Clinical Topics & News

People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.

“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.

“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.

Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.

“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.

The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.

“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”

The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.

Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.

The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”

Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).

In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1­-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.

“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.

“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”

The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”

The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.

 

People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.

“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.

“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.

Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.

“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.

The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.

“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”

The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.

Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.

The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”

Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).

In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1­-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.

“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.

“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”

The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”

The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.

 

People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.

“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.

“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.

Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.

“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.

The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.

“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”

The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.

Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.

The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”

Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).

In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1­-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.

“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.

“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”

The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”

The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.

 

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

Thinglass/iStock Editorial/Getty Images

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

Thinglass/iStock Editorial/Getty Images

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

Thinglass/iStock Editorial/Getty Images

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Questions about how to prescribe statins for primary prevention abound more than 3 decades after the drugs swept into clinical practice to become a first-line medical approach to cutting cardiovascular (CV) risk. Statin usage recommendations from different bodies can vary in ways both limited and fundamental, spurring the kind of debate that accompanies such a document newly issued by the United States Preventive Services Task Force.

The document, little changed from the draft guidance released for public comment in February, was published online Aug. 23 in JAMA and the USPSTF website. It replaces a similar document issued by the task force in 2016.

The guidance has much in common with, but also sharp differences from, the influential 2018 guidelines on blood cholesterol management developed by the American College of Cardiology, American Heart Association, and 10 other medical societies.

And it is provocative enough to elicit at least four editorials issued the same day across the JAMA family of journals. They highlight key differences between the two documents, among them the USPSTF guidance’s consistent, narrow reliance on 7.5% and 10% cut points for 10-year risk levels as estimated from the ACC/AHA pooled cohort equations (PCE).  

The guidance pairs the 10-year risk metric with at least one of only four prescribed CV risk factors to arrive at a limited choice of statin therapy recommendations. But its decision process isn’t bolstered by coronary artery calcium (CAC) scores or the prespecified “risk enhancers” that allowed the ACC/AHA-multisociety guidelines to be applied broadly and still be closely personalized. Those guidelines provide more PCE-based risk tiers for greater discrimination of risk and allow statins to be considered across a broader age group.

The USPSTF guidance’s evidence base consists of 23 clinical trials and three observational studies that directly compared a statin to either placebo or no statin, task force member John B. Wong, MD, Tufts University School of Medicine, Boston, told this news organization.

“In either kind of study, we found that the vast majority of patients had one or more of four risk factors – dyslipidemia, hypertension, diabetes, or smoking. So, when we categorized high risk or increased risk, we included the presence of one or more of those risk factors,” said Dr. Wong, who is director of comparative effectiveness research at Tufts Clinical Translational Science Institute.
 

‘Sensible and practical’

The USPSTF guidance applies only to adults aged 40-75 without CV signs or symptoms and recommends a statin prescription for persons at “high risk,” that is with an estimated 10-year PCE-based risk for death or CV events of 10% or higher plus at least one of the four risk factors, a level B recommendation.

It recommends that “clinicians selectively offer a statin” to such persons at “increased risk,” who have at least one of the risk factors and an estimated 10-year risk for death or CV events of 7.5% to less than 10%, a level C recommendation. “The likelihood of benefit is smaller in this group” than in persons at high risk, the document states.

“These recommendations from the USPSTF are sensible and practical,” states Salim S. Virani, MD, PhD, DeBakey Veterans Affairs Medical Center, Houston, in a related editorial published the same day in JAMA Network Open. He calls the former B-level recommendation “a conservative approach” and the latter C-level recommendation a “nuanced approach.”

Both are “understandable” given that some studies suggest that the PCE may overestimate the CV risk, Dr. Virani observes. “On the other hand, statin therapy has been shown to be efficacious” at 10-year CV-risk levels down to about 5%.

The USPSTF document “I think is going to perpetuate a problem that we have in this country, which is vast undertreatment of lipids,” Eric D. Peterson, MD, MPH, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“We have a ton of good drugs that can lower cholesterol like crazy. If you lower cholesterol a lot, you improve outcomes,” he said. Dyslipidemia needs to be more widely and consistently treated, but “right now we have a pool of people in primary prevention who undertreat lipids and wait until disease happens – and then cardiologists get engaged. That’s an avoidable miss,” Dr. Peterson adds. He and JAMA Cardiology associate editor Ann Marie Navar, MD, PhD, provided JAMA with an editorial that accompanies the USPSTF guidance.

“My own personal bias would be that the [ACC/AHA-multisociety guidelines] are closer to being right,” Dr. Peterson said. They – unlike the USPSTF guidance – cover people with risk levels below 7.5%, down to at least 5%. They allow risk enhancers like metabolic syndrome, inflammatory diseases, or family history into the decision process. “And they’re more aggressive in diabetes and more aggressive in older people,” he said.
 

Higher threshold for therapy

The USPSTF guidance also explicitly omits some high-risk groups and makes little accommodation for others who might especially benefit from statins, several of the editorials contend. For example, states a related JAMA Cardiology editorial published the same day, “The USPSTF does not comment on familial hypercholesterolemia or an LDL-C level of 190 mg/dL or higher,” yet they are covered by the ACC/AHA-multispecialty guidelines.

In addition, write the editorialists, led by Neil J. Stone, MD, Northwestern University, Chicago, “the USPSTF uses a slightly higher threshold for initiation of statin therapy” than was used in the ACC/AHA-multisociety guidelines. USPSTF, for example, calls for 10-year risk to reach 10% before recommending a statin prescription.

“One concern about the USPSTF setting the bar higher for statin initiation is that it reduces the number of young patients (age 40-50 years) at risk for premature myocardial infarction considered for treatment,” write Dr. Stone and colleagues.

That may be related to a weakness of the PCE-based decision process. “Because the PCE estimates of 10-year CV disease risk rely so heavily on age, sex, and race, use of these estimates to identify candidates for statins results in significant skewing of the population recommended for statins,” write Dr. Navar and Dr. Peterson in their JAMA editorial.

The risk enhancers in the ACC/AHA-multispecialty guidelines, about a dozen of them, compensate for that limitation to some extent. But the PCE-dominated USPSTF risk estimates will likely miss some groups that could potentially benefit from statin therapy, Dr. Peterson agreed in an interview.  

For example, younger adults facing years of high LDL-cholesterol levels could easily have PCE-based 10-year risk below 10%. “Having a high LDL over a lifetime puts you at really high risk,” he said. “Young people are missed even though their longitudinal risk is high.” So, by waiting for the lofty 10% level of risk over 10 years, “we limit the use of medicine that’s pretty cheap and highly effective.”

Dose intensity, adverse events

Also at variance from the ACC/AHA-multispecialty guidelines, the USPSTF states that, “Based on available evidence, use of moderate-intensity statin therapy seems reasonable for the primary prevention of CV disease in most persons.”  

The task force specifically explored whether evidence supports some use of high-intensity vs. moderate-intensity statins, Tufts University’s Dr. Wong said. “We found only one study that looked at that particular question, and it didn’t give us a strong answer.” An elevated rosuvastatin-related diabetes risk was apparent in the JUPITER trial, “but for the other studies, we did not find that association.”  

Most of the studies that explored statins for reducing risk for a first stroke or myocardial infarction used a moderate-dose statin, Dr. Wong said. “So that’s what we would usually recommend.”

But, Dr. Virani writes, consistent with the ACC/AHA-multispecialty guidelines, “clinicians should consider titrating the intensity of therapy to the risk of the individual.” Persons in certain high-risk primary prevention groups, such as those with end-organ injury from diabetes or LDL cholesterol at least 190 mg/dL, “may derive further benefit from the use of high-intensity statin therapy.”

Low-intensity statins are another potential option, but “in contrast with its 2016 recommendations, the USPSTF no longer recommends use of low-intensity statins in certain situations,” observes a fourth editorial published the same day in JAMA Internal Medicine, with lead author Anand R. Habib, MD, MPhil, and senior author Rita F. Redberg, MD, MSc, both of the University of California, San Francisco. Dr. Redberg is the journal’s editor and has long expressed cautions about statin safety.

“While it is understandable that the Task Force was limited by lack of data on dosing, this change is unfortunate for patients because the frequency of adverse effects increases as the statin dose increases,” the editorial states. Although USPSTF did not find statistically significant harm from the drugs, “in clinical practice, adverse events are commonly reported with use of statins.”

It continues: “At present, there are further reasons to curb our enthusiasm about the use of statins for primary prevention of CV disease.” To illustrate, the editorial questioned primary-prevention statins’ balance of risk vs. clinically meaningful benefit, not benefit that is merely statistically significant.

“The purported benefits of statins in terms of relative risk reduction are fairly constant across baseline lipid levels and cardiovascular risk score categories for primary prevention,” the editorial states.

“Therefore, the absolute benefit for those in lower-risk categories is likely small given that their baseline absolute risk is low, while the chance of adverse effects is constant across risk categories.”

However, USPSTF states, “In pooled analyses of trial data, statin therapy was not associated with increased risk of study withdrawal due to adverse events or serious adverse events.” Nor did it find significant associations with cancers, liver enzyme abnormalities, or diabetes, including new-onset diabetes.

And, the USPSTF adds, “Evidence on the association between statins and renal or cognitive harms is very limited but does not indicate increased risk.”

USPSTF is supported by the U.S. Agency for Healthcare Research and Quality. Dr. Virani discloses receiving grants from the Department of Veterans Affairs, National Institutes of Health, and the World Heart Federation; and personal fees from the American College of Cardiology. Dr. Peterson discloses serving on the JAMA editorial board and receiving research support to his institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and consulting fees from Novo Nordisk, Bayer, and Novartis. Dr. Navar discloses receiving research support to her institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and receiving honoraria and consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Lilly, Novo Nordisk, Novartis, New Amsterdam, and Pfizer. Dr. Stone discloses receiving an honorarium from Knowledge to Practice, an educational company not associated with the pharmaceutical industry; disclosures for the other authors are in the report. Dr. Redberg discloses receiving research funding from the Arnold Ventures Foundation and the Greenwall Foundation.

A version of this article first appeared on Medscape.com.

Questions about how to prescribe statins for primary prevention abound more than 3 decades after the drugs swept into clinical practice to become a first-line medical approach to cutting cardiovascular (CV) risk. Statin usage recommendations from different bodies can vary in ways both limited and fundamental, spurring the kind of debate that accompanies such a document newly issued by the United States Preventive Services Task Force.

The document, little changed from the draft guidance released for public comment in February, was published online Aug. 23 in JAMA and the USPSTF website. It replaces a similar document issued by the task force in 2016.

The guidance has much in common with, but also sharp differences from, the influential 2018 guidelines on blood cholesterol management developed by the American College of Cardiology, American Heart Association, and 10 other medical societies.

And it is provocative enough to elicit at least four editorials issued the same day across the JAMA family of journals. They highlight key differences between the two documents, among them the USPSTF guidance’s consistent, narrow reliance on 7.5% and 10% cut points for 10-year risk levels as estimated from the ACC/AHA pooled cohort equations (PCE).  

The guidance pairs the 10-year risk metric with at least one of only four prescribed CV risk factors to arrive at a limited choice of statin therapy recommendations. But its decision process isn’t bolstered by coronary artery calcium (CAC) scores or the prespecified “risk enhancers” that allowed the ACC/AHA-multisociety guidelines to be applied broadly and still be closely personalized. Those guidelines provide more PCE-based risk tiers for greater discrimination of risk and allow statins to be considered across a broader age group.

The USPSTF guidance’s evidence base consists of 23 clinical trials and three observational studies that directly compared a statin to either placebo or no statin, task force member John B. Wong, MD, Tufts University School of Medicine, Boston, told this news organization.

“In either kind of study, we found that the vast majority of patients had one or more of four risk factors – dyslipidemia, hypertension, diabetes, or smoking. So, when we categorized high risk or increased risk, we included the presence of one or more of those risk factors,” said Dr. Wong, who is director of comparative effectiveness research at Tufts Clinical Translational Science Institute.
 

‘Sensible and practical’

The USPSTF guidance applies only to adults aged 40-75 without CV signs or symptoms and recommends a statin prescription for persons at “high risk,” that is with an estimated 10-year PCE-based risk for death or CV events of 10% or higher plus at least one of the four risk factors, a level B recommendation.

It recommends that “clinicians selectively offer a statin” to such persons at “increased risk,” who have at least one of the risk factors and an estimated 10-year risk for death or CV events of 7.5% to less than 10%, a level C recommendation. “The likelihood of benefit is smaller in this group” than in persons at high risk, the document states.

“These recommendations from the USPSTF are sensible and practical,” states Salim S. Virani, MD, PhD, DeBakey Veterans Affairs Medical Center, Houston, in a related editorial published the same day in JAMA Network Open. He calls the former B-level recommendation “a conservative approach” and the latter C-level recommendation a “nuanced approach.”

Both are “understandable” given that some studies suggest that the PCE may overestimate the CV risk, Dr. Virani observes. “On the other hand, statin therapy has been shown to be efficacious” at 10-year CV-risk levels down to about 5%.

The USPSTF document “I think is going to perpetuate a problem that we have in this country, which is vast undertreatment of lipids,” Eric D. Peterson, MD, MPH, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“We have a ton of good drugs that can lower cholesterol like crazy. If you lower cholesterol a lot, you improve outcomes,” he said. Dyslipidemia needs to be more widely and consistently treated, but “right now we have a pool of people in primary prevention who undertreat lipids and wait until disease happens – and then cardiologists get engaged. That’s an avoidable miss,” Dr. Peterson adds. He and JAMA Cardiology associate editor Ann Marie Navar, MD, PhD, provided JAMA with an editorial that accompanies the USPSTF guidance.

“My own personal bias would be that the [ACC/AHA-multisociety guidelines] are closer to being right,” Dr. Peterson said. They – unlike the USPSTF guidance – cover people with risk levels below 7.5%, down to at least 5%. They allow risk enhancers like metabolic syndrome, inflammatory diseases, or family history into the decision process. “And they’re more aggressive in diabetes and more aggressive in older people,” he said.
 

Higher threshold for therapy

The USPSTF guidance also explicitly omits some high-risk groups and makes little accommodation for others who might especially benefit from statins, several of the editorials contend. For example, states a related JAMA Cardiology editorial published the same day, “The USPSTF does not comment on familial hypercholesterolemia or an LDL-C level of 190 mg/dL or higher,” yet they are covered by the ACC/AHA-multispecialty guidelines.

In addition, write the editorialists, led by Neil J. Stone, MD, Northwestern University, Chicago, “the USPSTF uses a slightly higher threshold for initiation of statin therapy” than was used in the ACC/AHA-multisociety guidelines. USPSTF, for example, calls for 10-year risk to reach 10% before recommending a statin prescription.

“One concern about the USPSTF setting the bar higher for statin initiation is that it reduces the number of young patients (age 40-50 years) at risk for premature myocardial infarction considered for treatment,” write Dr. Stone and colleagues.

