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Patient-Reported Outcomes Predict Mortality in Cutaneous Chronic GVHD
. Independent of potential confounders, these PROs moreover predicted non-relapse mortality for all three disease subtypes, making PROs potentially useful adjuncts for risk stratification and treatment decisions, the study authors said.
“These two findings highlight the importance of patient-reported outcomes in measuring this disease,” lead author Emily Baumrin, MD, MSCE, assistant professor of dermatology and medicine at the University of Pennsylvania, Philadelphia, told this news organization. The study was published online February 28 in JAMA Dermatology.
Symptoms and QOL
The investigators monitored 436 patients from the Chronic GVHD Consortium until December 2020. The Lee Symptom Scale (LSS) skin subscale was used to evaluate symptom burden and the Functional Assessment of Cancer Therapy–Bone Marrow Transplantation (FACT-BMT) was used to measure quality of life.
Patients with sclerotic GVHD and combination disease at diagnosis had significantly worse median LSS scores than did those with epidermal disease (25, 35, and 20 points, respectively; P = .01). Patients with sclerotic disease had worse median FACT-BMT scores versus those with epidermal involvement (104 versus 109 points, respectively; P = .08).
Although these scores improved with all skin subtypes, LSS skin subscale and FACT-BMT scores remained significantly worse (by 9.0 points and 6.1 points, respectively) for patients with combination and sclerotic disease versus those with epidermal disease after adjusting for potential confounders.
Regarding mortality, every 7-point worsening (clinically meaningful difference) in FACT-BMT score at diagnosis of skin chronic GVHD conferred 9.1% increases in odds of both all-cause mortality and non-relapse mortality, after adjustment for factors such as age and sex. Likewise, for every 11 points worsening (clinically meaningful difference) in LSS skin subscale scores at diagnosis, researchers observed odds increases of 10% in all-cause mortality and 16.4% in non-relapse mortality.
Because patients with combination disease had only slightly more epidermal body surface area (BSA) involvement but significantly higher symptom burden than the other subtypes, the authors added, combination disease may represent a distinct phenotype. “Since we’ve also shown that the severity of patient-reported outcomes is associated with mortality,” Dr. Baumrin said in the interview, “perhaps these patients are at the highest risk of mortality as well.”
A growing population
Although many might think of chronic GVHD as rare, she noted, the number of allogeneic hematopoietic cell transplant (HCT) survivors living in the United States is growing. In a modeling study published in October of 2013 in Biology of Blood and Marrow Transplantation, authors predicted that by 2030, this figure will reach 502,000 — about half of whom will develop chronic GVHD, she said.
With more HCTs being performed each year and ongoing improvements in supportive care, patients are living longer post transplant. “Therefore, many transplant survivors are being taken care of in the community outside of transplant centers.”
Accordingly, Dr. Baumrin said, study findings are relevant to dermatologists in academic and transplant centers and the community who provide skin cancer screenings or other dermatologic care for transplant recipients. “Upon diagnosis of chronic GVHD, the evaluation of disease burden by patient-reported outcome measures may assist in assessing disease severity and response to treatments over time — and to stratify patients at higher risk for mortality and communicate that back to transplant physicians.”
Incorporating PROs into clinical practice might prove especially helpful for patients with sclerotic chronic cutaneous GVHD. Currently, clinicians assess cutaneous GVHD clinically, using parameters including skin thickness. The National Institutes of Health (NIH) Skin Score, used in clinical trials, also measures BSA.
“The issue with sclerosis is, it’s hard to determine clinical severity based on physical examination alone,” Dr. Baumrin said. It can be difficult to quantify skin thickness and changes over time. “So it’s hard to detect improvements, which are often slow. Patient-reported outcome measures may be a more sensitive way to detect response to treatment than our clinical assessments, which are often crude for sclerotic disease.”
In a secondary analysis of the phase 2 clinical trial of belumosudil, a treatment for chronic GVHD, published in October 2022 in Transplantation and Cellular Therapy, response rate was around 30% measured by NIH Skin Score and 77% by PROs. “Our clinical examination in sclerotic type disease falls short in terms of determining therapeutic benefit. PROs might complement those clinical measures,” she said.
Future research will involve determining and validating which PROs matter most clinically and to patients, added Dr. Baumrin. Although widely used in evaluating transplant patients, LSS skin subscale and FACT-BMT scores may not represent patients’ experience of living with cutaneous chronic GVHD as effectively as might other tools such as the Dermatology Life Quality Index (DLQI) or Patient-Reported Outcomes Measurement Information System (PROMIS) measures, she explained.
Study strengths included authors’ use of well-validated PROs rather than novel unvalidated measures, Sandra A. Mitchell, PhD, CRNP, of the National Cancer Institute, Rockville, Maryland, and Edward W. Cowen, MD, MHSc, of the Dermatology Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, Maryland, wrote in an accompanying editorial in JAMA Dermatology. However, they added, incorporating causes of death might have revealed that the excess mortality associated with sclerotic disease stemmed at least partly from adverse effects of prolonged immunosuppression, particularly infection.
If future studies establish this to be the case, said Dr. Baumrin, reducing immunosuppression might be warranted for these patients. “And if death is primarily due to chronic GVHD itself, maybe we should treat more aggressively. PROs can help guide this decision.”
The study was supported by the NIH/NIAMS and the University of Pennsylvania. Dr. Baumrin and three coauthors report no relevant financial relationships; other authors had disclosures related to several pharmaceutical companies. Dr. Mitchell and Dr. Cowen had no disclosures.
. Independent of potential confounders, these PROs moreover predicted non-relapse mortality for all three disease subtypes, making PROs potentially useful adjuncts for risk stratification and treatment decisions, the study authors said.
“These two findings highlight the importance of patient-reported outcomes in measuring this disease,” lead author Emily Baumrin, MD, MSCE, assistant professor of dermatology and medicine at the University of Pennsylvania, Philadelphia, told this news organization. The study was published online February 28 in JAMA Dermatology.
Symptoms and QOL
The investigators monitored 436 patients from the Chronic GVHD Consortium until December 2020. The Lee Symptom Scale (LSS) skin subscale was used to evaluate symptom burden and the Functional Assessment of Cancer Therapy–Bone Marrow Transplantation (FACT-BMT) was used to measure quality of life.
Patients with sclerotic GVHD and combination disease at diagnosis had significantly worse median LSS scores than did those with epidermal disease (25, 35, and 20 points, respectively; P = .01). Patients with sclerotic disease had worse median FACT-BMT scores versus those with epidermal involvement (104 versus 109 points, respectively; P = .08).
Although these scores improved with all skin subtypes, LSS skin subscale and FACT-BMT scores remained significantly worse (by 9.0 points and 6.1 points, respectively) for patients with combination and sclerotic disease versus those with epidermal disease after adjusting for potential confounders.
Regarding mortality, every 7-point worsening (clinically meaningful difference) in FACT-BMT score at diagnosis of skin chronic GVHD conferred 9.1% increases in odds of both all-cause mortality and non-relapse mortality, after adjustment for factors such as age and sex. Likewise, for every 11 points worsening (clinically meaningful difference) in LSS skin subscale scores at diagnosis, researchers observed odds increases of 10% in all-cause mortality and 16.4% in non-relapse mortality.
Because patients with combination disease had only slightly more epidermal body surface area (BSA) involvement but significantly higher symptom burden than the other subtypes, the authors added, combination disease may represent a distinct phenotype. “Since we’ve also shown that the severity of patient-reported outcomes is associated with mortality,” Dr. Baumrin said in the interview, “perhaps these patients are at the highest risk of mortality as well.”
A growing population
Although many might think of chronic GVHD as rare, she noted, the number of allogeneic hematopoietic cell transplant (HCT) survivors living in the United States is growing. In a modeling study published in October of 2013 in Biology of Blood and Marrow Transplantation, authors predicted that by 2030, this figure will reach 502,000 — about half of whom will develop chronic GVHD, she said.
With more HCTs being performed each year and ongoing improvements in supportive care, patients are living longer post transplant. “Therefore, many transplant survivors are being taken care of in the community outside of transplant centers.”
Accordingly, Dr. Baumrin said, study findings are relevant to dermatologists in academic and transplant centers and the community who provide skin cancer screenings or other dermatologic care for transplant recipients. “Upon diagnosis of chronic GVHD, the evaluation of disease burden by patient-reported outcome measures may assist in assessing disease severity and response to treatments over time — and to stratify patients at higher risk for mortality and communicate that back to transplant physicians.”
Incorporating PROs into clinical practice might prove especially helpful for patients with sclerotic chronic cutaneous GVHD. Currently, clinicians assess cutaneous GVHD clinically, using parameters including skin thickness. The National Institutes of Health (NIH) Skin Score, used in clinical trials, also measures BSA.
“The issue with sclerosis is, it’s hard to determine clinical severity based on physical examination alone,” Dr. Baumrin said. It can be difficult to quantify skin thickness and changes over time. “So it’s hard to detect improvements, which are often slow. Patient-reported outcome measures may be a more sensitive way to detect response to treatment than our clinical assessments, which are often crude for sclerotic disease.”
In a secondary analysis of the phase 2 clinical trial of belumosudil, a treatment for chronic GVHD, published in October 2022 in Transplantation and Cellular Therapy, response rate was around 30% measured by NIH Skin Score and 77% by PROs. “Our clinical examination in sclerotic type disease falls short in terms of determining therapeutic benefit. PROs might complement those clinical measures,” she said.
Future research will involve determining and validating which PROs matter most clinically and to patients, added Dr. Baumrin. Although widely used in evaluating transplant patients, LSS skin subscale and FACT-BMT scores may not represent patients’ experience of living with cutaneous chronic GVHD as effectively as might other tools such as the Dermatology Life Quality Index (DLQI) or Patient-Reported Outcomes Measurement Information System (PROMIS) measures, she explained.
Study strengths included authors’ use of well-validated PROs rather than novel unvalidated measures, Sandra A. Mitchell, PhD, CRNP, of the National Cancer Institute, Rockville, Maryland, and Edward W. Cowen, MD, MHSc, of the Dermatology Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, Maryland, wrote in an accompanying editorial in JAMA Dermatology. However, they added, incorporating causes of death might have revealed that the excess mortality associated with sclerotic disease stemmed at least partly from adverse effects of prolonged immunosuppression, particularly infection.
If future studies establish this to be the case, said Dr. Baumrin, reducing immunosuppression might be warranted for these patients. “And if death is primarily due to chronic GVHD itself, maybe we should treat more aggressively. PROs can help guide this decision.”
The study was supported by the NIH/NIAMS and the University of Pennsylvania. Dr. Baumrin and three coauthors report no relevant financial relationships; other authors had disclosures related to several pharmaceutical companies. Dr. Mitchell and Dr. Cowen had no disclosures.
. Independent of potential confounders, these PROs moreover predicted non-relapse mortality for all three disease subtypes, making PROs potentially useful adjuncts for risk stratification and treatment decisions, the study authors said.
“These two findings highlight the importance of patient-reported outcomes in measuring this disease,” lead author Emily Baumrin, MD, MSCE, assistant professor of dermatology and medicine at the University of Pennsylvania, Philadelphia, told this news organization. The study was published online February 28 in JAMA Dermatology.
Symptoms and QOL
The investigators monitored 436 patients from the Chronic GVHD Consortium until December 2020. The Lee Symptom Scale (LSS) skin subscale was used to evaluate symptom burden and the Functional Assessment of Cancer Therapy–Bone Marrow Transplantation (FACT-BMT) was used to measure quality of life.
Patients with sclerotic GVHD and combination disease at diagnosis had significantly worse median LSS scores than did those with epidermal disease (25, 35, and 20 points, respectively; P = .01). Patients with sclerotic disease had worse median FACT-BMT scores versus those with epidermal involvement (104 versus 109 points, respectively; P = .08).
Although these scores improved with all skin subtypes, LSS skin subscale and FACT-BMT scores remained significantly worse (by 9.0 points and 6.1 points, respectively) for patients with combination and sclerotic disease versus those with epidermal disease after adjusting for potential confounders.
Regarding mortality, every 7-point worsening (clinically meaningful difference) in FACT-BMT score at diagnosis of skin chronic GVHD conferred 9.1% increases in odds of both all-cause mortality and non-relapse mortality, after adjustment for factors such as age and sex. Likewise, for every 11 points worsening (clinically meaningful difference) in LSS skin subscale scores at diagnosis, researchers observed odds increases of 10% in all-cause mortality and 16.4% in non-relapse mortality.
Because patients with combination disease had only slightly more epidermal body surface area (BSA) involvement but significantly higher symptom burden than the other subtypes, the authors added, combination disease may represent a distinct phenotype. “Since we’ve also shown that the severity of patient-reported outcomes is associated with mortality,” Dr. Baumrin said in the interview, “perhaps these patients are at the highest risk of mortality as well.”
A growing population
Although many might think of chronic GVHD as rare, she noted, the number of allogeneic hematopoietic cell transplant (HCT) survivors living in the United States is growing. In a modeling study published in October of 2013 in Biology of Blood and Marrow Transplantation, authors predicted that by 2030, this figure will reach 502,000 — about half of whom will develop chronic GVHD, she said.
With more HCTs being performed each year and ongoing improvements in supportive care, patients are living longer post transplant. “Therefore, many transplant survivors are being taken care of in the community outside of transplant centers.”
Accordingly, Dr. Baumrin said, study findings are relevant to dermatologists in academic and transplant centers and the community who provide skin cancer screenings or other dermatologic care for transplant recipients. “Upon diagnosis of chronic GVHD, the evaluation of disease burden by patient-reported outcome measures may assist in assessing disease severity and response to treatments over time — and to stratify patients at higher risk for mortality and communicate that back to transplant physicians.”
Incorporating PROs into clinical practice might prove especially helpful for patients with sclerotic chronic cutaneous GVHD. Currently, clinicians assess cutaneous GVHD clinically, using parameters including skin thickness. The National Institutes of Health (NIH) Skin Score, used in clinical trials, also measures BSA.
“The issue with sclerosis is, it’s hard to determine clinical severity based on physical examination alone,” Dr. Baumrin said. It can be difficult to quantify skin thickness and changes over time. “So it’s hard to detect improvements, which are often slow. Patient-reported outcome measures may be a more sensitive way to detect response to treatment than our clinical assessments, which are often crude for sclerotic disease.”
In a secondary analysis of the phase 2 clinical trial of belumosudil, a treatment for chronic GVHD, published in October 2022 in Transplantation and Cellular Therapy, response rate was around 30% measured by NIH Skin Score and 77% by PROs. “Our clinical examination in sclerotic type disease falls short in terms of determining therapeutic benefit. PROs might complement those clinical measures,” she said.
Future research will involve determining and validating which PROs matter most clinically and to patients, added Dr. Baumrin. Although widely used in evaluating transplant patients, LSS skin subscale and FACT-BMT scores may not represent patients’ experience of living with cutaneous chronic GVHD as effectively as might other tools such as the Dermatology Life Quality Index (DLQI) or Patient-Reported Outcomes Measurement Information System (PROMIS) measures, she explained.
Study strengths included authors’ use of well-validated PROs rather than novel unvalidated measures, Sandra A. Mitchell, PhD, CRNP, of the National Cancer Institute, Rockville, Maryland, and Edward W. Cowen, MD, MHSc, of the Dermatology Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, Maryland, wrote in an accompanying editorial in JAMA Dermatology. However, they added, incorporating causes of death might have revealed that the excess mortality associated with sclerotic disease stemmed at least partly from adverse effects of prolonged immunosuppression, particularly infection.
If future studies establish this to be the case, said Dr. Baumrin, reducing immunosuppression might be warranted for these patients. “And if death is primarily due to chronic GVHD itself, maybe we should treat more aggressively. PROs can help guide this decision.”
The study was supported by the NIH/NIAMS and the University of Pennsylvania. Dr. Baumrin and three coauthors report no relevant financial relationships; other authors had disclosures related to several pharmaceutical companies. Dr. Mitchell and Dr. Cowen had no disclosures.
FROM JAMA DERMATOLOGY
Bigfoot, Bermuda Triangle, ‘No Lido With Epi’?
“Fingers, toes, ears, and nose are places where epinephrine never goes,” Thomas Ehlers, DPM, wrote in Podiatry Today. “That is an adage I heard during podiatry school, my clerkships, and from various attendings throughout my training.”
But as Dr. Ehlers added, epinephrine gets a bad rap. The catchy admonition “has been proven a myth time and time again.”
So Although medical trainees across multiple disciplines are taught to fear the practice, citing the potential for gangrene, its reputation for harm is not supported by the evidence.
Lack of Feeling Doesn’t Care About Your Facts
The debate surfaced anew in response to a recent column by Kenny Lin, MD, MPH, family physician and associate director of the Lancaster General Hospital Family Medicine Residency, in Lancaster, Pennsylvania, about the rather pedestrian topic of why he no longer performs surgery to correct ingrown toenails. Dr. Lin’s admission that he used to do the procedure with a combination of epinephrine and lidocaine turned into a major focus of the comments — many of them harshly critical of the practice:
“Epinephrine is not an appropriate drug to use for podiatry or use in any peripheral area. Gangrene?” one commenter posted.
“Leave epi out of lidocaine to fingers, toes, nose, and ear lobes,” another wrote.
“No lido with epi, whether or not it is contraindicated, because: If there’s any adverse outcome, a lawyer will find plenty of references saying it was contraindicated,” a reader chimed in.
Other commenters disagreed, with one saying, “Please, folks, don’t show that you trained 50 years ago and haven’t changed practice since…”
For Dr. Lin, the response was surprising given what he believes to be the lack of evidence supporting the purported dangers.
“When I think about this, it’s something that was taught to me during residency — that they should not be used on certain areas,” Dr. Lin said. “But since then, studies have been published looking at thousands of cases of people using epinephrine with lidocaine and haven’t found any cases of necrosis.”
Many doctors, like Dr. Lin, say they were cautioned against this in their training. Others don’t remember exactly where they’ve heard it but recognize the idea has a nebulous hold on practice.
Combining epinephrine with lidocaine helps make the numbing last longer, stops bleeding, and reduces the use of lidocaine required, all of which improve the chances of an effective and comfortable intervention for the patient, Dr. Lin said. The approach also reduces the use of tourniquets, which come with their own risks including nerve injury.
However, in areas with limited circulation, this vasoconstrictive effect may be more pronounced, potentially leading to complications for patients with complicating factors.
Clinicians who regularly use the combination of epinephrine and lidocaine for surgery do concede that it can pose certain hazards and considerations in areas without robust blood flow.
But the literature largely points to its safety.
In 2001, California-based plastic and reconstructive surgeon Keith Denkler, MD, published a deep dive on the topic starting in the 19th century, including a review of Index Medicus from 1880 to 1966, a computer review of the National Library of Medicine database from 1966 to 2000, and major textbooks from 1900 to 2000.
He found a total of 48 cases of digital gangrene — but most involved the use of cocaine or procaine. Of the 48 cases, 21 involved the use of epinephrine, and 17 used an unknown concentration based on manual dilution.
“Multiple other concurrent conditions (hot soaks, tight tourniquets, and infection) existed in these case reports, making it difficult to determine the exact cause of the tissue insult,” Dr. Denkler wrote.
In a 2010 retrospective review in the Journal of the American Society of Plastic Surgeons, authors examined 1111 cases involving digital and hand surgery. Of the 611 patients who received injections of 1% lidocaine with epinephrine, none experienced digital necrosis.
Another review from 2003 touted the combination’s safety, in hopes to “help dispel the myth that epinephrine has no place in podiatric anesthesia.” But authors noted limitations of use, including “known sensitivity, thyrotoxicosis, and use of either tricyclic antidepressants or monoamine oxidase inhibitors.”
