantia nigra pars compacta and the ventral tegmental area – in the hope of restoring healthy AADC enzyme activity in those neurons.
The study’s corresponding author, Krystof Bankiewicz, MD, PhD, professor and vice chair of research at Ohio State University, director of the Brain Health and Performance Center at Ohio State University, and professor emeritus and vice chair for research at UCSF, said in an interview that the brain regions chosen for this trial resulted from years of efforts to identify an ideal target in this disease.
“This particular vector undergoes axonal transport,” he said. “If you inject it into specific regions of the brain it will be transported into the terminals [of the nerve fibers]. And by looking at the imaging of these patients, we found that they still have the wiring in the brain that’s so critical. So we decided to aim at a much more difficult target, going directly to the source of the problem, which is the substantia nigra and the ventral tegmental area. This targets two critical pathways in the brain: one that drives motor responses and another that controls emotions.”
‘Surprising’ improvement seen
The children in the study – four girls and three boys – underwent surgery from 2016 to the end of 2018, and were divided into two dose cohorts, with one receiving three times the amount of vector as the other. Both groups, however, saw similar levels of improvement.
All but one child saw complete resolution of a hallmark symptom of the disease – oculogyric crises, or prolonged spasms of muscles controlling eye movement – within 3 months of surgery. Of the children followed at least 18 months, six attained head control within a year, two became able to eat and drink by mouth, and four gained the ability to sit up unaided in that time. At 18 months one child had learned to speak 50 words using an augmentative communication device.
One child died unexpectedly 7 months after the procedure, Dr. Bankiewicz said in an interview. This death appeared to be caused by cardiac complications of his disease, Dr. Bankiewicz said, which are common in AADC deficiency.
While the investigators are now looking at delivering the AADC gene therapy in younger children – who were excluded from this trial because of safety concerns surrounding the complex procedure – investigators were surprised by the level of improvement seen in older children.
“We initially didn’t believe – at least not all of us – that we could actually make an impact in the older patients, and that is not the case,” said Dr. Bankiewicz, who has since used the same gene therapy on a compassionate-use basis in Europe and seen durable clinical improvement in patients as old as 26. “The fact that we saw a response in that patient tells us something about how incredibly plastic the brain is.”
While the new study does not detail improvements in the children’s social and emotional well-being, Dr. Bankiewicz said these, too, were pronounced. “Kids fall into oculogyric crises in stress-inducing situation. They might be in a stroller being taken for a walk, and something in the environment would stress them. Sometimes they had to be kept in a dark room isolated from stress.” Following the gene therapy, “they’re laughing, they’re social, they can interact with their environment. It’s really touching to see them able to develop a bond now with their caregivers.”
Implication for other disorders
Dr. Bankiewicz and colleagues have previously used the same gene to boost AADC activity in patients with Parkinson’s disease. The group is also in trials to deliver a neuroprotective gene to the brains of people with early-stage Alzheimer’s disease, and a gene-silencing therapy in patients with Huntington’s disease. They will also continue recruiting pediatric patients for trials of the AADC gene therapy.
“We have been developing a method for safely treating younger children, so now we will go to 3 years old and maybe even below,” Dr. Bankiewicz said. “Earlier is probably better, but for technical and safety considerations we needed to be conservative first. It is hugely stressful to go into very sick patients with that type of therapy in that part of the brain. We had to get it right the first time, and it looks like we did.”
The study was funded by the National Institutes of Health, the AADC Research Trust, the Pediatric Neurotransmitter Disease Association, and Ohio State University, with materials and technical support donated by ClearPoint Neuro. Several coauthors disclosed financial relationships with producers of diagnostic tests or biotechnology firms. Dr. Bankiewicz is a founder and shareholder of Brain Neurotherapy Bio, a company that develops gene therapies for Parkinson’s and other diseases.
An experimental gene therapy produced marked clinical improvement in children with aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder that affects the synthesis of key neurotransmitters to cause severe developmental and motor disability.
In an article published July 12, 2021, in Nature Communications, a group of researchers based at the University of California, San Francisco, and Ohio State University, Columbus, described results from seven children ages 4-9 with AADC deficiency who underwent a novel form of surgery to deliver a viral vector expressing the human AADC gene to the midbrain.
Previous trials of this gene therapy in children with AADC deficiency targeted a different region of the brain, the putamen, with only slight clinical improvement. Here, investigators chose two midbrain regions – the substantia nigra pars compacta and the ventral tegmental area – in the hope of restoring healthy AADC enzyme activity in those neurons.
The study’s corresponding author, Krystof Bankiewicz, MD, PhD, professor and vice chair of research at Ohio State University, director of the Brain Health and Performance Center at Ohio State University, and professor emeritus and vice chair for research at UCSF, said in an interview that the brain regions chosen for this trial resulted from years of efforts to identify an ideal target in this disease.
“This particular vector undergoes axonal transport,” he said. “If you inject it into specific regions of the brain it will be transported into the terminals [of the nerve fibers]. And by looking at the imaging of these patients, we found that they still have the wiring in the brain that’s so critical. So we decided to aim at a much more difficult target, going directly to the source of the problem, which is the substantia nigra and the ventral tegmental area. This targets two critical pathways in the brain: one that drives motor responses and another that controls emotions.”
‘Surprising’ improvement seen
The children in the study – four girls and three boys – underwent surgery from 2016 to the end of 2018, and were divided into two dose cohorts, with one receiving three times the amount of vector as the other. Both groups, however, saw similar levels of improvement.
All but one child saw complete resolution of a hallmark symptom of the disease – oculogyric crises, or prolonged spasms of muscles controlling eye movement – within 3 months of surgery. Of the children followed at least 18 months, six attained head control within a year, two became able to eat and drink by mouth, and four gained the ability to sit up unaided in that time. At 18 months one child had learned to speak 50 words using an augmentative communication device.
One child died unexpectedly 7 months after the procedure, Dr. Bankiewicz said in an interview. This death appeared to be caused by cardiac complications of his disease, Dr. Bankiewicz said, which are common in AADC deficiency.
While the investigators are now looking at delivering the AADC gene therapy in younger children – who were excluded from this trial because of safety concerns surrounding the complex procedure – investigators were surprised by the level of improvement seen in older children.
“We initially didn’t believe – at least not all of us – that we could actually make an impact in the older patients, and that is not the case,” said Dr. Bankiewicz, who has since used the same gene therapy on a compassionate-use basis in Europe and seen durable clinical improvement in patients as old as 26. “The fact that we saw a response in that patient tells us something about how incredibly plastic the brain is.”
While the new study does not detail improvements in the children’s social and emotional well-being, Dr. Bankiewicz said these, too, were pronounced. “Kids fall into oculogyric crises in stress-inducing situation. They might be in a stroller being taken for a walk, and something in the environment would stress them. Sometimes they had to be kept in a dark room isolated from stress.” Following the gene therapy, “they’re laughing, they’re social, they can interact with their environment. It’s really touching to see them able to develop a bond now with their caregivers.”
Implication for other disorders
Dr. Bankiewicz and colleagues have previously used the same gene to boost AADC activity in patients with Parkinson’s disease. The group is also in trials to deliver a neuroprotective gene to the brains of people with early-stage Alzheimer’s disease, and a gene-silencing therapy in patients with Huntington’s disease. They will also continue recruiting pediatric patients for trials of the AADC gene therapy.
“We have been developing a method for safely treating younger children, so now we will go to 3 years old and maybe even below,” Dr. Bankiewicz said. “Earlier is probably better, but for technical and safety considerations we needed to be conservative first. It is hugely stressful to go into very sick patients with that type of therapy in that part of the brain. We had to get it right the first time, and it looks like we did.”
The study was funded by the National Institutes of Health, the AADC Research Trust, the Pediatric Neurotransmitter Disease Association, and Ohio State University, with materials and technical support donated by ClearPoint Neuro. Several coauthors disclosed financial relationships with producers of diagnostic tests or biotechnology firms. Dr. Bankiewicz is a founder and shareholder of Brain Neurotherapy Bio, a company that develops gene therapies for Parkinson’s and other diseases.
FROM NATURE COMMUNICATIONS
Updated consensus statement assesses new migraine treatments
“Because the benefit–risk profiles of newer treatments will continue to evolve as clinical trial and real-world data accrue, the American Headache Society intends to review this statement regularly and update, if appropriate, based on the emergence of evidence with implications for clinical practice,” wrote lead author Jessica Ailani, MD, of the department of neurology at Medstar Georgetown University Hospital, Washington, and colleagues. The statement was published in Headache.
To assess recent data on the efficacy, safety, and clinical use of newly introduced acute and preventive migraine treatments, the AHS convened a small task force to review relevant literature published from December 2018 through February 2021. The society’s board of directors, along with patients and patient advocates associated with the American Migraine Foundation, also provided pertinent commentary.
New migraine treatment
Five recently approved acute migraine treatments were specifically noted: two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists – rimegepant and ubrogepant – along with the nonsteroidal anti-inflammatory drug celecoxib, the serotonin 5-HT1F agonist lasmiditan, and remote electrical neuromodulation (REN). Highlighted risks include serious cardiovascular thrombotic events in patients on celecoxib, along with driving impairment, sleepiness, and the possibility of overuse in patients on lasmiditan. The authors added, however, that REN “has shown good tolerability and safety in clinical trials” and that frequent use of rimegepant or ubrogepant does not appear to lead to medication-overuse headache.
Regarding acute treatment overall, the statement recommended nonsteroidal anti-inflammatory drugs (NSAIDs), nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations – such as aspirin plus acetaminophen plus caffeine – for mild to moderate attacks. For moderate or severe attacks, they recommended migraine-specific agents such as triptans, small-molecule CGRP receptor antagonists (gepants), or selective serotonin 5-HT1F receptor agonists (ditans). No matter the prescribed treatment, the statement pushed for patients to “treat at the first sign of pain to improve the probability of achieving freedom from pain and reduce attack-related disability.”
The authors added that 30% of patients on triptans have an “insufficient response” and as such may benefit from a second triptan or – if certain criteria are met – switching to a gepant, a ditan, or a neuromodulatory device. They also recommended a nonoral formulation for patients whose attacks are often accompanied by severe nausea or vomiting.
More broadly, they addressed the tolerability and safety issues associated with certain treatments, including the gastrointestinal and cardiovascular side effects of NSAIDs and the dangers of using triptans in patients with coronary artery disease or other vascular disorders. And while gepants and ditans appeared in clinical trials to be safe choices for patients with stable cardiovascular disease, “benefit-risk should be assessed in each patient as the real-world database for these therapies grows,” they wrote.
Only one recently approved preventive treatment – eptinezumab, an intravenous anti-CGRP ligand monoclonal antibody (MAB) – was highlighted. The authors noted that its benefits can begin within 24 hours, and it can reduce acute medication use and therefore the risk of medication-overuse headache.
Regarding preventive treatments overall, the authors stated that prevention should be offered if patients suffer from 6 or more days of headache per month, or 3-4 days of headache plus some-to-severe disability. Preventive treatments should be considered in patients who range from at least 2 days of headache per month plus severe disability to 4 or 5 days of headache. Prevention should also be considered in patients with uncommon migraine subtypes, including hemiplegic migraine, migraine with brainstem aura, and migraine with prolonged aura.
Initiating treatment
When considering initiation of treatment with one of the four Food and Drug Administration–approved CGRP MABs – eptinezumab, erenumab, fremanezumab, or galcanezumab – the authors recommend their use if migraine patients show an inability to tolerate or respond to a trial of two or more older oral medications or other established effective therapies. Though they emphasized that oral preventive medications should be started at a low dose and titrated slowly until the target response is reached or tolerability issues emerge, no such need was specified for the parenteral treatments. They also endorsed the approach of patients staying on oral preventive drugs for a minimum of 8 weeks to determine effectiveness or a lack thereof; at that point, switching to another treatment is recommended.
The dual use of therapies such as neuromodulation, biobehavioral therapies, and gepants were also examined, including gepants’ potential as a “continuum between the acute and preventive treatment of migraine” and the limited use of neuromodulatory devices in clinical practice despite clear benefits in patients who prefer to avoid medication or those suffering from frequent attacks and subsequent medication overuse. In addition, it was stated that biobehavioral therapies have “grade A evidence” supporting their use in patients who either prefer nonpharmacologic treatments or have an adverse or poor reaction to the drugs.