That may be related to a weakness of the PCE-based decision process. “Because the PCE estimates of 10-year CV disease risk rely so heavily on age, sex, and race, use of these estimates to identify candidates for statins results in significant skewing of the population recommended for statins,” write Dr. Navar and Dr. Peterson in their JAMA editorial.

The risk enhancers in the ACC/AHA-multispecialty guidelines, about a dozen of them, compensate for that limitation to some extent. But the PCE-dominated USPSTF risk estimates will likely miss some groups that could potentially benefit from statin therapy, Dr. Peterson agreed in an interview.  

For example, younger adults facing years of high LDL-cholesterol levels could easily have PCE-based 10-year risk below 10%. “Having a high LDL over a lifetime puts you at really high risk,” he said. “Young people are missed even though their longitudinal risk is high.” So, by waiting for the lofty 10% level of risk over 10 years, “we limit the use of medicine that’s pretty cheap and highly effective.”

Dose intensity, adverse events

Also at variance from the ACC/AHA-multispecialty guidelines, the USPSTF states that, “Based on available evidence, use of moderate-intensity statin therapy seems reasonable for the primary prevention of CV disease in most persons.”  

The task force specifically explored whether evidence supports some use of high-intensity vs. moderate-intensity statins, Tufts University’s Dr. Wong said. “We found only one study that looked at that particular question, and it didn’t give us a strong answer.” An elevated rosuvastatin-related diabetes risk was apparent in the JUPITER trial, “but for the other studies, we did not find that association.”  

Most of the studies that explored statins for reducing risk for a first stroke or myocardial infarction used a moderate-dose statin, Dr. Wong said. “So that’s what we would usually recommend.”

But, Dr. Virani writes, consistent with the ACC/AHA-multispecialty guidelines, “clinicians should consider titrating the intensity of therapy to the risk of the individual.” Persons in certain high-risk primary prevention groups, such as those with end-organ injury from diabetes or LDL cholesterol at least 190 mg/dL, “may derive further benefit from the use of high-intensity statin therapy.”

Low-intensity statins are another potential option, but “in contrast with its 2016 recommendations, the USPSTF no longer recommends use of low-intensity statins in certain situations,” observes a fourth editorial published the same day in JAMA Internal Medicine, with lead author Anand R. Habib, MD, MPhil, and senior author Rita F. Redberg, MD, MSc, both of the University of California, San Francisco. Dr. Redberg is the journal’s editor and has long expressed cautions about statin safety.

“While it is understandable that the Task Force was limited by lack of data on dosing, this change is unfortunate for patients because the frequency of adverse effects increases as the statin dose increases,” the editorial states. Although USPSTF did not find statistically significant harm from the drugs, “in clinical practice, adverse events are commonly reported with use of statins.”

It continues: “At present, there are further reasons to curb our enthusiasm about the use of statins for primary prevention of CV disease.” To illustrate, the editorial questioned primary-prevention statins’ balance of risk vs. clinically meaningful benefit, not benefit that is merely statistically significant.

“The purported benefits of statins in terms of relative risk reduction are fairly constant across baseline lipid levels and cardiovascular risk score categories for primary prevention,” the editorial states.

“Therefore, the absolute benefit for those in lower-risk categories is likely small given that their baseline absolute risk is low, while the chance of adverse effects is constant across risk categories.”

However, USPSTF states, “In pooled analyses of trial data, statin therapy was not associated with increased risk of study withdrawal due to adverse events or serious adverse events.” Nor did it find significant associations with cancers, liver enzyme abnormalities, or diabetes, including new-onset diabetes.

And, the USPSTF adds, “Evidence on the association between statins and renal or cognitive harms is very limited but does not indicate increased risk.”

USPSTF is supported by the U.S. Agency for Healthcare Research and Quality. Dr. Virani discloses receiving grants from the Department of Veterans Affairs, National Institutes of Health, and the World Heart Federation; and personal fees from the American College of Cardiology. Dr. Peterson discloses serving on the JAMA editorial board and receiving research support to his institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and consulting fees from Novo Nordisk, Bayer, and Novartis. Dr. Navar discloses receiving research support to her institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and receiving honoraria and consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Lilly, Novo Nordisk, Novartis, New Amsterdam, and Pfizer. Dr. Stone discloses receiving an honorarium from Knowledge to Practice, an educational company not associated with the pharmaceutical industry; disclosures for the other authors are in the report. Dr. Redberg discloses receiving research funding from the Arnold Ventures Foundation and the Greenwall Foundation.

A version of this article first appeared on Medscape.com.

Questions about how to prescribe statins for primary prevention abound more than 3 decades after the drugs swept into clinical practice to become a first-line medical approach to cutting cardiovascular (CV) risk. Statin usage recommendations from different bodies can vary in ways both limited and fundamental, spurring the kind of debate that accompanies such a document newly issued by the United States Preventive Services Task Force.

The document, little changed from the draft guidance released for public comment in February, was published online Aug. 23 in JAMA and the USPSTF website. It replaces a similar document issued by the task force in 2016.

The guidance has much in common with, but also sharp differences from, the influential 2018 guidelines on blood cholesterol management developed by the American College of Cardiology, American Heart Association, and 10 other medical societies.

And it is provocative enough to elicit at least four editorials issued the same day across the JAMA family of journals. They highlight key differences between the two documents, among them the USPSTF guidance’s consistent, narrow reliance on 7.5% and 10% cut points for 10-year risk levels as estimated from the ACC/AHA pooled cohort equations (PCE).  

The guidance pairs the 10-year risk metric with at least one of only four prescribed CV risk factors to arrive at a limited choice of statin therapy recommendations. But its decision process isn’t bolstered by coronary artery calcium (CAC) scores or the prespecified “risk enhancers” that allowed the ACC/AHA-multisociety guidelines to be applied broadly and still be closely personalized. Those guidelines provide more PCE-based risk tiers for greater discrimination of risk and allow statins to be considered across a broader age group.

The USPSTF guidance’s evidence base consists of 23 clinical trials and three observational studies that directly compared a statin to either placebo or no statin, task force member John B. Wong, MD, Tufts University School of Medicine, Boston, told this news organization.

“In either kind of study, we found that the vast majority of patients had one or more of four risk factors – dyslipidemia, hypertension, diabetes, or smoking. So, when we categorized high risk or increased risk, we included the presence of one or more of those risk factors,” said Dr. Wong, who is director of comparative effectiveness research at Tufts Clinical Translational Science Institute.
 

‘Sensible and practical’

The USPSTF guidance applies only to adults aged 40-75 without CV signs or symptoms and recommends a statin prescription for persons at “high risk,” that is with an estimated 10-year PCE-based risk for death or CV events of 10% or higher plus at least one of the four risk factors, a level B recommendation.

It recommends that “clinicians selectively offer a statin” to such persons at “increased risk,” who have at least one of the risk factors and an estimated 10-year risk for death or CV events of 7.5% to less than 10%, a level C recommendation. “The likelihood of benefit is smaller in this group” than in persons at high risk, the document states.

“These recommendations from the USPSTF are sensible and practical,” states Salim S. Virani, MD, PhD, DeBakey Veterans Affairs Medical Center, Houston, in a related editorial published the same day in JAMA Network Open. He calls the former B-level recommendation “a conservative approach” and the latter C-level recommendation a “nuanced approach.”

Both are “understandable” given that some studies suggest that the PCE may overestimate the CV risk, Dr. Virani observes. “On the other hand, statin therapy has been shown to be efficacious” at 10-year CV-risk levels down to about 5%.

The USPSTF document “I think is going to perpetuate a problem that we have in this country, which is vast undertreatment of lipids,” Eric D. Peterson, MD, MPH, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“We have a ton of good drugs that can lower cholesterol like crazy. If you lower cholesterol a lot, you improve outcomes,” he said. Dyslipidemia needs to be more widely and consistently treated, but “right now we have a pool of people in primary prevention who undertreat lipids and wait until disease happens – and then cardiologists get engaged. That’s an avoidable miss,” Dr. Peterson adds. He and JAMA Cardiology associate editor Ann Marie Navar, MD, PhD, provided JAMA with an editorial that accompanies the USPSTF guidance.

“My own personal bias would be that the [ACC/AHA-multisociety guidelines] are closer to being right,” Dr. Peterson said. They – unlike the USPSTF guidance – cover people with risk levels below 7.5%, down to at least 5%. They allow risk enhancers like metabolic syndrome, inflammatory diseases, or family history into the decision process. “And they’re more aggressive in diabetes and more aggressive in older people,” he said.
 

Higher threshold for therapy

The USPSTF guidance also explicitly omits some high-risk groups and makes little accommodation for others who might especially benefit from statins, several of the editorials contend. For example, states a related JAMA Cardiology editorial published the same day, “The USPSTF does not comment on familial hypercholesterolemia or an LDL-C level of 190 mg/dL or higher,” yet they are covered by the ACC/AHA-multispecialty guidelines.

In addition, write the editorialists, led by Neil J. Stone, MD, Northwestern University, Chicago, “the USPSTF uses a slightly higher threshold for initiation of statin therapy” than was used in the ACC/AHA-multisociety guidelines. USPSTF, for example, calls for 10-year risk to reach 10% before recommending a statin prescription.

“One concern about the USPSTF setting the bar higher for statin initiation is that it reduces the number of young patients (age 40-50 years) at risk for premature myocardial infarction considered for treatment,” write Dr. Stone and colleagues.

That may be related to a weakness of the PCE-based decision process. “Because the PCE estimates of 10-year CV disease risk rely so heavily on age, sex, and race, use of these estimates to identify candidates for statins results in significant skewing of the population recommended for statins,” write Dr. Navar and Dr. Peterson in their JAMA editorial.

The risk enhancers in the ACC/AHA-multispecialty guidelines, about a dozen of them, compensate for that limitation to some extent. But the PCE-dominated USPSTF risk estimates will likely miss some groups that could potentially benefit from statin therapy, Dr. Peterson agreed in an interview.  

For example, younger adults facing years of high LDL-cholesterol levels could easily have PCE-based 10-year risk below 10%. “Having a high LDL over a lifetime puts you at really high risk,” he said. “Young people are missed even though their longitudinal risk is high.” So, by waiting for the lofty 10% level of risk over 10 years, “we limit the use of medicine that’s pretty cheap and highly effective.”

Dose intensity, adverse events

Also at variance from the ACC/AHA-multispecialty guidelines, the USPSTF states that, “Based on available evidence, use of moderate-intensity statin therapy seems reasonable for the primary prevention of CV disease in most persons.”  

The task force specifically explored whether evidence supports some use of high-intensity vs. moderate-intensity statins, Tufts University’s Dr. Wong said. “We found only one study that looked at that particular question, and it didn’t give us a strong answer.” An elevated rosuvastatin-related diabetes risk was apparent in the JUPITER trial, “but for the other studies, we did not find that association.”  

Most of the studies that explored statins for reducing risk for a first stroke or myocardial infarction used a moderate-dose statin, Dr. Wong said. “So that’s what we would usually recommend.”

But, Dr. Virani writes, consistent with the ACC/AHA-multispecialty guidelines, “clinicians should consider titrating the intensity of therapy to the risk of the individual.” Persons in certain high-risk primary prevention groups, such as those with end-organ injury from diabetes or LDL cholesterol at least 190 mg/dL, “may derive further benefit from the use of high-intensity statin therapy.”

Low-intensity statins are another potential option, but “in contrast with its 2016 recommendations, the USPSTF no longer recommends use of low-intensity statins in certain situations,” observes a fourth editorial published the same day in JAMA Internal Medicine, with lead author Anand R. Habib, MD, MPhil, and senior author Rita F. Redberg, MD, MSc, both of the University of California, San Francisco. Dr. Redberg is the journal’s editor and has long expressed cautions about statin safety.

“While it is understandable that the Task Force was limited by lack of data on dosing, this change is unfortunate for patients because the frequency of adverse effects increases as the statin dose increases,” the editorial states. Although USPSTF did not find statistically significant harm from the drugs, “in clinical practice, adverse events are commonly reported with use of statins.”

It continues: “At present, there are further reasons to curb our enthusiasm about the use of statins for primary prevention of CV disease.” To illustrate, the editorial questioned primary-prevention statins’ balance of risk vs. clinically meaningful benefit, not benefit that is merely statistically significant.

“The purported benefits of statins in terms of relative risk reduction are fairly constant across baseline lipid levels and cardiovascular risk score categories for primary prevention,” the editorial states.

“Therefore, the absolute benefit for those in lower-risk categories is likely small given that their baseline absolute risk is low, while the chance of adverse effects is constant across risk categories.”

However, USPSTF states, “In pooled analyses of trial data, statin therapy was not associated with increased risk of study withdrawal due to adverse events or serious adverse events.” Nor did it find significant associations with cancers, liver enzyme abnormalities, or diabetes, including new-onset diabetes.

And, the USPSTF adds, “Evidence on the association between statins and renal or cognitive harms is very limited but does not indicate increased risk.”

USPSTF is supported by the U.S. Agency for Healthcare Research and Quality. Dr. Virani discloses receiving grants from the Department of Veterans Affairs, National Institutes of Health, and the World Heart Federation; and personal fees from the American College of Cardiology. Dr. Peterson discloses serving on the JAMA editorial board and receiving research support to his institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and consulting fees from Novo Nordisk, Bayer, and Novartis. Dr. Navar discloses receiving research support to her institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and receiving honoraria and consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Lilly, Novo Nordisk, Novartis, New Amsterdam, and Pfizer. Dr. Stone discloses receiving an honorarium from Knowledge to Practice, an educational company not associated with the pharmaceutical industry; disclosures for the other authors are in the report. Dr. Redberg discloses receiving research funding from the Arnold Ventures Foundation and the Greenwall Foundation.

A version of this article first appeared on Medscape.com.

Pfizer has sent an application to the Food and Drug Administration for emergency use authorization of its updated COVID-19 booster vaccine for the fall of 2022, the company announced on Aug. 22.

The vaccine, which is adapted for the BA.4 and BA.5 Omicron variants, would be meant for ages 12 and older. If authorized by the FDA, the doses could ship as soon as September.

“Having rapidly scaled up production, we are positioned to immediately begin distribution of the bivalent Omicron BA.4/BA.5 boosters, if authorized, to help protect individuals and families as we prepare for potential fall and winter surges,” Albert Bourla, PhD, Pfizer’s chairman and CEO, said in the statement.

Earlier this year, the FDA ordered vaccine makers such as Pfizer and Moderna to update their shots to target BA.4 and BA.5, which are better at escaping immunity from earlier vaccines and previous infections.

The United States has a contract to buy 105 million of the Pfizer doses and 66 million of the Moderna doses, according to The Associated Press. Moderna is expected to file its FDA application soon as well.

The new shots target both the original spike protein on the coronavirus and the spike mutations carried by BA.4 and BA.5. For now, BA.5 is causing 89% of new infections in the United States, followed by BA.4.6 with 6.3% and BA.4 with 4.3%, according to the latest Centers for Disease Control and Prevention data.