James Christina, DPM, executive director and CEO of the American Podiatric Medical Association, echoed that sentiment. He said he regularly used the combination to correct bunions, hammer toes, and ingrown toenails over his 20 years of practicing but acknowledged the technique is not appropriate for all such patients.
“There’s always been caution when using epinephrine with local anesthetic,” Dr. Christina told this news organization. “You need a healthy patient with normal circulation and no other complications; someone without vascular compromise.”
Marie Hanna, MD, MEHP, chief of regional anesthesia and acute pain management at Johns Hopkins University, Baltimore, counts herself among the cautious. Citing Principles of Office Anesthesia: Part I. Infiltrative Anesthesia, Dr. Hanna said epinephrine should never be used in digital and penile blocks or in skin flaps with marginal viability.
“It is perfectly fine in certain areas, like the wrist or the arm,” Dr. Hanna said. “But specifically for use in end organs like nose, fingers, ears, toes — all of these with tenuous blood supply — it is not good practice.”
The divide among doctors comes down to theoretical concern, rather than empirical basis, said Rebecca Johnson, MD, chair of the American Society of Anesthesiologists committee on Regional Anesthesia and Acute Pain Medicine and a faculty member at Mayo Clinic, in Rochester, Minnesota.
“It’s just one of those myths we have in practice,” she said.
And legally, Dr. Johnson noted, the mere existence of a myth can be enough of a deterrent for medical practitioners: “Like anything, when you’re trying to do the right thing, if a complication would occur for another reason, you’d want to make sure a jury of your peers didn’t bring up that myth.”
The sources in this story reported no relevant financial conflicts of interest.
A version of this article appeared on Medscape.com.
“Fingers, toes, ears, and nose are places where epinephrine never goes,” Thomas Ehlers, DPM, wrote in Podiatry Today. “That is an adage I heard during podiatry school, my clerkships, and from various attendings throughout my training.”
But as Dr. Ehlers added, epinephrine gets a bad rap. The catchy admonition “has been proven a myth time and time again.”
So Although medical trainees across multiple disciplines are taught to fear the practice, citing the potential for gangrene, its reputation for harm is not supported by the evidence.
Lack of Feeling Doesn’t Care About Your Facts
The debate surfaced anew in response to a recent column by Kenny Lin, MD, MPH, family physician and associate director of the Lancaster General Hospital Family Medicine Residency, in Lancaster, Pennsylvania, about the rather pedestrian topic of why he no longer performs surgery to correct ingrown toenails. Dr. Lin’s admission that he used to do the procedure with a combination of epinephrine and lidocaine turned into a major focus of the comments — many of them harshly critical of the practice:
“Epinephrine is not an appropriate drug to use for podiatry or use in any peripheral area. Gangrene?” one commenter posted.
“Leave epi out of lidocaine to fingers, toes, nose, and ear lobes,” another wrote.
“No lido with epi, whether or not it is contraindicated, because: If there’s any adverse outcome, a lawyer will find plenty of references saying it was contraindicated,” a reader chimed in.
Other commenters disagreed, with one saying, “Please, folks, don’t show that you trained 50 years ago and haven’t changed practice since…”
For Dr. Lin, the response was surprising given what he believes to be the lack of evidence supporting the purported dangers.
“When I think about this, it’s something that was taught to me during residency — that they should not be used on certain areas,” Dr. Lin said. “But since then, studies have been published looking at thousands of cases of people using epinephrine with lidocaine and haven’t found any cases of necrosis.”
Many doctors, like Dr. Lin, say they were cautioned against this in their training. Others don’t remember exactly where they’ve heard it but recognize the idea has a nebulous hold on practice.
Combining epinephrine with lidocaine helps make the numbing last longer, stops bleeding, and reduces the use of lidocaine required, all of which improve the chances of an effective and comfortable intervention for the patient, Dr. Lin said. The approach also reduces the use of tourniquets, which come with their own risks including nerve injury.
However, in areas with limited circulation, this vasoconstrictive effect may be more pronounced, potentially leading to complications for patients with complicating factors.
Clinicians who regularly use the combination of epinephrine and lidocaine for surgery do concede that it can pose certain hazards and considerations in areas without robust blood flow.
But the literature largely points to its safety.
In 2001, California-based plastic and reconstructive surgeon Keith Denkler, MD, published a deep dive on the topic starting in the 19th century, including a review of Index Medicus from 1880 to 1966, a computer review of the National Library of Medicine database from 1966 to 2000, and major textbooks from 1900 to 2000.
He found a total of 48 cases of digital gangrene — but most involved the use of cocaine or procaine. Of the 48 cases, 21 involved the use of epinephrine, and 17 used an unknown concentration based on manual dilution.
“Multiple other concurrent conditions (hot soaks, tight tourniquets, and infection) existed in these case reports, making it difficult to determine the exact cause of the tissue insult,” Dr. Denkler wrote.
In a 2010 retrospective review in the Journal of the American Society of Plastic Surgeons, authors examined 1111 cases involving digital and hand surgery. Of the 611 patients who received injections of 1% lidocaine with epinephrine, none experienced digital necrosis.
Another review from 2003 touted the combination’s safety, in hopes to “help dispel the myth that epinephrine has no place in podiatric anesthesia.” But authors noted limitations of use, including “known sensitivity, thyrotoxicosis, and use of either tricyclic antidepressants or monoamine oxidase inhibitors.”
James Christina, DPM, executive director and CEO of the American Podiatric Medical Association, echoed that sentiment. He said he regularly used the combination to correct bunions, hammer toes, and ingrown toenails over his 20 years of practicing but acknowledged the technique is not appropriate for all such patients.
“There’s always been caution when using epinephrine with local anesthetic,” Dr. Christina told this news organization. “You need a healthy patient with normal circulation and no other complications; someone without vascular compromise.”
Marie Hanna, MD, MEHP, chief of regional anesthesia and acute pain management at Johns Hopkins University, Baltimore, counts herself among the cautious. Citing Principles of Office Anesthesia: Part I. Infiltrative Anesthesia, Dr. Hanna said epinephrine should never be used in digital and penile blocks or in skin flaps with marginal viability.
“It is perfectly fine in certain areas, like the wrist or the arm,” Dr. Hanna said. “But specifically for use in end organs like nose, fingers, ears, toes — all of these with tenuous blood supply — it is not good practice.”
The divide among doctors comes down to theoretical concern, rather than empirical basis, said Rebecca Johnson, MD, chair of the American Society of Anesthesiologists committee on Regional Anesthesia and Acute Pain Medicine and a faculty member at Mayo Clinic, in Rochester, Minnesota.
“It’s just one of those myths we have in practice,” she said.
And legally, Dr. Johnson noted, the mere existence of a myth can be enough of a deterrent for medical practitioners: “Like anything, when you’re trying to do the right thing, if a complication would occur for another reason, you’d want to make sure a jury of your peers didn’t bring up that myth.”
The sources in this story reported no relevant financial conflicts of interest.
A version of this article appeared on Medscape.com.
“Fingers, toes, ears, and nose are places where epinephrine never goes,” Thomas Ehlers, DPM, wrote in Podiatry Today. “That is an adage I heard during podiatry school, my clerkships, and from various attendings throughout my training.”
But as Dr. Ehlers added, epinephrine gets a bad rap. The catchy admonition “has been proven a myth time and time again.”
So Although medical trainees across multiple disciplines are taught to fear the practice, citing the potential for gangrene, its reputation for harm is not supported by the evidence.
Lack of Feeling Doesn’t Care About Your Facts
The debate surfaced anew in response to a recent column by Kenny Lin, MD, MPH, family physician and associate director of the Lancaster General Hospital Family Medicine Residency, in Lancaster, Pennsylvania, about the rather pedestrian topic of why he no longer performs surgery to correct ingrown toenails. Dr. Lin’s admission that he used to do the procedure with a combination of epinephrine and lidocaine turned into a major focus of the comments — many of them harshly critical of the practice:
“Epinephrine is not an appropriate drug to use for podiatry or use in any peripheral area. Gangrene?” one commenter posted.
“Leave epi out of lidocaine to fingers, toes, nose, and ear lobes,” another wrote.
“No lido with epi, whether or not it is contraindicated, because: If there’s any adverse outcome, a lawyer will find plenty of references saying it was contraindicated,” a reader chimed in.
Other commenters disagreed, with one saying, “Please, folks, don’t show that you trained 50 years ago and haven’t changed practice since…”
For Dr. Lin, the response was surprising given what he believes to be the lack of evidence supporting the purported dangers.
“When I think about this, it’s something that was taught to me during residency — that they should not be used on certain areas,” Dr. Lin said. “But since then, studies have been published looking at thousands of cases of people using epinephrine with lidocaine and haven’t found any cases of necrosis.”
Many doctors, like Dr. Lin, say they were cautioned against this in their training. Others don’t remember exactly where they’ve heard it but recognize the idea has a nebulous hold on practice.
Combining epinephrine with lidocaine helps make the numbing last longer, stops bleeding, and reduces the use of lidocaine required, all of which improve the chances of an effective and comfortable intervention for the patient, Dr. Lin said. The approach also reduces the use of tourniquets, which come with their own risks including nerve injury.
However, in areas with limited circulation, this vasoconstrictive effect may be more pronounced, potentially leading to complications for patients with complicating factors.
Clinicians who regularly use the combination of epinephrine and lidocaine for surgery do concede that it can pose certain hazards and considerations in areas without robust blood flow.
But the literature largely points to its safety.
In 2001, California-based plastic and reconstructive surgeon Keith Denkler, MD, published a deep dive on the topic starting in the 19th century, including a review of Index Medicus from 1880 to 1966, a computer review of the National Library of Medicine database from 1966 to 2000, and major textbooks from 1900 to 2000.
He found a total of 48 cases of digital gangrene — but most involved the use of cocaine or procaine. Of the 48 cases, 21 involved the use of epinephrine, and 17 used an unknown concentration based on manual dilution.
“Multiple other concurrent conditions (hot soaks, tight tourniquets, and infection) existed in these case reports, making it difficult to determine the exact cause of the tissue insult,” Dr. Denkler wrote.
In a 2010 retrospective review in the Journal of the American Society of Plastic Surgeons, authors examined 1111 cases involving digital and hand surgery. Of the 611 patients who received injections of 1% lidocaine with epinephrine, none experienced digital necrosis.
Another review from 2003 touted the combination’s safety, in hopes to “help dispel the myth that epinephrine has no place in podiatric anesthesia.” But authors noted limitations of use, including “known sensitivity, thyrotoxicosis, and use of either tricyclic antidepressants or monoamine oxidase inhibitors.”
James Christina, DPM, executive director and CEO of the American Podiatric Medical Association, echoed that sentiment. He said he regularly used the combination to correct bunions, hammer toes, and ingrown toenails over his 20 years of practicing but acknowledged the technique is not appropriate for all such patients.
“There’s always been caution when using epinephrine with local anesthetic,” Dr. Christina told this news organization. “You need a healthy patient with normal circulation and no other complications; someone without vascular compromise.”
Marie Hanna, MD, MEHP, chief of regional anesthesia and acute pain management at Johns Hopkins University, Baltimore, counts herself among the cautious. Citing Principles of Office Anesthesia: Part I. Infiltrative Anesthesia, Dr. Hanna said epinephrine should never be used in digital and penile blocks or in skin flaps with marginal viability.
“It is perfectly fine in certain areas, like the wrist or the arm,” Dr. Hanna said. “But specifically for use in end organs like nose, fingers, ears, toes — all of these with tenuous blood supply — it is not good practice.”
The divide among doctors comes down to theoretical concern, rather than empirical basis, said Rebecca Johnson, MD, chair of the American Society of Anesthesiologists committee on Regional Anesthesia and Acute Pain Medicine and a faculty member at Mayo Clinic, in Rochester, Minnesota.
“It’s just one of those myths we have in practice,” she said.
And legally, Dr. Johnson noted, the mere existence of a myth can be enough of a deterrent for medical practitioners: “Like anything, when you’re trying to do the right thing, if a complication would occur for another reason, you’d want to make sure a jury of your peers didn’t bring up that myth.”
The sources in this story reported no relevant financial conflicts of interest.
A version of this article appeared on Medscape.com.
Oral Herpes Tied to Double Dementia Risk in Older Adults
TOPLINE:
A history of herpes simplex virus (HSV) is associated with a more than doubling of the risk for dementia in older people, results of a prospective epidemiological study showed.
METHODOLOGY:
- The study included 1002 dementia-free 70-year-olds from the Prospective Investigation of Vasculature in Uppsala Seniors cohort who were assessed at baseline and at age 75 and 80 years and followed through medical records at age 85 years.
- Researchers collected and analyzed blood samples to detect anti-HSV and anti-HSV-1 immunoglobulin (Ig) G, anti-cytomegalovirus (CMV) IgG, anti-HSV IgM, and anti-HSV and anti-CMV IgG levels and apolipoprotein epsilon 4 (APOE 4) status of participants.
- Investigators collected information on anti-herpesvirus drug treatment and reviewed dementia diagnoses obtained from medical records to classify as established or probable dementia or Alzheimer’s disease (AD).
TAKEAWAY:
- 82% of participants were anti-HSV IgG carriers, of which 6% had received drug treatment for herpes virus, and 7% of participants developed all-cause dementia and 4% AD during the median 15-year follow up.
- In HSV and HSV-1 subsamples, treatment for herpes virus was not significantly associated with lower risks for AD (HR, 1.46, P = .532 and HR, 1.64; P = .419, respectively) or dementia (HR 1.70; P = .222 and HR, 1.60; P = .320, respectively).
- There was no significant interaction between anti-HSV IgG seroprevalence and APOE 4 with regard to dementia risk, likely due to underpowering, and there were no associations between anti-CMV IgG positivity or anti-HSV IgM positivity and AD or dementia.
IN PRACTICE:
“What’s special about this particular study is that the participants are roughly the same age, which makes the results even more reliable since age differences, which are otherwise linked to the development of dementia, cannot confuse the results,” lead author Erika Vestin, a medical student in the Department of Public Health and Caring Sciences, Clinical Geriatrics, Uppsala University, Sweden, said in a press release. Findings may drive dementia research further towards treating the illness at an early stage using common anti-herpes virus drugs, Ms. Vestin added.
SOURCE:
The study, with Ms. Vestin as lead author, was published online on February 14, 2024, in the Journal of Alzheimer’s Disease.
LIMITATIONS:
The study underrepresented people with diabetes, heart failure, and stroke and lacked information on treatment compliance, dosage, and length and number of prescriptions, which prevented analysis of dose dependency. Since dementia data collection relied on medical records, dementia cases may be underreported. Some cases of AD could have been misclassified as vascular dementia or other dementia.
DISCLOSURES:
The study was supported by the Gun and Bertil Stohne’s Foundation, Swedish Dementia Association, Swedish Society of Medicine, Märta Lundqvist Foundation, Thureus Foundation, Region Uppsala, Gamla Tjänarinnor Foundation, and Swedish Brain Foundation. The authors had no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
A history of herpes simplex virus (HSV) is associated with a more than doubling of the risk for dementia in older people, results of a prospective epidemiological study showed.
METHODOLOGY:
- The study included 1002 dementia-free 70-year-olds from the Prospective Investigation of Vasculature in Uppsala Seniors cohort who were assessed at baseline and at age 75 and 80 years and followed through medical records at age 85 years.
- Researchers collected and analyzed blood samples to detect anti-HSV and anti-HSV-1 immunoglobulin (Ig) G, anti-cytomegalovirus (CMV) IgG, anti-HSV IgM, and anti-HSV and anti-CMV IgG levels and apolipoprotein epsilon 4 (APOE 4) status of participants.
- Investigators collected information on anti-herpesvirus drug treatment and reviewed dementia diagnoses obtained from medical records to classify as established or probable dementia or Alzheimer’s disease (AD).
TAKEAWAY:
- 82% of participants were anti-HSV IgG carriers, of which 6% had received drug treatment for herpes virus, and 7% of participants developed all-cause dementia and 4% AD during the median 15-year follow up.
- In HSV and HSV-1 subsamples, treatment for herpes virus was not significantly associated with lower risks for AD (HR, 1.46, P = .532 and HR, 1.64; P = .419, respectively) or dementia (HR 1.70; P = .222 and HR, 1.60; P = .320, respectively).
- There was no significant interaction between anti-HSV IgG seroprevalence and APOE 4 with regard to dementia risk, likely due to underpowering, and there were no associations between anti-CMV IgG positivity or anti-HSV IgM positivity and AD or dementia.
IN PRACTICE:
“What’s special about this particular study is that the participants are roughly the same age, which makes the results even more reliable since age differences, which are otherwise linked to the development of dementia, cannot confuse the results,” lead author Erika Vestin, a medical student in the Department of Public Health and Caring Sciences, Clinical Geriatrics, Uppsala University, Sweden, said in a press release. Findings may drive dementia research further towards treating the illness at an early stage using common anti-herpes virus drugs, Ms. Vestin added.
SOURCE:
The study, with Ms. Vestin as lead author, was published online on February 14, 2024, in the Journal of Alzheimer’s Disease.
LIMITATIONS:
The study underrepresented people with diabetes, heart failure, and stroke and lacked information on treatment compliance, dosage, and length and number of prescriptions, which prevented analysis of dose dependency. Since dementia data collection relied on medical records, dementia cases may be underreported. Some cases of AD could have been misclassified as vascular dementia or other dementia.
DISCLOSURES:
The study was supported by the Gun and Bertil Stohne’s Foundation, Swedish Dementia Association, Swedish Society of Medicine, Märta Lundqvist Foundation, Thureus Foundation, Region Uppsala, Gamla Tjänarinnor Foundation, and Swedish Brain Foundation. The authors had no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
A history of herpes simplex virus (HSV) is associated with a more than doubling of the risk for dementia in older people, results of a prospective epidemiological study showed.
METHODOLOGY:
- The study included 1002 dementia-free 70-year-olds from the Prospective Investigation of Vasculature in Uppsala Seniors cohort who were assessed at baseline and at age 75 and 80 years and followed through medical records at age 85 years.
- Researchers collected and analyzed blood samples to detect anti-HSV and anti-HSV-1 immunoglobulin (Ig) G, anti-cytomegalovirus (CMV) IgG, anti-HSV IgM, and anti-HSV and anti-CMV IgG levels and apolipoprotein epsilon 4 (APOE 4) status of participants.
- Investigators collected information on anti-herpesvirus drug treatment and reviewed dementia diagnoses obtained from medical records to classify as established or probable dementia or Alzheimer’s disease (AD).
TAKEAWAY:
- 82% of participants were anti-HSV IgG carriers, of which 6% had received drug treatment for herpes virus, and 7% of participants developed all-cause dementia and 4% AD during the median 15-year follow up.
- In HSV and HSV-1 subsamples, treatment for herpes virus was not significantly associated with lower risks for AD (HR, 1.46, P = .532 and HR, 1.64; P = .419, respectively) or dementia (HR 1.70; P = .222 and HR, 1.60; P = .320, respectively).
- There was no significant interaction between anti-HSV IgG seroprevalence and APOE 4 with regard to dementia risk, likely due to underpowering, and there were no associations between anti-CMV IgG positivity or anti-HSV IgM positivity and AD or dementia.
IN PRACTICE:
“What’s special about this particular study is that the participants are roughly the same age, which makes the results even more reliable since age differences, which are otherwise linked to the development of dementia, cannot confuse the results,” lead author Erika Vestin, a medical student in the Department of Public Health and Caring Sciences, Clinical Geriatrics, Uppsala University, Sweden, said in a press release. Findings may drive dementia research further towards treating the illness at an early stage using common anti-herpes virus drugs, Ms. Vestin added.
SOURCE:
The study, with Ms. Vestin as lead author, was published online on February 14, 2024, in the Journal of Alzheimer’s Disease.