From the patient perspective, one of the six reviewers shared concerns about migraine patients being required to try two established preventive medications before starting a recently introduced option, noting that the older drugs have lower efficacy and tolerability. Two reviewers would have liked to see the statement focus more on nonpharmacologic and device-related therapies, and one reviewer noted the possible value in guidance regarding “exploratory approaches” such as cannabis.
The authors acknowledged numerous potential conflicts of interest, including receiving speaking and consulting fees, grants, personal fees, and honoraria from various pharmaceutical and publishing companies.
Not everyone agrees
Commenting on the AHS consensus statement, James A Charles, MD, and Ira Turner, MD, had this to say: “This Consensus Statement incorporates the best available evidence including the newer CGRP therapies as well as the older treatments. The AHS posture is that the CGRP abortive and preventive treatments have a lesser amount of data and experience than the older treatments which have a wealth of literature and data because they have been around longer. As a result, there are 2 statements in these guidelines that the insurance companies quote in their manual of policies:
1. Inadequate response to two or more oral triptans before using a gepant as abortive treatment
2. Inadequate response to an 8-week trial at a dose established to be potentially effective of two or more of the following before using CGRP MAB for preventive treatment: topiramate, divalproex sodium/valproate sodium; beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol; tricyclic antidepressant: amitriptyline, nortriptyline; serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine; other Level A or B treatments.”
Dr. Charles, who is affiliated with Holy Name Medical Center in Teaneck N.J., and Dr. Turner, who is affiliated with the Center for Headache Care and Research at Island Neurological Associates in Plainview, N.Y., further said that “giving the CGRP MABs and gepants second-class status because they have not been around as long as the old boys is an insult to the research, development, and successful execution of gepant and CGRP MAB therapies in the last several years. The authors omitted the Hepp study and the long list of adverse effects of triptans leading to high discontinuance rates, and how trying a second triptan will probably not work.” Importantly, they said, “the authors have given the insurance carriers a weapon to deny direct access to gepants and CGRP MABs making direct access to these agents difficult for patients and physicians and their staffs.”
Dr. Charles and Dr. Turner point out that the AHS guidelines use the term “cost effective” – that it is better to use the cheaper, older drugs first. “Ineffective treatment of a patient for 8 weeks before using CGRP blocking therapies and using 2 triptans before a gepant is cost ineffective,” they said. “Inadequate delayed treatment results in loss of work productivity and loss of school and family participation and excessive use of ER visits. These guidelines forget that we ameliorate current disability and prevent chronification by treating with the most effective abortive and preventive therapies which may not commence with the cheaper old drugs.”
They explain: “Of course, we would use a beta-blocker for comorbid hypertension and/or anxiety, and venlafaxine for comorbid depression. And if a patient is pain free in 2 hrs with no adverse effects from a triptan used less than 10 times a month, it would not be appropriate to switch to a gepant. However, a treatment naive migraineur with accelerating migraine should have the option of going directly to a gepant and CGRP blocking MAB.” Dr. Charles and Dr. Turner concur that the phrase in the AHS consensus statement regarding the staging of therapy – two triptans before a gepant and two oral preventatives for 8 weeks before a CGRP MAB – “should be removed so that the CGRP drugs get the equal credit they deserve, as can be attested to by the migraine voices of lives saved by the sound research that led to their development and approval by the FDA.”
Ultimately, Dr. Charles and Dr. Turner said, “the final decision on treatment should be made by the physician and patient, not the insurance company or consensus statements.”
Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, former president of the International Headache Society, and editor-in-chief of Neurology Reviews, said, “Although I think the consensus statement is well done, and the authors have the right to make the statements they have made, Drs. Charles and Turner are excellent experienced clinicians and they should be heard. They properly state that the restrictive statements highlighted by the authors have already been used by insurance companies to prevent access to the more expensive but more effective therapies with fewer adverse effects.”
Dr. Rapoport goes on to say, “I believe that the patient’s individual headache history and past responses to therapies must be analyzed by the treating physician and an appropriate treatment be agreed upon between the patient and doctor. It is time to let experienced headache-interested doctors make their own correct decision about treatment without the heavy hand of the insurance company, which is often more intent on saving money than helping the patient.
Suggested reading
Hepp Z et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-88.
Alam A et al. Triptan use and discontinuation in a representative sample of persons with migraine: Results from Migraine in America Symptoms and Treatment (MAST) study. Headache. 2018;58:68‐69.
Buse DC et al. Adding additional acute medications to a triptan regimen for migraine and observed changes in headache-related disability: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2015 Jun;55(6):825-39.
“Because the benefit–risk profiles of newer treatments will continue to evolve as clinical trial and real-world data accrue, the American Headache Society intends to review this statement regularly and update, if appropriate, based on the emergence of evidence with implications for clinical practice,” wrote lead author Jessica Ailani, MD, of the department of neurology at Medstar Georgetown University Hospital, Washington, and colleagues. The statement was published in Headache.
To assess recent data on the efficacy, safety, and clinical use of newly introduced acute and preventive migraine treatments, the AHS convened a small task force to review relevant literature published from December 2018 through February 2021. The society’s board of directors, along with patients and patient advocates associated with the American Migraine Foundation, also provided pertinent commentary.
New migraine treatment
Five recently approved acute migraine treatments were specifically noted: two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists – rimegepant and ubrogepant – along with the nonsteroidal anti-inflammatory drug celecoxib, the serotonin 5-HT1F agonist lasmiditan, and remote electrical neuromodulation (REN). Highlighted risks include serious cardiovascular thrombotic events in patients on celecoxib, along with driving impairment, sleepiness, and the possibility of overuse in patients on lasmiditan. The authors added, however, that REN “has shown good tolerability and safety in clinical trials” and that frequent use of rimegepant or ubrogepant does not appear to lead to medication-overuse headache.
Regarding acute treatment overall, the statement recommended nonsteroidal anti-inflammatory drugs (NSAIDs), nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations – such as aspirin plus acetaminophen plus caffeine – for mild to moderate attacks. For moderate or severe attacks, they recommended migraine-specific agents such as triptans, small-molecule CGRP receptor antagonists (gepants), or selective serotonin 5-HT1F receptor agonists (ditans). No matter the prescribed treatment, the statement pushed for patients to “treat at the first sign of pain to improve the probability of achieving freedom from pain and reduce attack-related disability.”
The authors added that 30% of patients on triptans have an “insufficient response” and as such may benefit from a second triptan or – if certain criteria are met – switching to a gepant, a ditan, or a neuromodulatory device. They also recommended a nonoral formulation for patients whose attacks are often accompanied by severe nausea or vomiting.
More broadly, they addressed the tolerability and safety issues associated with certain treatments, including the gastrointestinal and cardiovascular side effects of NSAIDs and the dangers of using triptans in patients with coronary artery disease or other vascular disorders. And while gepants and ditans appeared in clinical trials to be safe choices for patients with stable cardiovascular disease, “benefit-risk should be assessed in each patient as the real-world database for these therapies grows,” they wrote.
Only one recently approved preventive treatment – eptinezumab, an intravenous anti-CGRP ligand monoclonal antibody (MAB) – was highlighted. The authors noted that its benefits can begin within 24 hours, and it can reduce acute medication use and therefore the risk of medication-overuse headache.
Regarding preventive treatments overall, the authors stated that prevention should be offered if patients suffer from 6 or more days of headache per month, or 3-4 days of headache plus some-to-severe disability. Preventive treatments should be considered in patients who range from at least 2 days of headache per month plus severe disability to 4 or 5 days of headache. Prevention should also be considered in patients with uncommon migraine subtypes, including hemiplegic migraine, migraine with brainstem aura, and migraine with prolonged aura.
Initiating treatment
When considering initiation of treatment with one of the four Food and Drug Administration–approved CGRP MABs – eptinezumab, erenumab, fremanezumab, or galcanezumab – the authors recommend their use if migraine patients show an inability to tolerate or respond to a trial of two or more older oral medications or other established effective therapies. Though they emphasized that oral preventive medications should be started at a low dose and titrated slowly until the target response is reached or tolerability issues emerge, no such need was specified for the parenteral treatments. They also endorsed the approach of patients staying on oral preventive drugs for a minimum of 8 weeks to determine effectiveness or a lack thereof; at that point, switching to another treatment is recommended.
The dual use of therapies such as neuromodulation, biobehavioral therapies, and gepants were also examined, including gepants’ potential as a “continuum between the acute and preventive treatment of migraine” and the limited use of neuromodulatory devices in clinical practice despite clear benefits in patients who prefer to avoid medication or those suffering from frequent attacks and subsequent medication overuse. In addition, it was stated that biobehavioral therapies have “grade A evidence” supporting their use in patients who either prefer nonpharmacologic treatments or have an adverse or poor reaction to the drugs.
From the patient perspective, one of the six reviewers shared concerns about migraine patients being required to try two established preventive medications before starting a recently introduced option, noting that the older drugs have lower efficacy and tolerability. Two reviewers would have liked to see the statement focus more on nonpharmacologic and device-related therapies, and one reviewer noted the possible value in guidance regarding “exploratory approaches” such as cannabis.
The authors acknowledged numerous potential conflicts of interest, including receiving speaking and consulting fees, grants, personal fees, and honoraria from various pharmaceutical and publishing companies.
Not everyone agrees
Commenting on the AHS consensus statement, James A Charles, MD, and Ira Turner, MD, had this to say: “This Consensus Statement incorporates the best available evidence including the newer CGRP therapies as well as the older treatments. The AHS posture is that the CGRP abortive and preventive treatments have a lesser amount of data and experience than the older treatments which have a wealth of literature and data because they have been around longer. As a result, there are 2 statements in these guidelines that the insurance companies quote in their manual of policies:
1. Inadequate response to two or more oral triptans before using a gepant as abortive treatment
2. Inadequate response to an 8-week trial at a dose established to be potentially effective of two or more of the following before using CGRP MAB for preventive treatment: topiramate, divalproex sodium/valproate sodium; beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol; tricyclic antidepressant: amitriptyline, nortriptyline; serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine; other Level A or B treatments.”
Dr. Charles, who is affiliated with Holy Name Medical Center in Teaneck N.J., and Dr. Turner, who is affiliated with the Center for Headache Care and Research at Island Neurological Associates in Plainview, N.Y., further said that “giving the CGRP MABs and gepants second-class status because they have not been around as long as the old boys is an insult to the research, development, and successful execution of gepant and CGRP MAB therapies in the last several years. The authors omitted the Hepp study and the long list of adverse effects of triptans leading to high discontinuance rates, and how trying a second triptan will probably not work.” Importantly, they said, “the authors have given the insurance carriers a weapon to deny direct access to gepants and CGRP MABs making direct access to these agents difficult for patients and physicians and their staffs.”
Dr. Charles and Dr. Turner point out that the AHS guidelines use the term “cost effective” – that it is better to use the cheaper, older drugs first. “Ineffective treatment of a patient for 8 weeks before using CGRP blocking therapies and using 2 triptans before a gepant is cost ineffective,” they said. “Inadequate delayed treatment results in loss of work productivity and loss of school and family participation and excessive use of ER visits. These guidelines forget that we ameliorate current disability and prevent chronification by treating with the most effective abortive and preventive therapies which may not commence with the cheaper old drugs.”
They explain: “Of course, we would use a beta-blocker for comorbid hypertension and/or anxiety, and venlafaxine for comorbid depression. And if a patient is pain free in 2 hrs with no adverse effects from a triptan used less than 10 times a month, it would not be appropriate to switch to a gepant. However, a treatment naive migraineur with accelerating migraine should have the option of going directly to a gepant and CGRP blocking MAB.” Dr. Charles and Dr. Turner concur that the phrase in the AHS consensus statement regarding the staging of therapy – two triptans before a gepant and two oral preventatives for 8 weeks before a CGRP MAB – “should be removed so that the CGRP drugs get the equal credit they deserve, as can be attested to by the migraine voices of lives saved by the sound research that led to their development and approval by the FDA.”