There’s no way to tell if BA.5 will still be the dominant strain this winter or if new variant will replace it, the AP reported. But public health officials have supported the updated boosters as a way to target the most recent strains and increase immunity again.

On Aug. 15, Great Britain became the first country to authorize another one of Moderna’s updated vaccines, which adds protection against BA.1, or the original Omicron strain that became dominant in the winter of 2021-2022. European regulators are considering this shot, the AP reported, but the United States opted not to use this version since new Omicron variants have become dominant.

To approve the latest Pfizer shot, the FDA will rely on scientific testing of prior updates to the vaccine, rather than the newest boosters, to decide whether to fast-track the updated shots for fall, the AP reported. This method is like how flu vaccines are updated each year without large studies that take months.

Previously, Pfizer announced results from a study that found the earlier Omicron update significantly boosted antibodies capable of fighting the BA.1 variant and provided some protection against BA.4 and BA.5. The company’s latest FDA application contains that data and animal testing on the newest booster, the AP reported.

Pfizer will start a trial using the BA.4/BA.5 booster in coming weeks to get more data on how well the latest shot works. Moderna has begun a similar study.

The full results from these studies won’t be available before a fall booster campaign, which is why the FDA and public health officials have called for an updated shot to be ready for distribution in September.

“It’s clear that none of these vaccines are going to completely prevent infection,” Rachel Presti, MD, a researcher with the Moderna trial and an infectious diseases specialist at Washington University in St. Louis, told the AP.

But previous studies of variant booster candidates have shown that “you still get a broader immune response giving a variant booster than giving the same booster,” she said.

A version of this article first appeared on WebMD.com.

Pfizer has sent an application to the Food and Drug Administration for emergency use authorization of its updated COVID-19 booster vaccine for the fall of 2022, the company announced on Aug. 22.

The vaccine, which is adapted for the BA.4 and BA.5 Omicron variants, would be meant for ages 12 and older. If authorized by the FDA, the doses could ship as soon as September.

“Having rapidly scaled up production, we are positioned to immediately begin distribution of the bivalent Omicron BA.4/BA.5 boosters, if authorized, to help protect individuals and families as we prepare for potential fall and winter surges,” Albert Bourla, PhD, Pfizer’s chairman and CEO, said in the statement.

Earlier this year, the FDA ordered vaccine makers such as Pfizer and Moderna to update their shots to target BA.4 and BA.5, which are better at escaping immunity from earlier vaccines and previous infections.

The United States has a contract to buy 105 million of the Pfizer doses and 66 million of the Moderna doses, according to The Associated Press. Moderna is expected to file its FDA application soon as well.

The new shots target both the original spike protein on the coronavirus and the spike mutations carried by BA.4 and BA.5. For now, BA.5 is causing 89% of new infections in the United States, followed by BA.4.6 with 6.3% and BA.4 with 4.3%, according to the latest Centers for Disease Control and Prevention data.

There’s no way to tell if BA.5 will still be the dominant strain this winter or if new variant will replace it, the AP reported. But public health officials have supported the updated boosters as a way to target the most recent strains and increase immunity again.

On Aug. 15, Great Britain became the first country to authorize another one of Moderna’s updated vaccines, which adds protection against BA.1, or the original Omicron strain that became dominant in the winter of 2021-2022. European regulators are considering this shot, the AP reported, but the United States opted not to use this version since new Omicron variants have become dominant.

To approve the latest Pfizer shot, the FDA will rely on scientific testing of prior updates to the vaccine, rather than the newest boosters, to decide whether to fast-track the updated shots for fall, the AP reported. This method is like how flu vaccines are updated each year without large studies that take months.

Previously, Pfizer announced results from a study that found the earlier Omicron update significantly boosted antibodies capable of fighting the BA.1 variant and provided some protection against BA.4 and BA.5. The company’s latest FDA application contains that data and animal testing on the newest booster, the AP reported.

Pfizer will start a trial using the BA.4/BA.5 booster in coming weeks to get more data on how well the latest shot works. Moderna has begun a similar study.

The full results from these studies won’t be available before a fall booster campaign, which is why the FDA and public health officials have called for an updated shot to be ready for distribution in September.

“It’s clear that none of these vaccines are going to completely prevent infection,” Rachel Presti, MD, a researcher with the Moderna trial and an infectious diseases specialist at Washington University in St. Louis, told the AP.

But previous studies of variant booster candidates have shown that “you still get a broader immune response giving a variant booster than giving the same booster,” she said.

A version of this article first appeared on WebMD.com.

Pfizer has sent an application to the Food and Drug Administration for emergency use authorization of its updated COVID-19 booster vaccine for the fall of 2022, the company announced on Aug. 22.

The vaccine, which is adapted for the BA.4 and BA.5 Omicron variants, would be meant for ages 12 and older. If authorized by the FDA, the doses could ship as soon as September.

“Having rapidly scaled up production, we are positioned to immediately begin distribution of the bivalent Omicron BA.4/BA.5 boosters, if authorized, to help protect individuals and families as we prepare for potential fall and winter surges,” Albert Bourla, PhD, Pfizer’s chairman and CEO, said in the statement.

Earlier this year, the FDA ordered vaccine makers such as Pfizer and Moderna to update their shots to target BA.4 and BA.5, which are better at escaping immunity from earlier vaccines and previous infections.

The United States has a contract to buy 105 million of the Pfizer doses and 66 million of the Moderna doses, according to The Associated Press. Moderna is expected to file its FDA application soon as well.

The new shots target both the original spike protein on the coronavirus and the spike mutations carried by BA.4 and BA.5. For now, BA.5 is causing 89% of new infections in the United States, followed by BA.4.6 with 6.3% and BA.4 with 4.3%, according to the latest Centers for Disease Control and Prevention data.

There’s no way to tell if BA.5 will still be the dominant strain this winter or if new variant will replace it, the AP reported. But public health officials have supported the updated boosters as a way to target the most recent strains and increase immunity again.

On Aug. 15, Great Britain became the first country to authorize another one of Moderna’s updated vaccines, which adds protection against BA.1, or the original Omicron strain that became dominant in the winter of 2021-2022. European regulators are considering this shot, the AP reported, but the United States opted not to use this version since new Omicron variants have become dominant.

To approve the latest Pfizer shot, the FDA will rely on scientific testing of prior updates to the vaccine, rather than the newest boosters, to decide whether to fast-track the updated shots for fall, the AP reported. This method is like how flu vaccines are updated each year without large studies that take months.

Previously, Pfizer announced results from a study that found the earlier Omicron update significantly boosted antibodies capable of fighting the BA.1 variant and provided some protection against BA.4 and BA.5. The company’s latest FDA application contains that data and animal testing on the newest booster, the AP reported.

Pfizer will start a trial using the BA.4/BA.5 booster in coming weeks to get more data on how well the latest shot works. Moderna has begun a similar study.

The full results from these studies won’t be available before a fall booster campaign, which is why the FDA and public health officials have called for an updated shot to be ready for distribution in September.

“It’s clear that none of these vaccines are going to completely prevent infection,” Rachel Presti, MD, a researcher with the Moderna trial and an infectious diseases specialist at Washington University in St. Louis, told the AP.

But previous studies of variant booster candidates have shown that “you still get a broader immune response giving a variant booster than giving the same booster,” she said.

A version of this article first appeared on WebMD.com.

Gender differences in patient satisfaction with medical care have been evaluated in multiple settings; however, studies specific to the unique population of women veterans with cancer are lacking. Women are reported to value privacy, psychosocial support, and communication to a higher degree compared with men.¹ Factors affecting satisfaction include the following: discomfort in sharing treatment rooms with the opposite gender, a desire for privacy with treatment and restroom use, anatomic or illness differences, and a personal history of abuse^.2-4 Regrettably, up to 1 in 3 women in the United States are victims of sexual trauma in their lifetimes, and up to 1 in 4 women in the military are victims of military sexual trauma. Incidence in both settings is suspected to be higher due to underreporting^.5,6

Chemotherapy treatment units are often uniquely designed as an open space, with several patients sharing a treatment area. The design reduces isolation and facilitates quick nurse-patient access during potentially toxic treatments known to have frequent adverse effects. Data suggest that nursing staff prefer open models to facilitate quick patient assessments and interventions as needed; however, patients and families prefer private treatment rooms, especially among women patients or those receiving longer infusions.⁷

The Veterans Health Administration (VHA) patient population is male predominant, comprised only of 10% female patients.8 Although the proportion of female patients in the VHA is expected to rise annually to about 16% by 2043, the low percentage of female veterans will persist for the foreseeable future.⁸ This low percentage of female veterans is reflected in the Veterans Affairs Portland Health Care System (VAPHCS) cancer patient population and in the use of the chemotherapy infusion unit, which is used for the ambulatory treatment of veterans undergoing cancer therapy.

The VHA has previously explored gender differences in health care, such as with cardiovascular disease, transgender care, and access to mental health.^9-11 However, to the best of our knowledge, no analysis has explored gender differences within the outpatient cancer treatment experience. Patient satisfaction with outpatient cancer care may be magnified in the VHA setting due to the uniquely unequal gender populations, shared treatment space design, and high incidence of sexual abuse among women veterans. Given this, we aimed to identify gender-related preferences in outpatient cancer care in our chemotherapy infusion unit.

In our study, we used the terms male and female to reflect statistical data from the literature or labeled data from the electronic health record (EHR); whereas the terms men and women were used to describe and encompass the cultural implications and context of gender.¹²

Methods

This study was designated as a quality improvement (QI) project by the VAPHCS research office and Institutional Review Board in accordance with VHA policies.

The VAPHCS outpatient chemotherapy infusion unit is designed with 6 rooms for chemotherapy administration. One room is a large open space with 6 chairs for patients. The other rooms are smaller with glass dividers between the rooms, and 3 chairs inside each for patients. There are 2 private bathrooms, each gender neutral. Direct patient care is provided by physicians, nurse practitioners (NPs), infusion unit nurses, and nurse coordinators. Men represent the majority of hematology and oncology physicians (13 of 20 total: 5 women fellow physicians and 2 women attending physicians), and 2 of 4 NPs. Women represent 10 of 12 infusion unit and cancer coordinator nurses. We used the VHA Computerized Patient Record System (CPRS) EHR, to create a list of veterans treated at the VAPHCS outpatient chemotherapy infusion unit for a 2-year period (January 1, 2018, to December 31, 2020).

Male and female patient lists were first generated based on CPRS categorization. We identified all female veterans treated in the ambulatory infusion unit during the study period. Male patients were then chosen at random, recording the most recent names for each year until a matched number per year compared with the female cohort was reached. Patients were recorded only once even though they had multiple infusion unit visits. Patients were excluded who were deceased, on hospice care, lost to follow-up, could not be reached by phone, refused to take the survey, had undeliverable email addresses, or lacked internet or email access.

After filing the appropriate request through the VAPHCS Institutional Review Board committee in January 2021, patient records were reviewed for demographics data, contact information, and infusion treatment history. The survey was then conducted over a 2-week period during January and February 2021. Each patient was invited by phone to complete a 25-question anonymous online survey. The survey questions were created from patient-relayed experiences, then modeled into survey questions in a format similar to other patient satisfaction questionnaires described in cancer care and gender differences.^2,13,14 The survey included self-identification of gender and was multiple choice for all except 2 questions, which allowed an open-ended response (Appendix). Only 1 answer per question was permitted. Only 1 survey link was sent to each veteran who gave permission for the survey. To protect anonymity for the small patient population, we excluded those identifying as gender nonbinary or transgender.

Statistical Analysis

Patient, disease, and treatment features are separated by male and female cohorts to reflect information from the EHR (Table 1). Survey percentages were calculated to reflect the affirmative response of the question asked (Table 2). Questions with answer options of not important, minimally important, important, or very important were calculated to reflect the sum of any importance in both cohorts. Questions with answer options of never, once, often, or every time were calculated to reflect any occurrence (sum of once, often, or every time) in both patient groups. Questions with answer options of strongly agree, somewhat agree, somewhat disagree, and strongly disagree were calculated to reflect any agreement (somewhat agree and strongly agree summed together) for both groups. Comparisons between cohorts were then conducted using a Fisher exact test. A Welch t test was used to calculate the significance of the continuous variable and overall ranking of the infusion unit experience between groups.

Results 

In 2020, 414 individual patients were treated at the VAPAHCS outpatient infusion unit. Of these, 23 (5.6%) were female, and 18 agreed to take the survey. After deceased and duplicate names from 2020 were removed, another 14 eligible 2019 female patients were invited and 6 agreed to participate; 6 eligible 2018 female patients were invited and 4 agreed to take the survey (Figure). Thirty female veterans were sent a survey link and 21 (70%) responses were collected. Twenty-one male 2020 patients were contacted and 18 agreed to take the survey. After removing duplicate names and deceased individuals, 17 of 21 eligible 2019 male patients and 4 of 6 eligible 2018 patients agreed to take the survey. Five additional male veterans declined the online-based survey method. In total, 39 male veterans were reached who agreed to have the survey link emailed, and 20 (51%) total responses were collected.

Most respondents answered all questions in the survey. The most frequently skipped questions included 3 questions that were contingent on a yes answer to a prior question, and 2 openended questions asking for a write-in response. Percentages for female and male respondents were adjusted for number of responses when applicable.

Thirteen (62%) female patients were aged < 65 years, while 18 (90%) of male patients were aged ≥ 65 years. Education beyond high school was reported in 20 female and 15 male respondents. Almost all treatment administered in the infusion unit was for cancer-directed treatment, with only 1 reporting a noncancer treatment (IV iron). The most common malignancy among female patients was breast cancer (n = 11, 52%); for male patients prostate cancer (n = 4, 20%) and hematologic malignancy (n = 4, 20%) were most common. Four (19%) female and 8 (40%) male respondents reported having a metastatic diagnosis. Overall patient satisfaction ranked high with an average score of 9.1 on a 10-point scale. The mean (SD) satisfaction score for female respondents was 1 point lower than that for men: 8.7 (2.2) vs 9.6 (0.6) in men (P = .11).

Eighteen (86%) women reported a history of sexual abuse or harassment compared with 2 (10%) men (P < .001). The sexual abuse assailant was a different gender for 17 of 18 female respondents and of the same gender for both male respondents. Of those with sexual abuse history, 4 women reported feeling uncomfortable around their assailant’s gender vs no men (P = .11), but this difference was not statistically significant. Six women (29%) and 2 (10%) men reported feeling uncomfortable during clinical examinations from comments made by the clinician or during treatment administration (P = .24). Six (29%) women and no men reported that they “felt uncomfortable in the infusion unit by other patients” (P = .02). Six (29%) women and no men reported feeling unable to “voice uncomfortable experiences” to the infusion unit clinician (P = .02).

Ten (48%) women and 6 (30%) men reported emotional support when receiving treatments provided by staff of the same gender (P = .34). Eight (38%) women and 4 (20%) men noted that access to treatment with the same gender was important (P = .31). Six (29%) women and 4 (20%) men indicated that access to a sex or gender-specific restroom was important (P = .72). No gender preferences were identified in the survey questions regarding importance of private treatment room access and level of emotional support when receiving treatment with others of the same malignancy. These relationships were not statistically significant.