LIMITATIONS:
The study underrepresented people with diabetes, heart failure, and stroke and lacked information on treatment compliance, dosage, and length and number of prescriptions, which prevented analysis of dose dependency. Since dementia data collection relied on medical records, dementia cases may be underreported. Some cases of AD could have been misclassified as vascular dementia or other dementia.
DISCLOSURES:
The study was supported by the Gun and Bertil Stohne’s Foundation, Swedish Dementia Association, Swedish Society of Medicine, Märta Lundqvist Foundation, Thureus Foundation, Region Uppsala, Gamla Tjänarinnor Foundation, and Swedish Brain Foundation. The authors had no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
FDA Removes Harmful Chemicals From Food Packaging
Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.
In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.
PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
Endocrine Society Report Sounds the Alarm About PFAS and Others
The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.
“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.
The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.
At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”
Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”
While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.
Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.
Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.
“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
New Data on Four Classes of EDCs
Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.
The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.
Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.
Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.
The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’
Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.
The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”
The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.
A version of this article appeared on Medscape.com.
Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.
In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.
PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
Endocrine Society Report Sounds the Alarm About PFAS and Others
The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.
“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.
The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.
At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”
Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”
While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.
Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.
Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.
“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
New Data on Four Classes of EDCs
Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.
The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.
Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.
Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.
The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’
Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.
The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”
The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.
A version of this article appeared on Medscape.com.
Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.
In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.
PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
Endocrine Society Report Sounds the Alarm About PFAS and Others
The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.
“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.
The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.
At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”
Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”
While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.
Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.
Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.
“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
New Data on Four Classes of EDCs
Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.
The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.
Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.
Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.
The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’
Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.
The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”
The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.
A version of this article appeared on Medscape.com.
Shining a Light on Colorectal Cancer
For more than two decades, March has been designated Colorectal Cancer Awareness Month. This annual observance serves as a reminder to spread the word in our local and national communities regarding the value of colorectal cancer screening and prevention. CRC prevention through screening and surveillance is a core part of our practice as gastroenterologists and plays a critical role in improving outcomes and reducing mortality from the second leading cause of cancer deaths in the US.
While we have made great strides in increasing awareness among patients of the need for screening, overall screening rates remain well below our national target of 80% and significant disparities in screening persist. By disseminating key information about risk factors, promoting early detection through evidence-based screening, continuing to improve access to care by reducing financial and other barriers, and educating patients about available screening options that best fit their needs and preferences, we can continue to move the needle in improving overall screening rates and optimizing outcomes.
In this month’s issue of GIHN, we feature an excellent narrative review by Dr. Samir Gupta and colleagues describing the phenomenon of “birth cohort CRC,” which is thought to explain recent changes in CRC epidemiology, including rising incidence of early-onset colorectal cancer. We also highlight a timely study out of Kaiser Permanente investigating how best to communicate with patients with prior low-risk adenomas regarding updated colonoscopy intervals given recent guideline changes extending surveillance intervals from 5 to 7-10 years. This question is particularly relevant to resource-constrained healthcare settings, where proactive de-implementation of outdated surveillance intervals could improve access for other patients with more immediate need.
In our March Member Spotlight, we feature Dr. Andy Tau of Austin Gastroenterology, who shares important insights regarding his career as a GI hospitalist, a growing area of GI practice. Finally, in this month’s Perspectives column, Drs. Michael Weinstein of Capital Digestive Care and Paul Berggreen of GI Alliance provide powerful contrasting perspectives highlighting the pros and cons of private equity in GI and how to evaluate if it’s right for your practice. I found it to be a particularly fascinating read!
Megan A. Adams, MD, JD, MSc
Editor-in-Chief
For more than two decades, March has been designated Colorectal Cancer Awareness Month. This annual observance serves as a reminder to spread the word in our local and national communities regarding the value of colorectal cancer screening and prevention. CRC prevention through screening and surveillance is a core part of our practice as gastroenterologists and plays a critical role in improving outcomes and reducing mortality from the second leading cause of cancer deaths in the US.
While we have made great strides in increasing awareness among patients of the need for screening, overall screening rates remain well below our national target of 80% and significant disparities in screening persist. By disseminating key information about risk factors, promoting early detection through evidence-based screening, continuing to improve access to care by reducing financial and other barriers, and educating patients about available screening options that best fit their needs and preferences, we can continue to move the needle in improving overall screening rates and optimizing outcomes.
In this month’s issue of GIHN, we feature an excellent narrative review by Dr. Samir Gupta and colleagues describing the phenomenon of “birth cohort CRC,” which is thought to explain recent changes in CRC epidemiology, including rising incidence of early-onset colorectal cancer. We also highlight a timely study out of Kaiser Permanente investigating how best to communicate with patients with prior low-risk adenomas regarding updated colonoscopy intervals given recent guideline changes extending surveillance intervals from 5 to 7-10 years. This question is particularly relevant to resource-constrained healthcare settings, where proactive de-implementation of outdated surveillance intervals could improve access for other patients with more immediate need.
In our March Member Spotlight, we feature Dr. Andy Tau of Austin Gastroenterology, who shares important insights regarding his career as a GI hospitalist, a growing area of GI practice. Finally, in this month’s Perspectives column, Drs. Michael Weinstein of Capital Digestive Care and Paul Berggreen of GI Alliance provide powerful contrasting perspectives highlighting the pros and cons of private equity in GI and how to evaluate if it’s right for your practice. I found it to be a particularly fascinating read!
Megan A. Adams, MD, JD, MSc
Editor-in-Chief
For more than two decades, March has been designated Colorectal Cancer Awareness Month. This annual observance serves as a reminder to spread the word in our local and national communities regarding the value of colorectal cancer screening and prevention. CRC prevention through screening and surveillance is a core part of our practice as gastroenterologists and plays a critical role in improving outcomes and reducing mortality from the second leading cause of cancer deaths in the US.
While we have made great strides in increasing awareness among patients of the need for screening, overall screening rates remain well below our national target of 80% and significant disparities in screening persist. By disseminating key information about risk factors, promoting early detection through evidence-based screening, continuing to improve access to care by reducing financial and other barriers, and educating patients about available screening options that best fit their needs and preferences, we can continue to move the needle in improving overall screening rates and optimizing outcomes.
In this month’s issue of GIHN, we feature an excellent narrative review by Dr. Samir Gupta and colleagues describing the phenomenon of “birth cohort CRC,” which is thought to explain recent changes in CRC epidemiology, including rising incidence of early-onset colorectal cancer. We also highlight a timely study out of Kaiser Permanente investigating how best to communicate with patients with prior low-risk adenomas regarding updated colonoscopy intervals given recent guideline changes extending surveillance intervals from 5 to 7-10 years. This question is particularly relevant to resource-constrained healthcare settings, where proactive de-implementation of outdated surveillance intervals could improve access for other patients with more immediate need.
In our March Member Spotlight, we feature Dr. Andy Tau of Austin Gastroenterology, who shares important insights regarding his career as a GI hospitalist, a growing area of GI practice. Finally, in this month’s Perspectives column, Drs. Michael Weinstein of Capital Digestive Care and Paul Berggreen of GI Alliance provide powerful contrasting perspectives highlighting the pros and cons of private equity in GI and how to evaluate if it’s right for your practice. I found it to be a particularly fascinating read!
Megan A. Adams, MD, JD, MSc
Editor-in-Chief
‘There’s Nothing Left to Try’: Oncologists on Managing Grief
Dr. Lewis was well acquainted with cancer grief long before he became an oncologist. Dr. Lewis’ father died of a rare, hereditary cancer syndrome when he was only 14. The condition, which causes tumors to grow in the endocrine glands, can be hard to identify and, if found late, deadly.
In some ways, Dr. Lewis’ career caring for patients with advanced cancers was born out of that first loss. He centered his practice around helping patients diagnosed at late stages, like his father.
But that comes at a cost. Many patients will die.
Dr. Lewis’ encounter with his colleague led him to inventory his practice. He found that well over half of his patients died within 2 years following their advanced cancer diagnosis.
To stave off the grief of so many losses, Dr. Lewis became an eternal optimist in the clinic, in search of the Hail Mary chemotherapy, any way to eke out a few more months only to be ambushed by grief when a patient did finally pass.
At funerals — which he made every effort to attend — Dr. Lewis couldn’t help but think, “If I had done my job better, none of us with be here.” His grief started to mingle with this sense of guilt.
It became a cycle: Denial shrouded in optimism, grief, then a toxic guilt. The pattern became untenable for his colleagues. And his partner finally called him out.
Few medical specialties draw physicians as close to their patients as oncology. The long courses of treatment-spanning years can foster an intimacy that is comforting for patients and fulfilling for physicians. But that closeness can also set doctors up for an acute grief when the end of life comes.
Experts agree that no amount of training in medical school prepares an oncologist to navigate the grief that comes with losing patients. Five oncologists spoke with this news organization about the boundaries they rely on to sustain their careers.
Don’t Go to Funerals
Don Dizon, MD, who specializes in women’s cancers, established an essential boundary 20 years ago: Never go to funerals. In his early days at Memorial Sloan Kettering Cancer Center, the death of each patient dealt him a crushing blow. He’d go to the funerals in search of closure, but that only added to the weight of his grief.
“When I started in oncology, I just remember the most tragic cases were the ones I was taking care of,” recalled Dr. Dizon, now director of the Pelvic Malignancies Program at Lifespan Cancer Institute in Lincoln, Rhode Island.
Dr. Dizon recalled one young mother who was diagnosed with ovarian cancer. She responded to treatment, but it was short-lived, and her cancer progressed, he said. Multiple treatments followed, but none were effective. Eventually, Dr. Dizon had to tell her that “there’s nothing left to try.”
At her funeral, watching her grieving husband with their daughter who had just started to walk, Dr. Dizon was overwhelmed with despair.
“When you have to do this multiple times a year,” the grief becomes untenable, he said. Sensing the difficulty I was having as a new attending, “my boss stopped sending me patients because he knew I was in trouble emotionally.”
That’s when Dr. Dizon started looking for other ways to get closure.
Today, he tries to say his goodbyes before a patient dies. After the final treatment or before hospice, Dr. Dizon has a parting conversation with his patients to express the privilege of caring for them and all he learned from them. These talks help him and his patient connect in their last moments together.
The Price of Wildly Happy Days
Molly Taylor, MD, MS, a pediatric oncologist in Seattle, sees the deeply sad days as the price an oncologist pays to be witness to the “wildly happy ones.”
Dr. Taylor has gone to patients’ funerals, has even been asked to speak at them, but she has also attended patients’ weddings.
To some degree, doctors get good at compartmentalizing, and they become accustomed to tragedy, she said. But there are some patients who stick with you, “and that is a whole other level of grief,” Dr. Taylor said.
Several years into her practice, one of Dr. Taylor’s patients, someone who reminded her of her own child, died. The death came as a surprise, and the finality of it took her breath away, she said. The sadness only deepened as days went by. “I felt that mother’s grief and still do,” she said.
The patient’s funeral was one of the most difficult moments in her career as an oncologist. Even weeks later, she caught herself picturing the family huddled together that day.
Taking long walks, commiserating with colleagues who get it, and watching the occasional cat video can help take the immediate sting away. But the pain of losing a patient can be long lasting and processing that grief can be a lonely endeavor.
“We need space to recognize grief for all providers, all the people that touch these patients’ lives — the nurses, the translators, the cleaning staff,” Dr. Taylor said. Otherwise, you start to believe you’re the only one feeling the weight of the loss.
While it doesn’t make the losses any less poignant, Dr. Taylor finds solace in the good moments: Patient graduations and weddings, survivors who now volunteer at the hospital, and a patient who had a baby of her own this past year. If facing grief daily has taught Dr. Taylor anything, it is to not let the good moments pass unnoticed.
Towing the Line
Ten years ago, Tina Rizack, MD, walked into the ICU to see a young mother holding her 6-year-old daughter. The mother had necrotizing fasciitis that had gone undiagnosed.
As Dr. Rizack stood in the doorway watching the embrace, she saw a grim future: A child without her mother. This realization hit too close to home, she said. “I still think about that case.”
In her training, Dr. Rizack, now medical director of hematology/oncology at St. Anne’s in Fall River, Massachusetts, worked with a social worker who taught her how to deal with these tough cases — most importantly, how to not take them home with her.
Over the years, Dr. Rizack learned how to build and sustain a firm barrier between work and outside work.
She doesn’t go to funerals or give out her cell phone number. If charts need to be done, she prefers to stay late at the clinic instead of bringing them home.
And she invests in the simple moments that help her detach from the day-to-day in the clinic — rooting for her kids at their games, carving out time for family meals most days, and having relaxed movie nights on the couch.
“It’s hard sometimes,” she said. But “I really do need the line.” Because without it, she can’t show up for her patients the way she wants and needs to.
Establishing the work-life boundary means that when at work, Dr. Rizack can be all in for her patients. Even after her patients’ treatment ends, she makes sure to check on them at home or in hospice. For her, sticking with patients over the long term offers some closure.
“I want to love work, and if I’m there all the time, I’m not going to love it,” she said.
Trading Funerals for the Bedside
Like many other oncologists, Charles Blanke, MD, finds that going to patients’ funerals makes the loss seem more profound. Being at the bedside when they die is not as painful, he said. In fact, being there when his patients die offers him some comfort. He rarely misses a patient’s death because now Dr. Blanke’s patients can schedule their departure.
An oncologist at the Knight Cancer Institute in Portland, Oregon, Dr. Blanke specializes in end-of-life care with an emphasis on death with dignity, also known as medical aid in dying. He admits it’s not a role every physician is comfortable with.
“If you’re paralyzed by grief, you can’t do this for a living,” he said. But he’s able to do the work because he genuinely feels he’s helping patients get “the relief they so strongly desire” in their last moments.
When cancer care can’t give them the life they wanted, he can give them control over when and how they die. And the ability to honor their last wishes offers him some closure as well.
“You know what kind of end they have. You know it was peaceful. You see them achieve the thing that was the most important to them,” he said.
Despite this process, he still encounters some circumstances utterly heart-wrenching — the very young patients who have advanced disease. Some of these patients choose to die because they can’t afford to continue treatment. Others don’t have a support system. In these instances, Dr. Blanke is often the only one in the room.
Believe it or not, he said, the paperwork — and there’s a lot of it in his line of work — helps remind Dr. Blanke that patients’ last wishes are being honored.
Making Changes
After Dr. Lewis was confronted by his partner, he began to face the shortcomings of his own coping strategies. His practice hired a social worker to help staff process difficult experiences. After the loss of every patient, the practice comes together to share and process the loss.
For him, funerals remain helpful, providing a sort of solace, so he continues to go when he can. But how to grieve is something each doctor has to figure out, he said.
Deaths still hit hard, especially the ones he doesn’t see coming. The patients who remind him of his dad can also be hard. They restart a cycle of grief from his teenage years.
The difference now is he has space to voice those concerns and someone objective to help his process.
“It’s a privilege to prepare [patients for death] and help them build their legacy,” he said. But it’s also an unrelenting challenge to navigate that grief, he said.
Still, the grief lets Dr. Lewis know he’s still engaged.
“The day I don’t feel something is probably the day I need to take a break or walk away.”
A version of this article appeared on Medscape.com.
Dr. Lewis was well acquainted with cancer grief long before he became an oncologist. Dr. Lewis’ father died of a rare, hereditary cancer syndrome when he was only 14. The condition, which causes tumors to grow in the endocrine glands, can be hard to identify and, if found late, deadly.
In some ways, Dr. Lewis’ career caring for patients with advanced cancers was born out of that first loss. He centered his practice around helping patients diagnosed at late stages, like his father.
But that comes at a cost. Many patients will die.
Dr. Lewis’ encounter with his colleague led him to inventory his practice. He found that well over half of his patients died within 2 years following their advanced cancer diagnosis.
To stave off the grief of so many losses, Dr. Lewis became an eternal optimist in the clinic, in search of the Hail Mary chemotherapy, any way to eke out a few more months only to be ambushed by grief when a patient did finally pass.
At funerals — which he made every effort to attend — Dr. Lewis couldn’t help but think, “If I had done my job better, none of us with be here.” His grief started to mingle with this sense of guilt.
It became a cycle: Denial shrouded in optimism, grief, then a toxic guilt. The pattern became untenable for his colleagues. And his partner finally called him out.
Few medical specialties draw physicians as close to their patients as oncology. The long courses of treatment-spanning years can foster an intimacy that is comforting for patients and fulfilling for physicians. But that closeness can also set doctors up for an acute grief when the end of life comes.
Experts agree that no amount of training in medical school prepares an oncologist to navigate the grief that comes with losing patients. Five oncologists spoke with this news organization about the boundaries they rely on to sustain their careers.
Don’t Go to Funerals
Don Dizon, MD, who specializes in women’s cancers, established an essential boundary 20 years ago: Never go to funerals. In his early days at Memorial Sloan Kettering Cancer Center, the death of each patient dealt him a crushing blow. He’d go to the funerals in search of closure, but that only added to the weight of his grief.
“When I started in oncology, I just remember the most tragic cases were the ones I was taking care of,” recalled Dr. Dizon, now director of the Pelvic Malignancies Program at Lifespan Cancer Institute in Lincoln, Rhode Island.
Dr. Dizon recalled one young mother who was diagnosed with ovarian cancer. She responded to treatment, but it was short-lived, and her cancer progressed, he said. Multiple treatments followed, but none were effective. Eventually, Dr. Dizon had to tell her that “there’s nothing left to try.”
At her funeral, watching her grieving husband with their daughter who had just started to walk, Dr. Dizon was overwhelmed with despair.
“When you have to do this multiple times a year,” the grief becomes untenable, he said. Sensing the difficulty I was having as a new attending, “my boss stopped sending me patients because he knew I was in trouble emotionally.”
That’s when Dr. Dizon started looking for other ways to get closure.
Today, he tries to say his goodbyes before a patient dies. After the final treatment or before hospice, Dr. Dizon has a parting conversation with his patients to express the privilege of caring for them and all he learned from them. These talks help him and his patient connect in their last moments together.
The Price of Wildly Happy Days
Molly Taylor, MD, MS, a pediatric oncologist in Seattle, sees the deeply sad days as the price an oncologist pays to be witness to the “wildly happy ones.”
Dr. Taylor has gone to patients’ funerals, has even been asked to speak at them, but she has also attended patients’ weddings.
To some degree, doctors get good at compartmentalizing, and they become accustomed to tragedy, she said. But there are some patients who stick with you, “and that is a whole other level of grief,” Dr. Taylor said.
Several years into her practice, one of Dr. Taylor’s patients, someone who reminded her of her own child, died. The death came as a surprise, and the finality of it took her breath away, she said. The sadness only deepened as days went by. “I felt that mother’s grief and still do,” she said.
The patient’s funeral was one of the most difficult moments in her career as an oncologist. Even weeks later, she caught herself picturing the family huddled together that day.
Taking long walks, commiserating with colleagues who get it, and watching the occasional cat video can help take the immediate sting away. But the pain of losing a patient can be long lasting and processing that grief can be a lonely endeavor.
“We need space to recognize grief for all providers, all the people that touch these patients’ lives — the nurses, the translators, the cleaning staff,” Dr. Taylor said. Otherwise, you start to believe you’re the only one feeling the weight of the loss.
While it doesn’t make the losses any less poignant, Dr. Taylor finds solace in the good moments: Patient graduations and weddings, survivors who now volunteer at the hospital, and a patient who had a baby of her own this past year. If facing grief daily has taught Dr. Taylor anything, it is to not let the good moments pass unnoticed.
Towing the Line
Ten years ago, Tina Rizack, MD, walked into the ICU to see a young mother holding her 6-year-old daughter. The mother had necrotizing fasciitis that had gone undiagnosed.
As Dr. Rizack stood in the doorway watching the embrace, she saw a grim future: A child without her mother. This realization hit too close to home, she said. “I still think about that case.”