Ultimately, Dr. Charles and Dr. Turner said, “the final decision on treatment should be made by the physician and patient, not the insurance company or consensus statements.”
Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, former president of the International Headache Society, and editor-in-chief of Neurology Reviews, said, “Although I think the consensus statement is well done, and the authors have the right to make the statements they have made, Drs. Charles and Turner are excellent experienced clinicians and they should be heard. They properly state that the restrictive statements highlighted by the authors have already been used by insurance companies to prevent access to the more expensive but more effective therapies with fewer adverse effects.”
Dr. Rapoport goes on to say, “I believe that the patient’s individual headache history and past responses to therapies must be analyzed by the treating physician and an appropriate treatment be agreed upon between the patient and doctor. It is time to let experienced headache-interested doctors make their own correct decision about treatment without the heavy hand of the insurance company, which is often more intent on saving money than helping the patient.
Suggested reading
Hepp Z et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-88.
Alam A et al. Triptan use and discontinuation in a representative sample of persons with migraine: Results from Migraine in America Symptoms and Treatment (MAST) study. Headache. 2018;58:68‐69.
Buse DC et al. Adding additional acute medications to a triptan regimen for migraine and observed changes in headache-related disability: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2015 Jun;55(6):825-39.
“Because the benefit–risk profiles of newer treatments will continue to evolve as clinical trial and real-world data accrue, the American Headache Society intends to review this statement regularly and update, if appropriate, based on the emergence of evidence with implications for clinical practice,” wrote lead author Jessica Ailani, MD, of the department of neurology at Medstar Georgetown University Hospital, Washington, and colleagues. The statement was published in Headache.
To assess recent data on the efficacy, safety, and clinical use of newly introduced acute and preventive migraine treatments, the AHS convened a small task force to review relevant literature published from December 2018 through February 2021. The society’s board of directors, along with patients and patient advocates associated with the American Migraine Foundation, also provided pertinent commentary.
New migraine treatment
Five recently approved acute migraine treatments were specifically noted: two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists – rimegepant and ubrogepant – along with the nonsteroidal anti-inflammatory drug celecoxib, the serotonin 5-HT1F agonist lasmiditan, and remote electrical neuromodulation (REN). Highlighted risks include serious cardiovascular thrombotic events in patients on celecoxib, along with driving impairment, sleepiness, and the possibility of overuse in patients on lasmiditan. The authors added, however, that REN “has shown good tolerability and safety in clinical trials” and that frequent use of rimegepant or ubrogepant does not appear to lead to medication-overuse headache.
Regarding acute treatment overall, the statement recommended nonsteroidal anti-inflammatory drugs (NSAIDs), nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations – such as aspirin plus acetaminophen plus caffeine – for mild to moderate attacks. For moderate or severe attacks, they recommended migraine-specific agents such as triptans, small-molecule CGRP receptor antagonists (gepants), or selective serotonin 5-HT1F receptor agonists (ditans). No matter the prescribed treatment, the statement pushed for patients to “treat at the first sign of pain to improve the probability of achieving freedom from pain and reduce attack-related disability.”
The authors added that 30% of patients on triptans have an “insufficient response” and as such may benefit from a second triptan or – if certain criteria are met – switching to a gepant, a ditan, or a neuromodulatory device. They also recommended a nonoral formulation for patients whose attacks are often accompanied by severe nausea or vomiting.
More broadly, they addressed the tolerability and safety issues associated with certain treatments, including the gastrointestinal and cardiovascular side effects of NSAIDs and the dangers of using triptans in patients with coronary artery disease or other vascular disorders. And while gepants and ditans appeared in clinical trials to be safe choices for patients with stable cardiovascular disease, “benefit-risk should be assessed in each patient as the real-world database for these therapies grows,” they wrote.
Only one recently approved preventive treatment – eptinezumab, an intravenous anti-CGRP ligand monoclonal antibody (MAB) – was highlighted. The authors noted that its benefits can begin within 24 hours, and it can reduce acute medication use and therefore the risk of medication-overuse headache.
Regarding preventive treatments overall, the authors stated that prevention should be offered if patients suffer from 6 or more days of headache per month, or 3-4 days of headache plus some-to-severe disability. Preventive treatments should be considered in patients who range from at least 2 days of headache per month plus severe disability to 4 or 5 days of headache. Prevention should also be considered in patients with uncommon migraine subtypes, including hemiplegic migraine, migraine with brainstem aura, and migraine with prolonged aura.
Initiating treatment
When considering initiation of treatment with one of the four Food and Drug Administration–approved CGRP MABs – eptinezumab, erenumab, fremanezumab, or galcanezumab – the authors recommend their use if migraine patients show an inability to tolerate or respond to a trial of two or more older oral medications or other established effective therapies. Though they emphasized that oral preventive medications should be started at a low dose and titrated slowly until the target response is reached or tolerability issues emerge, no such need was specified for the parenteral treatments. They also endorsed the approach of patients staying on oral preventive drugs for a minimum of 8 weeks to determine effectiveness or a lack thereof; at that point, switching to another treatment is recommended.
The dual use of therapies such as neuromodulation, biobehavioral therapies, and gepants were also examined, including gepants’ potential as a “continuum between the acute and preventive treatment of migraine” and the limited use of neuromodulatory devices in clinical practice despite clear benefits in patients who prefer to avoid medication or those suffering from frequent attacks and subsequent medication overuse. In addition, it was stated that biobehavioral therapies have “grade A evidence” supporting their use in patients who either prefer nonpharmacologic treatments or have an adverse or poor reaction to the drugs.
From the patient perspective, one of the six reviewers shared concerns about migraine patients being required to try two established preventive medications before starting a recently introduced option, noting that the older drugs have lower efficacy and tolerability. Two reviewers would have liked to see the statement focus more on nonpharmacologic and device-related therapies, and one reviewer noted the possible value in guidance regarding “exploratory approaches” such as cannabis.
The authors acknowledged numerous potential conflicts of interest, including receiving speaking and consulting fees, grants, personal fees, and honoraria from various pharmaceutical and publishing companies.
Not everyone agrees
Commenting on the AHS consensus statement, James A Charles, MD, and Ira Turner, MD, had this to say: “This Consensus Statement incorporates the best available evidence including the newer CGRP therapies as well as the older treatments. The AHS posture is that the CGRP abortive and preventive treatments have a lesser amount of data and experience than the older treatments which have a wealth of literature and data because they have been around longer. As a result, there are 2 statements in these guidelines that the insurance companies quote in their manual of policies:
1. Inadequate response to two or more oral triptans before using a gepant as abortive treatment
2. Inadequate response to an 8-week trial at a dose established to be potentially effective of two or more of the following before using CGRP MAB for preventive treatment: topiramate, divalproex sodium/valproate sodium; beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol; tricyclic antidepressant: amitriptyline, nortriptyline; serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine; other Level A or B treatments.”
Dr. Charles, who is affiliated with Holy Name Medical Center in Teaneck N.J., and Dr. Turner, who is affiliated with the Center for Headache Care and Research at Island Neurological Associates in Plainview, N.Y., further said that “giving the CGRP MABs and gepants second-class status because they have not been around as long as the old boys is an insult to the research, development, and successful execution of gepant and CGRP MAB therapies in the last several years. The authors omitted the Hepp study and the long list of adverse effects of triptans leading to high discontinuance rates, and how trying a second triptan will probably not work.” Importantly, they said, “the authors have given the insurance carriers a weapon to deny direct access to gepants and CGRP MABs making direct access to these agents difficult for patients and physicians and their staffs.”
Dr. Charles and Dr. Turner point out that the AHS guidelines use the term “cost effective” – that it is better to use the cheaper, older drugs first. “Ineffective treatment of a patient for 8 weeks before using CGRP blocking therapies and using 2 triptans before a gepant is cost ineffective,” they said. “Inadequate delayed treatment results in loss of work productivity and loss of school and family participation and excessive use of ER visits. These guidelines forget that we ameliorate current disability and prevent chronification by treating with the most effective abortive and preventive therapies which may not commence with the cheaper old drugs.”
They explain: “Of course, we would use a beta-blocker for comorbid hypertension and/or anxiety, and venlafaxine for comorbid depression. And if a patient is pain free in 2 hrs with no adverse effects from a triptan used less than 10 times a month, it would not be appropriate to switch to a gepant. However, a treatment naive migraineur with accelerating migraine should have the option of going directly to a gepant and CGRP blocking MAB.” Dr. Charles and Dr. Turner concur that the phrase in the AHS consensus statement regarding the staging of therapy – two triptans before a gepant and two oral preventatives for 8 weeks before a CGRP MAB – “should be removed so that the CGRP drugs get the equal credit they deserve, as can be attested to by the migraine voices of lives saved by the sound research that led to their development and approval by the FDA.”
Ultimately, Dr. Charles and Dr. Turner said, “the final decision on treatment should be made by the physician and patient, not the insurance company or consensus statements.”
Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, former president of the International Headache Society, and editor-in-chief of Neurology Reviews, said, “Although I think the consensus statement is well done, and the authors have the right to make the statements they have made, Drs. Charles and Turner are excellent experienced clinicians and they should be heard. They properly state that the restrictive statements highlighted by the authors have already been used by insurance companies to prevent access to the more expensive but more effective therapies with fewer adverse effects.”
Dr. Rapoport goes on to say, “I believe that the patient’s individual headache history and past responses to therapies must be analyzed by the treating physician and an appropriate treatment be agreed upon between the patient and doctor. It is time to let experienced headache-interested doctors make their own correct decision about treatment without the heavy hand of the insurance company, which is often more intent on saving money than helping the patient.
Suggested reading
Hepp Z et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-88.
Alam A et al. Triptan use and discontinuation in a representative sample of persons with migraine: Results from Migraine in America Symptoms and Treatment (MAST) study. Headache. 2018;58:68‐69.
Buse DC et al. Adding additional acute medications to a triptan regimen for migraine and observed changes in headache-related disability: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2015 Jun;55(6):825-39.
FROM HEADACHE
Cancer mortality continues to drop in females as breast cancer reversal looms
Overall cancer mortality in females continues to decrease in the United States, but “previous declining trends in death rates slowed” for breast cancer in recent years, according to an annual report by several national organizations.
The analysis of long-term trends in cancer death rates shows that a decline of 1.4% per year from 2001 to 2016 accelerated to 2.1% per year in 2016-2018, the American Cancer Society, Centers for Disease Control and Prevention, National Cancer Institute, and the North American Association of Central Cancer Registries said.
Decreases in overall cancer mortality were seen in females of all races and ethnic groups over the most recent 5-year period included in the report, 2014-2018, varying from –1.6% per year in both non-Hispanic Blacks and Whites to –0.9% for non-Hispanic American Indians/Alaska Natives (AI/ANs), Farhad Islami, MD, PhD, of the American Cancer Society, Atlanta, and associates said in the Journal of the National Cancer Institute.
Over those 5 years, death rates fell for 14 of the 20 most common cancers in females; increased for liver, uterus, brain, pancreas, and soft tissue including heart; and remained stable for cancers of the oral cavity/pharynx, they reported.
Breast cancer was among those that declined, but the rate of that decline has been slowing. Mortality declined by an average of 2.3% per year in 2003-2007, by 1.6% a year in 2007-2014, and by just 1.0% annually during 2014-2018, based on data from the National Center for Health Statistics’ National Vital Statistics System.
Mortality from all cancers in 2014-2018 was 133.5 deaths per 100,000 standard population, with the racial/ethnic gap ranging from 85.4 per 100,000 (non-Hispanic Asian/Pacific Islander) to 154.9 (non-Hispanic Black), Dr. Islami and associates said.
Melanoma had the largest decline in mortality over that period among the 20 most common cancers in females, falling by an average of 4.4% per year, with lung cancer next at 4.3%. Among those with increased death rates, uterine cancer saw the largest rise at 2.0% a year, the research team said.