In addition, 2 open-ended questions were asked. Seventeen women and 14 men responded. Contact the corresponding author for more information on the questions and responses.

Discussion

Overall patient satisfaction was high among the men and women veterans with cancer who received treatment in our outpatient infusion unit; however, notable gender differences existed. Three items in the survey revealed statistically significant differences in the patient experience between men and women veterans: history of sexual abuse or harassment, uncomfortable feelings among other patients, and discomfort in relaying uncomfortable feelings to a clinician. Other items in the survey did not reach statistical significance; however, we have included discussion of the findings as they may highlight important trends and be of clinical significance.

We suspect differences among genders in patient satisfaction to be related to the high incidence of sexual abuse or harassment history reported by women, much higher at 86% than the one-third to one-fourth incidence rates estimated by the existing literature for civilian or military sexual abuse in women.5,6 These high sexual abuse or harassment rates are present in a majority of women who receive cancer-directed treatment toward a gender-specific breast malignancy, surrounded predominantly among men in a shared treatment space. Together, these factors are likely key reasons behind the differences in satisfaction observed. This sentiment is expressed in our cohort, where one-fifth of women with a sexual abuse or harassment history continue to remain uncomfortable around men, and 29% of women reporting some uncomfortable feelings during their treatment experience compared with none of the men. Additionally, 6 (29%) women vs no men felt uncomfortable in reporting an uncomfortable experience with a clinician; this represents a significant barrier in providing care for these patients.

A key gender preference among women included access to shared treatment rooms with other women and that sharing a treatment space with other women resulted in feeling more emotional support during treatments. Access to gender-specific restrooms was also preferred by women more than men. Key findings in both genders were that about half of men and women valued access to a private treatment room and would derive more emotional support when surrounded by others with the same cancer.

Prior studies on gender and patient satisfaction in general medical care and cancer care have found women value privacy more than men.^1-3 Wessels and colleagues performed an analysis of 386 patients with cancer in Europe and found gender to be the strongest influence in patient preferences within cancer care. Specifically, the highest statically significant association in care preferences among women included privacy, support/counseling/rehabilitation access, and decreased wait times.2 These findings were most pronounced in those with breast cancer compared with other malignancy type and highlights that malignancy type and gender predominance impact care satisfaction.

Traditionally a shared treatment space design has been used in outpatient chemotherapy units, similar to the design of the VAPHCS. However, recent data report on the patient preference for a private treatment space, which was especially prominent among women and those receiving longer infusions.7 In another study that evaluated 225 patients with cancer preferences in sharing a treatment space with those of a different sexual orientation or gender identify, differences were found. Both men and women had a similar level of comfort in sharing a treatment room with someone of a different sexual orientation; however, more women reported discomfort in sharing a treatment space with a transgender woman compared with men who felt more comfortable sharing a space with a transgender man.4 We noted a gender preference may be present to explain the difference. Within our cohort, women valued access to treatment with other women and derived more emotional support when with other women; however, we did not inquire about feelings in sharing a treatment space among transgender individuals or differing sexual orientation.

Gender differences for privacy and in shared room preferences may result from the lasting impacts of prior sexual abuse or harassment. A history of sexual abuse negatively impacts later medical care access and use.15 Those veterans who experienced sexual abuse/harrassment reported higher feelings of lack of control, vulnerability, depression, and pursued less medical care.^15,16 Within cancer care, these feelings are most pronounced among women with gender-specific malignancies, such as gynecologic cancers or breast cancer. Treatment, screening, and physical examinations by clinicians who are of the same gender as the sexual abuse/harassment assailant can recreate traumatic feelings.^15,16

A majority of women (n = 18, 86%) in our cohort reported a history of sexual abuse or harassment and breast malignancy was the most common cancer among women. However women represent just 5.6% of the VAPHCS infusion unit treatment population. This combination of factors may explain the reasons for women veterans’ preference for privacy during treatments, access to gender-specific restrooms, and feeling more emotional support when surrounded by other women. Strategies to help patients with a history of abuse have been described and include discussions from the clinician asking about abuse history, allowing time for the patient to express fears with an examination or test, and training on how to deliver sensitive care for those with trauma.^17,18

Quality Improvement

Project In the VAPHCS infusion unit, several low-cost interventions have been undertaken as a result of our survey findings. We presented our survey data to the VAPHCS Cancer Committee, accredited through the national American College of Surgeons Commission on Cancer. The committee awarded support for a yearlong QI project, including a formal framework of quarterly multidisciplinary meetings to discuss project updates, challenges, and resources. The QI project centers on education to raise awareness of survey results as well as specific interventions for improvement.

Education efforts have been applied through multiple department-wide emails, in-person education to our chemotherapy unit staff, abstract submission to national oncology conferences, and grand rounds department presentations at VAPHCS and at other VHA-affiliated university programs. Additionally, education to clinicians with specific contact information for psychology and women’s health to support mental health, trauma, and sexual abuse histories has been given to each clinician who cares for veterans in the chemotherapy unit.

We also have implemented a mandatory cancer care navigation consultation for all women veterans who have a new cancer or infusion need. The cancer care navigator has received specialized training in sensitive history-taking and provides women veterans with a direct number to reach the cancer care navigation nurse. Cancer care navigation also provides a continuum of support and referral access for psychosocial needs as indicated between infusion or health care visits. Our hope is that these resources may help offset the sentiment reflected in our cohort of women feeling unable to voice concerns to a clinician.

Other interventions underway include offering designated scheduling time each week to women so they can receive infusions in an area with other women. This may help mitigate the finding that women veterans felt more uncomfortable around other patients during infusion treatments compared with how men felt in the chemotherapy unit. We also have implemented gender-specific restrooms labeled with a sign on each bathroom door so men and women can have access to a designated restroom. Offering private or semiprivate treatment rooms is currently limited by space and capacity; however, these may offer the greatest opportunity to improve patient satisfaction, especially among women veterans. Working with the support of the VAPHCS Cancer Committee, we aim to reevaluate the impact of the education and QI efforts on gender differences and patient satisfaction at completion of the 1-year award.

Limitations

Limitations to our study include the overall small sample size. This is due to the combination of the low number of women treated at VAPHCS and many with advanced cancer who, unfortunately, have a limited overall survival and hinders accrual of a larger sample size. Other limitations included age as a possible confounder in our findings, with women representing a younger demographic compared with men. We did not collect responses on duration of infusion time, which also may impact overall satisfaction and patient experience. We also acknowledge that biologic male or female sex may not correspond to a specific individual’s gender. Use of CPRS to obtain a matched number of male and female patients through random selection relied on labeled data from the EHR. This potentially may have excluded male patients who identify as another gender that would have been captured on the anonymous survey.

Conclusions

Our findings may have broad applications to other VHA facilities and other cancer-directed treatment centers where the patient demographic and open shared infusion unit design may be similar. The study also may serve as a model of survey design and implementation from which other centers may consider improving patient satisfaction. We hope these survey results and interventions can provide insight and be used to improve patient satisfaction among all cancer patients at infusion units serving veterans and nonveterans.

Acknowledgments

We are very thankful to our cancer patients who took the time to take the survey. We also are very grateful to the VHA infusion unit nurses, staff, nurse practitioners, and physicians who have embraced this project and welcomed any changes that may positively impact treatment of veterans. Also, thank you to Tia Kohs for statistical support and Sophie West for gender discussions. Last, we specifically thank Barbara, for her pursuit of better care for women and for all veterans.

Gender differences in patient satisfaction with medical care have been evaluated in multiple settings; however, studies specific to the unique population of women veterans with cancer are lacking. Women are reported to value privacy, psychosocial support, and communication to a higher degree compared with men.¹ Factors affecting satisfaction include the following: discomfort in sharing treatment rooms with the opposite gender, a desire for privacy with treatment and restroom use, anatomic or illness differences, and a personal history of abuse^.2-4 Regrettably, up to 1 in 3 women in the United States are victims of sexual trauma in their lifetimes, and up to 1 in 4 women in the military are victims of military sexual trauma. Incidence in both settings is suspected to be higher due to underreporting^.5,6

Chemotherapy treatment units are often uniquely designed as an open space, with several patients sharing a treatment area. The design reduces isolation and facilitates quick nurse-patient access during potentially toxic treatments known to have frequent adverse effects. Data suggest that nursing staff prefer open models to facilitate quick patient assessments and interventions as needed; however, patients and families prefer private treatment rooms, especially among women patients or those receiving longer infusions.⁷

The Veterans Health Administration (VHA) patient population is male predominant, comprised only of 10% female patients.8 Although the proportion of female patients in the VHA is expected to rise annually to about 16% by 2043, the low percentage of female veterans will persist for the foreseeable future.⁸ This low percentage of female veterans is reflected in the Veterans Affairs Portland Health Care System (VAPHCS) cancer patient population and in the use of the chemotherapy infusion unit, which is used for the ambulatory treatment of veterans undergoing cancer therapy.

The VHA has previously explored gender differences in health care, such as with cardiovascular disease, transgender care, and access to mental health.^9-11 However, to the best of our knowledge, no analysis has explored gender differences within the outpatient cancer treatment experience. Patient satisfaction with outpatient cancer care may be magnified in the VHA setting due to the uniquely unequal gender populations, shared treatment space design, and high incidence of sexual abuse among women veterans. Given this, we aimed to identify gender-related preferences in outpatient cancer care in our chemotherapy infusion unit.

In our study, we used the terms male and female to reflect statistical data from the literature or labeled data from the electronic health record (EHR); whereas the terms men and women were used to describe and encompass the cultural implications and context of gender.¹²

Methods

This study was designated as a quality improvement (QI) project by the VAPHCS research office and Institutional Review Board in accordance with VHA policies.

The VAPHCS outpatient chemotherapy infusion unit is designed with 6 rooms for chemotherapy administration. One room is a large open space with 6 chairs for patients. The other rooms are smaller with glass dividers between the rooms, and 3 chairs inside each for patients. There are 2 private bathrooms, each gender neutral. Direct patient care is provided by physicians, nurse practitioners (NPs), infusion unit nurses, and nurse coordinators. Men represent the majority of hematology and oncology physicians (13 of 20 total: 5 women fellow physicians and 2 women attending physicians), and 2 of 4 NPs. Women represent 10 of 12 infusion unit and cancer coordinator nurses. We used the VHA Computerized Patient Record System (CPRS) EHR, to create a list of veterans treated at the VAPHCS outpatient chemotherapy infusion unit for a 2-year period (January 1, 2018, to December 31, 2020).

Male and female patient lists were first generated based on CPRS categorization. We identified all female veterans treated in the ambulatory infusion unit during the study period. Male patients were then chosen at random, recording the most recent names for each year until a matched number per year compared with the female cohort was reached. Patients were recorded only once even though they had multiple infusion unit visits. Patients were excluded who were deceased, on hospice care, lost to follow-up, could not be reached by phone, refused to take the survey, had undeliverable email addresses, or lacked internet or email access.

After filing the appropriate request through the VAPHCS Institutional Review Board committee in January 2021, patient records were reviewed for demographics data, contact information, and infusion treatment history. The survey was then conducted over a 2-week period during January and February 2021. Each patient was invited by phone to complete a 25-question anonymous online survey. The survey questions were created from patient-relayed experiences, then modeled into survey questions in a format similar to other patient satisfaction questionnaires described in cancer care and gender differences.^2,13,14 The survey included self-identification of gender and was multiple choice for all except 2 questions, which allowed an open-ended response (Appendix). Only 1 answer per question was permitted. Only 1 survey link was sent to each veteran who gave permission for the survey. To protect anonymity for the small patient population, we excluded those identifying as gender nonbinary or transgender.

Statistical Analysis

Patient, disease, and treatment features are separated by male and female cohorts to reflect information from the EHR (Table 1). Survey percentages were calculated to reflect the affirmative response of the question asked (Table 2). Questions with answer options of not important, minimally important, important, or very important were calculated to reflect the sum of any importance in both cohorts. Questions with answer options of never, once, often, or every time were calculated to reflect any occurrence (sum of once, often, or every time) in both patient groups. Questions with answer options of strongly agree, somewhat agree, somewhat disagree, and strongly disagree were calculated to reflect any agreement (somewhat agree and strongly agree summed together) for both groups. Comparisons between cohorts were then conducted using a Fisher exact test. A Welch t test was used to calculate the significance of the continuous variable and overall ranking of the infusion unit experience between groups.

Results 

In 2020, 414 individual patients were treated at the VAPAHCS outpatient infusion unit. Of these, 23 (5.6%) were female, and 18 agreed to take the survey. After deceased and duplicate names from 2020 were removed, another 14 eligible 2019 female patients were invited and 6 agreed to participate; 6 eligible 2018 female patients were invited and 4 agreed to take the survey (Figure). Thirty female veterans were sent a survey link and 21 (70%) responses were collected. Twenty-one male 2020 patients were contacted and 18 agreed to take the survey. After removing duplicate names and deceased individuals, 17 of 21 eligible 2019 male patients and 4 of 6 eligible 2018 patients agreed to take the survey. Five additional male veterans declined the online-based survey method. In total, 39 male veterans were reached who agreed to have the survey link emailed, and 20 (51%) total responses were collected.

Most respondents answered all questions in the survey. The most frequently skipped questions included 3 questions that were contingent on a yes answer to a prior question, and 2 openended questions asking for a write-in response. Percentages for female and male respondents were adjusted for number of responses when applicable.

Thirteen (62%) female patients were aged < 65 years, while 18 (90%) of male patients were aged ≥ 65 years. Education beyond high school was reported in 20 female and 15 male respondents. Almost all treatment administered in the infusion unit was for cancer-directed treatment, with only 1 reporting a noncancer treatment (IV iron). The most common malignancy among female patients was breast cancer (n = 11, 52%); for male patients prostate cancer (n = 4, 20%) and hematologic malignancy (n = 4, 20%) were most common. Four (19%) female and 8 (40%) male respondents reported having a metastatic diagnosis. Overall patient satisfaction ranked high with an average score of 9.1 on a 10-point scale. The mean (SD) satisfaction score for female respondents was 1 point lower than that for men: 8.7 (2.2) vs 9.6 (0.6) in men (P = .11).

Eighteen (86%) women reported a history of sexual abuse or harassment compared with 2 (10%) men (P < .001). The sexual abuse assailant was a different gender for 17 of 18 female respondents and of the same gender for both male respondents. Of those with sexual abuse history, 4 women reported feeling uncomfortable around their assailant’s gender vs no men (P = .11), but this difference was not statistically significant. Six women (29%) and 2 (10%) men reported feeling uncomfortable during clinical examinations from comments made by the clinician or during treatment administration (P = .24). Six (29%) women and no men reported that they “felt uncomfortable in the infusion unit by other patients” (P = .02). Six (29%) women and no men reported feeling unable to “voice uncomfortable experiences” to the infusion unit clinician (P = .02).