In her training, Dr. Rizack, now medical director of hematology/oncology at St. Anne’s in Fall River, Massachusetts, worked with a social worker who taught her how to deal with these tough cases — most importantly, how to not take them home with her.
Over the years, Dr. Rizack learned how to build and sustain a firm barrier between work and outside work.
She doesn’t go to funerals or give out her cell phone number. If charts need to be done, she prefers to stay late at the clinic instead of bringing them home.
And she invests in the simple moments that help her detach from the day-to-day in the clinic — rooting for her kids at their games, carving out time for family meals most days, and having relaxed movie nights on the couch.
“It’s hard sometimes,” she said. But “I really do need the line.” Because without it, she can’t show up for her patients the way she wants and needs to.
Establishing the work-life boundary means that when at work, Dr. Rizack can be all in for her patients. Even after her patients’ treatment ends, she makes sure to check on them at home or in hospice. For her, sticking with patients over the long term offers some closure.
“I want to love work, and if I’m there all the time, I’m not going to love it,” she said.
Trading Funerals for the Bedside
Like many other oncologists, Charles Blanke, MD, finds that going to patients’ funerals makes the loss seem more profound. Being at the bedside when they die is not as painful, he said. In fact, being there when his patients die offers him some comfort. He rarely misses a patient’s death because now Dr. Blanke’s patients can schedule their departure.
An oncologist at the Knight Cancer Institute in Portland, Oregon, Dr. Blanke specializes in end-of-life care with an emphasis on death with dignity, also known as medical aid in dying. He admits it’s not a role every physician is comfortable with.
“If you’re paralyzed by grief, you can’t do this for a living,” he said. But he’s able to do the work because he genuinely feels he’s helping patients get “the relief they so strongly desire” in their last moments.
When cancer care can’t give them the life they wanted, he can give them control over when and how they die. And the ability to honor their last wishes offers him some closure as well.
“You know what kind of end they have. You know it was peaceful. You see them achieve the thing that was the most important to them,” he said.
Despite this process, he still encounters some circumstances utterly heart-wrenching — the very young patients who have advanced disease. Some of these patients choose to die because they can’t afford to continue treatment. Others don’t have a support system. In these instances, Dr. Blanke is often the only one in the room.
Believe it or not, he said, the paperwork — and there’s a lot of it in his line of work — helps remind Dr. Blanke that patients’ last wishes are being honored.
Making Changes
After Dr. Lewis was confronted by his partner, he began to face the shortcomings of his own coping strategies. His practice hired a social worker to help staff process difficult experiences. After the loss of every patient, the practice comes together to share and process the loss.
For him, funerals remain helpful, providing a sort of solace, so he continues to go when he can. But how to grieve is something each doctor has to figure out, he said.
Deaths still hit hard, especially the ones he doesn’t see coming. The patients who remind him of his dad can also be hard. They restart a cycle of grief from his teenage years.
The difference now is he has space to voice those concerns and someone objective to help his process.
“It’s a privilege to prepare [patients for death] and help them build their legacy,” he said. But it’s also an unrelenting challenge to navigate that grief, he said.
Still, the grief lets Dr. Lewis know he’s still engaged.
“The day I don’t feel something is probably the day I need to take a break or walk away.”
A version of this article appeared on Medscape.com.
Dr. Lewis was well acquainted with cancer grief long before he became an oncologist. Dr. Lewis’ father died of a rare, hereditary cancer syndrome when he was only 14. The condition, which causes tumors to grow in the endocrine glands, can be hard to identify and, if found late, deadly.
In some ways, Dr. Lewis’ career caring for patients with advanced cancers was born out of that first loss. He centered his practice around helping patients diagnosed at late stages, like his father.
But that comes at a cost. Many patients will die.
Dr. Lewis’ encounter with his colleague led him to inventory his practice. He found that well over half of his patients died within 2 years following their advanced cancer diagnosis.
To stave off the grief of so many losses, Dr. Lewis became an eternal optimist in the clinic, in search of the Hail Mary chemotherapy, any way to eke out a few more months only to be ambushed by grief when a patient did finally pass.
At funerals — which he made every effort to attend — Dr. Lewis couldn’t help but think, “If I had done my job better, none of us with be here.” His grief started to mingle with this sense of guilt.
It became a cycle: Denial shrouded in optimism, grief, then a toxic guilt. The pattern became untenable for his colleagues. And his partner finally called him out.
Few medical specialties draw physicians as close to their patients as oncology. The long courses of treatment-spanning years can foster an intimacy that is comforting for patients and fulfilling for physicians. But that closeness can also set doctors up for an acute grief when the end of life comes.
Experts agree that no amount of training in medical school prepares an oncologist to navigate the grief that comes with losing patients. Five oncologists spoke with this news organization about the boundaries they rely on to sustain their careers.
Don’t Go to Funerals
Don Dizon, MD, who specializes in women’s cancers, established an essential boundary 20 years ago: Never go to funerals. In his early days at Memorial Sloan Kettering Cancer Center, the death of each patient dealt him a crushing blow. He’d go to the funerals in search of closure, but that only added to the weight of his grief.
“When I started in oncology, I just remember the most tragic cases were the ones I was taking care of,” recalled Dr. Dizon, now director of the Pelvic Malignancies Program at Lifespan Cancer Institute in Lincoln, Rhode Island.
Dr. Dizon recalled one young mother who was diagnosed with ovarian cancer. She responded to treatment, but it was short-lived, and her cancer progressed, he said. Multiple treatments followed, but none were effective. Eventually, Dr. Dizon had to tell her that “there’s nothing left to try.”
At her funeral, watching her grieving husband with their daughter who had just started to walk, Dr. Dizon was overwhelmed with despair.
“When you have to do this multiple times a year,” the grief becomes untenable, he said. Sensing the difficulty I was having as a new attending, “my boss stopped sending me patients because he knew I was in trouble emotionally.”
That’s when Dr. Dizon started looking for other ways to get closure.
Today, he tries to say his goodbyes before a patient dies. After the final treatment or before hospice, Dr. Dizon has a parting conversation with his patients to express the privilege of caring for them and all he learned from them. These talks help him and his patient connect in their last moments together.
The Price of Wildly Happy Days
Molly Taylor, MD, MS, a pediatric oncologist in Seattle, sees the deeply sad days as the price an oncologist pays to be witness to the “wildly happy ones.”
Dr. Taylor has gone to patients’ funerals, has even been asked to speak at them, but she has also attended patients’ weddings.
To some degree, doctors get good at compartmentalizing, and they become accustomed to tragedy, she said. But there are some patients who stick with you, “and that is a whole other level of grief,” Dr. Taylor said.
Several years into her practice, one of Dr. Taylor’s patients, someone who reminded her of her own child, died. The death came as a surprise, and the finality of it took her breath away, she said. The sadness only deepened as days went by. “I felt that mother’s grief and still do,” she said.
The patient’s funeral was one of the most difficult moments in her career as an oncologist. Even weeks later, she caught herself picturing the family huddled together that day.
Taking long walks, commiserating with colleagues who get it, and watching the occasional cat video can help take the immediate sting away. But the pain of losing a patient can be long lasting and processing that grief can be a lonely endeavor.
“We need space to recognize grief for all providers, all the people that touch these patients’ lives — the nurses, the translators, the cleaning staff,” Dr. Taylor said. Otherwise, you start to believe you’re the only one feeling the weight of the loss.
While it doesn’t make the losses any less poignant, Dr. Taylor finds solace in the good moments: Patient graduations and weddings, survivors who now volunteer at the hospital, and a patient who had a baby of her own this past year. If facing grief daily has taught Dr. Taylor anything, it is to not let the good moments pass unnoticed.
Towing the Line
Ten years ago, Tina Rizack, MD, walked into the ICU to see a young mother holding her 6-year-old daughter. The mother had necrotizing fasciitis that had gone undiagnosed.
As Dr. Rizack stood in the doorway watching the embrace, she saw a grim future: A child without her mother. This realization hit too close to home, she said. “I still think about that case.”
In her training, Dr. Rizack, now medical director of hematology/oncology at St. Anne’s in Fall River, Massachusetts, worked with a social worker who taught her how to deal with these tough cases — most importantly, how to not take them home with her.
Over the years, Dr. Rizack learned how to build and sustain a firm barrier between work and outside work.
She doesn’t go to funerals or give out her cell phone number. If charts need to be done, she prefers to stay late at the clinic instead of bringing them home.
And she invests in the simple moments that help her detach from the day-to-day in the clinic — rooting for her kids at their games, carving out time for family meals most days, and having relaxed movie nights on the couch.
“It’s hard sometimes,” she said. But “I really do need the line.” Because without it, she can’t show up for her patients the way she wants and needs to.
Establishing the work-life boundary means that when at work, Dr. Rizack can be all in for her patients. Even after her patients’ treatment ends, she makes sure to check on them at home or in hospice. For her, sticking with patients over the long term offers some closure.
“I want to love work, and if I’m there all the time, I’m not going to love it,” she said.
Trading Funerals for the Bedside
Like many other oncologists, Charles Blanke, MD, finds that going to patients’ funerals makes the loss seem more profound. Being at the bedside when they die is not as painful, he said. In fact, being there when his patients die offers him some comfort. He rarely misses a patient’s death because now Dr. Blanke’s patients can schedule their departure.
An oncologist at the Knight Cancer Institute in Portland, Oregon, Dr. Blanke specializes in end-of-life care with an emphasis on death with dignity, also known as medical aid in dying. He admits it’s not a role every physician is comfortable with.
“If you’re paralyzed by grief, you can’t do this for a living,” he said. But he’s able to do the work because he genuinely feels he’s helping patients get “the relief they so strongly desire” in their last moments.
When cancer care can’t give them the life they wanted, he can give them control over when and how they die. And the ability to honor their last wishes offers him some closure as well.
“You know what kind of end they have. You know it was peaceful. You see them achieve the thing that was the most important to them,” he said.
Despite this process, he still encounters some circumstances utterly heart-wrenching — the very young patients who have advanced disease. Some of these patients choose to die because they can’t afford to continue treatment. Others don’t have a support system. In these instances, Dr. Blanke is often the only one in the room.
Believe it or not, he said, the paperwork — and there’s a lot of it in his line of work — helps remind Dr. Blanke that patients’ last wishes are being honored.
Making Changes
After Dr. Lewis was confronted by his partner, he began to face the shortcomings of his own coping strategies. His practice hired a social worker to help staff process difficult experiences. After the loss of every patient, the practice comes together to share and process the loss.
For him, funerals remain helpful, providing a sort of solace, so he continues to go when he can. But how to grieve is something each doctor has to figure out, he said.
Deaths still hit hard, especially the ones he doesn’t see coming. The patients who remind him of his dad can also be hard. They restart a cycle of grief from his teenage years.
The difference now is he has space to voice those concerns and someone objective to help his process.
“It’s a privilege to prepare [patients for death] and help them build their legacy,” he said. But it’s also an unrelenting challenge to navigate that grief, he said.
Still, the grief lets Dr. Lewis know he’s still engaged.
“The day I don’t feel something is probably the day I need to take a break or walk away.”
A version of this article appeared on Medscape.com.
Will 2024 Be Easier on the Eyes?
The burdens that monthly or every-other-month injections in the eye impose on patients with retinal diseases are well-known to be barriers to care for many people with these conditions. Making treatment less onerous has driven research into new treatments since the US Food and Drug Administration (FDA) approved ranibizumab (Lucentis) in 2006 as the first anti–vascular endothelial growth factor (VEGF) for the treatment of age-related macular degeneration (AMD) and other retinal diseases.
Those Several of those investigational therapies are poised to hit meaningful milestones in 2024.
Regular Eye Injections: How We Got Here
Ranibizumab originally received approval as a monthly injection. Since then, protocols have evolved to space those injections out to every other month in some, but not all, patients.
New drugs have emerged that require less frequent injections. In 2022, the anti-VEGF and angiopoietin-2 inhibitor faricimab (Vabysmo) was approved for dosing up to every 4 months. Last year, the FDA approved a high-dose formulation of the anti-VEGF treatment aflibercept 8 mg (Eylea HD) to be given every 2-4 months, as well.
But even these treatments require patients going to the office at least three or four times a year for injections, Reginald Sanders, MD, president of the American Society of Retina Specialist, Chicago, and a retina specialist in Washington, DC, told this news organization. “Now with injections, you have the anxiety of getting the injections, you have the inconvenience of coming in on a regular basis to get the injections, and you have mild discomfort — but you don’t go blind,” Dr. Sanders said.
Studies have shown patients with AMD or diabetic macular edema are better off getting more frequent injections, but still drug developers are seeking the holy grail of fewer injections. “How do we make these treatments last longer?” Dr. Sanders said. “Durability has become the catchword in our field. Instead of lasting a month or 2, can it last 3 months? Can it last 6 months? Or even a year? Can you get one injection and be done with it?”
Or, no injection at all?
“We’re looking for incremental improvements and longer-acting drugs, trying to lengthen the time between injections for wet AMD patients,” said David Boyer, MD, a retina specialist in Los Angeles.
Two Drugs May Be Better Than One
One combination treatment, sozinibercept, targets VEGF-C and D. The therapy is in two phase 3 trials: One in combination with aflibercept 2 mg (Eylea), which targets VEGF-A and B along with placental growth factor, and the other in combination with ranibizumab, which targets VEGF-A only. Data from one of those trials are expected this year, Dr. Boyer said.
A phase 2 trial last year reported that patients on combination sozinibercept-ranibizumab had significantly better visual acuity improvement than patients on ranibizumab only. The phase 3 trials ShORe with ranibizumab and COAST with aflibercept are evaluating improvements in visual acuity and retinal anatomy.
Two other combination therapies are in phase 2 trials, both with aflibercept: UBX1325 or foselutoclax, a small-molecule inhibitor of B-cell lymphoma extra-large, and umedaptanib pegol, an anti-fibroblast growth factor-2 aptamer. In the foselutoclax-aflibercept trial, 40% of patients didn’t need a supplemental anti-VEGF injection through 48 weeks, and 64% went treatment-free for more than 24 weeks.
Phase 2 trials of intravitreal umedaptanib pegol-aflibercept combination therapy in nAMD last year showed no superiority in vision and anatomical improvements over aflibercept alone but did find the combination halted disease progression, with “striking improvement” in previously untreated patients.
Novel Drug Delivery Systems
A host of novel drug delivery systems that could stretch out intervals between injections are in human trials. In 2021, the FDA approved one such system, the refillable port delivery system (PDS) implant with ranibizumab (Susvimo). PDS is a small cylinder implanted into the eye and filled with 100 mg/mL of ranibizumab, to be released for 6 months or so, then refilled in the physician’s office when it’s empty.
But new implants of PDS were halted in 2022 after the manufacturer, Genentech, received reports the device leaked. Genentech said it has fixed those problems and confirmed the device should again become available for implants this year.
The most advanced novel drug delivery system in clinical trials is EYP-1901, a depot that contains the tyrosine kinase inhibitor (TKI) vorolanib. The depot is inserted under the ocular surface, where it biodegrades over 6 months as it releases the drug. A phase 3 trial is due to start enrollment at midyear.
An intravitreal implant with the TKI axitinib (Axpaxli) is in a phase 3 trial in nAMD and is due to start a phase 3 trial in diabetic retinopathy this year. At least four other implants, some of which biodegrade as they release the active ingredient, are in phase 1 or 2 trials.
TKIs themselves are a drug class worth watching in retina, said Jennifer I. Lim, MD, director of the retina service at the University of Illinois Chicago and president of the Retina Society.
“With TKIs, which activate intracellularly, in combination with anti-VEGFs will result in enhanced durability and possibly more efficacy for AMD,” Dr. Lim said. “TKIs in the phase 2 studies showed a marked reduction in the need for anti-VEGF injections in previously difficult-to-treat, high-need patient.”
Potential for Orals and Topicals
Topical eye drops are commonly used for anti-glaucoma drugs and antibiotics and corticosteroids for eye infections and inflammation, but using them for retinal disease has been a challenge. By the time the drug reaches the back of the eye, it has lost much of its pharmacokinetic activity. Three drops are in clinical trials for diabetic eye disease, with one, OCS-01, a preservative-free formulation of the corticosteroid dexamethasone, scheduled this year to enter a phase 3 trial.
At least four oral tablets are in early-stage human trials for diabetic eye disease. Four others are in clinical trials to treat geographic atrophy or early-stage dry AMD. They include tinlarebant, which is in phase 3 trials for geographic atrophy and Stargardt disease, an inherited retinal disorder.
Two other oral tablets are in human trials for inherited retinal disease. Like tinlarebant, emixustat has been in a phase 3 trial for Stargardt disease but showed no clinically significant improvement in macular atrophy. An early readout of an ongoing phase 2 trial of glideuretinol, a modified form of vitamin A, demonstrated slowed growth of macular atrophy in Stargardt.
These new and emerging treatments may potentially enable retina specialists to manage a rapidly growing aging population more efficiently, Dr. Sanders said.
“We have to figure out, on one hand, how do we catch the disease earlier? Like in other fields of medicine, the earlier you treat someone, the better,” Dr. Sanders said. “And also, how do we efficiently see these patients earlier to get therapy? Using implants or more durable drugs may be able to help us to treat more people more efficiently.”
Dr. Lim disclosed financial relationships with AbbVie/Allergan, Adverum Biotechnologies, Alimera Sciences, Bausch + Lomb, Chengdu Kanghong Biotechnology, Eyepoint Pharmaceuticals, Genentech/ Roche, Graybug Vision, Iveric Bio, Janssen Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RegenxBio, Santen, SparingVision, Stealth BioTherapeutics, Unity Biotechnology, and Viridian.
Dr. Boyer disclosed financial relationships with 4D Molecular Therapeutics, AbbVie/Allergan, Adverum Biotechnologies, Aldeyra Therapeutics, Alimera Sciences, Alkahest, Allegro, Amgen, Annexon Biosciences, Apellis Pharmaceuticals, AsclepiX Therapeutics, Aviceda Therapeutics, Bausch + Lomb, Bayer, Belite Bio, Clearside Biomedical, Eyepoint Pharmaceuticals, Genentech/ Roche, Graybug Vision, Iveric Bio, Janssen Pharmaceuticals, Nano scope Therapeutics, Novartis, Ocugen, Oculist, Ocuphire Pharma, Opthea, Pfizer, Regeneron Pharmaceuticals, RegenxBio, Sanofi, Stilbite Zhuhai, Stealth BioTherapeutics, Thea Laboratories, and Unity Biotechnology. Dr. Sanders had no relevant disclosures.
A version of this article appeared on Medscape.com.
The burdens that monthly or every-other-month injections in the eye impose on patients with retinal diseases are well-known to be barriers to care for many people with these conditions. Making treatment less onerous has driven research into new treatments since the US Food and Drug Administration (FDA) approved ranibizumab (Lucentis) in 2006 as the first anti–vascular endothelial growth factor (VEGF) for the treatment of age-related macular degeneration (AMD) and other retinal diseases.
Those Several of those investigational therapies are poised to hit meaningful milestones in 2024.
Regular Eye Injections: How We Got Here
Ranibizumab originally received approval as a monthly injection. Since then, protocols have evolved to space those injections out to every other month in some, but not all, patients.
New drugs have emerged that require less frequent injections. In 2022, the anti-VEGF and angiopoietin-2 inhibitor faricimab (Vabysmo) was approved for dosing up to every 4 months. Last year, the FDA approved a high-dose formulation of the anti-VEGF treatment aflibercept 8 mg (Eylea HD) to be given every 2-4 months, as well.
But even these treatments require patients going to the office at least three or four times a year for injections, Reginald Sanders, MD, president of the American Society of Retina Specialist, Chicago, and a retina specialist in Washington, DC, told this news organization. “Now with injections, you have the anxiety of getting the injections, you have the inconvenience of coming in on a regular basis to get the injections, and you have mild discomfort — but you don’t go blind,” Dr. Sanders said.