The deaths caused by cancer of the uterus were most common in non-Hispanic Black females, 8.9 per 100,000 population, followed by non-Hispanic White (4.5), Hispanic (4.1), non-Hispanic AI/AN (4.0), and non-Hispanic Asian/Pacific Islander (3.3), they reported.
“Long-term increasing trends in uterine cancer death rates parallel trends in incidence, although death rates are increasing at a somewhat faster rate. Increasing uterine cancer incidence has been attributed to increasing obesity prevalence and decreased use of combined hormone replacement therapy,” Dr. Islami and associates pointed out.
Breast cancer deaths also were most common among Blacks in 2014-2018, occurring at a rate of 28.2 per 100,000, as were deaths from cancer of the cervix (3.4 per 100,000), while ovarian cancers deaths were highest in White females (7.1 per 100,000), the researchers noted.
The continuing racial and ethnic disparity “largely reflects a combination of multiple intertwined factors” of tumor biology, diagnosis, treatment, and systemic discrimination, they wrote, adding that Black persons “are more likely to have a higher exposure to some cancer risk factors and limited access to healthy food, safe places for physical activity, and evidence-based cancer preventive services.”
The report was funded by the four participating groups. Six of the 12 investigators are employees of the American Cancer Society whose salaries are solely paid by the society; the other authors had no conflicts of interest to disclose.
Overall cancer mortality in females continues to decrease in the United States, but “previous declining trends in death rates slowed” for breast cancer in recent years, according to an annual report by several national organizations.
The analysis of long-term trends in cancer death rates shows that a decline of 1.4% per year from 2001 to 2016 accelerated to 2.1% per year in 2016-2018, the American Cancer Society, Centers for Disease Control and Prevention, National Cancer Institute, and the North American Association of Central Cancer Registries said.
Decreases in overall cancer mortality were seen in females of all races and ethnic groups over the most recent 5-year period included in the report, 2014-2018, varying from –1.6% per year in both non-Hispanic Blacks and Whites to –0.9% for non-Hispanic American Indians/Alaska Natives (AI/ANs), Farhad Islami, MD, PhD, of the American Cancer Society, Atlanta, and associates said in the Journal of the National Cancer Institute.
Over those 5 years, death rates fell for 14 of the 20 most common cancers in females; increased for liver, uterus, brain, pancreas, and soft tissue including heart; and remained stable for cancers of the oral cavity/pharynx, they reported.
Breast cancer was among those that declined, but the rate of that decline has been slowing. Mortality declined by an average of 2.3% per year in 2003-2007, by 1.6% a year in 2007-2014, and by just 1.0% annually during 2014-2018, based on data from the National Center for Health Statistics’ National Vital Statistics System.
Mortality from all cancers in 2014-2018 was 133.5 deaths per 100,000 standard population, with the racial/ethnic gap ranging from 85.4 per 100,000 (non-Hispanic Asian/Pacific Islander) to 154.9 (non-Hispanic Black), Dr. Islami and associates said.
Melanoma had the largest decline in mortality over that period among the 20 most common cancers in females, falling by an average of 4.4% per year, with lung cancer next at 4.3%. Among those with increased death rates, uterine cancer saw the largest rise at 2.0% a year, the research team said.
The deaths caused by cancer of the uterus were most common in non-Hispanic Black females, 8.9 per 100,000 population, followed by non-Hispanic White (4.5), Hispanic (4.1), non-Hispanic AI/AN (4.0), and non-Hispanic Asian/Pacific Islander (3.3), they reported.
“Long-term increasing trends in uterine cancer death rates parallel trends in incidence, although death rates are increasing at a somewhat faster rate. Increasing uterine cancer incidence has been attributed to increasing obesity prevalence and decreased use of combined hormone replacement therapy,” Dr. Islami and associates pointed out.
Breast cancer deaths also were most common among Blacks in 2014-2018, occurring at a rate of 28.2 per 100,000, as were deaths from cancer of the cervix (3.4 per 100,000), while ovarian cancers deaths were highest in White females (7.1 per 100,000), the researchers noted.
The continuing racial and ethnic disparity “largely reflects a combination of multiple intertwined factors” of tumor biology, diagnosis, treatment, and systemic discrimination, they wrote, adding that Black persons “are more likely to have a higher exposure to some cancer risk factors and limited access to healthy food, safe places for physical activity, and evidence-based cancer preventive services.”
The report was funded by the four participating groups. Six of the 12 investigators are employees of the American Cancer Society whose salaries are solely paid by the society; the other authors had no conflicts of interest to disclose.
Overall cancer mortality in females continues to decrease in the United States, but “previous declining trends in death rates slowed” for breast cancer in recent years, according to an annual report by several national organizations.
The analysis of long-term trends in cancer death rates shows that a decline of 1.4% per year from 2001 to 2016 accelerated to 2.1% per year in 2016-2018, the American Cancer Society, Centers for Disease Control and Prevention, National Cancer Institute, and the North American Association of Central Cancer Registries said.
Decreases in overall cancer mortality were seen in females of all races and ethnic groups over the most recent 5-year period included in the report, 2014-2018, varying from –1.6% per year in both non-Hispanic Blacks and Whites to –0.9% for non-Hispanic American Indians/Alaska Natives (AI/ANs), Farhad Islami, MD, PhD, of the American Cancer Society, Atlanta, and associates said in the Journal of the National Cancer Institute.
Over those 5 years, death rates fell for 14 of the 20 most common cancers in females; increased for liver, uterus, brain, pancreas, and soft tissue including heart; and remained stable for cancers of the oral cavity/pharynx, they reported.
Breast cancer was among those that declined, but the rate of that decline has been slowing. Mortality declined by an average of 2.3% per year in 2003-2007, by 1.6% a year in 2007-2014, and by just 1.0% annually during 2014-2018, based on data from the National Center for Health Statistics’ National Vital Statistics System.
Mortality from all cancers in 2014-2018 was 133.5 deaths per 100,000 standard population, with the racial/ethnic gap ranging from 85.4 per 100,000 (non-Hispanic Asian/Pacific Islander) to 154.9 (non-Hispanic Black), Dr. Islami and associates said.
Melanoma had the largest decline in mortality over that period among the 20 most common cancers in females, falling by an average of 4.4% per year, with lung cancer next at 4.3%. Among those with increased death rates, uterine cancer saw the largest rise at 2.0% a year, the research team said.
The deaths caused by cancer of the uterus were most common in non-Hispanic Black females, 8.9 per 100,000 population, followed by non-Hispanic White (4.5), Hispanic (4.1), non-Hispanic AI/AN (4.0), and non-Hispanic Asian/Pacific Islander (3.3), they reported.
“Long-term increasing trends in uterine cancer death rates parallel trends in incidence, although death rates are increasing at a somewhat faster rate. Increasing uterine cancer incidence has been attributed to increasing obesity prevalence and decreased use of combined hormone replacement therapy,” Dr. Islami and associates pointed out.
Breast cancer deaths also were most common among Blacks in 2014-2018, occurring at a rate of 28.2 per 100,000, as were deaths from cancer of the cervix (3.4 per 100,000), while ovarian cancers deaths were highest in White females (7.1 per 100,000), the researchers noted.
The continuing racial and ethnic disparity “largely reflects a combination of multiple intertwined factors” of tumor biology, diagnosis, treatment, and systemic discrimination, they wrote, adding that Black persons “are more likely to have a higher exposure to some cancer risk factors and limited access to healthy food, safe places for physical activity, and evidence-based cancer preventive services.”
The report was funded by the four participating groups. Six of the 12 investigators are employees of the American Cancer Society whose salaries are solely paid by the society; the other authors had no conflicts of interest to disclose.
FROM THE JOURNAL OF THE NATIONAL CANCER INSTITUTE
Chronic stress and genetics can raise the risk of Alzheimer’s disease
The researchers also proposed a mechanism to account for how genetic factors may affect HPA axis reactivity and lead to inflammation, which is a core component of neurodegeneration.
“Chronic stress can impact the way immune cells in the brain function and increase inflammation. Genetic variants within that stress response can further affect the function of immune cells,” lead author Ayeisha Milligan Armstrong, a PhD candidate at Curtin Health Innovation Research Institute in Perth, Australia, said in an interview.
The findings were published online June 22 in Biological Reviews).
Research has found that long-term stress during early and mid-life is increasingly associated with cognitive decline and neurodegeneration. There is already evidence to suggest that chronic stress is a risk factor for the “sporadic” or late-onset subtype of Alzheimer’s disease.
A cascade of events
Stress activates the HPA, which in turn regulates bodily levels of cortisol, a glucocorticoid stress hormone. Increased levels of cortisol are frequently observed in patients with Alzheimer’s disease and “make a major contribution to the disease process,” the authors wrote. For example, the hippocampus – a part of the brain involved in processing and forming memories – has numerous glucocorticoid receptors and is “therefore particularly sensitive to the effects of glucocorticoids.” However, the molecular mechanisms involved remain poorly understood.
“There is an intimate interplay between exposure to chronic stress and pathways influencing the body’s reaction to such stress,” senior author David Groth, PhD, said in a statement. Dr. Groth is an associate professor at Curtin University in Perth, Australia.
There is variation between individuals with regard to how sensitive they are to stress and glucocorticoid responses. Environmental factors such as stress are thought to be at least partly responsible, as are genetic factors such as genetic polymorphisms and epigenetics. “Genetic variations within these pathways can influence the way the brain’s immune system behaves, leading to a dysfunctional response. In the brain, this leads to a chronic disruption of normal brain processes, increasing the risk of subsequent neurodegeneration and ultimately dementia,” Dr. Groth said.
The researchers suggested that these variations may prime the immune cells of the brain, the microglia, to cause inflammation in the brain. Normally, microglia are involved in monitoring the brain tissue for and responding to damage and infections to keep the brain healthy. However, in an inflammatory state, the microglia instead contribute to a “more neurotoxic environment through the production of proinflammatory cytokines, altered synaptic pruning, and the reduced production of protective neurotrophic factors,” the authors wrote. Microglia may also promote the accumulation of amyloid beta and tau protein, which damage the brain tissue and can cause neurodegeneration. There are different groups of microglia in the brain, each of which may respond differently to genetic and environmental stressors.
“Genome-wide association studies have found that of the genes identified as being associated with Alzheimer’s disease, 60.5% are expressed in microglia,” the authors noted.
To connect the roles of chronic stress and brain inflammation in Alzheimer’s disease, the researchers proposed a “two-hit” hypothesis: Early or mid-life exposure to stress primes the microglia to enter an inflammatory state in response to a secondary stimulus later in life.
Pay attention to stress
For clinicians, this paper highlights the importance of managing stress in patients and their families.
“Clinicians need to be attuned to the effects of stress on patients and their caregivers, and how that [stress] can affect their morbidity and mortality,” Cynthia Munro, PhD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said in an interview. She added that attention must be paid to modifiable risk factors such as poor sleep and diet.
Although managing stress is important, that doesn’t mean that everyone who’s experienced chronic stress will develop Alzheimer’s disease. “Chronic stress can alter the HPA axis but it doesn’t necessarily do so in everyone. A cascade of events needs to occur,” said Dr. Munro. “People should always try to reduce the effects of stress to the extent that they can. Stress can lead to a whole host of negative health outcomes, not just Alzheimer’s disease.”
Next steps
Moving forward, the researchers plan to further investigate the molecular mechanisms responsible for the role of stress in Alzheimer’s disease and how genetic variants affect neurodegeneration, Ms. Armstrong said. Ultimately, understanding how stress and genetics contribute to Alzheimer’s disease may lead to the identification of possible therapeutic targets.
Ms. Armstrong and Dr. Munro declared no relevant financial relationships. The study was independently funded.
The researchers also proposed a mechanism to account for how genetic factors may affect HPA axis reactivity and lead to inflammation, which is a core component of neurodegeneration.
“Chronic stress can impact the way immune cells in the brain function and increase inflammation. Genetic variants within that stress response can further affect the function of immune cells,” lead author Ayeisha Milligan Armstrong, a PhD candidate at Curtin Health Innovation Research Institute in Perth, Australia, said in an interview.
The findings were published online June 22 in Biological Reviews).