Ten (48%) women and 6 (30%) men reported emotional support when receiving treatments provided by staff of the same gender (P = .34). Eight (38%) women and 4 (20%) men noted that access to treatment with the same gender was important (P = .31). Six (29%) women and 4 (20%) men indicated that access to a sex or gender-specific restroom was important (P = .72). No gender preferences were identified in the survey questions regarding importance of private treatment room access and level of emotional support when receiving treatment with others of the same malignancy. These relationships were not statistically significant.

In addition, 2 open-ended questions were asked. Seventeen women and 14 men responded. Contact the corresponding author for more information on the questions and responses.

Discussion

Overall patient satisfaction was high among the men and women veterans with cancer who received treatment in our outpatient infusion unit; however, notable gender differences existed. Three items in the survey revealed statistically significant differences in the patient experience between men and women veterans: history of sexual abuse or harassment, uncomfortable feelings among other patients, and discomfort in relaying uncomfortable feelings to a clinician. Other items in the survey did not reach statistical significance; however, we have included discussion of the findings as they may highlight important trends and be of clinical significance.

We suspect differences among genders in patient satisfaction to be related to the high incidence of sexual abuse or harassment history reported by women, much higher at 86% than the one-third to one-fourth incidence rates estimated by the existing literature for civilian or military sexual abuse in women.5,6 These high sexual abuse or harassment rates are present in a majority of women who receive cancer-directed treatment toward a gender-specific breast malignancy, surrounded predominantly among men in a shared treatment space. Together, these factors are likely key reasons behind the differences in satisfaction observed. This sentiment is expressed in our cohort, where one-fifth of women with a sexual abuse or harassment history continue to remain uncomfortable around men, and 29% of women reporting some uncomfortable feelings during their treatment experience compared with none of the men. Additionally, 6 (29%) women vs no men felt uncomfortable in reporting an uncomfortable experience with a clinician; this represents a significant barrier in providing care for these patients.

A key gender preference among women included access to shared treatment rooms with other women and that sharing a treatment space with other women resulted in feeling more emotional support during treatments. Access to gender-specific restrooms was also preferred by women more than men. Key findings in both genders were that about half of men and women valued access to a private treatment room and would derive more emotional support when surrounded by others with the same cancer.

Prior studies on gender and patient satisfaction in general medical care and cancer care have found women value privacy more than men.^1-3 Wessels and colleagues performed an analysis of 386 patients with cancer in Europe and found gender to be the strongest influence in patient preferences within cancer care. Specifically, the highest statically significant association in care preferences among women included privacy, support/counseling/rehabilitation access, and decreased wait times.2 These findings were most pronounced in those with breast cancer compared with other malignancy type and highlights that malignancy type and gender predominance impact care satisfaction.

Traditionally a shared treatment space design has been used in outpatient chemotherapy units, similar to the design of the VAPHCS. However, recent data report on the patient preference for a private treatment space, which was especially prominent among women and those receiving longer infusions.7 In another study that evaluated 225 patients with cancer preferences in sharing a treatment space with those of a different sexual orientation or gender identify, differences were found. Both men and women had a similar level of comfort in sharing a treatment room with someone of a different sexual orientation; however, more women reported discomfort in sharing a treatment space with a transgender woman compared with men who felt more comfortable sharing a space with a transgender man.4 We noted a gender preference may be present to explain the difference. Within our cohort, women valued access to treatment with other women and derived more emotional support when with other women; however, we did not inquire about feelings in sharing a treatment space among transgender individuals or differing sexual orientation.

Gender differences for privacy and in shared room preferences may result from the lasting impacts of prior sexual abuse or harassment. A history of sexual abuse negatively impacts later medical care access and use.15 Those veterans who experienced sexual abuse/harrassment reported higher feelings of lack of control, vulnerability, depression, and pursued less medical care.^15,16 Within cancer care, these feelings are most pronounced among women with gender-specific malignancies, such as gynecologic cancers or breast cancer. Treatment, screening, and physical examinations by clinicians who are of the same gender as the sexual abuse/harassment assailant can recreate traumatic feelings.^15,16

A majority of women (n = 18, 86%) in our cohort reported a history of sexual abuse or harassment and breast malignancy was the most common cancer among women. However women represent just 5.6% of the VAPHCS infusion unit treatment population. This combination of factors may explain the reasons for women veterans’ preference for privacy during treatments, access to gender-specific restrooms, and feeling more emotional support when surrounded by other women. Strategies to help patients with a history of abuse have been described and include discussions from the clinician asking about abuse history, allowing time for the patient to express fears with an examination or test, and training on how to deliver sensitive care for those with trauma.^17,18

Quality Improvement

Project In the VAPHCS infusion unit, several low-cost interventions have been undertaken as a result of our survey findings. We presented our survey data to the VAPHCS Cancer Committee, accredited through the national American College of Surgeons Commission on Cancer. The committee awarded support for a yearlong QI project, including a formal framework of quarterly multidisciplinary meetings to discuss project updates, challenges, and resources. The QI project centers on education to raise awareness of survey results as well as specific interventions for improvement.

Education efforts have been applied through multiple department-wide emails, in-person education to our chemotherapy unit staff, abstract submission to national oncology conferences, and grand rounds department presentations at VAPHCS and at other VHA-affiliated university programs. Additionally, education to clinicians with specific contact information for psychology and women’s health to support mental health, trauma, and sexual abuse histories has been given to each clinician who cares for veterans in the chemotherapy unit.

We also have implemented a mandatory cancer care navigation consultation for all women veterans who have a new cancer or infusion need. The cancer care navigator has received specialized training in sensitive history-taking and provides women veterans with a direct number to reach the cancer care navigation nurse. Cancer care navigation also provides a continuum of support and referral access for psychosocial needs as indicated between infusion or health care visits. Our hope is that these resources may help offset the sentiment reflected in our cohort of women feeling unable to voice concerns to a clinician.

Other interventions underway include offering designated scheduling time each week to women so they can receive infusions in an area with other women. This may help mitigate the finding that women veterans felt more uncomfortable around other patients during infusion treatments compared with how men felt in the chemotherapy unit. We also have implemented gender-specific restrooms labeled with a sign on each bathroom door so men and women can have access to a designated restroom. Offering private or semiprivate treatment rooms is currently limited by space and capacity; however, these may offer the greatest opportunity to improve patient satisfaction, especially among women veterans. Working with the support of the VAPHCS Cancer Committee, we aim to reevaluate the impact of the education and QI efforts on gender differences and patient satisfaction at completion of the 1-year award.

Limitations

Limitations to our study include the overall small sample size. This is due to the combination of the low number of women treated at VAPHCS and many with advanced cancer who, unfortunately, have a limited overall survival and hinders accrual of a larger sample size. Other limitations included age as a possible confounder in our findings, with women representing a younger demographic compared with men. We did not collect responses on duration of infusion time, which also may impact overall satisfaction and patient experience. We also acknowledge that biologic male or female sex may not correspond to a specific individual’s gender. Use of CPRS to obtain a matched number of male and female patients through random selection relied on labeled data from the EHR. This potentially may have excluded male patients who identify as another gender that would have been captured on the anonymous survey.

Conclusions

Our findings may have broad applications to other VHA facilities and other cancer-directed treatment centers where the patient demographic and open shared infusion unit design may be similar. The study also may serve as a model of survey design and implementation from which other centers may consider improving patient satisfaction. We hope these survey results and interventions can provide insight and be used to improve patient satisfaction among all cancer patients at infusion units serving veterans and nonveterans.

Acknowledgments

We are very thankful to our cancer patients who took the time to take the survey. We also are very grateful to the VHA infusion unit nurses, staff, nurse practitioners, and physicians who have embraced this project and welcomed any changes that may positively impact treatment of veterans. Also, thank you to Tia Kohs for statistical support and Sophie West for gender discussions. Last, we specifically thank Barbara, for her pursuit of better care for women and for all veterans.

Gender differences in patient satisfaction with medical care have been evaluated in multiple settings; however, studies specific to the unique population of women veterans with cancer are lacking. Women are reported to value privacy, psychosocial support, and communication to a higher degree compared with men.¹ Factors affecting satisfaction include the following: discomfort in sharing treatment rooms with the opposite gender, a desire for privacy with treatment and restroom use, anatomic or illness differences, and a personal history of abuse^.2-4 Regrettably, up to 1 in 3 women in the United States are victims of sexual trauma in their lifetimes, and up to 1 in 4 women in the military are victims of military sexual trauma. Incidence in both settings is suspected to be higher due to underreporting^.5,6

Chemotherapy treatment units are often uniquely designed as an open space, with several patients sharing a treatment area. The design reduces isolation and facilitates quick nurse-patient access during potentially toxic treatments known to have frequent adverse effects. Data suggest that nursing staff prefer open models to facilitate quick patient assessments and interventions as needed; however, patients and families prefer private treatment rooms, especially among women patients or those receiving longer infusions.⁷

The Veterans Health Administration (VHA) patient population is male predominant, comprised only of 10% female patients.8 Although the proportion of female patients in the VHA is expected to rise annually to about 16% by 2043, the low percentage of female veterans will persist for the foreseeable future.⁸ This low percentage of female veterans is reflected in the Veterans Affairs Portland Health Care System (VAPHCS) cancer patient population and in the use of the chemotherapy infusion unit, which is used for the ambulatory treatment of veterans undergoing cancer therapy.

The VHA has previously explored gender differences in health care, such as with cardiovascular disease, transgender care, and access to mental health.^9-11 However, to the best of our knowledge, no analysis has explored gender differences within the outpatient cancer treatment experience. Patient satisfaction with outpatient cancer care may be magnified in the VHA setting due to the uniquely unequal gender populations, shared treatment space design, and high incidence of sexual abuse among women veterans. Given this, we aimed to identify gender-related preferences in outpatient cancer care in our chemotherapy infusion unit.

In our study, we used the terms male and female to reflect statistical data from the literature or labeled data from the electronic health record (EHR); whereas the terms men and women were used to describe and encompass the cultural implications and context of gender.¹²

Methods

This study was designated as a quality improvement (QI) project by the VAPHCS research office and Institutional Review Board in accordance with VHA policies.

The VAPHCS outpatient chemotherapy infusion unit is designed with 6 rooms for chemotherapy administration. One room is a large open space with 6 chairs for patients. The other rooms are smaller with glass dividers between the rooms, and 3 chairs inside each for patients. There are 2 private bathrooms, each gender neutral. Direct patient care is provided by physicians, nurse practitioners (NPs), infusion unit nurses, and nurse coordinators. Men represent the majority of hematology and oncology physicians (13 of 20 total: 5 women fellow physicians and 2 women attending physicians), and 2 of 4 NPs. Women represent 10 of 12 infusion unit and cancer coordinator nurses. We used the VHA Computerized Patient Record System (CPRS) EHR, to create a list of veterans treated at the VAPHCS outpatient chemotherapy infusion unit for a 2-year period (January 1, 2018, to December 31, 2020).

Male and female patient lists were first generated based on CPRS categorization. We identified all female veterans treated in the ambulatory infusion unit during the study period. Male patients were then chosen at random, recording the most recent names for each year until a matched number per year compared with the female cohort was reached. Patients were recorded only once even though they had multiple infusion unit visits. Patients were excluded who were deceased, on hospice care, lost to follow-up, could not be reached by phone, refused to take the survey, had undeliverable email addresses, or lacked internet or email access.

After filing the appropriate request through the VAPHCS Institutional Review Board committee in January 2021, patient records were reviewed for demographics data, contact information, and infusion treatment history. The survey was then conducted over a 2-week period during January and February 2021. Each patient was invited by phone to complete a 25-question anonymous online survey. The survey questions were created from patient-relayed experiences, then modeled into survey questions in a format similar to other patient satisfaction questionnaires described in cancer care and gender differences.^2,13,14 The survey included self-identification of gender and was multiple choice for all except 2 questions, which allowed an open-ended response (Appendix). Only 1 answer per question was permitted. Only 1 survey link was sent to each veteran who gave permission for the survey. To protect anonymity for the small patient population, we excluded those identifying as gender nonbinary or transgender.

Statistical Analysis

Patient, disease, and treatment features are separated by male and female cohorts to reflect information from the EHR (Table 1). Survey percentages were calculated to reflect the affirmative response of the question asked (Table 2). Questions with answer options of not important, minimally important, important, or very important were calculated to reflect the sum of any importance in both cohorts. Questions with answer options of never, once, often, or every time were calculated to reflect any occurrence (sum of once, often, or every time) in both patient groups. Questions with answer options of strongly agree, somewhat agree, somewhat disagree, and strongly disagree were calculated to reflect any agreement (somewhat agree and strongly agree summed together) for both groups. Comparisons between cohorts were then conducted using a Fisher exact test. A Welch t test was used to calculate the significance of the continuous variable and overall ranking of the infusion unit experience between groups.

Results 

In 2020, 414 individual patients were treated at the VAPAHCS outpatient infusion unit. Of these, 23 (5.6%) were female, and 18 agreed to take the survey. After deceased and duplicate names from 2020 were removed, another 14 eligible 2019 female patients were invited and 6 agreed to participate; 6 eligible 2018 female patients were invited and 4 agreed to take the survey (Figure). Thirty female veterans were sent a survey link and 21 (70%) responses were collected. Twenty-one male 2020 patients were contacted and 18 agreed to take the survey. After removing duplicate names and deceased individuals, 17 of 21 eligible 2019 male patients and 4 of 6 eligible 2018 patients agreed to take the survey. Five additional male veterans declined the online-based survey method. In total, 39 male veterans were reached who agreed to have the survey link emailed, and 20 (51%) total responses were collected.

Most respondents answered all questions in the survey. The most frequently skipped questions included 3 questions that were contingent on a yes answer to a prior question, and 2 openended questions asking for a write-in response. Percentages for female and male respondents were adjusted for number of responses when applicable.

Thirteen (62%) female patients were aged < 65 years, while 18 (90%) of male patients were aged ≥ 65 years. Education beyond high school was reported in 20 female and 15 male respondents. Almost all treatment administered in the infusion unit was for cancer-directed treatment, with only 1 reporting a noncancer treatment (IV iron). The most common malignancy among female patients was breast cancer (n = 11, 52%); for male patients prostate cancer (n = 4, 20%) and hematologic malignancy (n = 4, 20%) were most common. Four (19%) female and 8 (40%) male respondents reported having a metastatic diagnosis. Overall patient satisfaction ranked high with an average score of 9.1 on a 10-point scale. The mean (SD) satisfaction score for female respondents was 1 point lower than that for men: 8.7 (2.2) vs 9.6 (0.6) in men (P = .11).