Studies have shown patients with AMD or diabetic macular edema are better off getting more frequent injections, but still drug developers are seeking the holy grail of fewer injections. “How do we make these treatments last longer?” Dr. Sanders said. “Durability has become the catchword in our field. Instead of lasting a month or 2, can it last 3 months? Can it last 6 months? Or even a year? Can you get one injection and be done with it?”
Or, no injection at all?
“We’re looking for incremental improvements and longer-acting drugs, trying to lengthen the time between injections for wet AMD patients,” said David Boyer, MD, a retina specialist in Los Angeles.
Two Drugs May Be Better Than One
One combination treatment, sozinibercept, targets VEGF-C and D. The therapy is in two phase 3 trials: One in combination with aflibercept 2 mg (Eylea), which targets VEGF-A and B along with placental growth factor, and the other in combination with ranibizumab, which targets VEGF-A only. Data from one of those trials are expected this year, Dr. Boyer said.
A phase 2 trial last year reported that patients on combination sozinibercept-ranibizumab had significantly better visual acuity improvement than patients on ranibizumab only. The phase 3 trials ShORe with ranibizumab and COAST with aflibercept are evaluating improvements in visual acuity and retinal anatomy.
Two other combination therapies are in phase 2 trials, both with aflibercept: UBX1325 or foselutoclax, a small-molecule inhibitor of B-cell lymphoma extra-large, and umedaptanib pegol, an anti-fibroblast growth factor-2 aptamer. In the foselutoclax-aflibercept trial, 40% of patients didn’t need a supplemental anti-VEGF injection through 48 weeks, and 64% went treatment-free for more than 24 weeks.
Phase 2 trials of intravitreal umedaptanib pegol-aflibercept combination therapy in nAMD last year showed no superiority in vision and anatomical improvements over aflibercept alone but did find the combination halted disease progression, with “striking improvement” in previously untreated patients.
Novel Drug Delivery Systems
A host of novel drug delivery systems that could stretch out intervals between injections are in human trials. In 2021, the FDA approved one such system, the refillable port delivery system (PDS) implant with ranibizumab (Susvimo). PDS is a small cylinder implanted into the eye and filled with 100 mg/mL of ranibizumab, to be released for 6 months or so, then refilled in the physician’s office when it’s empty.
But new implants of PDS were halted in 2022 after the manufacturer, Genentech, received reports the device leaked. Genentech said it has fixed those problems and confirmed the device should again become available for implants this year.
The most advanced novel drug delivery system in clinical trials is EYP-1901, a depot that contains the tyrosine kinase inhibitor (TKI) vorolanib. The depot is inserted under the ocular surface, where it biodegrades over 6 months as it releases the drug. A phase 3 trial is due to start enrollment at midyear.
An intravitreal implant with the TKI axitinib (Axpaxli) is in a phase 3 trial in nAMD and is due to start a phase 3 trial in diabetic retinopathy this year. At least four other implants, some of which biodegrade as they release the active ingredient, are in phase 1 or 2 trials.
TKIs themselves are a drug class worth watching in retina, said Jennifer I. Lim, MD, director of the retina service at the University of Illinois Chicago and president of the Retina Society.
“With TKIs, which activate intracellularly, in combination with anti-VEGFs will result in enhanced durability and possibly more efficacy for AMD,” Dr. Lim said. “TKIs in the phase 2 studies showed a marked reduction in the need for anti-VEGF injections in previously difficult-to-treat, high-need patient.”
Potential for Orals and Topicals
Topical eye drops are commonly used for anti-glaucoma drugs and antibiotics and corticosteroids for eye infections and inflammation, but using them for retinal disease has been a challenge. By the time the drug reaches the back of the eye, it has lost much of its pharmacokinetic activity. Three drops are in clinical trials for diabetic eye disease, with one, OCS-01, a preservative-free formulation of the corticosteroid dexamethasone, scheduled this year to enter a phase 3 trial.
At least four oral tablets are in early-stage human trials for diabetic eye disease. Four others are in clinical trials to treat geographic atrophy or early-stage dry AMD. They include tinlarebant, which is in phase 3 trials for geographic atrophy and Stargardt disease, an inherited retinal disorder.
Two other oral tablets are in human trials for inherited retinal disease. Like tinlarebant, emixustat has been in a phase 3 trial for Stargardt disease but showed no clinically significant improvement in macular atrophy. An early readout of an ongoing phase 2 trial of glideuretinol, a modified form of vitamin A, demonstrated slowed growth of macular atrophy in Stargardt.
These new and emerging treatments may potentially enable retina specialists to manage a rapidly growing aging population more efficiently, Dr. Sanders said.
“We have to figure out, on one hand, how do we catch the disease earlier? Like in other fields of medicine, the earlier you treat someone, the better,” Dr. Sanders said. “And also, how do we efficiently see these patients earlier to get therapy? Using implants or more durable drugs may be able to help us to treat more people more efficiently.”
Dr. Lim disclosed financial relationships with AbbVie/Allergan, Adverum Biotechnologies, Alimera Sciences, Bausch + Lomb, Chengdu Kanghong Biotechnology, Eyepoint Pharmaceuticals, Genentech/ Roche, Graybug Vision, Iveric Bio, Janssen Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RegenxBio, Santen, SparingVision, Stealth BioTherapeutics, Unity Biotechnology, and Viridian.
Dr. Boyer disclosed financial relationships with 4D Molecular Therapeutics, AbbVie/Allergan, Adverum Biotechnologies, Aldeyra Therapeutics, Alimera Sciences, Alkahest, Allegro, Amgen, Annexon Biosciences, Apellis Pharmaceuticals, AsclepiX Therapeutics, Aviceda Therapeutics, Bausch + Lomb, Bayer, Belite Bio, Clearside Biomedical, Eyepoint Pharmaceuticals, Genentech/ Roche, Graybug Vision, Iveric Bio, Janssen Pharmaceuticals, Nano scope Therapeutics, Novartis, Ocugen, Oculist, Ocuphire Pharma, Opthea, Pfizer, Regeneron Pharmaceuticals, RegenxBio, Sanofi, Stilbite Zhuhai, Stealth BioTherapeutics, Thea Laboratories, and Unity Biotechnology. Dr. Sanders had no relevant disclosures.
A version of this article appeared on Medscape.com.
The burdens that monthly or every-other-month injections in the eye impose on patients with retinal diseases are well-known to be barriers to care for many people with these conditions. Making treatment less onerous has driven research into new treatments since the US Food and Drug Administration (FDA) approved ranibizumab (Lucentis) in 2006 as the first anti–vascular endothelial growth factor (VEGF) for the treatment of age-related macular degeneration (AMD) and other retinal diseases.
Those Several of those investigational therapies are poised to hit meaningful milestones in 2024.
Regular Eye Injections: How We Got Here
Ranibizumab originally received approval as a monthly injection. Since then, protocols have evolved to space those injections out to every other month in some, but not all, patients.
New drugs have emerged that require less frequent injections. In 2022, the anti-VEGF and angiopoietin-2 inhibitor faricimab (Vabysmo) was approved for dosing up to every 4 months. Last year, the FDA approved a high-dose formulation of the anti-VEGF treatment aflibercept 8 mg (Eylea HD) to be given every 2-4 months, as well.
But even these treatments require patients going to the office at least three or four times a year for injections, Reginald Sanders, MD, president of the American Society of Retina Specialist, Chicago, and a retina specialist in Washington, DC, told this news organization. “Now with injections, you have the anxiety of getting the injections, you have the inconvenience of coming in on a regular basis to get the injections, and you have mild discomfort — but you don’t go blind,” Dr. Sanders said.
Studies have shown patients with AMD or diabetic macular edema are better off getting more frequent injections, but still drug developers are seeking the holy grail of fewer injections. “How do we make these treatments last longer?” Dr. Sanders said. “Durability has become the catchword in our field. Instead of lasting a month or 2, can it last 3 months? Can it last 6 months? Or even a year? Can you get one injection and be done with it?”
Or, no injection at all?
“We’re looking for incremental improvements and longer-acting drugs, trying to lengthen the time between injections for wet AMD patients,” said David Boyer, MD, a retina specialist in Los Angeles.
Two Drugs May Be Better Than One
One combination treatment, sozinibercept, targets VEGF-C and D. The therapy is in two phase 3 trials: One in combination with aflibercept 2 mg (Eylea), which targets VEGF-A and B along with placental growth factor, and the other in combination with ranibizumab, which targets VEGF-A only. Data from one of those trials are expected this year, Dr. Boyer said.
A phase 2 trial last year reported that patients on combination sozinibercept-ranibizumab had significantly better visual acuity improvement than patients on ranibizumab only. The phase 3 trials ShORe with ranibizumab and COAST with aflibercept are evaluating improvements in visual acuity and retinal anatomy.
Two other combination therapies are in phase 2 trials, both with aflibercept: UBX1325 or foselutoclax, a small-molecule inhibitor of B-cell lymphoma extra-large, and umedaptanib pegol, an anti-fibroblast growth factor-2 aptamer. In the foselutoclax-aflibercept trial, 40% of patients didn’t need a supplemental anti-VEGF injection through 48 weeks, and 64% went treatment-free for more than 24 weeks.
Phase 2 trials of intravitreal umedaptanib pegol-aflibercept combination therapy in nAMD last year showed no superiority in vision and anatomical improvements over aflibercept alone but did find the combination halted disease progression, with “striking improvement” in previously untreated patients.
Novel Drug Delivery Systems
A host of novel drug delivery systems that could stretch out intervals between injections are in human trials. In 2021, the FDA approved one such system, the refillable port delivery system (PDS) implant with ranibizumab (Susvimo). PDS is a small cylinder implanted into the eye and filled with 100 mg/mL of ranibizumab, to be released for 6 months or so, then refilled in the physician’s office when it’s empty.
But new implants of PDS were halted in 2022 after the manufacturer, Genentech, received reports the device leaked. Genentech said it has fixed those problems and confirmed the device should again become available for implants this year.
The most advanced novel drug delivery system in clinical trials is EYP-1901, a depot that contains the tyrosine kinase inhibitor (TKI) vorolanib. The depot is inserted under the ocular surface, where it biodegrades over 6 months as it releases the drug. A phase 3 trial is due to start enrollment at midyear.
An intravitreal implant with the TKI axitinib (Axpaxli) is in a phase 3 trial in nAMD and is due to start a phase 3 trial in diabetic retinopathy this year. At least four other implants, some of which biodegrade as they release the active ingredient, are in phase 1 or 2 trials.
TKIs themselves are a drug class worth watching in retina, said Jennifer I. Lim, MD, director of the retina service at the University of Illinois Chicago and president of the Retina Society.
“With TKIs, which activate intracellularly, in combination with anti-VEGFs will result in enhanced durability and possibly more efficacy for AMD,” Dr. Lim said. “TKIs in the phase 2 studies showed a marked reduction in the need for anti-VEGF injections in previously difficult-to-treat, high-need patient.”
Potential for Orals and Topicals
Topical eye drops are commonly used for anti-glaucoma drugs and antibiotics and corticosteroids for eye infections and inflammation, but using them for retinal disease has been a challenge. By the time the drug reaches the back of the eye, it has lost much of its pharmacokinetic activity. Three drops are in clinical trials for diabetic eye disease, with one, OCS-01, a preservative-free formulation of the corticosteroid dexamethasone, scheduled this year to enter a phase 3 trial.
At least four oral tablets are in early-stage human trials for diabetic eye disease. Four others are in clinical trials to treat geographic atrophy or early-stage dry AMD. They include tinlarebant, which is in phase 3 trials for geographic atrophy and Stargardt disease, an inherited retinal disorder.
Two other oral tablets are in human trials for inherited retinal disease. Like tinlarebant, emixustat has been in a phase 3 trial for Stargardt disease but showed no clinically significant improvement in macular atrophy. An early readout of an ongoing phase 2 trial of glideuretinol, a modified form of vitamin A, demonstrated slowed growth of macular atrophy in Stargardt.
These new and emerging treatments may potentially enable retina specialists to manage a rapidly growing aging population more efficiently, Dr. Sanders said.
“We have to figure out, on one hand, how do we catch the disease earlier? Like in other fields of medicine, the earlier you treat someone, the better,” Dr. Sanders said. “And also, how do we efficiently see these patients earlier to get therapy? Using implants or more durable drugs may be able to help us to treat more people more efficiently.”
Dr. Lim disclosed financial relationships with AbbVie/Allergan, Adverum Biotechnologies, Alimera Sciences, Bausch + Lomb, Chengdu Kanghong Biotechnology, Eyepoint Pharmaceuticals, Genentech/ Roche, Graybug Vision, Iveric Bio, Janssen Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RegenxBio, Santen, SparingVision, Stealth BioTherapeutics, Unity Biotechnology, and Viridian.
Dr. Boyer disclosed financial relationships with 4D Molecular Therapeutics, AbbVie/Allergan, Adverum Biotechnologies, Aldeyra Therapeutics, Alimera Sciences, Alkahest, Allegro, Amgen, Annexon Biosciences, Apellis Pharmaceuticals, AsclepiX Therapeutics, Aviceda Therapeutics, Bausch + Lomb, Bayer, Belite Bio, Clearside Biomedical, Eyepoint Pharmaceuticals, Genentech/ Roche, Graybug Vision, Iveric Bio, Janssen Pharmaceuticals, Nano scope Therapeutics, Novartis, Ocugen, Oculist, Ocuphire Pharma, Opthea, Pfizer, Regeneron Pharmaceuticals, RegenxBio, Sanofi, Stilbite Zhuhai, Stealth BioTherapeutics, Thea Laboratories, and Unity Biotechnology. Dr. Sanders had no relevant disclosures.
A version of this article appeared on Medscape.com.
New Trials in Leukemia and Lymphoma: Could Your Patient Benefit?
Several clinical trials in leukemia and lymphoma have started enrolling recently. Maybe one of your patients could benefit from taking part?
run by the Center for International Blood and Bone Marrow Transplant Research.
The purpose of the study is to test whether cyclophosphamide, which is given to prevent a dreaded complication of stem cell transplantation called graft-versus-host disease, can be safely reduced without increasing infection or reducing protection. All participants will receive cyclophosphamide on days 3 and 4 post transplant. One group will receive a reduced dose of cyclophosphamide (25 mg/kg per dose), and the other will be given a usual dose (37.5 mg/kg).
Sites in Michigan, Missouri, Oregon, Virginia, and Washington started recruiting for 190 participants in December 2023. Study centers in Florida, Massachusetts, New York, and Wisconsin are also planned. Infection-free survival is the primary endpoint, and overall survival is a secondary measure. Quality of life (QoL) is not recorded. More details at clinicaltrials.gov.
Untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Adults who are newly diagnosed with this type of cancer and have active disease may wish to consider a randomized, open-label, phase 3 trial testing an experimental Bruton tyrosine kinase (BTK) inhibitor, nemtabrutinib (from Merck Sharp & Dohme), against standard-of-care BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence).
BTK inhibitors target B-cell proliferation in B-cell cancers such as CLL/SLL and allow for chemotherapy-free treatment of some hematological malignancies. In this study, until disease progression, unacceptable toxicity, or another reason for discontinuation occurs, participants will take daily oral nemtabrutinib, ibrutinib, or acalabrutinib.
The study opened in December 2023 in Pennsylvania, Washington, Taiwan, Israel, and the United Kingdom seeking 1200 participants. The primary outcomes are objective response rate and progression-free survival. Overall survival is a secondary outcome, and QoL is not measured. More details at clinicaltrials.gov.
Relapsed or refractory leukemia with a KMT2A-gene rearrangement (KMT2A-r). Children aged 1 month to younger than 6 years with this diagnosis may be able to join an open-label, nonrandomized, Children’s Oncology Group phase 2 study to determine the most tolerable and/or effective dose of an experimental oral drug called revumenib when added to chemotherapy.
KMT2A-gene alterations are associated with a poor prognosis in leukemia. These alterations cause blood cells to dedifferentiate and start proliferating uncontrollably as leukemia cells. The expression of the damaged KMT2A gene relies on a protein called menin. Revumenib, from Syndax Pharmaceuticals, blocks menin and prevents expression of KMT2A.
Children in the study will receive two different regimens of revumenib in combination with chemotherapy for up to a year, or until disease progression or unacceptable toxicity, and will then be followed for up to 5 years. Trial centers in 12 US states opened their doors in January 2024 looking for 78 participants. Toxicities and minimal residual disease are the primary outcomes; overall survival is a secondary outcome, and QoL is not assessed. More details at clinicaltrials.gov.
Previously untreated follicular lymphoma or diffuse large B-cell lymphoma. Adults with one of these types of lymphoma may be eligible for one of three open-label, randomized, phase 3 trials testing odronextamab (from Regeneron). This bispecific antibody is designed to ‘lock together’ CD20 on cancer cells with CD3-expressing cancer-killing T cells. It has shown anti-lymphoma activity in heavily pretreated patients.
Late in 2023, three phase 3 trials turned the spotlight on treatment-naive patients and started recruiting 2115 participants to assess odronextamab in this setting. The trial OLYMPIA-1 will compare odronextamab with standard-of-care rituximab (Rituxan) plus chemotherapy in follicular lymphoma. OLYMPIA-2 will test the drug in combination with chemotherapy, also in follicular lymphoma. OLYMPIA-3 will evaluate odronextamab plus chemotherapy against rituximab and chemotherapy in people with large B-cell lymphoma.
All study drugs, including odronextamab, will be administered by intravenous infusion, and participants will be followed for up to 5 years. Research centers across eight US states and Australia, Czechia, France, Italy, Poland, Spain, Turkey, and Thailand are currently accepting participants for the three trials. The primary outcomes are various measures of toxicity and complete response at 30 months in the follicular lymphoma studies and toxicity and progression-free survival in large B-cell lymphoma. All three trials are measuring overall survival and QoL as secondary endpoints.
Previously untreated stage II, III, or IV follicular lymphoma. Adults with this type of cancer may be eligible to participate in a randomized, open-label, phase 3 study testing whether an experimental therapy called epcoritamab (from AbbVie) improves disease response and is tolerable when added to standard therapy. For up to 120 weeks, one group of participants will receive a combination of intravenous rituximab and oral lenalidomide (Revlimid), while a second group will also receive subcutaneous injections of epcoritamab. Some participants may be offered investigators’ choice of chemotherapy as well.
Sites across Iowa, Maryland, Missouri, Ohio, Washington, and Montana started welcoming their 900 participants in February 2024. The primary outcome is complete response at 30 months. Overall survival and QoL are secondary outcomes. More details at clinicaltrials.gov.
Relapsed or refractory mantle cell lymphoma. Adults facing one of these clinical scenarios can join an Academic and Community Cancer Research United open label, phase 2 trial examining the effectiveness of combining tafasitamab (Monjuvi), lenalidomide, and venetoclax (Venclexta) for such patients.
Frontline therapy does not cure mantle cell lymphoma, and continued relapses are common. In this situation, treatments can include acalabrutinib, ibrutinib, stem cell transplantation, venetoclax, lenalidomide, and rituximab.
In this study, participants will take venetoclax and lenalidomide daily and receive intravenous tafasitamab every 2 weeks after an initial ramp-up period as per clinic standards. Participants will be followed for 5 years after entering the trial. The Mayo Clinic in Rochester, Minnesota, began recruiting the planned 100 trial participants in January 2024. The primary outcome is objective response rate; overall survival is a secondary outcome, and QoL will not be tracked. More details at clinicaltrials.gov.
All trial information is from the National Institutes of Health US National Library of Medicine (online at clinicaltrials.gov).
A version of this article appeared on Medscape.com .
Several clinical trials in leukemia and lymphoma have started enrolling recently. Maybe one of your patients could benefit from taking part?
run by the Center for International Blood and Bone Marrow Transplant Research.