Research has found that long-term stress during early and mid-life is increasingly associated with cognitive decline and neurodegeneration. There is already evidence to suggest that chronic stress is a risk factor for the “sporadic” or late-onset subtype of Alzheimer’s disease.
A cascade of events
Stress activates the HPA, which in turn regulates bodily levels of cortisol, a glucocorticoid stress hormone. Increased levels of cortisol are frequently observed in patients with Alzheimer’s disease and “make a major contribution to the disease process,” the authors wrote. For example, the hippocampus – a part of the brain involved in processing and forming memories – has numerous glucocorticoid receptors and is “therefore particularly sensitive to the effects of glucocorticoids.” However, the molecular mechanisms involved remain poorly understood.
“There is an intimate interplay between exposure to chronic stress and pathways influencing the body’s reaction to such stress,” senior author David Groth, PhD, said in a statement. Dr. Groth is an associate professor at Curtin University in Perth, Australia.
There is variation between individuals with regard to how sensitive they are to stress and glucocorticoid responses. Environmental factors such as stress are thought to be at least partly responsible, as are genetic factors such as genetic polymorphisms and epigenetics. “Genetic variations within these pathways can influence the way the brain’s immune system behaves, leading to a dysfunctional response. In the brain, this leads to a chronic disruption of normal brain processes, increasing the risk of subsequent neurodegeneration and ultimately dementia,” Dr. Groth said.
The researchers suggested that these variations may prime the immune cells of the brain, the microglia, to cause inflammation in the brain. Normally, microglia are involved in monitoring the brain tissue for and responding to damage and infections to keep the brain healthy. However, in an inflammatory state, the microglia instead contribute to a “more neurotoxic environment through the production of proinflammatory cytokines, altered synaptic pruning, and the reduced production of protective neurotrophic factors,” the authors wrote. Microglia may also promote the accumulation of amyloid beta and tau protein, which damage the brain tissue and can cause neurodegeneration. There are different groups of microglia in the brain, each of which may respond differently to genetic and environmental stressors.
“Genome-wide association studies have found that of the genes identified as being associated with Alzheimer’s disease, 60.5% are expressed in microglia,” the authors noted.
To connect the roles of chronic stress and brain inflammation in Alzheimer’s disease, the researchers proposed a “two-hit” hypothesis: Early or mid-life exposure to stress primes the microglia to enter an inflammatory state in response to a secondary stimulus later in life.
Pay attention to stress
For clinicians, this paper highlights the importance of managing stress in patients and their families.
“Clinicians need to be attuned to the effects of stress on patients and their caregivers, and how that [stress] can affect their morbidity and mortality,” Cynthia Munro, PhD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said in an interview. She added that attention must be paid to modifiable risk factors such as poor sleep and diet.
Although managing stress is important, that doesn’t mean that everyone who’s experienced chronic stress will develop Alzheimer’s disease. “Chronic stress can alter the HPA axis but it doesn’t necessarily do so in everyone. A cascade of events needs to occur,” said Dr. Munro. “People should always try to reduce the effects of stress to the extent that they can. Stress can lead to a whole host of negative health outcomes, not just Alzheimer’s disease.”
Next steps
Moving forward, the researchers plan to further investigate the molecular mechanisms responsible for the role of stress in Alzheimer’s disease and how genetic variants affect neurodegeneration, Ms. Armstrong said. Ultimately, understanding how stress and genetics contribute to Alzheimer’s disease may lead to the identification of possible therapeutic targets.
Ms. Armstrong and Dr. Munro declared no relevant financial relationships. The study was independently funded.
The researchers also proposed a mechanism to account for how genetic factors may affect HPA axis reactivity and lead to inflammation, which is a core component of neurodegeneration.
“Chronic stress can impact the way immune cells in the brain function and increase inflammation. Genetic variants within that stress response can further affect the function of immune cells,” lead author Ayeisha Milligan Armstrong, a PhD candidate at Curtin Health Innovation Research Institute in Perth, Australia, said in an interview.
The findings were published online June 22 in Biological Reviews).
Research has found that long-term stress during early and mid-life is increasingly associated with cognitive decline and neurodegeneration. There is already evidence to suggest that chronic stress is a risk factor for the “sporadic” or late-onset subtype of Alzheimer’s disease.
A cascade of events
Stress activates the HPA, which in turn regulates bodily levels of cortisol, a glucocorticoid stress hormone. Increased levels of cortisol are frequently observed in patients with Alzheimer’s disease and “make a major contribution to the disease process,” the authors wrote. For example, the hippocampus – a part of the brain involved in processing and forming memories – has numerous glucocorticoid receptors and is “therefore particularly sensitive to the effects of glucocorticoids.” However, the molecular mechanisms involved remain poorly understood.
“There is an intimate interplay between exposure to chronic stress and pathways influencing the body’s reaction to such stress,” senior author David Groth, PhD, said in a statement. Dr. Groth is an associate professor at Curtin University in Perth, Australia.
There is variation between individuals with regard to how sensitive they are to stress and glucocorticoid responses. Environmental factors such as stress are thought to be at least partly responsible, as are genetic factors such as genetic polymorphisms and epigenetics. “Genetic variations within these pathways can influence the way the brain’s immune system behaves, leading to a dysfunctional response. In the brain, this leads to a chronic disruption of normal brain processes, increasing the risk of subsequent neurodegeneration and ultimately dementia,” Dr. Groth said.
The researchers suggested that these variations may prime the immune cells of the brain, the microglia, to cause inflammation in the brain. Normally, microglia are involved in monitoring the brain tissue for and responding to damage and infections to keep the brain healthy. However, in an inflammatory state, the microglia instead contribute to a “more neurotoxic environment through the production of proinflammatory cytokines, altered synaptic pruning, and the reduced production of protective neurotrophic factors,” the authors wrote. Microglia may also promote the accumulation of amyloid beta and tau protein, which damage the brain tissue and can cause neurodegeneration. There are different groups of microglia in the brain, each of which may respond differently to genetic and environmental stressors.
“Genome-wide association studies have found that of the genes identified as being associated with Alzheimer’s disease, 60.5% are expressed in microglia,” the authors noted.
To connect the roles of chronic stress and brain inflammation in Alzheimer’s disease, the researchers proposed a “two-hit” hypothesis: Early or mid-life exposure to stress primes the microglia to enter an inflammatory state in response to a secondary stimulus later in life.
Pay attention to stress
For clinicians, this paper highlights the importance of managing stress in patients and their families.
“Clinicians need to be attuned to the effects of stress on patients and their caregivers, and how that [stress] can affect their morbidity and mortality,” Cynthia Munro, PhD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said in an interview. She added that attention must be paid to modifiable risk factors such as poor sleep and diet.
Although managing stress is important, that doesn’t mean that everyone who’s experienced chronic stress will develop Alzheimer’s disease. “Chronic stress can alter the HPA axis but it doesn’t necessarily do so in everyone. A cascade of events needs to occur,” said Dr. Munro. “People should always try to reduce the effects of stress to the extent that they can. Stress can lead to a whole host of negative health outcomes, not just Alzheimer’s disease.”
Next steps
Moving forward, the researchers plan to further investigate the molecular mechanisms responsible for the role of stress in Alzheimer’s disease and how genetic variants affect neurodegeneration, Ms. Armstrong said. Ultimately, understanding how stress and genetics contribute to Alzheimer’s disease may lead to the identification of possible therapeutic targets.
Ms. Armstrong and Dr. Munro declared no relevant financial relationships. The study was independently funded.
FROM BIOLOGICAL REVIEWS
Therapeutic Approaches in Advanced Breast Cancer
More than 280,000 women in the United States will be diagnosed with invasive breast cancer this year. For those with metastatic breast cancer with distant spread, the 5-year survival rate is approximately 28%. Whether advanced disease is discovered at initial diagnosis or in relapsed disease, it is imperative to understand the molecular characteristics of the metastatic tumor.
Dr Susan Domchek, from the University of Pennsylvania, discusses the importance of retesting for estrogen receptor, progesterone receptor, and HER2/neu on a metastatic tumor focus in order to identify potential discordance between the primary cancer and metastatic disease.
Additionally, Dr Domchek discusses the importance of molecular testing for targetable mutations, including P13K and germline BRCA1/2, for which approved therapies have shown survival benefit.
The list of targetable mutations in breast cancer continues to expand. In the tumor-agnostic studies, pembrolizumab has shown survival benefit in tumors that have mismatch repair deficiency and microsatellite instability, and TRK inhibitors have shown efficacy in tumors positive for NTRK fusions. Numerous clinical trials are available looking at additional molecular-based therapies.
--
Susan M. Domchek, MD, Basser Professor, Department of Oncology; Executive Director, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia.
Susan M. Domchek, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: AstraZeneca; Clovis; Bristol Myers Squibb.
More than 280,000 women in the United States will be diagnosed with invasive breast cancer this year. For those with metastatic breast cancer with distant spread, the 5-year survival rate is approximately 28%. Whether advanced disease is discovered at initial diagnosis or in relapsed disease, it is imperative to understand the molecular characteristics of the metastatic tumor.
Dr Susan Domchek, from the University of Pennsylvania, discusses the importance of retesting for estrogen receptor, progesterone receptor, and HER2/neu on a metastatic tumor focus in order to identify potential discordance between the primary cancer and metastatic disease.
Additionally, Dr Domchek discusses the importance of molecular testing for targetable mutations, including P13K and germline BRCA1/2, for which approved therapies have shown survival benefit.
The list of targetable mutations in breast cancer continues to expand. In the tumor-agnostic studies, pembrolizumab has shown survival benefit in tumors that have mismatch repair deficiency and microsatellite instability, and TRK inhibitors have shown efficacy in tumors positive for NTRK fusions. Numerous clinical trials are available looking at additional molecular-based therapies.
--
Susan M. Domchek, MD, Basser Professor, Department of Oncology; Executive Director, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia.
Susan M. Domchek, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: AstraZeneca; Clovis; Bristol Myers Squibb.
More than 280,000 women in the United States will be diagnosed with invasive breast cancer this year. For those with metastatic breast cancer with distant spread, the 5-year survival rate is approximately 28%. Whether advanced disease is discovered at initial diagnosis or in relapsed disease, it is imperative to understand the molecular characteristics of the metastatic tumor.
Dr Susan Domchek, from the University of Pennsylvania, discusses the importance of retesting for estrogen receptor, progesterone receptor, and HER2/neu on a metastatic tumor focus in order to identify potential discordance between the primary cancer and metastatic disease.
Additionally, Dr Domchek discusses the importance of molecular testing for targetable mutations, including P13K and germline BRCA1/2, for which approved therapies have shown survival benefit.
The list of targetable mutations in breast cancer continues to expand. In the tumor-agnostic studies, pembrolizumab has shown survival benefit in tumors that have mismatch repair deficiency and microsatellite instability, and TRK inhibitors have shown efficacy in tumors positive for NTRK fusions. Numerous clinical trials are available looking at additional molecular-based therapies.
--
Susan M. Domchek, MD, Basser Professor, Department of Oncology; Executive Director, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia.
Susan M. Domchek, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: AstraZeneca; Clovis; Bristol Myers Squibb.
Focus on cancer risk
Hereditary cancer risk assessment is the key to identifying patients and families who are at increased risk for developing cancer. The knowledge generated by cancer risk assessment impacts clinical decisions that obstetricians and gynecologists and their patients make every day. Previvors—patients predisposed to developing cancer, because of their family history or a pathogenic gene variant, who have not had cancer—benefit from counseling, heightened surveillance, and medical and surgical options.
For the last 25 years, this field has been growing dramatically, and although the scientific advances are present, only 15.3% of patients with a personal history of breast or ovarian cancer who meet hereditary cancer testing criteria have been tested.1 As many as 1 in 4 women who present for a gynecologic examination may have a personal history or a family history that qualifies them for genetic testing.2
Cancer risk app considerations
The ability to leverage mobile device applications can provide clinicians and patients with a useful screening tool to identify women who are at increased cancer risk. Only a handful of apps are available today and most are geared to patients. Such apps explore the different testing modalities, including genetic testing, as well as treatment options. When evaluating the best app for patients, using the ACOG-recommended rubric shown on page 35, the qualities to keep in mind and that should score 4 out of 4 include design, authority, usefulness, and accuracy.