Eighteen (86%) women reported a history of sexual abuse or harassment compared with 2 (10%) men (P < .001). The sexual abuse assailant was a different gender for 17 of 18 female respondents and of the same gender for both male respondents. Of those with sexual abuse history, 4 women reported feeling uncomfortable around their assailant’s gender vs no men (P = .11), but this difference was not statistically significant. Six women (29%) and 2 (10%) men reported feeling uncomfortable during clinical examinations from comments made by the clinician or during treatment administration (P = .24). Six (29%) women and no men reported that they “felt uncomfortable in the infusion unit by other patients” (P = .02). Six (29%) women and no men reported feeling unable to “voice uncomfortable experiences” to the infusion unit clinician (P = .02).

Ten (48%) women and 6 (30%) men reported emotional support when receiving treatments provided by staff of the same gender (P = .34). Eight (38%) women and 4 (20%) men noted that access to treatment with the same gender was important (P = .31). Six (29%) women and 4 (20%) men indicated that access to a sex or gender-specific restroom was important (P = .72). No gender preferences were identified in the survey questions regarding importance of private treatment room access and level of emotional support when receiving treatment with others of the same malignancy. These relationships were not statistically significant.

In addition, 2 open-ended questions were asked. Seventeen women and 14 men responded. Contact the corresponding author for more information on the questions and responses.

Discussion

Overall patient satisfaction was high among the men and women veterans with cancer who received treatment in our outpatient infusion unit; however, notable gender differences existed. Three items in the survey revealed statistically significant differences in the patient experience between men and women veterans: history of sexual abuse or harassment, uncomfortable feelings among other patients, and discomfort in relaying uncomfortable feelings to a clinician. Other items in the survey did not reach statistical significance; however, we have included discussion of the findings as they may highlight important trends and be of clinical significance.

We suspect differences among genders in patient satisfaction to be related to the high incidence of sexual abuse or harassment history reported by women, much higher at 86% than the one-third to one-fourth incidence rates estimated by the existing literature for civilian or military sexual abuse in women.5,6 These high sexual abuse or harassment rates are present in a majority of women who receive cancer-directed treatment toward a gender-specific breast malignancy, surrounded predominantly among men in a shared treatment space. Together, these factors are likely key reasons behind the differences in satisfaction observed. This sentiment is expressed in our cohort, where one-fifth of women with a sexual abuse or harassment history continue to remain uncomfortable around men, and 29% of women reporting some uncomfortable feelings during their treatment experience compared with none of the men. Additionally, 6 (29%) women vs no men felt uncomfortable in reporting an uncomfortable experience with a clinician; this represents a significant barrier in providing care for these patients.

A key gender preference among women included access to shared treatment rooms with other women and that sharing a treatment space with other women resulted in feeling more emotional support during treatments. Access to gender-specific restrooms was also preferred by women more than men. Key findings in both genders were that about half of men and women valued access to a private treatment room and would derive more emotional support when surrounded by others with the same cancer.

Prior studies on gender and patient satisfaction in general medical care and cancer care have found women value privacy more than men.^1-3 Wessels and colleagues performed an analysis of 386 patients with cancer in Europe and found gender to be the strongest influence in patient preferences within cancer care. Specifically, the highest statically significant association in care preferences among women included privacy, support/counseling/rehabilitation access, and decreased wait times.2 These findings were most pronounced in those with breast cancer compared with other malignancy type and highlights that malignancy type and gender predominance impact care satisfaction.

Traditionally a shared treatment space design has been used in outpatient chemotherapy units, similar to the design of the VAPHCS. However, recent data report on the patient preference for a private treatment space, which was especially prominent among women and those receiving longer infusions.7 In another study that evaluated 225 patients with cancer preferences in sharing a treatment space with those of a different sexual orientation or gender identify, differences were found. Both men and women had a similar level of comfort in sharing a treatment room with someone of a different sexual orientation; however, more women reported discomfort in sharing a treatment space with a transgender woman compared with men who felt more comfortable sharing a space with a transgender man.4 We noted a gender preference may be present to explain the difference. Within our cohort, women valued access to treatment with other women and derived more emotional support when with other women; however, we did not inquire about feelings in sharing a treatment space among transgender individuals or differing sexual orientation.

Gender differences for privacy and in shared room preferences may result from the lasting impacts of prior sexual abuse or harassment. A history of sexual abuse negatively impacts later medical care access and use.15 Those veterans who experienced sexual abuse/harrassment reported higher feelings of lack of control, vulnerability, depression, and pursued less medical care.^15,16 Within cancer care, these feelings are most pronounced among women with gender-specific malignancies, such as gynecologic cancers or breast cancer. Treatment, screening, and physical examinations by clinicians who are of the same gender as the sexual abuse/harassment assailant can recreate traumatic feelings.^15,16

A majority of women (n = 18, 86%) in our cohort reported a history of sexual abuse or harassment and breast malignancy was the most common cancer among women. However women represent just 5.6% of the VAPHCS infusion unit treatment population. This combination of factors may explain the reasons for women veterans’ preference for privacy during treatments, access to gender-specific restrooms, and feeling more emotional support when surrounded by other women. Strategies to help patients with a history of abuse have been described and include discussions from the clinician asking about abuse history, allowing time for the patient to express fears with an examination or test, and training on how to deliver sensitive care for those with trauma.^17,18

Quality Improvement

Project In the VAPHCS infusion unit, several low-cost interventions have been undertaken as a result of our survey findings. We presented our survey data to the VAPHCS Cancer Committee, accredited through the national American College of Surgeons Commission on Cancer. The committee awarded support for a yearlong QI project, including a formal framework of quarterly multidisciplinary meetings to discuss project updates, challenges, and resources. The QI project centers on education to raise awareness of survey results as well as specific interventions for improvement.

Education efforts have been applied through multiple department-wide emails, in-person education to our chemotherapy unit staff, abstract submission to national oncology conferences, and grand rounds department presentations at VAPHCS and at other VHA-affiliated university programs. Additionally, education to clinicians with specific contact information for psychology and women’s health to support mental health, trauma, and sexual abuse histories has been given to each clinician who cares for veterans in the chemotherapy unit.

We also have implemented a mandatory cancer care navigation consultation for all women veterans who have a new cancer or infusion need. The cancer care navigator has received specialized training in sensitive history-taking and provides women veterans with a direct number to reach the cancer care navigation nurse. Cancer care navigation also provides a continuum of support and referral access for psychosocial needs as indicated between infusion or health care visits. Our hope is that these resources may help offset the sentiment reflected in our cohort of women feeling unable to voice concerns to a clinician.

Other interventions underway include offering designated scheduling time each week to women so they can receive infusions in an area with other women. This may help mitigate the finding that women veterans felt more uncomfortable around other patients during infusion treatments compared with how men felt in the chemotherapy unit. We also have implemented gender-specific restrooms labeled with a sign on each bathroom door so men and women can have access to a designated restroom. Offering private or semiprivate treatment rooms is currently limited by space and capacity; however, these may offer the greatest opportunity to improve patient satisfaction, especially among women veterans. Working with the support of the VAPHCS Cancer Committee, we aim to reevaluate the impact of the education and QI efforts on gender differences and patient satisfaction at completion of the 1-year award.

Limitations

Limitations to our study include the overall small sample size. This is due to the combination of the low number of women treated at VAPHCS and many with advanced cancer who, unfortunately, have a limited overall survival and hinders accrual of a larger sample size. Other limitations included age as a possible confounder in our findings, with women representing a younger demographic compared with men. We did not collect responses on duration of infusion time, which also may impact overall satisfaction and patient experience. We also acknowledge that biologic male or female sex may not correspond to a specific individual’s gender. Use of CPRS to obtain a matched number of male and female patients through random selection relied on labeled data from the EHR. This potentially may have excluded male patients who identify as another gender that would have been captured on the anonymous survey.

Conclusions

Our findings may have broad applications to other VHA facilities and other cancer-directed treatment centers where the patient demographic and open shared infusion unit design may be similar. The study also may serve as a model of survey design and implementation from which other centers may consider improving patient satisfaction. We hope these survey results and interventions can provide insight and be used to improve patient satisfaction among all cancer patients at infusion units serving veterans and nonveterans.

Acknowledgments

We are very thankful to our cancer patients who took the time to take the survey. We also are very grateful to the VHA infusion unit nurses, staff, nurse practitioners, and physicians who have embraced this project and welcomed any changes that may positively impact treatment of veterans. Also, thank you to Tia Kohs for statistical support and Sophie West for gender discussions. Last, we specifically thank Barbara, for her pursuit of better care for women and for all veterans.

Children born near fracking and other “unconventional” drilling sites are at two to three times greater risk of developing childhood leukemia, according to new research.

The study, published in the journal Environmental Health Perspectives, compared proximity of homes to unconventional oil and gas development (UOGD) sites and risk of the most common form of childhood leukemia, acute lymphoblastic leukemia (ALL).

Researchers looked at 405 children aged 2-7 diagnosed with ALL in Pennsylvania from 2009 to 2017. These children were compared to a control group of 2,080 without the disease matched on the year of birth.

“Unconventional oil and gas development can both use and release chemicals that have been linked to cancer,” study coauthor Nicole Deziel, PhD, of the Yale School of Public Health, New Haven, Conn., said in a  statement . She noted that the possibility that children living in close proximity to such sites are “exposed to these chemical carcinogens is a major public health concern.”

About 17 million Americans live within a half-mile of active oil and gas production, according to the Oil & Gas Threat Map, Common Dreams reports. That number includes 4 million children.

The Yale study also found that drinking water could be an important pathway of exposure to oil- and gas-related chemicals used in the UOGD methods of extraction.

Researchers used a new metric that measures exposure to contaminated drinking water and distance to a well. They were able to identify UOGD-affected wells that fell within watersheds where children and their families likely obtained their water.

“Previous health studies have found links between proximity to oil and gas drilling and various children’s health outcomes,” said Dr. Deziel. “This study is among the few to focus on drinking water specifically and the first to apply a novel metric designed to capture potential exposure through this pathway.”

A version of this article first appeared on WebMD.com.

Children born near fracking and other “unconventional” drilling sites are at two to three times greater risk of developing childhood leukemia, according to new research.

The study, published in the journal Environmental Health Perspectives, compared proximity of homes to unconventional oil and gas development (UOGD) sites and risk of the most common form of childhood leukemia, acute lymphoblastic leukemia (ALL).

Researchers looked at 405 children aged 2-7 diagnosed with ALL in Pennsylvania from 2009 to 2017. These children were compared to a control group of 2,080 without the disease matched on the year of birth.

“Unconventional oil and gas development can both use and release chemicals that have been linked to cancer,” study coauthor Nicole Deziel, PhD, of the Yale School of Public Health, New Haven, Conn., said in a  statement . She noted that the possibility that children living in close proximity to such sites are “exposed to these chemical carcinogens is a major public health concern.”

About 17 million Americans live within a half-mile of active oil and gas production, according to the Oil & Gas Threat Map, Common Dreams reports. That number includes 4 million children.

The Yale study also found that drinking water could be an important pathway of exposure to oil- and gas-related chemicals used in the UOGD methods of extraction.

Researchers used a new metric that measures exposure to contaminated drinking water and distance to a well. They were able to identify UOGD-affected wells that fell within watersheds where children and their families likely obtained their water.

“Previous health studies have found links between proximity to oil and gas drilling and various children’s health outcomes,” said Dr. Deziel. “This study is among the few to focus on drinking water specifically and the first to apply a novel metric designed to capture potential exposure through this pathway.”

A version of this article first appeared on WebMD.com.

Children born near fracking and other “unconventional” drilling sites are at two to three times greater risk of developing childhood leukemia, according to new research.

The study, published in the journal Environmental Health Perspectives, compared proximity of homes to unconventional oil and gas development (UOGD) sites and risk of the most common form of childhood leukemia, acute lymphoblastic leukemia (ALL).

Researchers looked at 405 children aged 2-7 diagnosed with ALL in Pennsylvania from 2009 to 2017. These children were compared to a control group of 2,080 without the disease matched on the year of birth.

“Unconventional oil and gas development can both use and release chemicals that have been linked to cancer,” study coauthor Nicole Deziel, PhD, of the Yale School of Public Health, New Haven, Conn., said in a  statement . She noted that the possibility that children living in close proximity to such sites are “exposed to these chemical carcinogens is a major public health concern.”

About 17 million Americans live within a half-mile of active oil and gas production, according to the Oil & Gas Threat Map, Common Dreams reports. That number includes 4 million children.

The Yale study also found that drinking water could be an important pathway of exposure to oil- and gas-related chemicals used in the UOGD methods of extraction.

Researchers used a new metric that measures exposure to contaminated drinking water and distance to a well. They were able to identify UOGD-affected wells that fell within watersheds where children and their families likely obtained their water.

“Previous health studies have found links between proximity to oil and gas drilling and various children’s health outcomes,” said Dr. Deziel. “This study is among the few to focus on drinking water specifically and the first to apply a novel metric designed to capture potential exposure through this pathway.”

A version of this article first appeared on WebMD.com.

New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.

Researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.

The study was published online in the journal Cell.


 

Gut reaction?

Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that these sweeteners affect the microbiome of mice in ways that could affect glycemic responses.

They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.

BigRedCurlyGuy/Thinkstock

Weighing the evidence

Several experts weighed in on the results in a statement from the U.K. nonprofit organization, Science Media Centre.

Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).

“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Dr. Mellor says.

Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, concurs, saying “this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals.”

The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.

“Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a ‘stepping stone’ allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet,” Dr. Mellor suggests.

Kevin McConway, PhD, with the Open University, Milton Keynes, England, said it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.

“But exactly what the health consequences of all this, if any, might be is a subject for future research,” Dr. McConway added.

Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth (England) agrees.

“We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small,” she says.

The International Sweeteners Association also weighs in, saying, “No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes.”

They add “a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota.”

Nevertheless, Dr. Redfern says the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer-term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”

The study had no specific funding. Dr. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Dr. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Dr. Barrett, Dr. McConway, and Dr. Redfern report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

This article was updated 8/29/22.

New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.

Researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.

The study was published online in the journal Cell.


 

Gut reaction?

Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that these sweeteners affect the microbiome of mice in ways that could affect glycemic responses.

They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.

BigRedCurlyGuy/Thinkstock

Weighing the evidence

Several experts weighed in on the results in a statement from the U.K. nonprofit organization, Science Media Centre.

Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).

“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Dr. Mellor says.

Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, concurs, saying “this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals.”

The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.

“Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a ‘stepping stone’ allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet,” Dr. Mellor suggests.

Kevin McConway, PhD, with the Open University, Milton Keynes, England, said it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.

“But exactly what the health consequences of all this, if any, might be is a subject for future research,” Dr. McConway added.

Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth (England) agrees.

“We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small,” she says.

The International Sweeteners Association also weighs in, saying, “No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes.”

They add “a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota.”

Nevertheless, Dr. Redfern says the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer-term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”

The study had no specific funding. Dr. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Dr. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Dr. Barrett, Dr. McConway, and Dr. Redfern report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

This article was updated 8/29/22.

New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.

Researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.

The study was published online in the journal Cell.


 

Gut reaction?

Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that these sweeteners affect the microbiome of mice in ways that could affect glycemic responses.

They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.