The purpose of the study is to test whether cyclophosphamide, which is given to prevent a dreaded complication of stem cell transplantation called graft-versus-host disease, can be safely reduced without increasing infection or reducing protection. All participants will receive cyclophosphamide on days 3 and 4 post transplant. One group will receive a reduced dose of cyclophosphamide (25 mg/kg per dose), and the other will be given a usual dose (37.5 mg/kg).
Sites in Michigan, Missouri, Oregon, Virginia, and Washington started recruiting for 190 participants in December 2023. Study centers in Florida, Massachusetts, New York, and Wisconsin are also planned. Infection-free survival is the primary endpoint, and overall survival is a secondary measure. Quality of life (QoL) is not recorded. More details at clinicaltrials.gov.
Untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Adults who are newly diagnosed with this type of cancer and have active disease may wish to consider a randomized, open-label, phase 3 trial testing an experimental Bruton tyrosine kinase (BTK) inhibitor, nemtabrutinib (from Merck Sharp & Dohme), against standard-of-care BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence).
BTK inhibitors target B-cell proliferation in B-cell cancers such as CLL/SLL and allow for chemotherapy-free treatment of some hematological malignancies. In this study, until disease progression, unacceptable toxicity, or another reason for discontinuation occurs, participants will take daily oral nemtabrutinib, ibrutinib, or acalabrutinib.
The study opened in December 2023 in Pennsylvania, Washington, Taiwan, Israel, and the United Kingdom seeking 1200 participants. The primary outcomes are objective response rate and progression-free survival. Overall survival is a secondary outcome, and QoL is not measured. More details at clinicaltrials.gov.
Relapsed or refractory leukemia with a KMT2A-gene rearrangement (KMT2A-r). Children aged 1 month to younger than 6 years with this diagnosis may be able to join an open-label, nonrandomized, Children’s Oncology Group phase 2 study to determine the most tolerable and/or effective dose of an experimental oral drug called revumenib when added to chemotherapy.
KMT2A-gene alterations are associated with a poor prognosis in leukemia. These alterations cause blood cells to dedifferentiate and start proliferating uncontrollably as leukemia cells. The expression of the damaged KMT2A gene relies on a protein called menin. Revumenib, from Syndax Pharmaceuticals, blocks menin and prevents expression of KMT2A.
Children in the study will receive two different regimens of revumenib in combination with chemotherapy for up to a year, or until disease progression or unacceptable toxicity, and will then be followed for up to 5 years. Trial centers in 12 US states opened their doors in January 2024 looking for 78 participants. Toxicities and minimal residual disease are the primary outcomes; overall survival is a secondary outcome, and QoL is not assessed. More details at clinicaltrials.gov.
Previously untreated follicular lymphoma or diffuse large B-cell lymphoma. Adults with one of these types of lymphoma may be eligible for one of three open-label, randomized, phase 3 trials testing odronextamab (from Regeneron). This bispecific antibody is designed to ‘lock together’ CD20 on cancer cells with CD3-expressing cancer-killing T cells. It has shown anti-lymphoma activity in heavily pretreated patients.
Late in 2023, three phase 3 trials turned the spotlight on treatment-naive patients and started recruiting 2115 participants to assess odronextamab in this setting. The trial OLYMPIA-1 will compare odronextamab with standard-of-care rituximab (Rituxan) plus chemotherapy in follicular lymphoma. OLYMPIA-2 will test the drug in combination with chemotherapy, also in follicular lymphoma. OLYMPIA-3 will evaluate odronextamab plus chemotherapy against rituximab and chemotherapy in people with large B-cell lymphoma.
All study drugs, including odronextamab, will be administered by intravenous infusion, and participants will be followed for up to 5 years. Research centers across eight US states and Australia, Czechia, France, Italy, Poland, Spain, Turkey, and Thailand are currently accepting participants for the three trials. The primary outcomes are various measures of toxicity and complete response at 30 months in the follicular lymphoma studies and toxicity and progression-free survival in large B-cell lymphoma. All three trials are measuring overall survival and QoL as secondary endpoints.
Previously untreated stage II, III, or IV follicular lymphoma. Adults with this type of cancer may be eligible to participate in a randomized, open-label, phase 3 study testing whether an experimental therapy called epcoritamab (from AbbVie) improves disease response and is tolerable when added to standard therapy. For up to 120 weeks, one group of participants will receive a combination of intravenous rituximab and oral lenalidomide (Revlimid), while a second group will also receive subcutaneous injections of epcoritamab. Some participants may be offered investigators’ choice of chemotherapy as well.
Sites across Iowa, Maryland, Missouri, Ohio, Washington, and Montana started welcoming their 900 participants in February 2024. The primary outcome is complete response at 30 months. Overall survival and QoL are secondary outcomes. More details at clinicaltrials.gov.
Relapsed or refractory mantle cell lymphoma. Adults facing one of these clinical scenarios can join an Academic and Community Cancer Research United open label, phase 2 trial examining the effectiveness of combining tafasitamab (Monjuvi), lenalidomide, and venetoclax (Venclexta) for such patients.
Frontline therapy does not cure mantle cell lymphoma, and continued relapses are common. In this situation, treatments can include acalabrutinib, ibrutinib, stem cell transplantation, venetoclax, lenalidomide, and rituximab.
In this study, participants will take venetoclax and lenalidomide daily and receive intravenous tafasitamab every 2 weeks after an initial ramp-up period as per clinic standards. Participants will be followed for 5 years after entering the trial. The Mayo Clinic in Rochester, Minnesota, began recruiting the planned 100 trial participants in January 2024. The primary outcome is objective response rate; overall survival is a secondary outcome, and QoL will not be tracked. More details at clinicaltrials.gov.
All trial information is from the National Institutes of Health US National Library of Medicine (online at clinicaltrials.gov).
A version of this article appeared on Medscape.com .
Several clinical trials in leukemia and lymphoma have started enrolling recently. Maybe one of your patients could benefit from taking part?
run by the Center for International Blood and Bone Marrow Transplant Research.
The purpose of the study is to test whether cyclophosphamide, which is given to prevent a dreaded complication of stem cell transplantation called graft-versus-host disease, can be safely reduced without increasing infection or reducing protection. All participants will receive cyclophosphamide on days 3 and 4 post transplant. One group will receive a reduced dose of cyclophosphamide (25 mg/kg per dose), and the other will be given a usual dose (37.5 mg/kg).
Sites in Michigan, Missouri, Oregon, Virginia, and Washington started recruiting for 190 participants in December 2023. Study centers in Florida, Massachusetts, New York, and Wisconsin are also planned. Infection-free survival is the primary endpoint, and overall survival is a secondary measure. Quality of life (QoL) is not recorded. More details at clinicaltrials.gov.
Untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Adults who are newly diagnosed with this type of cancer and have active disease may wish to consider a randomized, open-label, phase 3 trial testing an experimental Bruton tyrosine kinase (BTK) inhibitor, nemtabrutinib (from Merck Sharp & Dohme), against standard-of-care BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence).
BTK inhibitors target B-cell proliferation in B-cell cancers such as CLL/SLL and allow for chemotherapy-free treatment of some hematological malignancies. In this study, until disease progression, unacceptable toxicity, or another reason for discontinuation occurs, participants will take daily oral nemtabrutinib, ibrutinib, or acalabrutinib.
The study opened in December 2023 in Pennsylvania, Washington, Taiwan, Israel, and the United Kingdom seeking 1200 participants. The primary outcomes are objective response rate and progression-free survival. Overall survival is a secondary outcome, and QoL is not measured. More details at clinicaltrials.gov.
Relapsed or refractory leukemia with a KMT2A-gene rearrangement (KMT2A-r). Children aged 1 month to younger than 6 years with this diagnosis may be able to join an open-label, nonrandomized, Children’s Oncology Group phase 2 study to determine the most tolerable and/or effective dose of an experimental oral drug called revumenib when added to chemotherapy.
KMT2A-gene alterations are associated with a poor prognosis in leukemia. These alterations cause blood cells to dedifferentiate and start proliferating uncontrollably as leukemia cells. The expression of the damaged KMT2A gene relies on a protein called menin. Revumenib, from Syndax Pharmaceuticals, blocks menin and prevents expression of KMT2A.
Children in the study will receive two different regimens of revumenib in combination with chemotherapy for up to a year, or until disease progression or unacceptable toxicity, and will then be followed for up to 5 years. Trial centers in 12 US states opened their doors in January 2024 looking for 78 participants. Toxicities and minimal residual disease are the primary outcomes; overall survival is a secondary outcome, and QoL is not assessed. More details at clinicaltrials.gov.
Previously untreated follicular lymphoma or diffuse large B-cell lymphoma. Adults with one of these types of lymphoma may be eligible for one of three open-label, randomized, phase 3 trials testing odronextamab (from Regeneron). This bispecific antibody is designed to ‘lock together’ CD20 on cancer cells with CD3-expressing cancer-killing T cells. It has shown anti-lymphoma activity in heavily pretreated patients.
Late in 2023, three phase 3 trials turned the spotlight on treatment-naive patients and started recruiting 2115 participants to assess odronextamab in this setting. The trial OLYMPIA-1 will compare odronextamab with standard-of-care rituximab (Rituxan) plus chemotherapy in follicular lymphoma. OLYMPIA-2 will test the drug in combination with chemotherapy, also in follicular lymphoma. OLYMPIA-3 will evaluate odronextamab plus chemotherapy against rituximab and chemotherapy in people with large B-cell lymphoma.
All study drugs, including odronextamab, will be administered by intravenous infusion, and participants will be followed for up to 5 years. Research centers across eight US states and Australia, Czechia, France, Italy, Poland, Spain, Turkey, and Thailand are currently accepting participants for the three trials. The primary outcomes are various measures of toxicity and complete response at 30 months in the follicular lymphoma studies and toxicity and progression-free survival in large B-cell lymphoma. All three trials are measuring overall survival and QoL as secondary endpoints.
Previously untreated stage II, III, or IV follicular lymphoma. Adults with this type of cancer may be eligible to participate in a randomized, open-label, phase 3 study testing whether an experimental therapy called epcoritamab (from AbbVie) improves disease response and is tolerable when added to standard therapy. For up to 120 weeks, one group of participants will receive a combination of intravenous rituximab and oral lenalidomide (Revlimid), while a second group will also receive subcutaneous injections of epcoritamab. Some participants may be offered investigators’ choice of chemotherapy as well.
Sites across Iowa, Maryland, Missouri, Ohio, Washington, and Montana started welcoming their 900 participants in February 2024. The primary outcome is complete response at 30 months. Overall survival and QoL are secondary outcomes. More details at clinicaltrials.gov.
Relapsed or refractory mantle cell lymphoma. Adults facing one of these clinical scenarios can join an Academic and Community Cancer Research United open label, phase 2 trial examining the effectiveness of combining tafasitamab (Monjuvi), lenalidomide, and venetoclax (Venclexta) for such patients.
Frontline therapy does not cure mantle cell lymphoma, and continued relapses are common. In this situation, treatments can include acalabrutinib, ibrutinib, stem cell transplantation, venetoclax, lenalidomide, and rituximab.
In this study, participants will take venetoclax and lenalidomide daily and receive intravenous tafasitamab every 2 weeks after an initial ramp-up period as per clinic standards. Participants will be followed for 5 years after entering the trial. The Mayo Clinic in Rochester, Minnesota, began recruiting the planned 100 trial participants in January 2024. The primary outcome is objective response rate; overall survival is a secondary outcome, and QoL will not be tracked. More details at clinicaltrials.gov.
All trial information is from the National Institutes of Health US National Library of Medicine (online at clinicaltrials.gov).
A version of this article appeared on Medscape.com .
Could EHR Pharmacy Errors Put Veterans at Risk?
Will the new US Department of Veterans Affairs (VA) pharmacy software be safe and effective? That was the topic when David Case, the VA Deputy Inspector General, spoke in the US House of Representatives Veterans Affairs Committee technology modernization subcommittee hearing on February 15.
Questions like that have dogged the project since 2018, when the VA began rolling out the Oracle Cerner electronic health record (EHR) system as the successor to ViSTA.
The Oracle system has been beset by one glitch after another since its arrival. And in that time, Case said, the VA Office of Inspector General (OIG) has been engaging with VA employees at sites in Washington, Oregon, Ohio, Illinois, and other locations where the modernization program has been piloted.
The most recent OIG investigation of pharmacy-related patient safety issues began with a review of an allegation of a prescription backlog at Columbus, Ohio, where the system went live on April 30, 2022. The OIG found that facility leaders took “timely and sustainable steps” to manage that issue. However, other unresolved patient safety issues came to light, such as medication inaccuracies, inaccurate medication data, and insufficient staffing. The OIG also found staff were creating “numerous work arounds” to provide patient care, and that the volume of staff educational materials for pharmacy-related functions was “overwhelming.”
Those problems were just the latest in a long queue. In May 2021, after the first VA deployment of the new EHR at the Mann-Grandstaff VA Medical Center in Spokane, Washington, a pharmacy patient safety team under the VA National Center for Patient Safety (NCPS) also had identified patient safety issues and “multiple” concerns regarding the system’s usability. For example, updates to a patient’s active medication list were not routinely reflected at the patient’s next appointment. Despite knowing about such challenges, Case noted in his report, VA leaders deployed the new EHR at 4 more VA medical centers.
Cerner/ViSTA Communication
One major cause of the current problems is the way the systems “talk” to each other. EHR information is communicated between VHA facilities through channels that include the Joint Longitudinal Viewer (JLV) and the Health Data Repository, which stores patient-specific clinical information from both the legacy and the new EHR systems. The JLV application allows clinicians to access a read only version of a patient’s EHR from both systems.
Every medication used in VHA has a VA Unique Identifier (VUID). When a patient is prescribed a medication at a new EHR site, that medication’s VUID is sent to the Health Data Repository. If that patient seeks care from a legacy health care practitioner (HCP), and that HCP enters a medication order, a software interface accesses the VUID from the Health Data Repository to verify that the medication being prescribed is safe and compatible with the medications and allergies previously documented in the patient’s record.
However, on March 31, 2023, staff from a ViSTA site found an incorrect medication order when prescribing a new medication to a patient who had received care and medications at a new EHR site. This in turn led to the discovery that an error in Oracle software coding had resulted in the “widespread transmission” of incorrect VUIDs from new EHR sites to legacy EHR sites, the OIG found. VA leaders and HCPs were notified of the potential clinical impact and were given specific instructions on how to mitigate the issue. They were asked to “please share widely.”
On top of that, days later, patient safety managers across the Veterans Health Administration (VHA) were told that drug-to-drug interactions, duplicate medication orders, and allergy checks were not functioning as expected, and they too were provided with remedial actions.
Oracle applied a successful software patch on in April 2023, to ensure accurate VUIDs were attached to all mail order pharmacy–processed prescriptions from that date forward. However, the OIG learned the incorrect VUIDs sent from new EHR sites and stored in the Health Data Repository from as far back as October 2020 had not been corrected. Case told the subcommittee that on November 29, 2023, the VHA Pharmacy Council reported withdrawing a request for Oracle to send corrected medication VUID data to the Health Data Repository, on the presumption that remaining inaccurate VUIDs would expire in early April 2024, and the data would be corrected at that time.
The OIG is concerned, Case said, that patient medication data remains inaccurate almost a year after VA learned of the issue. The mail order pharmacy-related data generated from approximately 120,000 patients served by new EHR sites are still incorrect. These patients face an ongoing risk of an adverse medication-related event if they receive care and medications from a VA medical center using the legacy EHR system.
The OIG also learned of other problems associated with transmission of medication and allergy information, which could have consequences such as:
- Patient medications being discontinued or stopped by new HCPs using Cerner that appear in ViSTA as active and current prescriptions;
- Allergy-warning messages not appearing when intended or inappropriately appearing for the wrong medication;
- Duplicate medication order checks not appearing when intended or inappropriately appearing for the wrong drug;
- Patient active medication lists having incomplete or inaccurate information, such as missing prescriptions, duplicate prescriptions, or incorrect medication order statuses.
The OIG warned VHA employees about the risks, although it wasn’t possible to determine who might actually be at risk. A VHA leader told the OIG that all patients who have been prescribed any medications or have medication allergies documented at a at a Cerner site are at risk. That could mean as many as 250,000 patients: As of September 2023, approximately 190,000 patients had a medication prescribed and 126,000 had an allergy documented at a new EHR site.
Case Example
Not surprisingly, “the OIG is not confident in [EHRM-Integration Office] leaders’ oversight and control of the new systems’ Health Data Repository interface programming,” Case said. He cited the case of a patient with posttraumatic stress disorder and traumatic brain injury with adrenal insufficiency. Four days prior to admission, a ViSTA site pharmacist used the EHR to perform a medication reconciliation for the patient. The data available did not include the patient’s most recent prednisone prescription, which had been ordered by an HCP at a facility using Cerner.
A nurse practitioner performed another reconciliation when the patient was admitted to the residential program, but the patient was unsure of all their medications. Because the most recent prednisone prescription was not visible in ViSTA, the prednisone appeared to have been completed at least 3 months prior to admission and was therefore not prescribed in the admission medication orders.
Five days into the residential program, the patient began exhibiting unusual behaviors associated with the lack of prednisone. The patient realized they needed more prednisone, but the nurse explained there was no prednisone on the patient’s medication list. Eventually, the patient found the active prednisone order on their personal cell phone and was transferred to a local emergency department for care.
Work Arounds
The VHA’s efforts to forestall or mitigate system errors have in some cases had a cascade effect. For example, HCPs must essentially back up what the automated software is intended to do, with “complex, time-consuming” multistep manual safety checks when prescribing new medications for patients previously cared for at a Cerner site. The OIG is concerned that this increased vigilance is “unsustainable” by pharmacists and frontline staff and could lead to burnout and medication-related patient safety events. After the new EHR launched, the OIG found, burnout symptoms for pharmacy staff increased. Nonetheless, Case told the committee, OIG staff “have observed [employees’] unwavering commitment to prioritizing the care of patients while mitigating implementation challenges.”
EHR-related workload burdens have necessitated other adjustments. Columbus, for instance, hired 9 full-time clinical pharmacists—a 62% staffing increase—to help reduce the backlog. Pharmacy leaders created approximately 29 additional work-arounds to support pharmacy staff and prevent delays. Facility pharmacy leaders also developed approximately 25 educational materials, such as tip sheets, reference guides, and job aids. The OIG’s concern—apart from the overwhelming amount of information for staff to implement—is that such prophylactic measures may in fact give rise to inconsistent practices, which increase risks to patient safety.
Committed to Working With the VA
Mike Sicilia, executive vice president of Oracle Corporation, told lawmakers in the hearing, “After the initial deployments, it became clear that the pharmacy system needed to be enhanced to better meet VA’s needs. To that end, in August 2022, shortly after Oracle completed its acquisition of Cerner, VA contracted with us for seven enhancements that overall would adapt the pharmacy system to a more bidirectional system between VA providers placing prescription orders and VA pharmacists fulfilling and dispensing them.” Those enhancements are all live for VA providers and pharmacists to use now, he said, except for one that is undergoing additional testing.
He added, “As with any healthcare technology system, there is a need for continuous improvements but that does not mean the system is not safe and effective in its current state. Oracle is committed to working with VA … throughout the reset period to identify workflows and other items that can be simplified or streamlined to improve the overall user and pharmacy experience.”
Standardizing workflows and ensuring training and communications to pharmacists about the latest updates will discourage use of work-arounds, Sicilia said, and “help with improving morale and satisfaction with the system.” During a visit in early February by VA and the Oracle team to the Lovell Federal Health Care Center in North Chicago, “feedback from pharmacists was positive about the training and readiness for using the new pharmacy system.”