A few apps provide reminders for appointments, such as mammograms, magnetic resonance imaging, or breast self-exams, and allow patients to track treatment plans. To date, no app addresses prevention and treatment opportunities that are specific to patients who have a hereditary predisposition. At least one app lists hereditary cancer testing guidelines. Many more apps are geared toward individuals with cancer rather than toward previvors.
As ObGyns, we have an opportunity to educate and identify women and, subsequently, better counsel women identified as at increased risk for developing cancer. We can utilize medical apps to efficiently incorporate this screening into clinical practice. ●
- Childers P, Childers KK, Maggard-Gibbons M, et al. National estimates of genetic testing in women with a history of breast or ovarian cancer. J Clin Oncol. 2017;35:3800-3806.
- DeFrancesco M, Waldman RN, Pearlstone MM, et al. Hereditary cancer risk assessment and genetic testing in a community practice setting. Obstet Gynecol. 2018;132:1121-1129.
Richard Waldman, MD
Dr. Waldman is Past President of the American College of Obstetricians and Gynecologists, Past President of Associates for Women’s Medicine, and Immediate Past Chairman, Department of Obstetrics and Gynecology, St. Joseph’s Hospital, Syracuse, New York.
The author reports no financial relationships relevant to this article.
Richard Waldman, MD
Dr. Waldman is Past President of the American College of Obstetricians and Gynecologists, Past President of Associates for Women’s Medicine, and Immediate Past Chairman, Department of Obstetrics and Gynecology, St. Joseph’s Hospital, Syracuse, New York.
The author reports no financial relationships relevant to this article.
Richard Waldman, MD
Dr. Waldman is Past President of the American College of Obstetricians and Gynecologists, Past President of Associates for Women’s Medicine, and Immediate Past Chairman, Department of Obstetrics and Gynecology, St. Joseph’s Hospital, Syracuse, New York.
The author reports no financial relationships relevant to this article.
Hereditary cancer risk assessment is the key to identifying patients and families who are at increased risk for developing cancer. The knowledge generated by cancer risk assessment impacts clinical decisions that obstetricians and gynecologists and their patients make every day. Previvors—patients predisposed to developing cancer, because of their family history or a pathogenic gene variant, who have not had cancer—benefit from counseling, heightened surveillance, and medical and surgical options.
For the last 25 years, this field has been growing dramatically, and although the scientific advances are present, only 15.3% of patients with a personal history of breast or ovarian cancer who meet hereditary cancer testing criteria have been tested.1 As many as 1 in 4 women who present for a gynecologic examination may have a personal history or a family history that qualifies them for genetic testing.2
Cancer risk app considerations
The ability to leverage mobile device applications can provide clinicians and patients with a useful screening tool to identify women who are at increased cancer risk. Only a handful of apps are available today and most are geared to patients. Such apps explore the different testing modalities, including genetic testing, as well as treatment options. When evaluating the best app for patients, using the ACOG-recommended rubric shown on page 35, the qualities to keep in mind and that should score 4 out of 4 include design, authority, usefulness, and accuracy.
A few apps provide reminders for appointments, such as mammograms, magnetic resonance imaging, or breast self-exams, and allow patients to track treatment plans. To date, no app addresses prevention and treatment opportunities that are specific to patients who have a hereditary predisposition. At least one app lists hereditary cancer testing guidelines. Many more apps are geared toward individuals with cancer rather than toward previvors.
As ObGyns, we have an opportunity to educate and identify women and, subsequently, better counsel women identified as at increased risk for developing cancer. We can utilize medical apps to efficiently incorporate this screening into clinical practice. ●
Hereditary cancer risk assessment is the key to identifying patients and families who are at increased risk for developing cancer. The knowledge generated by cancer risk assessment impacts clinical decisions that obstetricians and gynecologists and their patients make every day. Previvors—patients predisposed to developing cancer, because of their family history or a pathogenic gene variant, who have not had cancer—benefit from counseling, heightened surveillance, and medical and surgical options.
For the last 25 years, this field has been growing dramatically, and although the scientific advances are present, only 15.3% of patients with a personal history of breast or ovarian cancer who meet hereditary cancer testing criteria have been tested.1 As many as 1 in 4 women who present for a gynecologic examination may have a personal history or a family history that qualifies them for genetic testing.2
Cancer risk app considerations
The ability to leverage mobile device applications can provide clinicians and patients with a useful screening tool to identify women who are at increased cancer risk. Only a handful of apps are available today and most are geared to patients. Such apps explore the different testing modalities, including genetic testing, as well as treatment options. When evaluating the best app for patients, using the ACOG-recommended rubric shown on page 35, the qualities to keep in mind and that should score 4 out of 4 include design, authority, usefulness, and accuracy.
A few apps provide reminders for appointments, such as mammograms, magnetic resonance imaging, or breast self-exams, and allow patients to track treatment plans. To date, no app addresses prevention and treatment opportunities that are specific to patients who have a hereditary predisposition. At least one app lists hereditary cancer testing guidelines. Many more apps are geared toward individuals with cancer rather than toward previvors.
As ObGyns, we have an opportunity to educate and identify women and, subsequently, better counsel women identified as at increased risk for developing cancer. We can utilize medical apps to efficiently incorporate this screening into clinical practice. ●
- Childers P, Childers KK, Maggard-Gibbons M, et al. National estimates of genetic testing in women with a history of breast or ovarian cancer. J Clin Oncol. 2017;35:3800-3806.
- DeFrancesco M, Waldman RN, Pearlstone MM, et al. Hereditary cancer risk assessment and genetic testing in a community practice setting. Obstet Gynecol. 2018;132:1121-1129.
- Childers P, Childers KK, Maggard-Gibbons M, et al. National estimates of genetic testing in women with a history of breast or ovarian cancer. J Clin Oncol. 2017;35:3800-3806.
- DeFrancesco M, Waldman RN, Pearlstone MM, et al. Hereditary cancer risk assessment and genetic testing in a community practice setting. Obstet Gynecol. 2018;132:1121-1129.
Huge trial casts doubt on bisphosphonates for breast cancer
say researchers reporting new results from a phase 3 trial with almost 3,000 women.
Current guidelines call for 3-5 years of bisphosphonate therapy on the theory that these drugs might reduce breast cancer recurrence as well as treatment-related bone problems.
However, the new results show no difference in disease-free survival, distant disease-free survival, and overall survival – regardless of menopausal status – between the 1,540 women who received intravenous zoledronate over a 5-year period and 1,447 women who received such therapy over a 2-year period.
What they did find was a substantially higher risk for adverse events with prolonged bisphosphonate treatment, including risks for grade 3/4 events, bone pain, bone fractures, arthralgia, and jaw necrosis, a rare but well- recognized possibility with bisphosphonates.
Lead investigator Thomas Friedl, PhD, a statistician at University Hospital Ulm (Germany), and colleagues concluded that the current duration of treatment can be reduced and that, short of good reason to use bisphosphonates longer, such as decreased bone density, “treatment with zoledronate for 5 years should not be considered in patients with early breast cancer.”
The study was published online on June 24 in JAMA Oncology.
An accompanying editorial went even further, stating not only that “shorter duration of treatment is sufficient” but also that the whole idea of bisphosphonates for breast cancer is in doubt.
With “the modest outcomes of bisphosphonates, compared with no bone-targeted therapy, in historical trials” and the low rates of recurrence with modern treatment – less than 10% in the trial – “what, if any, is the benefit from adjuvant bisphosphonates? It’s time to reevaluate the guidelines,” said the editorialists, led by Alexandra Desnoyers, MD, a breast cancer fellow at the University of Toronto.
“We suggest that zoledronate or other amino-bisphosphonates should not be given as standard adjuvant therapy for unselected women with breast cancer,” they wrote.
Risk for necrosis with 5 years of zoledronate
The women in the trial had primary invasive breast cancer and were at high risk for recurrence. They had either positive nodes or high-risk features, including age (median, 53 years). They were treated at 250 centers in Germany.
The first part of the trial was to see whether use of gemcitabine improved outcomes when added to docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide adjuvant therapy following surgery. It did not, and the authors reported in 2020 that adjuvant gemcitabine should not be used in the treatment of high-risk early breast cancer.
The next phase of the trial involved zoledronate. Women were randomly assigned to receive zoledronate for 2 or 5 years after surgery and after undergoing chemotherapy. Dosing was 4 mg IV every 3 months for 2 years. The women in the 5-year group went on to receive 4 mg IV every 6 months for another 3 years.
At a mean of 5 years’ follow-up after the first zoledronate dose, there was no difference in any of the survival measures between the two dosage groups.
There was also no difference in rates of bone recurrence or in circulating tumor cells, which the bisphosphonates theory would have predicted. For instance, 10.5% of women in the 5-year group had one or more circulating tumor cells on follow-up versus 7.2% in the 2-year group.
Almost half of the women in the 5-year treatment group experienced adverse events with zoledronate – including 7.6% with grade 3/4 events – versus just over a quarter in the 2-year arm and only 5.1% with grade 3/4 events.
In the 5-year group, 8.3% of patients experienced bone pain and 5.1% experienced arthralgia versus 3.7% and 3.1%, respectively, in the 2-year arm.
Atypical fractures, such as femoral spiral fractures, are another concern with bisphosphonates. Although this trial did not report on fracture type, fractures were reported in 14 women in the 5-year group but in only 3 in the 2-year arm.
Jaw necrosis, another known adverse effect of bisphosphonates, was reported in 11 women in the 5-year group and in 5 in the 2-year group.
The study was funded by several pharmaceutical companies, including Novartis, the maker of zoledronate. The investigators have numerous industry ties. Dr. Friedl has received payments from Novartis.
A version of this article first appeared on Medscape.com.
say researchers reporting new results from a phase 3 trial with almost 3,000 women.
Current guidelines call for 3-5 years of bisphosphonate therapy on the theory that these drugs might reduce breast cancer recurrence as well as treatment-related bone problems.
However, the new results show no difference in disease-free survival, distant disease-free survival, and overall survival – regardless of menopausal status – between the 1,540 women who received intravenous zoledronate over a 5-year period and 1,447 women who received such therapy over a 2-year period.
What they did find was a substantially higher risk for adverse events with prolonged bisphosphonate treatment, including risks for grade 3/4 events, bone pain, bone fractures, arthralgia, and jaw necrosis, a rare but well- recognized possibility with bisphosphonates.
Lead investigator Thomas Friedl, PhD, a statistician at University Hospital Ulm (Germany), and colleagues concluded that the current duration of treatment can be reduced and that, short of good reason to use bisphosphonates longer, such as decreased bone density, “treatment with zoledronate for 5 years should not be considered in patients with early breast cancer.”
The study was published online on June 24 in JAMA Oncology.
An accompanying editorial went even further, stating not only that “shorter duration of treatment is sufficient” but also that the whole idea of bisphosphonates for breast cancer is in doubt.
With “the modest outcomes of bisphosphonates, compared with no bone-targeted therapy, in historical trials” and the low rates of recurrence with modern treatment – less than 10% in the trial – “what, if any, is the benefit from adjuvant bisphosphonates? It’s time to reevaluate the guidelines,” said the editorialists, led by Alexandra Desnoyers, MD, a breast cancer fellow at the University of Toronto.
“We suggest that zoledronate or other amino-bisphosphonates should not be given as standard adjuvant therapy for unselected women with breast cancer,” they wrote.
Risk for necrosis with 5 years of zoledronate
The women in the trial had primary invasive breast cancer and were at high risk for recurrence. They had either positive nodes or high-risk features, including age (median, 53 years). They were treated at 250 centers in Germany.
The first part of the trial was to see whether use of gemcitabine improved outcomes when added to docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide adjuvant therapy following surgery. It did not, and the authors reported in 2020 that adjuvant gemcitabine should not be used in the treatment of high-risk early breast cancer.
The next phase of the trial involved zoledronate. Women were randomly assigned to receive zoledronate for 2 or 5 years after surgery and after undergoing chemotherapy. Dosing was 4 mg IV every 3 months for 2 years. The women in the 5-year group went on to receive 4 mg IV every 6 months for another 3 years.