BigRedCurlyGuy/Thinkstock

Weighing the evidence

Several experts weighed in on the results in a statement from the U.K. nonprofit organization, Science Media Centre.

Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).

“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Dr. Mellor says.

Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, concurs, saying “this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals.”

The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.

“Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a ‘stepping stone’ allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet,” Dr. Mellor suggests.

Kevin McConway, PhD, with the Open University, Milton Keynes, England, said it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.

“But exactly what the health consequences of all this, if any, might be is a subject for future research,” Dr. McConway added.

Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth (England) agrees.

“We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small,” she says.

The International Sweeteners Association also weighs in, saying, “No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes.”

They add “a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota.”

Nevertheless, Dr. Redfern says the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer-term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”

The study had no specific funding. Dr. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Dr. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Dr. Barrett, Dr. McConway, and Dr. Redfern report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

This article was updated 8/29/22.

Lung disease as an adverse effect of the targeted cancer drug trastuzumab deruxtecan (T-DXd, Enhertu) is not negligible, although the benefit-to-risk relationship with use of the drug is still positive, say researchers who report a review of early clinical trials with the drug.

T-DXd is a monoclonal antibody that targets HER2. It is approved for use in HER2-positive breast, gastric, and lung cancers.

In the new study, investigators analyzed data from early clinical trials that involved patients with advanced cancers who had been heavily pretreated. They found an incidence of just over 15% for interstitial lung disease (ILD)/pneumonitis associated with the drug. Most patients (77.4%) had grade 1 or 2 ILD, but 2.2% of patients had grade 5 ILD.

“Interstitial lung disease is a known risk factor in patients treated with antibody conjugates for cancer,” commented lead author Charles Powell, MD, Icahn School of Medicine at Mount Sinai, New York. This adverse effect can lead to lung fibrosis and can become severe, life threatening, and even fatal, the authors warned.

The authors also discussed management of the event, which involves corticosteroids, and recommended that any patient who develops ILD of grade 3 or higher be hospitalized.

Close monitoring and proactive management may reduce the risk of ILD, they suggested.

Indeed, the incidence of this adverse effect was lower in a later phase 3 trial of the drug (10.5% in the DESTINY-Breast03 trial) and that the adverse events were less severe in this patient population (none of these events were of grade 4 or 5).

“Increased knowledge ... and implementation of ILD/pneumonitis monitoring, diagnosis, and management guidelines” may have resulted in this adverse effect being identified early and treated before it progressed, they commented.

ILD is highlighted in a boxed warning on the product label.

The study was published online in ESMO Open.

In their review, the investigators evaluated nine early-stage monotherapy clinical trials (phases 1 and 2) involving a total of 1,150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%, other cancers, 3.0%).

These patients had advanced cancer and had been heavily pretreated with a median of four prior lines of therapy. They received one or more doses of at least 5.4 mg/kg of T-DXd.

Nearly half of the cohort were treated for more than 6 months. A total of 276 potential ILD/pneumonitis events were sent for adjudication; of those, 85% were adjudicated as ILD/pneumonitis.

The overall incidence of adjudicated ILD/pneumonitis events was 15.4%; most were low-grade events. Some 87% of patients experienced their first ILD event within 12 months of treatment. The median time to experiencing an ILD/pneumonitis event was 5.4 months.

Some of the patients who developed grade 1 ILD/pneumonitis were treated and the adverse event resolved. These patients were then rechallenged with the drug. Only 3 of the 47 rechallenged patients experienced recurrence of ILD/pneumonitis, the authors noted.

“Rechallenge with T-DXd after complete resolution of grade 1 events is possible and warrants further investigation,” they commented. They cautioned, however, that rechallenge is not recommended for all patients, at least not for those with grade 2 or higher ILD/pneumonitis.

Overall, the authors concluded that the “benefit-risk of T-DXd treatment is positive,” but they warned that some patients may be at increased risk of developing ILD/pneumonitis

Baseline factors that increase the risk of developing an ILD/pneumonitis event include the following: being younger than 65 years, receiving a T-DXd dose of more than6.4 mg/kg, having a baseline oxygen saturation level of less than 95%, having moderate to severe renal impairment, and having lung comorbidities. In addition, patients who had initially been diagnosed with cancer more than 4 years before receiving the drug were at higher risk of developing ILD/pneumonitis.

“Using learnings from the early clinical trials experience, physician education and patient management protocols were revised and disseminated by the study sponsors [and] more recent trial data in earlier lines of therapy has demonstrated lower rates of ILD events, suggesting close monitoring and proactive management of ILD/pneumonitis is warranted for all patients,” Dr. Powell said in a statement.

The T-DXd clinical trials were sponsored by AstraZeneca and Daiichi Sankyo. Dr. Powell has received fees from Daiichi Sankyo, AstraZeneca, and Voluntis.

A version of this article first appeared on Medscape.com.

Lung disease as an adverse effect of the targeted cancer drug trastuzumab deruxtecan (T-DXd, Enhertu) is not negligible, although the benefit-to-risk relationship with use of the drug is still positive, say researchers who report a review of early clinical trials with the drug.

T-DXd is a monoclonal antibody that targets HER2. It is approved for use in HER2-positive breast, gastric, and lung cancers.

In the new study, investigators analyzed data from early clinical trials that involved patients with advanced cancers who had been heavily pretreated. They found an incidence of just over 15% for interstitial lung disease (ILD)/pneumonitis associated with the drug. Most patients (77.4%) had grade 1 or 2 ILD, but 2.2% of patients had grade 5 ILD.

“Interstitial lung disease is a known risk factor in patients treated with antibody conjugates for cancer,” commented lead author Charles Powell, MD, Icahn School of Medicine at Mount Sinai, New York. This adverse effect can lead to lung fibrosis and can become severe, life threatening, and even fatal, the authors warned.

The authors also discussed management of the event, which involves corticosteroids, and recommended that any patient who develops ILD of grade 3 or higher be hospitalized.

Close monitoring and proactive management may reduce the risk of ILD, they suggested.

Indeed, the incidence of this adverse effect was lower in a later phase 3 trial of the drug (10.5% in the DESTINY-Breast03 trial) and that the adverse events were less severe in this patient population (none of these events were of grade 4 or 5).

“Increased knowledge ... and implementation of ILD/pneumonitis monitoring, diagnosis, and management guidelines” may have resulted in this adverse effect being identified early and treated before it progressed, they commented.

ILD is highlighted in a boxed warning on the product label.

The study was published online in ESMO Open.

In their review, the investigators evaluated nine early-stage monotherapy clinical trials (phases 1 and 2) involving a total of 1,150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%, other cancers, 3.0%).

These patients had advanced cancer and had been heavily pretreated with a median of four prior lines of therapy. They received one or more doses of at least 5.4 mg/kg of T-DXd.

Nearly half of the cohort were treated for more than 6 months. A total of 276 potential ILD/pneumonitis events were sent for adjudication; of those, 85% were adjudicated as ILD/pneumonitis.

The overall incidence of adjudicated ILD/pneumonitis events was 15.4%; most were low-grade events. Some 87% of patients experienced their first ILD event within 12 months of treatment. The median time to experiencing an ILD/pneumonitis event was 5.4 months.

Some of the patients who developed grade 1 ILD/pneumonitis were treated and the adverse event resolved. These patients were then rechallenged with the drug. Only 3 of the 47 rechallenged patients experienced recurrence of ILD/pneumonitis, the authors noted.

“Rechallenge with T-DXd after complete resolution of grade 1 events is possible and warrants further investigation,” they commented. They cautioned, however, that rechallenge is not recommended for all patients, at least not for those with grade 2 or higher ILD/pneumonitis.

Overall, the authors concluded that the “benefit-risk of T-DXd treatment is positive,” but they warned that some patients may be at increased risk of developing ILD/pneumonitis

Baseline factors that increase the risk of developing an ILD/pneumonitis event include the following: being younger than 65 years, receiving a T-DXd dose of more than6.4 mg/kg, having a baseline oxygen saturation level of less than 95%, having moderate to severe renal impairment, and having lung comorbidities. In addition, patients who had initially been diagnosed with cancer more than 4 years before receiving the drug were at higher risk of developing ILD/pneumonitis.

“Using learnings from the early clinical trials experience, physician education and patient management protocols were revised and disseminated by the study sponsors [and] more recent trial data in earlier lines of therapy has demonstrated lower rates of ILD events, suggesting close monitoring and proactive management of ILD/pneumonitis is warranted for all patients,” Dr. Powell said in a statement.

The T-DXd clinical trials were sponsored by AstraZeneca and Daiichi Sankyo. Dr. Powell has received fees from Daiichi Sankyo, AstraZeneca, and Voluntis.

A version of this article first appeared on Medscape.com.

Lung disease as an adverse effect of the targeted cancer drug trastuzumab deruxtecan (T-DXd, Enhertu) is not negligible, although the benefit-to-risk relationship with use of the drug is still positive, say researchers who report a review of early clinical trials with the drug.

T-DXd is a monoclonal antibody that targets HER2. It is approved for use in HER2-positive breast, gastric, and lung cancers.

In the new study, investigators analyzed data from early clinical trials that involved patients with advanced cancers who had been heavily pretreated. They found an incidence of just over 15% for interstitial lung disease (ILD)/pneumonitis associated with the drug. Most patients (77.4%) had grade 1 or 2 ILD, but 2.2% of patients had grade 5 ILD.

“Interstitial lung disease is a known risk factor in patients treated with antibody conjugates for cancer,” commented lead author Charles Powell, MD, Icahn School of Medicine at Mount Sinai, New York. This adverse effect can lead to lung fibrosis and can become severe, life threatening, and even fatal, the authors warned.

The authors also discussed management of the event, which involves corticosteroids, and recommended that any patient who develops ILD of grade 3 or higher be hospitalized.

Close monitoring and proactive management may reduce the risk of ILD, they suggested.

Indeed, the incidence of this adverse effect was lower in a later phase 3 trial of the drug (10.5% in the DESTINY-Breast03 trial) and that the adverse events were less severe in this patient population (none of these events were of grade 4 or 5).

“Increased knowledge ... and implementation of ILD/pneumonitis monitoring, diagnosis, and management guidelines” may have resulted in this adverse effect being identified early and treated before it progressed, they commented.

ILD is highlighted in a boxed warning on the product label.

The study was published online in ESMO Open.

In their review, the investigators evaluated nine early-stage monotherapy clinical trials (phases 1 and 2) involving a total of 1,150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%, other cancers, 3.0%).

These patients had advanced cancer and had been heavily pretreated with a median of four prior lines of therapy. They received one or more doses of at least 5.4 mg/kg of T-DXd.

Nearly half of the cohort were treated for more than 6 months. A total of 276 potential ILD/pneumonitis events were sent for adjudication; of those, 85% were adjudicated as ILD/pneumonitis.

The overall incidence of adjudicated ILD/pneumonitis events was 15.4%; most were low-grade events. Some 87% of patients experienced their first ILD event within 12 months of treatment. The median time to experiencing an ILD/pneumonitis event was 5.4 months.

Some of the patients who developed grade 1 ILD/pneumonitis were treated and the adverse event resolved. These patients were then rechallenged with the drug. Only 3 of the 47 rechallenged patients experienced recurrence of ILD/pneumonitis, the authors noted.

“Rechallenge with T-DXd after complete resolution of grade 1 events is possible and warrants further investigation,” they commented. They cautioned, however, that rechallenge is not recommended for all patients, at least not for those with grade 2 or higher ILD/pneumonitis.

Overall, the authors concluded that the “benefit-risk of T-DXd treatment is positive,” but they warned that some patients may be at increased risk of developing ILD/pneumonitis

Baseline factors that increase the risk of developing an ILD/pneumonitis event include the following: being younger than 65 years, receiving a T-DXd dose of more than6.4 mg/kg, having a baseline oxygen saturation level of less than 95%, having moderate to severe renal impairment, and having lung comorbidities. In addition, patients who had initially been diagnosed with cancer more than 4 years before receiving the drug were at higher risk of developing ILD/pneumonitis.

“Using learnings from the early clinical trials experience, physician education and patient management protocols were revised and disseminated by the study sponsors [and] more recent trial data in earlier lines of therapy has demonstrated lower rates of ILD events, suggesting close monitoring and proactive management of ILD/pneumonitis is warranted for all patients,” Dr. Powell said in a statement.

The T-DXd clinical trials were sponsored by AstraZeneca and Daiichi Sankyo. Dr. Powell has received fees from Daiichi Sankyo, AstraZeneca, and Voluntis.

A version of this article first appeared on Medscape.com.

The field of radiation oncology has rapidly evolved in recent years, thanks in large part to findings from randomized clinical trials (RCTs) that have helped shift therapeutic standards, a review of the literature shows.

The authors assessed all RCTs involving radiotherapy from 2018 to 2021, with the goal of identifying the latest practice-changing data, emerging concepts, and areas that require further study.

Highlights from this research reveal how high-tech radiotherapy, such as hypofractionation and stereotactic body radiotherapy, has improved care for many patients, how personalized radiotherapy using image-based guidance has helped tailor treatments, and how endpoints that focus on quality of life and patient satisfaction are emerging.

For instance, Charles B. Simone II, MD, FACRO, who was not involved in the current work, pointed to “a proliferation of trials assessing hypofractionation in the curative setting and stereotactic body radiation therapy in the curative and poly- and oligometastatic settings that have allowed for increased patient convenience and dose intensification, respectively.”

Dr. Simone, chief medical officer, New York Proton Center, Memorial Sloan Kettering Cancer Center, also noted that the first personalized radiotherapy trials using imaging and biological markers have “the profound potential to individualize treatment and improve patient outcomes.”

The review was published in the European Journal of Cancer.
 

An evolving field

Given the fast-changing landscape for cancer therapeutics and a deluge of research studies, the authors wanted to understand the most notable advances established in recent trials as well as caveats to some approaches and emerging areas to watch.

In the review, Sophie Espenel, MD, from the department of radiation oncology, Gustave Roussy Cancer Campus, Villejuif, France, and colleagues identified 1,347 radiotherapy RCTs that were conducted from January 2018 to December 2021. Of these, the authors selected 110 large phase 2 or 3 RCTs that contained data showing practice-changing or emerging concepts.

Overall, the studies showed “great dynamism” in radiation oncology research and covered a wide range of radiotherapy practices, according to Dr. Espenel and coauthors.

A central area of research has focused on radioimmunotherapy, an approach that aims to enhance the antitumor immune response. One RCT in the preoperative setting showed, for instance, that concurrent stereotactic body radiotherapy delivered at 24 Gy over eight fractions, along with the anti–PD-L1 agent durvalumab, increased major pathologic complete response rates almost eightfold in comparison with durvalumab alone for patients with early-stage lung cancer (53.3% vs. 6.7%).

Although promising, not all trials that evaluated a concurrent chemoradiotherapy-immunotherapy strategy showed positive results. One RCT of locally advanced head and neck squamous cell carcinoma, for instance, found that median progression-free survival was not reached when adding the anti–PD-L1 avelumab to chemoradiotherapy. In addition, trials in the metastatic setting have shown conflicting results, the authors note.