The backlog, at least, may be resolved. Sicilia said on average more than 215,000 outpatient prescriptions are being filled each month. “The current live sites do not have a backlog in filling prescriptions. Recent data from this month show that three of the five live sites have zero prescriptions waiting to be processed that are older than seven days. The two other live sites have an average of two prescriptions older than seven days,” he said.
Although Oracle Health has since resolved some of the identified issues, the OIG is concerned that the new EHR will continue to be deployed at medical facilities despite “myriad” as-yet unresolved issues related to inaccurate medication ordering, reconciliation, and dispensing. The VHA has paused Cerner deployments multiple times.
“It is unclear whether identified problems are being adequately resolved before additional deployments,” Case said. “There is also the question of whether there is sufficient transparency and communication among EHRM-IO, VHA and facility leaders, VA leaders, and Oracle Health needed for quality control and critical coordination. Trust in VA is also dependent on patients being fully and quickly advised when issues affecting them are identified and addressed. As VA moves toward its deployment next month at a complex facility jointly operated with the Department of Defense, transparency, communication, and program management will be essential to getting it right. Failures in these areas risk cascading problems.”
Will the new US Department of Veterans Affairs (VA) pharmacy software be safe and effective? That was the topic when David Case, the VA Deputy Inspector General, spoke in the US House of Representatives Veterans Affairs Committee technology modernization subcommittee hearing on February 15.
Questions like that have dogged the project since 2018, when the VA began rolling out the Oracle Cerner electronic health record (EHR) system as the successor to ViSTA.
The Oracle system has been beset by one glitch after another since its arrival. And in that time, Case said, the VA Office of Inspector General (OIG) has been engaging with VA employees at sites in Washington, Oregon, Ohio, Illinois, and other locations where the modernization program has been piloted.
The most recent OIG investigation of pharmacy-related patient safety issues began with a review of an allegation of a prescription backlog at Columbus, Ohio, where the system went live on April 30, 2022. The OIG found that facility leaders took “timely and sustainable steps” to manage that issue. However, other unresolved patient safety issues came to light, such as medication inaccuracies, inaccurate medication data, and insufficient staffing. The OIG also found staff were creating “numerous work arounds” to provide patient care, and that the volume of staff educational materials for pharmacy-related functions was “overwhelming.”
Those problems were just the latest in a long queue. In May 2021, after the first VA deployment of the new EHR at the Mann-Grandstaff VA Medical Center in Spokane, Washington, a pharmacy patient safety team under the VA National Center for Patient Safety (NCPS) also had identified patient safety issues and “multiple” concerns regarding the system’s usability. For example, updates to a patient’s active medication list were not routinely reflected at the patient’s next appointment. Despite knowing about such challenges, Case noted in his report, VA leaders deployed the new EHR at 4 more VA medical centers.
Cerner/ViSTA Communication
One major cause of the current problems is the way the systems “talk” to each other. EHR information is communicated between VHA facilities through channels that include the Joint Longitudinal Viewer (JLV) and the Health Data Repository, which stores patient-specific clinical information from both the legacy and the new EHR systems. The JLV application allows clinicians to access a read only version of a patient’s EHR from both systems.
Every medication used in VHA has a VA Unique Identifier (VUID). When a patient is prescribed a medication at a new EHR site, that medication’s VUID is sent to the Health Data Repository. If that patient seeks care from a legacy health care practitioner (HCP), and that HCP enters a medication order, a software interface accesses the VUID from the Health Data Repository to verify that the medication being prescribed is safe and compatible with the medications and allergies previously documented in the patient’s record.
However, on March 31, 2023, staff from a ViSTA site found an incorrect medication order when prescribing a new medication to a patient who had received care and medications at a new EHR site. This in turn led to the discovery that an error in Oracle software coding had resulted in the “widespread transmission” of incorrect VUIDs from new EHR sites to legacy EHR sites, the OIG found. VA leaders and HCPs were notified of the potential clinical impact and were given specific instructions on how to mitigate the issue. They were asked to “please share widely.”
On top of that, days later, patient safety managers across the Veterans Health Administration (VHA) were told that drug-to-drug interactions, duplicate medication orders, and allergy checks were not functioning as expected, and they too were provided with remedial actions.
Oracle applied a successful software patch on in April 2023, to ensure accurate VUIDs were attached to all mail order pharmacy–processed prescriptions from that date forward. However, the OIG learned the incorrect VUIDs sent from new EHR sites and stored in the Health Data Repository from as far back as October 2020 had not been corrected. Case told the subcommittee that on November 29, 2023, the VHA Pharmacy Council reported withdrawing a request for Oracle to send corrected medication VUID data to the Health Data Repository, on the presumption that remaining inaccurate VUIDs would expire in early April 2024, and the data would be corrected at that time.
The OIG is concerned, Case said, that patient medication data remains inaccurate almost a year after VA learned of the issue. The mail order pharmacy-related data generated from approximately 120,000 patients served by new EHR sites are still incorrect. These patients face an ongoing risk of an adverse medication-related event if they receive care and medications from a VA medical center using the legacy EHR system.
The OIG also learned of other problems associated with transmission of medication and allergy information, which could have consequences such as:
- Patient medications being discontinued or stopped by new HCPs using Cerner that appear in ViSTA as active and current prescriptions;
- Allergy-warning messages not appearing when intended or inappropriately appearing for the wrong medication;
- Duplicate medication order checks not appearing when intended or inappropriately appearing for the wrong drug;
- Patient active medication lists having incomplete or inaccurate information, such as missing prescriptions, duplicate prescriptions, or incorrect medication order statuses.
The OIG warned VHA employees about the risks, although it wasn’t possible to determine who might actually be at risk. A VHA leader told the OIG that all patients who have been prescribed any medications or have medication allergies documented at a at a Cerner site are at risk. That could mean as many as 250,000 patients: As of September 2023, approximately 190,000 patients had a medication prescribed and 126,000 had an allergy documented at a new EHR site.
Case Example
Not surprisingly, “the OIG is not confident in [EHRM-Integration Office] leaders’ oversight and control of the new systems’ Health Data Repository interface programming,” Case said. He cited the case of a patient with posttraumatic stress disorder and traumatic brain injury with adrenal insufficiency. Four days prior to admission, a ViSTA site pharmacist used the EHR to perform a medication reconciliation for the patient. The data available did not include the patient’s most recent prednisone prescription, which had been ordered by an HCP at a facility using Cerner.
A nurse practitioner performed another reconciliation when the patient was admitted to the residential program, but the patient was unsure of all their medications. Because the most recent prednisone prescription was not visible in ViSTA, the prednisone appeared to have been completed at least 3 months prior to admission and was therefore not prescribed in the admission medication orders.
Five days into the residential program, the patient began exhibiting unusual behaviors associated with the lack of prednisone. The patient realized they needed more prednisone, but the nurse explained there was no prednisone on the patient’s medication list. Eventually, the patient found the active prednisone order on their personal cell phone and was transferred to a local emergency department for care.
Work Arounds
The VHA’s efforts to forestall or mitigate system errors have in some cases had a cascade effect. For example, HCPs must essentially back up what the automated software is intended to do, with “complex, time-consuming” multistep manual safety checks when prescribing new medications for patients previously cared for at a Cerner site. The OIG is concerned that this increased vigilance is “unsustainable” by pharmacists and frontline staff and could lead to burnout and medication-related patient safety events. After the new EHR launched, the OIG found, burnout symptoms for pharmacy staff increased. Nonetheless, Case told the committee, OIG staff “have observed [employees’] unwavering commitment to prioritizing the care of patients while mitigating implementation challenges.”
EHR-related workload burdens have necessitated other adjustments. Columbus, for instance, hired 9 full-time clinical pharmacists—a 62% staffing increase—to help reduce the backlog. Pharmacy leaders created approximately 29 additional work-arounds to support pharmacy staff and prevent delays. Facility pharmacy leaders also developed approximately 25 educational materials, such as tip sheets, reference guides, and job aids. The OIG’s concern—apart from the overwhelming amount of information for staff to implement—is that such prophylactic measures may in fact give rise to inconsistent practices, which increase risks to patient safety.
Committed to Working With the VA
Mike Sicilia, executive vice president of Oracle Corporation, told lawmakers in the hearing, “After the initial deployments, it became clear that the pharmacy system needed to be enhanced to better meet VA’s needs. To that end, in August 2022, shortly after Oracle completed its acquisition of Cerner, VA contracted with us for seven enhancements that overall would adapt the pharmacy system to a more bidirectional system between VA providers placing prescription orders and VA pharmacists fulfilling and dispensing them.” Those enhancements are all live for VA providers and pharmacists to use now, he said, except for one that is undergoing additional testing.
He added, “As with any healthcare technology system, there is a need for continuous improvements but that does not mean the system is not safe and effective in its current state. Oracle is committed to working with VA … throughout the reset period to identify workflows and other items that can be simplified or streamlined to improve the overall user and pharmacy experience.”
Standardizing workflows and ensuring training and communications to pharmacists about the latest updates will discourage use of work-arounds, Sicilia said, and “help with improving morale and satisfaction with the system.” During a visit in early February by VA and the Oracle team to the Lovell Federal Health Care Center in North Chicago, “feedback from pharmacists was positive about the training and readiness for using the new pharmacy system.”
The backlog, at least, may be resolved. Sicilia said on average more than 215,000 outpatient prescriptions are being filled each month. “The current live sites do not have a backlog in filling prescriptions. Recent data from this month show that three of the five live sites have zero prescriptions waiting to be processed that are older than seven days. The two other live sites have an average of two prescriptions older than seven days,” he said.
Although Oracle Health has since resolved some of the identified issues, the OIG is concerned that the new EHR will continue to be deployed at medical facilities despite “myriad” as-yet unresolved issues related to inaccurate medication ordering, reconciliation, and dispensing. The VHA has paused Cerner deployments multiple times.
“It is unclear whether identified problems are being adequately resolved before additional deployments,” Case said. “There is also the question of whether there is sufficient transparency and communication among EHRM-IO, VHA and facility leaders, VA leaders, and Oracle Health needed for quality control and critical coordination. Trust in VA is also dependent on patients being fully and quickly advised when issues affecting them are identified and addressed. As VA moves toward its deployment next month at a complex facility jointly operated with the Department of Defense, transparency, communication, and program management will be essential to getting it right. Failures in these areas risk cascading problems.”
Will the new US Department of Veterans Affairs (VA) pharmacy software be safe and effective? That was the topic when David Case, the VA Deputy Inspector General, spoke in the US House of Representatives Veterans Affairs Committee technology modernization subcommittee hearing on February 15.
Questions like that have dogged the project since 2018, when the VA began rolling out the Oracle Cerner electronic health record (EHR) system as the successor to ViSTA.
The Oracle system has been beset by one glitch after another since its arrival. And in that time, Case said, the VA Office of Inspector General (OIG) has been engaging with VA employees at sites in Washington, Oregon, Ohio, Illinois, and other locations where the modernization program has been piloted.
The most recent OIG investigation of pharmacy-related patient safety issues began with a review of an allegation of a prescription backlog at Columbus, Ohio, where the system went live on April 30, 2022. The OIG found that facility leaders took “timely and sustainable steps” to manage that issue. However, other unresolved patient safety issues came to light, such as medication inaccuracies, inaccurate medication data, and insufficient staffing. The OIG also found staff were creating “numerous work arounds” to provide patient care, and that the volume of staff educational materials for pharmacy-related functions was “overwhelming.”
Those problems were just the latest in a long queue. In May 2021, after the first VA deployment of the new EHR at the Mann-Grandstaff VA Medical Center in Spokane, Washington, a pharmacy patient safety team under the VA National Center for Patient Safety (NCPS) also had identified patient safety issues and “multiple” concerns regarding the system’s usability. For example, updates to a patient’s active medication list were not routinely reflected at the patient’s next appointment. Despite knowing about such challenges, Case noted in his report, VA leaders deployed the new EHR at 4 more VA medical centers.
Cerner/ViSTA Communication
One major cause of the current problems is the way the systems “talk” to each other. EHR information is communicated between VHA facilities through channels that include the Joint Longitudinal Viewer (JLV) and the Health Data Repository, which stores patient-specific clinical information from both the legacy and the new EHR systems. The JLV application allows clinicians to access a read only version of a patient’s EHR from both systems.
Every medication used in VHA has a VA Unique Identifier (VUID). When a patient is prescribed a medication at a new EHR site, that medication’s VUID is sent to the Health Data Repository. If that patient seeks care from a legacy health care practitioner (HCP), and that HCP enters a medication order, a software interface accesses the VUID from the Health Data Repository to verify that the medication being prescribed is safe and compatible with the medications and allergies previously documented in the patient’s record.
However, on March 31, 2023, staff from a ViSTA site found an incorrect medication order when prescribing a new medication to a patient who had received care and medications at a new EHR site. This in turn led to the discovery that an error in Oracle software coding had resulted in the “widespread transmission” of incorrect VUIDs from new EHR sites to legacy EHR sites, the OIG found. VA leaders and HCPs were notified of the potential clinical impact and were given specific instructions on how to mitigate the issue. They were asked to “please share widely.”
On top of that, days later, patient safety managers across the Veterans Health Administration (VHA) were told that drug-to-drug interactions, duplicate medication orders, and allergy checks were not functioning as expected, and they too were provided with remedial actions.
Oracle applied a successful software patch on in April 2023, to ensure accurate VUIDs were attached to all mail order pharmacy–processed prescriptions from that date forward. However, the OIG learned the incorrect VUIDs sent from new EHR sites and stored in the Health Data Repository from as far back as October 2020 had not been corrected. Case told the subcommittee that on November 29, 2023, the VHA Pharmacy Council reported withdrawing a request for Oracle to send corrected medication VUID data to the Health Data Repository, on the presumption that remaining inaccurate VUIDs would expire in early April 2024, and the data would be corrected at that time.
The OIG is concerned, Case said, that patient medication data remains inaccurate almost a year after VA learned of the issue. The mail order pharmacy-related data generated from approximately 120,000 patients served by new EHR sites are still incorrect. These patients face an ongoing risk of an adverse medication-related event if they receive care and medications from a VA medical center using the legacy EHR system.
The OIG also learned of other problems associated with transmission of medication and allergy information, which could have consequences such as:
- Patient medications being discontinued or stopped by new HCPs using Cerner that appear in ViSTA as active and current prescriptions;
- Allergy-warning messages not appearing when intended or inappropriately appearing for the wrong medication;
- Duplicate medication order checks not appearing when intended or inappropriately appearing for the wrong drug;
- Patient active medication lists having incomplete or inaccurate information, such as missing prescriptions, duplicate prescriptions, or incorrect medication order statuses.
The OIG warned VHA employees about the risks, although it wasn’t possible to determine who might actually be at risk. A VHA leader told the OIG that all patients who have been prescribed any medications or have medication allergies documented at a at a Cerner site are at risk. That could mean as many as 250,000 patients: As of September 2023, approximately 190,000 patients had a medication prescribed and 126,000 had an allergy documented at a new EHR site.
Case Example
Not surprisingly, “the OIG is not confident in [EHRM-Integration Office] leaders’ oversight and control of the new systems’ Health Data Repository interface programming,” Case said. He cited the case of a patient with posttraumatic stress disorder and traumatic brain injury with adrenal insufficiency. Four days prior to admission, a ViSTA site pharmacist used the EHR to perform a medication reconciliation for the patient. The data available did not include the patient’s most recent prednisone prescription, which had been ordered by an HCP at a facility using Cerner.
A nurse practitioner performed another reconciliation when the patient was admitted to the residential program, but the patient was unsure of all their medications. Because the most recent prednisone prescription was not visible in ViSTA, the prednisone appeared to have been completed at least 3 months prior to admission and was therefore not prescribed in the admission medication orders.
Five days into the residential program, the patient began exhibiting unusual behaviors associated with the lack of prednisone. The patient realized they needed more prednisone, but the nurse explained there was no prednisone on the patient’s medication list. Eventually, the patient found the active prednisone order on their personal cell phone and was transferred to a local emergency department for care.
Work Arounds
The VHA’s efforts to forestall or mitigate system errors have in some cases had a cascade effect. For example, HCPs must essentially back up what the automated software is intended to do, with “complex, time-consuming” multistep manual safety checks when prescribing new medications for patients previously cared for at a Cerner site. The OIG is concerned that this increased vigilance is “unsustainable” by pharmacists and frontline staff and could lead to burnout and medication-related patient safety events. After the new EHR launched, the OIG found, burnout symptoms for pharmacy staff increased. Nonetheless, Case told the committee, OIG staff “have observed [employees’] unwavering commitment to prioritizing the care of patients while mitigating implementation challenges.”
EHR-related workload burdens have necessitated other adjustments. Columbus, for instance, hired 9 full-time clinical pharmacists—a 62% staffing increase—to help reduce the backlog. Pharmacy leaders created approximately 29 additional work-arounds to support pharmacy staff and prevent delays. Facility pharmacy leaders also developed approximately 25 educational materials, such as tip sheets, reference guides, and job aids. The OIG’s concern—apart from the overwhelming amount of information for staff to implement—is that such prophylactic measures may in fact give rise to inconsistent practices, which increase risks to patient safety.
Committed to Working With the VA
Mike Sicilia, executive vice president of Oracle Corporation, told lawmakers in the hearing, “After the initial deployments, it became clear that the pharmacy system needed to be enhanced to better meet VA’s needs. To that end, in August 2022, shortly after Oracle completed its acquisition of Cerner, VA contracted with us for seven enhancements that overall would adapt the pharmacy system to a more bidirectional system between VA providers placing prescription orders and VA pharmacists fulfilling and dispensing them.” Those enhancements are all live for VA providers and pharmacists to use now, he said, except for one that is undergoing additional testing.
He added, “As with any healthcare technology system, there is a need for continuous improvements but that does not mean the system is not safe and effective in its current state. Oracle is committed to working with VA … throughout the reset period to identify workflows and other items that can be simplified or streamlined to improve the overall user and pharmacy experience.”
Standardizing workflows and ensuring training and communications to pharmacists about the latest updates will discourage use of work-arounds, Sicilia said, and “help with improving morale and satisfaction with the system.” During a visit in early February by VA and the Oracle team to the Lovell Federal Health Care Center in North Chicago, “feedback from pharmacists was positive about the training and readiness for using the new pharmacy system.”
The backlog, at least, may be resolved. Sicilia said on average more than 215,000 outpatient prescriptions are being filled each month. “The current live sites do not have a backlog in filling prescriptions. Recent data from this month show that three of the five live sites have zero prescriptions waiting to be processed that are older than seven days. The two other live sites have an average of two prescriptions older than seven days,” he said.
Although Oracle Health has since resolved some of the identified issues, the OIG is concerned that the new EHR will continue to be deployed at medical facilities despite “myriad” as-yet unresolved issues related to inaccurate medication ordering, reconciliation, and dispensing. The VHA has paused Cerner deployments multiple times.
“It is unclear whether identified problems are being adequately resolved before additional deployments,” Case said. “There is also the question of whether there is sufficient transparency and communication among EHRM-IO, VHA and facility leaders, VA leaders, and Oracle Health needed for quality control and critical coordination. Trust in VA is also dependent on patients being fully and quickly advised when issues affecting them are identified and addressed. As VA moves toward its deployment next month at a complex facility jointly operated with the Department of Defense, transparency, communication, and program management will be essential to getting it right. Failures in these areas risk cascading problems.”
Is Metformin a ‘Drug for All Diseases’?
In 2021 alone, clinicians wrote more than 91 million orders for the medication — up from 40 million 2004.
But is metformin just getting started? Emerging evidence suggests the drug may be effective for a much broader range of conditions beyond managing high blood glucose, including various cancers, obesity, liver disease, cardiovascular, neurodegenerative, and renal diseases. As the evidence for diverse uses accumulates, many trials have launched, with researchers looking to expand metformin’s indications and validate or explore new directions.