At a mean of 5 years’ follow-up after the first zoledronate dose, there was no difference in any of the survival measures between the two dosage groups.
There was also no difference in rates of bone recurrence or in circulating tumor cells, which the bisphosphonates theory would have predicted. For instance, 10.5% of women in the 5-year group had one or more circulating tumor cells on follow-up versus 7.2% in the 2-year group.
Almost half of the women in the 5-year treatment group experienced adverse events with zoledronate – including 7.6% with grade 3/4 events – versus just over a quarter in the 2-year arm and only 5.1% with grade 3/4 events.
In the 5-year group, 8.3% of patients experienced bone pain and 5.1% experienced arthralgia versus 3.7% and 3.1%, respectively, in the 2-year arm.
Atypical fractures, such as femoral spiral fractures, are another concern with bisphosphonates. Although this trial did not report on fracture type, fractures were reported in 14 women in the 5-year group but in only 3 in the 2-year arm.
Jaw necrosis, another known adverse effect of bisphosphonates, was reported in 11 women in the 5-year group and in 5 in the 2-year group.
The study was funded by several pharmaceutical companies, including Novartis, the maker of zoledronate. The investigators have numerous industry ties. Dr. Friedl has received payments from Novartis.
A version of this article first appeared on Medscape.com.
say researchers reporting new results from a phase 3 trial with almost 3,000 women.
Current guidelines call for 3-5 years of bisphosphonate therapy on the theory that these drugs might reduce breast cancer recurrence as well as treatment-related bone problems.
However, the new results show no difference in disease-free survival, distant disease-free survival, and overall survival – regardless of menopausal status – between the 1,540 women who received intravenous zoledronate over a 5-year period and 1,447 women who received such therapy over a 2-year period.
What they did find was a substantially higher risk for adverse events with prolonged bisphosphonate treatment, including risks for grade 3/4 events, bone pain, bone fractures, arthralgia, and jaw necrosis, a rare but well- recognized possibility with bisphosphonates.
Lead investigator Thomas Friedl, PhD, a statistician at University Hospital Ulm (Germany), and colleagues concluded that the current duration of treatment can be reduced and that, short of good reason to use bisphosphonates longer, such as decreased bone density, “treatment with zoledronate for 5 years should not be considered in patients with early breast cancer.”
The study was published online on June 24 in JAMA Oncology.
An accompanying editorial went even further, stating not only that “shorter duration of treatment is sufficient” but also that the whole idea of bisphosphonates for breast cancer is in doubt.
With “the modest outcomes of bisphosphonates, compared with no bone-targeted therapy, in historical trials” and the low rates of recurrence with modern treatment – less than 10% in the trial – “what, if any, is the benefit from adjuvant bisphosphonates? It’s time to reevaluate the guidelines,” said the editorialists, led by Alexandra Desnoyers, MD, a breast cancer fellow at the University of Toronto.
“We suggest that zoledronate or other amino-bisphosphonates should not be given as standard adjuvant therapy for unselected women with breast cancer,” they wrote.
Risk for necrosis with 5 years of zoledronate
The women in the trial had primary invasive breast cancer and were at high risk for recurrence. They had either positive nodes or high-risk features, including age (median, 53 years). They were treated at 250 centers in Germany.
The first part of the trial was to see whether use of gemcitabine improved outcomes when added to docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide adjuvant therapy following surgery. It did not, and the authors reported in 2020 that adjuvant gemcitabine should not be used in the treatment of high-risk early breast cancer.
The next phase of the trial involved zoledronate. Women were randomly assigned to receive zoledronate for 2 or 5 years after surgery and after undergoing chemotherapy. Dosing was 4 mg IV every 3 months for 2 years. The women in the 5-year group went on to receive 4 mg IV every 6 months for another 3 years.
At a mean of 5 years’ follow-up after the first zoledronate dose, there was no difference in any of the survival measures between the two dosage groups.
There was also no difference in rates of bone recurrence or in circulating tumor cells, which the bisphosphonates theory would have predicted. For instance, 10.5% of women in the 5-year group had one or more circulating tumor cells on follow-up versus 7.2% in the 2-year group.
Almost half of the women in the 5-year treatment group experienced adverse events with zoledronate – including 7.6% with grade 3/4 events – versus just over a quarter in the 2-year arm and only 5.1% with grade 3/4 events.
In the 5-year group, 8.3% of patients experienced bone pain and 5.1% experienced arthralgia versus 3.7% and 3.1%, respectively, in the 2-year arm.
Atypical fractures, such as femoral spiral fractures, are another concern with bisphosphonates. Although this trial did not report on fracture type, fractures were reported in 14 women in the 5-year group but in only 3 in the 2-year arm.
Jaw necrosis, another known adverse effect of bisphosphonates, was reported in 11 women in the 5-year group and in 5 in the 2-year group.
The study was funded by several pharmaceutical companies, including Novartis, the maker of zoledronate. The investigators have numerous industry ties. Dr. Friedl has received payments from Novartis.
A version of this article first appeared on Medscape.com.
Is walking speed following stroke a good predictor of recovery?
, suggests new research backed by imaging data.
In secondary analysis of a previous study, training enabled both “good” and “limited” walkers to increase travel distance during a 2-minute walk. However, for “dual-task” walking, good walkers improved their distance by approximately 10 m after training, whereas limited walkers improved by only 1 m. Brain imaging showed increased brain activity in the limited walkers, which could reduce cognitive resources available for performing a second task while walking.
These findings, which were published online May 30 in Clinical Rehabilitation, may explain the apparent lack of superiority, shown previously, of dual-task training compared with single-task training for patients with stroke and impaired walking ability, researchers noted.
“Imaging data were consistent with our hypothesis that walking automaticity might explain these results,” said lead author Johnny Collett, PhD, senior clinical research fellow at Oxford Brookes University, United Kingdom.
At baseline, participants who walked slowly had increased resting state connectivity between contralesional M1 and cortical areas associated with conscious gait control.
“In response to the intervention, we found increased connectivity with the precuneus in those who walked slowly at baseline, an adaptation that might support walking in more complex situations,” Dr. Collett said.
Benefits questioned
After stroke, many patients have difficulty walking while performing a second task, such as holding a conversation. Training in dual-task walking has provided uncertain benefits, according to clinical research.
In healthy individuals, walking is believed to be a largely automatic process that requires minimal executive resources. Previous studies have suggested that a certain minimum walking speed is required to enable automatic control of walking in the brain.
“We know that those with better walking ability after stroke are better able to cope with additional cognitive loads while walking,” said Dr. Collett. “Here, we proposed that increased automatic gait control may provide a mechanism whereby executive resources are freed up to attend to additional tasks,” he added.
The investigators further hypothesized that greater walking speed is required for automatic gait control. To test these hypotheses, they analyzed data from a previously conducted randomized trial of single- and dual-task walking interventions.
Trial participants were aged 18 years or older, had survived a stroke that had occurred at least 6 months before enrollment, had reduced 2-minute walk distance relative to their peers, and had no comorbid neurologic or psychologic disorders.
Over 10 weeks, participants underwent 20 sessions that included 30 minutes of walking on a treadmill. They were randomly assigned to undergo single-task walking or dual-task walking. The latter incorporated cognitive tasks as distractions.
Good versus limited walkers
In the current study, investigators analyzed various assessments that had been conducted at baseline and after completion of the training sessions, including distance on 2-minute walks with and without a distracting task. In addition, participants underwent imaging with functional near-infrared spectroscopy (fNIRS) and fMRI.
Using previous research as a basis, the researchers defined good walking speed as 0.8 m/sec. They categorized all participants, regardless of their intervention assignments, as having good walking capacity (0.8 m/sec or more) or limited walking capacity (less than 0.79 m/sec).
A total of 50 participants enrolled in the study (mean age, 62 years), and 45 completed the interventions. Of those who completed the interventions, 22 were randomly assigned to undergo single-task training, and 23 were assigned to dual-task training.
The researchers categorized 21 participants as having good walking capacity and 24 as having limited walking capacity. Participants in each category were divided approximately evenly between treatment assignments.
Barthel index score, which assesses functional independence, was higher in the group of good walkers.
Increased travel distance
Results showed that after the interventions, distance traveled during the single-task 2-minute walk increased by 8.9 m for good walkers and by 5.3 m for limited walkers. For the dual-task 2-minute walk, the distance traveled increased by 10.4 m among good walkers and by 1.3 m for limited walkers. Change from baseline on the dual-task walk was not significant for limited walkers.
There was no significant difference between good walkers and limited walkers in their perceptions of participation in community walking. Neither group increased its walking activity significantly following the interventions.
At baseline, limited walkers, in comparison with good walkers, had significantly greater activation in the contralesional hemisphere during dual-task walking, which consisted of incorporating a planning task.
In contrast, for many good walkers, there was a decrease in activation during dual-task walking. Activation in the contralesional hemisphere correlated negatively with dual-task 2-minute walk distance.
The researchers also found a negative correlation between activation and dual-task 2-minute walk distance when the second task was the Stroop task.
Initial step
“The original trial was never designed or powered to compare groups formed by walking speed or test our automaticity hypothesis, and the results need to be viewed within this context,” said Dr. Collett. The small sample size did not allow the researchers to detect small effects of the intervention, especially in the imaging data, he added.
It also prevented the investigators from comparing limited walking and good walking groups according to whether they underwent the single-task or dual-task intervention, “which would be a superior way to investigate our hypotheses,” Dr. Collett said.
“The result of this study should be seen as exploratory, with further investigation needed,” he noted.
Helping stroke survivors to walk in the community is challenging, and new interventions that enable them to navigate complex surroundings need to be designed, said Dr. Collett. “Research is required to better understand the conscious and automatic contribution to gait control, especially with neurological impairment,” he added.
Overall, “our results suggest that improving automatic walking may be an initial step to improve capacity to respond to more complex walking interventions. However, [future] trials are required to test this,” he concluded.
The next frontier?
Commenting on the findings, Louis R. Caplan, MD, professor of neurology at Harvard University and senior neurologist at Beth Israel Deaconess Medical Center, Boston, said that “recovery and rehab are going to be the next frontier in stroke neurology, because there has to be a limitation in the present emphasis on acute care.”
Some patients do not receive acute care on time, and current treatment is not curative, added Dr. Caplan, who was not involved with the research.
Little scientific attention has been paid to how doctors can enhance recovery after stroke, what interventions delay recovery, and what the natural history of recovery is, he said. “This is a very nice study about that.”
Although the study’s methodology was sound, there were some limitations, including that strokes and underlying brain lesions were heterogeneous and that the study population was relatively small, Dr. Caplan said.
He added that “it’s a difficult study to do” and that it is difficult to organize participants into homogeneous groups.
Another limitation cited was lack of long-term follow-up that could indicate whether training provided sustained improvements in walking.
“It would be nice to revisit the same people later and see if their walking has improved, if they’re doing it differently, and if their subjective responses are different,” said Dr. Caplan.
In addition, the study did not examine whether the interventions made it easier for participants to walk with other people or to socialize more. “It may be that it really requires some time for them to gain confidence and for them to integrate that into their social network,” Dr. Caplan said.
“I would call it a proof-of-principle study, not a final study,” he noted. “It’s a study that shows that you can scientifically study rehab” and indicates the possible methodology that could be used.
The study was funded by the Stroke Association. Dr. Collett and Dr. Caplan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, suggests new research backed by imaging data.
In secondary analysis of a previous study, training enabled both “good” and “limited” walkers to increase travel distance during a 2-minute walk. However, for “dual-task” walking, good walkers improved their distance by approximately 10 m after training, whereas limited walkers improved by only 1 m. Brain imaging showed increased brain activity in the limited walkers, which could reduce cognitive resources available for performing a second task while walking.
These findings, which were published online May 30 in Clinical Rehabilitation, may explain the apparent lack of superiority, shown previously, of dual-task training compared with single-task training for patients with stroke and impaired walking ability, researchers noted.