Metformin’s long history as a pharmaceutical includes an herbal ancestry, recognition in 1918 for its ability to lower blood glucose, being cast aside because of toxicity fears in the 1930s, rediscovery and synthesis in Europe in the 1940s, the first reported use for diabetes in 1957, and approval in the United States in 1994.
The drug has maintained its place as the preferred first-line treatment for type 2 diabetes since 2011, when it was first included in the World Health Organization’s essential medicines list.
“The focus hitherto has been primarily on its insulin sensitization effects,” Akshay Jain, MD, a clinical and research endocrinologist at TLC Diabetes and Endocrinology, in Surrey, British Columbia, Canada, told this news organization.
“The recent surge of renewed interest is in part related to its postulated effects on multiple other receptors,” he said. “In my mind, the metformin data on coronary artery disease reduction and cancer-protective effects have come farther along than other disease states.”
Cardiovascular Outcomes
Gregory G. Schwartz, MD, PhD, chief of the cardiology section at Rocky Mountain Regional VA Medical Center and professor of medicine at the University of Colorado School of Medicine in Aurora, is leading the VA-IMPACT trial. Despite metformin’s long history and widespread use, he said his study is the first placebo-controlled cardiovascular outcomes trial of the drug.
Launched in 2023, the study tests the hypothesis that metformin reduces the risk for death or nonfatal ischemic cardiovascular events in patients with prediabetes and established coronary, cerebrovascular, or peripheral artery disease, Dr. Schwartz said. The trial is being conducted at roughly 40 VA medical centers, with a planned enrollment of 7410 patients. The estimated completion date is March 2029.
“The principal mechanism of action of metformin is through activation of AMP [adenosine monophosphate]–activated protein kinase, a central pathway in metabolic regulation, cell protection, and survival,” Dr. Schwartz explained. “Experimental data have demonstrated attenuated development of atherosclerosis, reduced myocardial infarct size, improved endothelial function, and antiarrhythmic actions — none of those dependent on the presence of diabetes.”
Dr. Schwartz and his colleagues decided to test their hypothesis in people with prediabetes, rather than diabetes, to create a “true placebo-controlled comparison,” he said.
“If patients with type 2 diabetes had been chosen, there would be potential for confounding because a placebo group would require more treatment with other active antihyperglycemic medications to achieve the same degree of glycemic control as a metformin group,” Dr. Schwartz said.
“If proven efficacious in the VA-IMPACT trial, metformin could provide an inexpensive, generally safe, and well-tolerated approach to reduce cardiovascular morbidity and mortality in a large segment of the population,” Dr. Schwartz added. “Perhaps the old dog can learn some new tricks.”
Other recruiting trials looking at cardiovascular-related outcomes include Met-PEF, LIMIT, and Metformin as an Adjunctive Therapy to Catheter Ablation in Atrial Fibrillation.
Reducing Cancer Risks
Sai Yendamuri, MD, chair of the Department of Thoracic Surgery and director of the Thoracic Surgery Laboratory at Roswell Park Comprehensive Cancer Center in Buffalo, New York, is leading a phase 2 trial exploring whether metformin can prevent lung cancer in people with overweight or obesity who are at a high risk for the malignancy.
The study, which has accrued about 60% of its estimated enrollment, also will assess whether metformin can reprogram participants’ immune systems, with a view toward reducing the activity of regulatory T cells that are linked to development of tumors.
“In our preclinical and retrospective clinical data, we found that metformin had anticancer effects but only if the patients were overweight,” Dr. Yendamuri said. “In mice, we find that obesity increases regulatory T-cell function, which suppresses the immune system of the lungs. This effect is reversed by metformin.” The team is conducting the current study to examine if this happens in patients, as well. Results are expected next year.
Research is underway in other tumor types, including oral and endometrial, and brain cancers.
Preventing Alzheimer’s Disease
Cognitive function — or at least delaying its erosion — represents another front for metformin. José A. Luchsinger, MD, MPH, vice-chair for clinical and epidemiological research and director of the section on geriatrics, gerontology, and aging at Columbia University Irving Medical Center in New York City, is heading a phase 2/3 randomized controlled trial assessing the ability of the drug to prevent Alzheimer›s disease.
The study investigators hope to enroll 326 men and women aged 55-90 years with early and late mild cognitive impairment, overweight or obesity, and no diabetes.
“The hypothesis is that improving insulin and glucose levels can lead to lowering the risk of Alzheimer’s disease,” Dr. Luchsinger said. Recruitment should be complete by the end of 2024 and results are expected in late 2026.
Similar studies are underway in Europe and Asia.
Other areas of investigation, while tantalizing, are mostly in early stages, although bolstered by preclinical and mechanistic studies. The authors of a recent review on the potential mechanisms of action of metformin and existing evidence of the drug›s effectiveness — or lack thereof — in treating diseases other than diabetes, wrote: “Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an antihyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct antiviral actions.”
Off-Label Uses
Metformin currently is approved by the US Food and Drug Administration only for the treatment of type 2 diabetes, although it is also the only antidiabetic medication for prediabetes currently recommended by the American Diabetes Association.
Some studies currently are looking at its use in a variety of off-label indications, including obesity, gestational diabetes, weight gain from antipsychotics, and polycystic ovary syndrome.
For the most part, metformin is considered a safe drug, but it is not risk-free, Dr. Jain cautioned.
“Although it would certainly be helpful to see if this inexpensive medication that’s universally available can help in disease states, one shouldn’t overlook the potential risk of adverse effects, such as gastrointestinal, potential vitamin B12 deficiency, blunting of skeletal muscle development and the rare risk of lactic acidosis in those with kidney impairment,” he said.
“Similarly, with recent reports of the carcinogenic potential of certain formulations of long-acting metformin that contained NDMA [N-nitrosodimethylamine], it would be imperative that these kinks are removed before we incorporate metformin as the gift that keeps giving.”
Dr. Jain reported financial relationships with Abbott, Amgen, Boehringer Ingelheim, Dexcom, Eli Lilly, Janssen, Medtronic, Merck, and Novo Nordisk. Dr. Yendamuri disclosed serving on the scientific advisory board member of Karkinos Healthcare and research funding from Lumeda for the metformin study. Dr. Luchsinger reported receiving donated metformin and matching placebo from EMD Serono, a subsidiary of Merck, for the MAP study. Dr. Schwartz received research support from the US Department of Veterans Affairs as National Chair of the VA-IMPACT trial.
A version of this article appeared on Medscape.com.
In 2021 alone, clinicians wrote more than 91 million orders for the medication — up from 40 million 2004.
But is metformin just getting started? Emerging evidence suggests the drug may be effective for a much broader range of conditions beyond managing high blood glucose, including various cancers, obesity, liver disease, cardiovascular, neurodegenerative, and renal diseases. As the evidence for diverse uses accumulates, many trials have launched, with researchers looking to expand metformin’s indications and validate or explore new directions.
Metformin’s long history as a pharmaceutical includes an herbal ancestry, recognition in 1918 for its ability to lower blood glucose, being cast aside because of toxicity fears in the 1930s, rediscovery and synthesis in Europe in the 1940s, the first reported use for diabetes in 1957, and approval in the United States in 1994.
The drug has maintained its place as the preferred first-line treatment for type 2 diabetes since 2011, when it was first included in the World Health Organization’s essential medicines list.
“The focus hitherto has been primarily on its insulin sensitization effects,” Akshay Jain, MD, a clinical and research endocrinologist at TLC Diabetes and Endocrinology, in Surrey, British Columbia, Canada, told this news organization.
“The recent surge of renewed interest is in part related to its postulated effects on multiple other receptors,” he said. “In my mind, the metformin data on coronary artery disease reduction and cancer-protective effects have come farther along than other disease states.”
Cardiovascular Outcomes
Gregory G. Schwartz, MD, PhD, chief of the cardiology section at Rocky Mountain Regional VA Medical Center and professor of medicine at the University of Colorado School of Medicine in Aurora, is leading the VA-IMPACT trial. Despite metformin’s long history and widespread use, he said his study is the first placebo-controlled cardiovascular outcomes trial of the drug.
Launched in 2023, the study tests the hypothesis that metformin reduces the risk for death or nonfatal ischemic cardiovascular events in patients with prediabetes and established coronary, cerebrovascular, or peripheral artery disease, Dr. Schwartz said. The trial is being conducted at roughly 40 VA medical centers, with a planned enrollment of 7410 patients. The estimated completion date is March 2029.
“The principal mechanism of action of metformin is through activation of AMP [adenosine monophosphate]–activated protein kinase, a central pathway in metabolic regulation, cell protection, and survival,” Dr. Schwartz explained. “Experimental data have demonstrated attenuated development of atherosclerosis, reduced myocardial infarct size, improved endothelial function, and antiarrhythmic actions — none of those dependent on the presence of diabetes.”
Dr. Schwartz and his colleagues decided to test their hypothesis in people with prediabetes, rather than diabetes, to create a “true placebo-controlled comparison,” he said.
“If patients with type 2 diabetes had been chosen, there would be potential for confounding because a placebo group would require more treatment with other active antihyperglycemic medications to achieve the same degree of glycemic control as a metformin group,” Dr. Schwartz said.
“If proven efficacious in the VA-IMPACT trial, metformin could provide an inexpensive, generally safe, and well-tolerated approach to reduce cardiovascular morbidity and mortality in a large segment of the population,” Dr. Schwartz added. “Perhaps the old dog can learn some new tricks.”
Other recruiting trials looking at cardiovascular-related outcomes include Met-PEF, LIMIT, and Metformin as an Adjunctive Therapy to Catheter Ablation in Atrial Fibrillation.
Reducing Cancer Risks
Sai Yendamuri, MD, chair of the Department of Thoracic Surgery and director of the Thoracic Surgery Laboratory at Roswell Park Comprehensive Cancer Center in Buffalo, New York, is leading a phase 2 trial exploring whether metformin can prevent lung cancer in people with overweight or obesity who are at a high risk for the malignancy.
The study, which has accrued about 60% of its estimated enrollment, also will assess whether metformin can reprogram participants’ immune systems, with a view toward reducing the activity of regulatory T cells that are linked to development of tumors.
“In our preclinical and retrospective clinical data, we found that metformin had anticancer effects but only if the patients were overweight,” Dr. Yendamuri said. “In mice, we find that obesity increases regulatory T-cell function, which suppresses the immune system of the lungs. This effect is reversed by metformin.” The team is conducting the current study to examine if this happens in patients, as well. Results are expected next year.
Research is underway in other tumor types, including oral and endometrial, and brain cancers.
Preventing Alzheimer’s Disease
Cognitive function — or at least delaying its erosion — represents another front for metformin. José A. Luchsinger, MD, MPH, vice-chair for clinical and epidemiological research and director of the section on geriatrics, gerontology, and aging at Columbia University Irving Medical Center in New York City, is heading a phase 2/3 randomized controlled trial assessing the ability of the drug to prevent Alzheimer›s disease.
The study investigators hope to enroll 326 men and women aged 55-90 years with early and late mild cognitive impairment, overweight or obesity, and no diabetes.
“The hypothesis is that improving insulin and glucose levels can lead to lowering the risk of Alzheimer’s disease,” Dr. Luchsinger said. Recruitment should be complete by the end of 2024 and results are expected in late 2026.
Similar studies are underway in Europe and Asia.
Other areas of investigation, while tantalizing, are mostly in early stages, although bolstered by preclinical and mechanistic studies. The authors of a recent review on the potential mechanisms of action of metformin and existing evidence of the drug›s effectiveness — or lack thereof — in treating diseases other than diabetes, wrote: “Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an antihyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct antiviral actions.”
Off-Label Uses
Metformin currently is approved by the US Food and Drug Administration only for the treatment of type 2 diabetes, although it is also the only antidiabetic medication for prediabetes currently recommended by the American Diabetes Association.
Some studies currently are looking at its use in a variety of off-label indications, including obesity, gestational diabetes, weight gain from antipsychotics, and polycystic ovary syndrome.
For the most part, metformin is considered a safe drug, but it is not risk-free, Dr. Jain cautioned.
“Although it would certainly be helpful to see if this inexpensive medication that’s universally available can help in disease states, one shouldn’t overlook the potential risk of adverse effects, such as gastrointestinal, potential vitamin B12 deficiency, blunting of skeletal muscle development and the rare risk of lactic acidosis in those with kidney impairment,” he said.
“Similarly, with recent reports of the carcinogenic potential of certain formulations of long-acting metformin that contained NDMA [N-nitrosodimethylamine], it would be imperative that these kinks are removed before we incorporate metformin as the gift that keeps giving.”
Dr. Jain reported financial relationships with Abbott, Amgen, Boehringer Ingelheim, Dexcom, Eli Lilly, Janssen, Medtronic, Merck, and Novo Nordisk. Dr. Yendamuri disclosed serving on the scientific advisory board member of Karkinos Healthcare and research funding from Lumeda for the metformin study. Dr. Luchsinger reported receiving donated metformin and matching placebo from EMD Serono, a subsidiary of Merck, for the MAP study. Dr. Schwartz received research support from the US Department of Veterans Affairs as National Chair of the VA-IMPACT trial.
A version of this article appeared on Medscape.com.
In 2021 alone, clinicians wrote more than 91 million orders for the medication — up from 40 million 2004.
But is metformin just getting started? Emerging evidence suggests the drug may be effective for a much broader range of conditions beyond managing high blood glucose, including various cancers, obesity, liver disease, cardiovascular, neurodegenerative, and renal diseases. As the evidence for diverse uses accumulates, many trials have launched, with researchers looking to expand metformin’s indications and validate or explore new directions.
Metformin’s long history as a pharmaceutical includes an herbal ancestry, recognition in 1918 for its ability to lower blood glucose, being cast aside because of toxicity fears in the 1930s, rediscovery and synthesis in Europe in the 1940s, the first reported use for diabetes in 1957, and approval in the United States in 1994.
The drug has maintained its place as the preferred first-line treatment for type 2 diabetes since 2011, when it was first included in the World Health Organization’s essential medicines list.
“The focus hitherto has been primarily on its insulin sensitization effects,” Akshay Jain, MD, a clinical and research endocrinologist at TLC Diabetes and Endocrinology, in Surrey, British Columbia, Canada, told this news organization.
“The recent surge of renewed interest is in part related to its postulated effects on multiple other receptors,” he said. “In my mind, the metformin data on coronary artery disease reduction and cancer-protective effects have come farther along than other disease states.”
Cardiovascular Outcomes
Gregory G. Schwartz, MD, PhD, chief of the cardiology section at Rocky Mountain Regional VA Medical Center and professor of medicine at the University of Colorado School of Medicine in Aurora, is leading the VA-IMPACT trial. Despite metformin’s long history and widespread use, he said his study is the first placebo-controlled cardiovascular outcomes trial of the drug.
Launched in 2023, the study tests the hypothesis that metformin reduces the risk for death or nonfatal ischemic cardiovascular events in patients with prediabetes and established coronary, cerebrovascular, or peripheral artery disease, Dr. Schwartz said. The trial is being conducted at roughly 40 VA medical centers, with a planned enrollment of 7410 patients. The estimated completion date is March 2029.
“The principal mechanism of action of metformin is through activation of AMP [adenosine monophosphate]–activated protein kinase, a central pathway in metabolic regulation, cell protection, and survival,” Dr. Schwartz explained. “Experimental data have demonstrated attenuated development of atherosclerosis, reduced myocardial infarct size, improved endothelial function, and antiarrhythmic actions — none of those dependent on the presence of diabetes.”
Dr. Schwartz and his colleagues decided to test their hypothesis in people with prediabetes, rather than diabetes, to create a “true placebo-controlled comparison,” he said.
“If patients with type 2 diabetes had been chosen, there would be potential for confounding because a placebo group would require more treatment with other active antihyperglycemic medications to achieve the same degree of glycemic control as a metformin group,” Dr. Schwartz said.
“If proven efficacious in the VA-IMPACT trial, metformin could provide an inexpensive, generally safe, and well-tolerated approach to reduce cardiovascular morbidity and mortality in a large segment of the population,” Dr. Schwartz added. “Perhaps the old dog can learn some new tricks.”
Other recruiting trials looking at cardiovascular-related outcomes include Met-PEF, LIMIT, and Metformin as an Adjunctive Therapy to Catheter Ablation in Atrial Fibrillation.
Reducing Cancer Risks
Sai Yendamuri, MD, chair of the Department of Thoracic Surgery and director of the Thoracic Surgery Laboratory at Roswell Park Comprehensive Cancer Center in Buffalo, New York, is leading a phase 2 trial exploring whether metformin can prevent lung cancer in people with overweight or obesity who are at a high risk for the malignancy.
The study, which has accrued about 60% of its estimated enrollment, also will assess whether metformin can reprogram participants’ immune systems, with a view toward reducing the activity of regulatory T cells that are linked to development of tumors.
“In our preclinical and retrospective clinical data, we found that metformin had anticancer effects but only if the patients were overweight,” Dr. Yendamuri said. “In mice, we find that obesity increases regulatory T-cell function, which suppresses the immune system of the lungs. This effect is reversed by metformin.” The team is conducting the current study to examine if this happens in patients, as well. Results are expected next year.
Research is underway in other tumor types, including oral and endometrial, and brain cancers.
Preventing Alzheimer’s Disease
Cognitive function — or at least delaying its erosion — represents another front for metformin. José A. Luchsinger, MD, MPH, vice-chair for clinical and epidemiological research and director of the section on geriatrics, gerontology, and aging at Columbia University Irving Medical Center in New York City, is heading a phase 2/3 randomized controlled trial assessing the ability of the drug to prevent Alzheimer›s disease.
The study investigators hope to enroll 326 men and women aged 55-90 years with early and late mild cognitive impairment, overweight or obesity, and no diabetes.
“The hypothesis is that improving insulin and glucose levels can lead to lowering the risk of Alzheimer’s disease,” Dr. Luchsinger said. Recruitment should be complete by the end of 2024 and results are expected in late 2026.
Similar studies are underway in Europe and Asia.
Other areas of investigation, while tantalizing, are mostly in early stages, although bolstered by preclinical and mechanistic studies. The authors of a recent review on the potential mechanisms of action of metformin and existing evidence of the drug›s effectiveness — or lack thereof — in treating diseases other than diabetes, wrote: “Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an antihyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct antiviral actions.”
Off-Label Uses
Metformin currently is approved by the US Food and Drug Administration only for the treatment of type 2 diabetes, although it is also the only antidiabetic medication for prediabetes currently recommended by the American Diabetes Association.
Some studies currently are looking at its use in a variety of off-label indications, including obesity, gestational diabetes, weight gain from antipsychotics, and polycystic ovary syndrome.
For the most part, metformin is considered a safe drug, but it is not risk-free, Dr. Jain cautioned.
“Although it would certainly be helpful to see if this inexpensive medication that’s universally available can help in disease states, one shouldn’t overlook the potential risk of adverse effects, such as gastrointestinal, potential vitamin B12 deficiency, blunting of skeletal muscle development and the rare risk of lactic acidosis in those with kidney impairment,” he said.
“Similarly, with recent reports of the carcinogenic potential of certain formulations of long-acting metformin that contained NDMA [N-nitrosodimethylamine], it would be imperative that these kinks are removed before we incorporate metformin as the gift that keeps giving.”
Dr. Jain reported financial relationships with Abbott, Amgen, Boehringer Ingelheim, Dexcom, Eli Lilly, Janssen, Medtronic, Merck, and Novo Nordisk. Dr. Yendamuri disclosed serving on the scientific advisory board member of Karkinos Healthcare and research funding from Lumeda for the metformin study. Dr. Luchsinger reported receiving donated metformin and matching placebo from EMD Serono, a subsidiary of Merck, for the MAP study. Dr. Schwartz received research support from the US Department of Veterans Affairs as National Chair of the VA-IMPACT trial.
A version of this article appeared on Medscape.com.