“Imaging data were consistent with our hypothesis that walking automaticity might explain these results,” said lead author Johnny Collett, PhD, senior clinical research fellow at Oxford Brookes University, United Kingdom.
At baseline, participants who walked slowly had increased resting state connectivity between contralesional M1 and cortical areas associated with conscious gait control.
“In response to the intervention, we found increased connectivity with the precuneus in those who walked slowly at baseline, an adaptation that might support walking in more complex situations,” Dr. Collett said.
Benefits questioned
After stroke, many patients have difficulty walking while performing a second task, such as holding a conversation. Training in dual-task walking has provided uncertain benefits, according to clinical research.
In healthy individuals, walking is believed to be a largely automatic process that requires minimal executive resources. Previous studies have suggested that a certain minimum walking speed is required to enable automatic control of walking in the brain.
“We know that those with better walking ability after stroke are better able to cope with additional cognitive loads while walking,” said Dr. Collett. “Here, we proposed that increased automatic gait control may provide a mechanism whereby executive resources are freed up to attend to additional tasks,” he added.
The investigators further hypothesized that greater walking speed is required for automatic gait control. To test these hypotheses, they analyzed data from a previously conducted randomized trial of single- and dual-task walking interventions.
Trial participants were aged 18 years or older, had survived a stroke that had occurred at least 6 months before enrollment, had reduced 2-minute walk distance relative to their peers, and had no comorbid neurologic or psychologic disorders.
Over 10 weeks, participants underwent 20 sessions that included 30 minutes of walking on a treadmill. They were randomly assigned to undergo single-task walking or dual-task walking. The latter incorporated cognitive tasks as distractions.
Good versus limited walkers
In the current study, investigators analyzed various assessments that had been conducted at baseline and after completion of the training sessions, including distance on 2-minute walks with and without a distracting task. In addition, participants underwent imaging with functional near-infrared spectroscopy (fNIRS) and fMRI.
Using previous research as a basis, the researchers defined good walking speed as 0.8 m/sec. They categorized all participants, regardless of their intervention assignments, as having good walking capacity (0.8 m/sec or more) or limited walking capacity (less than 0.79 m/sec).
A total of 50 participants enrolled in the study (mean age, 62 years), and 45 completed the interventions. Of those who completed the interventions, 22 were randomly assigned to undergo single-task training, and 23 were assigned to dual-task training.
The researchers categorized 21 participants as having good walking capacity and 24 as having limited walking capacity. Participants in each category were divided approximately evenly between treatment assignments.
Barthel index score, which assesses functional independence, was higher in the group of good walkers.
Increased travel distance
Results showed that after the interventions, distance traveled during the single-task 2-minute walk increased by 8.9 m for good walkers and by 5.3 m for limited walkers. For the dual-task 2-minute walk, the distance traveled increased by 10.4 m among good walkers and by 1.3 m for limited walkers. Change from baseline on the dual-task walk was not significant for limited walkers.
There was no significant difference between good walkers and limited walkers in their perceptions of participation in community walking. Neither group increased its walking activity significantly following the interventions.
At baseline, limited walkers, in comparison with good walkers, had significantly greater activation in the contralesional hemisphere during dual-task walking, which consisted of incorporating a planning task.
In contrast, for many good walkers, there was a decrease in activation during dual-task walking. Activation in the contralesional hemisphere correlated negatively with dual-task 2-minute walk distance.
The researchers also found a negative correlation between activation and dual-task 2-minute walk distance when the second task was the Stroop task.
Initial step
“The original trial was never designed or powered to compare groups formed by walking speed or test our automaticity hypothesis, and the results need to be viewed within this context,” said Dr. Collett. The small sample size did not allow the researchers to detect small effects of the intervention, especially in the imaging data, he added.
It also prevented the investigators from comparing limited walking and good walking groups according to whether they underwent the single-task or dual-task intervention, “which would be a superior way to investigate our hypotheses,” Dr. Collett said.
“The result of this study should be seen as exploratory, with further investigation needed,” he noted.
Helping stroke survivors to walk in the community is challenging, and new interventions that enable them to navigate complex surroundings need to be designed, said Dr. Collett. “Research is required to better understand the conscious and automatic contribution to gait control, especially with neurological impairment,” he added.
Overall, “our results suggest that improving automatic walking may be an initial step to improve capacity to respond to more complex walking interventions. However, [future] trials are required to test this,” he concluded.
The next frontier?
Commenting on the findings, Louis R. Caplan, MD, professor of neurology at Harvard University and senior neurologist at Beth Israel Deaconess Medical Center, Boston, said that “recovery and rehab are going to be the next frontier in stroke neurology, because there has to be a limitation in the present emphasis on acute care.”
Some patients do not receive acute care on time, and current treatment is not curative, added Dr. Caplan, who was not involved with the research.
Little scientific attention has been paid to how doctors can enhance recovery after stroke, what interventions delay recovery, and what the natural history of recovery is, he said. “This is a very nice study about that.”
Although the study’s methodology was sound, there were some limitations, including that strokes and underlying brain lesions were heterogeneous and that the study population was relatively small, Dr. Caplan said.
He added that “it’s a difficult study to do” and that it is difficult to organize participants into homogeneous groups.
Another limitation cited was lack of long-term follow-up that could indicate whether training provided sustained improvements in walking.
“It would be nice to revisit the same people later and see if their walking has improved, if they’re doing it differently, and if their subjective responses are different,” said Dr. Caplan.
In addition, the study did not examine whether the interventions made it easier for participants to walk with other people or to socialize more. “It may be that it really requires some time for them to gain confidence and for them to integrate that into their social network,” Dr. Caplan said.
“I would call it a proof-of-principle study, not a final study,” he noted. “It’s a study that shows that you can scientifically study rehab” and indicates the possible methodology that could be used.
The study was funded by the Stroke Association. Dr. Collett and Dr. Caplan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, suggests new research backed by imaging data.
In secondary analysis of a previous study, training enabled both “good” and “limited” walkers to increase travel distance during a 2-minute walk. However, for “dual-task” walking, good walkers improved their distance by approximately 10 m after training, whereas limited walkers improved by only 1 m. Brain imaging showed increased brain activity in the limited walkers, which could reduce cognitive resources available for performing a second task while walking.
These findings, which were published online May 30 in Clinical Rehabilitation, may explain the apparent lack of superiority, shown previously, of dual-task training compared with single-task training for patients with stroke and impaired walking ability, researchers noted.
“Imaging data were consistent with our hypothesis that walking automaticity might explain these results,” said lead author Johnny Collett, PhD, senior clinical research fellow at Oxford Brookes University, United Kingdom.
At baseline, participants who walked slowly had increased resting state connectivity between contralesional M1 and cortical areas associated with conscious gait control.
“In response to the intervention, we found increased connectivity with the precuneus in those who walked slowly at baseline, an adaptation that might support walking in more complex situations,” Dr. Collett said.
Benefits questioned
After stroke, many patients have difficulty walking while performing a second task, such as holding a conversation. Training in dual-task walking has provided uncertain benefits, according to clinical research.
In healthy individuals, walking is believed to be a largely automatic process that requires minimal executive resources. Previous studies have suggested that a certain minimum walking speed is required to enable automatic control of walking in the brain.
“We know that those with better walking ability after stroke are better able to cope with additional cognitive loads while walking,” said Dr. Collett. “Here, we proposed that increased automatic gait control may provide a mechanism whereby executive resources are freed up to attend to additional tasks,” he added.
The investigators further hypothesized that greater walking speed is required for automatic gait control. To test these hypotheses, they analyzed data from a previously conducted randomized trial of single- and dual-task walking interventions.
Trial participants were aged 18 years or older, had survived a stroke that had occurred at least 6 months before enrollment, had reduced 2-minute walk distance relative to their peers, and had no comorbid neurologic or psychologic disorders.
Over 10 weeks, participants underwent 20 sessions that included 30 minutes of walking on a treadmill. They were randomly assigned to undergo single-task walking or dual-task walking. The latter incorporated cognitive tasks as distractions.
Good versus limited walkers
In the current study, investigators analyzed various assessments that had been conducted at baseline and after completion of the training sessions, including distance on 2-minute walks with and without a distracting task. In addition, participants underwent imaging with functional near-infrared spectroscopy (fNIRS) and fMRI.
Using previous research as a basis, the researchers defined good walking speed as 0.8 m/sec. They categorized all participants, regardless of their intervention assignments, as having good walking capacity (0.8 m/sec or more) or limited walking capacity (less than 0.79 m/sec).
A total of 50 participants enrolled in the study (mean age, 62 years), and 45 completed the interventions. Of those who completed the interventions, 22 were randomly assigned to undergo single-task training, and 23 were assigned to dual-task training.
The researchers categorized 21 participants as having good walking capacity and 24 as having limited walking capacity. Participants in each category were divided approximately evenly between treatment assignments.
Barthel index score, which assesses functional independence, was higher in the group of good walkers.
Increased travel distance
Results showed that after the interventions, distance traveled during the single-task 2-minute walk increased by 8.9 m for good walkers and by 5.3 m for limited walkers. For the dual-task 2-minute walk, the distance traveled increased by 10.4 m among good walkers and by 1.3 m for limited walkers. Change from baseline on the dual-task walk was not significant for limited walkers.
There was no significant difference between good walkers and limited walkers in their perceptions of participation in community walking. Neither group increased its walking activity significantly following the interventions.
At baseline, limited walkers, in comparison with good walkers, had significantly greater activation in the contralesional hemisphere during dual-task walking, which consisted of incorporating a planning task.
In contrast, for many good walkers, there was a decrease in activation during dual-task walking. Activation in the contralesional hemisphere correlated negatively with dual-task 2-minute walk distance.
The researchers also found a negative correlation between activation and dual-task 2-minute walk distance when the second task was the Stroop task.
Initial step
“The original trial was never designed or powered to compare groups formed by walking speed or test our automaticity hypothesis, and the results need to be viewed within this context,” said Dr. Collett. The small sample size did not allow the researchers to detect small effects of the intervention, especially in the imaging data, he added.
It also prevented the investigators from comparing limited walking and good walking groups according to whether they underwent the single-task or dual-task intervention, “which would be a superior way to investigate our hypotheses,” Dr. Collett said.
“The result of this study should be seen as exploratory, with further investigation needed,” he noted.
Helping stroke survivors to walk in the community is challenging, and new interventions that enable them to navigate complex surroundings need to be designed, said Dr. Collett. “Research is required to better understand the conscious and automatic contribution to gait control, especially with neurological impairment,” he added.
Overall, “our results suggest that improving automatic walking may be an initial step to improve capacity to respond to more complex walking interventions. However, [future] trials are required to test this,” he concluded.
The next frontier?
Commenting on the findings, Louis R. Caplan, MD, professor of neurology at Harvard University and senior neurologist at Beth Israel Deaconess Medical Center, Boston, said that “recovery and rehab are going to be the next frontier in stroke neurology, because there has to be a limitation in the present emphasis on acute care.”
Some patients do not receive acute care on time, and current treatment is not curative, added Dr. Caplan, who was not involved with the research.
Little scientific attention has been paid to how doctors can enhance recovery after stroke, what interventions delay recovery, and what the natural history of recovery is, he said. “This is a very nice study about that.”
Although the study’s methodology was sound, there were some limitations, including that strokes and underlying brain lesions were heterogeneous and that the study population was relatively small, Dr. Caplan said.
He added that “it’s a difficult study to do” and that it is difficult to organize participants into homogeneous groups.
Another limitation cited was lack of long-term follow-up that could indicate whether training provided sustained improvements in walking.
“It would be nice to revisit the same people later and see if their walking has improved, if they’re doing it differently, and if their subjective responses are different,” said Dr. Caplan.
In addition, the study did not examine whether the interventions made it easier for participants to walk with other people or to socialize more. “It may be that it really requires some time for them to gain confidence and for them to integrate that into their social network,” Dr. Caplan said.
“I would call it a proof-of-principle study, not a final study,” he noted. “It’s a study that shows that you can scientifically study rehab” and indicates the possible methodology that could be used.
The study was funded by the Stroke Association. Dr. Collett and Dr. Caplan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From Clinical Rehabilitation