Another topic of interest is that of newer radiosensitizers. A trial that evaluated high-risk locoregionally advanced head and neck squamous cell carcinoma highlighted the efficacy of xevinapant, a pro-apoptotic agent that inhibits apoptosis proteins. Xevinapant was used for the first time in conjunction with a standard high-dose cisplatin chemoradiotherapy. In this study, locoregional control at 18 months was achieved for 54% of patients who received xevinapant vs. 33% of those who received standard care. The toxicity profiles were similar.

The use of high-tech radiotherapy is gaining ground. It allows patients to receive more targeted treatments at lower doses and in shorter time frames. One trial found, for instance, that a more hypofractionated adjuvant whole breast approach, using 26 Gy in five fractions over a week, is as effective and safe as 40 Gy in 15 fractions over 3 weeks. The researchers found that there was no difference in the incidence of locoregional relapses, disease-free survival, and overall survival between the regimens.

Dr. Simone also noted that advanced treatment modalities, such as intensity-modulated radiotherapy, stereotactic radiosurgery, and proton therapy, have the potential to improve patient-reported adverse events and clinical outcomes. “I have seen this both in my clinical practice and in several recent publications,” he says.

Personalization of radiotherapy is also an emerging area that may allow for more tailored treatments with improved outcomes. The authors highlighted a study that found that PMSA PET-CT was better than conventional CT for accurately staging prostate cancer. This approach was also less expensive and led to less radiation exposure.

On the basis of this research, “PMSA PET-CT has since become the [standard of care] for prostate cancer staging,” the authors explain.

Dr. Espenel and colleagues note that as patients survive longer, quality of life and patient satisfaction are increasingly becoming endpoints in RCTs. Experts are focusing more attention on sequelae of treatments and advances in technology that can spare critical organs from radiation and reduce overall treatment time.

Shared decision-making is becoming increasingly possible in many cases as well. For example, with some clinical trials that involved different treatment modalities, outcomes were equivalent, but toxicity profiles differed, allowing patients to choose therapeutic options tailored to their preferences.

Overall, these data demonstrate “a great dynamism of radiation oncology research in most primary tumor types,” the researchers write.

The study received no outside financial support. The authors have disclosed no relevant financial relationships. Dr. Simone is chair of the American Society for Radiation Oncology Lung Resource Panel and the American Society for Radiation Oncology Veteran Affairs Radiation Oncology Quality Surveillance Blue Ribbon Lung Panel and has received honorarium from Varian Medical Systems.

A version of this article first appeared on Medscape.com.

The field of radiation oncology has rapidly evolved in recent years, thanks in large part to findings from randomized clinical trials (RCTs) that have helped shift therapeutic standards, a review of the literature shows.

The authors assessed all RCTs involving radiotherapy from 2018 to 2021, with the goal of identifying the latest practice-changing data, emerging concepts, and areas that require further study.

Highlights from this research reveal how high-tech radiotherapy, such as hypofractionation and stereotactic body radiotherapy, has improved care for many patients, how personalized radiotherapy using image-based guidance has helped tailor treatments, and how endpoints that focus on quality of life and patient satisfaction are emerging.

For instance, Charles B. Simone II, MD, FACRO, who was not involved in the current work, pointed to “a proliferation of trials assessing hypofractionation in the curative setting and stereotactic body radiation therapy in the curative and poly- and oligometastatic settings that have allowed for increased patient convenience and dose intensification, respectively.”

Dr. Simone, chief medical officer, New York Proton Center, Memorial Sloan Kettering Cancer Center, also noted that the first personalized radiotherapy trials using imaging and biological markers have “the profound potential to individualize treatment and improve patient outcomes.”

The review was published in the European Journal of Cancer.
 

An evolving field

Given the fast-changing landscape for cancer therapeutics and a deluge of research studies, the authors wanted to understand the most notable advances established in recent trials as well as caveats to some approaches and emerging areas to watch.

In the review, Sophie Espenel, MD, from the department of radiation oncology, Gustave Roussy Cancer Campus, Villejuif, France, and colleagues identified 1,347 radiotherapy RCTs that were conducted from January 2018 to December 2021. Of these, the authors selected 110 large phase 2 or 3 RCTs that contained data showing practice-changing or emerging concepts.

Overall, the studies showed “great dynamism” in radiation oncology research and covered a wide range of radiotherapy practices, according to Dr. Espenel and coauthors.

A central area of research has focused on radioimmunotherapy, an approach that aims to enhance the antitumor immune response. One RCT in the preoperative setting showed, for instance, that concurrent stereotactic body radiotherapy delivered at 24 Gy over eight fractions, along with the anti–PD-L1 agent durvalumab, increased major pathologic complete response rates almost eightfold in comparison with durvalumab alone for patients with early-stage lung cancer (53.3% vs. 6.7%).

Although promising, not all trials that evaluated a concurrent chemoradiotherapy-immunotherapy strategy showed positive results. One RCT of locally advanced head and neck squamous cell carcinoma, for instance, found that median progression-free survival was not reached when adding the anti–PD-L1 avelumab to chemoradiotherapy. In addition, trials in the metastatic setting have shown conflicting results, the authors note.

Another topic of interest is that of newer radiosensitizers. A trial that evaluated high-risk locoregionally advanced head and neck squamous cell carcinoma highlighted the efficacy of xevinapant, a pro-apoptotic agent that inhibits apoptosis proteins. Xevinapant was used for the first time in conjunction with a standard high-dose cisplatin chemoradiotherapy. In this study, locoregional control at 18 months was achieved for 54% of patients who received xevinapant vs. 33% of those who received standard care. The toxicity profiles were similar.

The use of high-tech radiotherapy is gaining ground. It allows patients to receive more targeted treatments at lower doses and in shorter time frames. One trial found, for instance, that a more hypofractionated adjuvant whole breast approach, using 26 Gy in five fractions over a week, is as effective and safe as 40 Gy in 15 fractions over 3 weeks. The researchers found that there was no difference in the incidence of locoregional relapses, disease-free survival, and overall survival between the regimens.

Dr. Simone also noted that advanced treatment modalities, such as intensity-modulated radiotherapy, stereotactic radiosurgery, and proton therapy, have the potential to improve patient-reported adverse events and clinical outcomes. “I have seen this both in my clinical practice and in several recent publications,” he says.

Personalization of radiotherapy is also an emerging area that may allow for more tailored treatments with improved outcomes. The authors highlighted a study that found that PMSA PET-CT was better than conventional CT for accurately staging prostate cancer. This approach was also less expensive and led to less radiation exposure.

On the basis of this research, “PMSA PET-CT has since become the [standard of care] for prostate cancer staging,” the authors explain.

Dr. Espenel and colleagues note that as patients survive longer, quality of life and patient satisfaction are increasingly becoming endpoints in RCTs. Experts are focusing more attention on sequelae of treatments and advances in technology that can spare critical organs from radiation and reduce overall treatment time.

Shared decision-making is becoming increasingly possible in many cases as well. For example, with some clinical trials that involved different treatment modalities, outcomes were equivalent, but toxicity profiles differed, allowing patients to choose therapeutic options tailored to their preferences.

Overall, these data demonstrate “a great dynamism of radiation oncology research in most primary tumor types,” the researchers write.

The study received no outside financial support. The authors have disclosed no relevant financial relationships. Dr. Simone is chair of the American Society for Radiation Oncology Lung Resource Panel and the American Society for Radiation Oncology Veteran Affairs Radiation Oncology Quality Surveillance Blue Ribbon Lung Panel and has received honorarium from Varian Medical Systems.

A version of this article first appeared on Medscape.com.

The field of radiation oncology has rapidly evolved in recent years, thanks in large part to findings from randomized clinical trials (RCTs) that have helped shift therapeutic standards, a review of the literature shows.

The authors assessed all RCTs involving radiotherapy from 2018 to 2021, with the goal of identifying the latest practice-changing data, emerging concepts, and areas that require further study.

Highlights from this research reveal how high-tech radiotherapy, such as hypofractionation and stereotactic body radiotherapy, has improved care for many patients, how personalized radiotherapy using image-based guidance has helped tailor treatments, and how endpoints that focus on quality of life and patient satisfaction are emerging.

For instance, Charles B. Simone II, MD, FACRO, who was not involved in the current work, pointed to “a proliferation of trials assessing hypofractionation in the curative setting and stereotactic body radiation therapy in the curative and poly- and oligometastatic settings that have allowed for increased patient convenience and dose intensification, respectively.”

Dr. Simone, chief medical officer, New York Proton Center, Memorial Sloan Kettering Cancer Center, also noted that the first personalized radiotherapy trials using imaging and biological markers have “the profound potential to individualize treatment and improve patient outcomes.”

The review was published in the European Journal of Cancer.
 

An evolving field

Given the fast-changing landscape for cancer therapeutics and a deluge of research studies, the authors wanted to understand the most notable advances established in recent trials as well as caveats to some approaches and emerging areas to watch.

In the review, Sophie Espenel, MD, from the department of radiation oncology, Gustave Roussy Cancer Campus, Villejuif, France, and colleagues identified 1,347 radiotherapy RCTs that were conducted from January 2018 to December 2021. Of these, the authors selected 110 large phase 2 or 3 RCTs that contained data showing practice-changing or emerging concepts.

Overall, the studies showed “great dynamism” in radiation oncology research and covered a wide range of radiotherapy practices, according to Dr. Espenel and coauthors.

A central area of research has focused on radioimmunotherapy, an approach that aims to enhance the antitumor immune response. One RCT in the preoperative setting showed, for instance, that concurrent stereotactic body radiotherapy delivered at 24 Gy over eight fractions, along with the anti–PD-L1 agent durvalumab, increased major pathologic complete response rates almost eightfold in comparison with durvalumab alone for patients with early-stage lung cancer (53.3% vs. 6.7%).

Although promising, not all trials that evaluated a concurrent chemoradiotherapy-immunotherapy strategy showed positive results. One RCT of locally advanced head and neck squamous cell carcinoma, for instance, found that median progression-free survival was not reached when adding the anti–PD-L1 avelumab to chemoradiotherapy. In addition, trials in the metastatic setting have shown conflicting results, the authors note.

Another topic of interest is that of newer radiosensitizers. A trial that evaluated high-risk locoregionally advanced head and neck squamous cell carcinoma highlighted the efficacy of xevinapant, a pro-apoptotic agent that inhibits apoptosis proteins. Xevinapant was used for the first time in conjunction with a standard high-dose cisplatin chemoradiotherapy. In this study, locoregional control at 18 months was achieved for 54% of patients who received xevinapant vs. 33% of those who received standard care. The toxicity profiles were similar.

The use of high-tech radiotherapy is gaining ground. It allows patients to receive more targeted treatments at lower doses and in shorter time frames. One trial found, for instance, that a more hypofractionated adjuvant whole breast approach, using 26 Gy in five fractions over a week, is as effective and safe as 40 Gy in 15 fractions over 3 weeks. The researchers found that there was no difference in the incidence of locoregional relapses, disease-free survival, and overall survival between the regimens.

Dr. Simone also noted that advanced treatment modalities, such as intensity-modulated radiotherapy, stereotactic radiosurgery, and proton therapy, have the potential to improve patient-reported adverse events and clinical outcomes. “I have seen this both in my clinical practice and in several recent publications,” he says.

Personalization of radiotherapy is also an emerging area that may allow for more tailored treatments with improved outcomes. The authors highlighted a study that found that PMSA PET-CT was better than conventional CT for accurately staging prostate cancer. This approach was also less expensive and led to less radiation exposure.

On the basis of this research, “PMSA PET-CT has since become the [standard of care] for prostate cancer staging,” the authors explain.

Dr. Espenel and colleagues note that as patients survive longer, quality of life and patient satisfaction are increasingly becoming endpoints in RCTs. Experts are focusing more attention on sequelae of treatments and advances in technology that can spare critical organs from radiation and reduce overall treatment time.

Shared decision-making is becoming increasingly possible in many cases as well. For example, with some clinical trials that involved different treatment modalities, outcomes were equivalent, but toxicity profiles differed, allowing patients to choose therapeutic options tailored to their preferences.

Overall, these data demonstrate “a great dynamism of radiation oncology research in most primary tumor types,” the researchers write.

The study received no outside financial support. The authors have disclosed no relevant financial relationships. Dr. Simone is chair of the American Society for Radiation Oncology Lung Resource Panel and the American Society for Radiation Oncology Veteran Affairs Radiation Oncology Quality Surveillance Blue Ribbon Lung Panel and has received honorarium from Varian Medical Systems.

A version of this article first appeared on Medscape.com.

Most diagnoses of acute myeloid leukemia (AML) are made during January. This finding strongly implies that seasonal factors, such as infectious agents or environmental triggers, influence the development or proliferation of the disease, which points to prevention opportunities. This was the conclusion of an international study led by a team from the Jiménez Díaz Foundation University Hospital Health Research Institute (IIS-FJD) in Madrid, in collaboration with colleagues from the University of Bristol, England. Their work was published in the British Journal of Haematology.

The study’s aim was to investigate the potential seasonal and long-term trends in AML diagnosis in an overall population and in subgroups according to sex and age. To do so, the researchers examined 26,472 cases of AML diagnosed in Spain between 2004 and 2015. They found seasonality in the diagnosis of this type of leukemia. This “could point to there being an underlying seasonal etiology at play,” noted one of the main authors of the study, Juan Manuel Alonso, MD, a physician in the IIS-FJD’s department of hematology and hemotherapy.

“The environmental triggers involved could be radiation, pollution, allergens, or infectious agents like viruses. We’re leaning toward viruses, because there are already distinct solid tumor and hematologic cancers that are caused by them and because, in the winter months, there’s an increased incidence of cancers due to viral infections,” Dr. Alonso said in an interview. “The etiological mechanism should be different from that exerted by chronic viral pressure, because here we’re dealing with an acute and aggressive disease that probably needs a short incubation period.”
 

Various hypotheses

In an interview, David Martínez, MD, a hematologist at La Fe University Hospital in Valencia, Spain, described the research as “an extremely well done and much-discussed study on AML, a disease that appears to be diagnosed more frequently at a certain time of year – namely, January.

“There’s no clear explanation for this finding,” Dr. Martínez said. “Several possible reasons have been put forward and are being talked about. The one that seems to hold the most water is the hypothesis that infectious agents and environmental factors may have a greater influence. This is because the idea that they’re involved in neoplastic diseases is nothing new. In fact, there are a lot of publications and a good amount of scientific evidence that link viral infections and environmental factors with the development of oncologic diseases.”

AML is a rare disease yet is responsible for many cancer-related deaths. Mutations that cause AML can occur due to an inherited mutant gene or exposure to certain carcinogens, such as chemotherapy, radiotherapy, ionizing radiation, tobacco, and benzene. These findings are broadly similar to those of a large U.S.-based study by Calip et al., who found a peak of adult AML diagnoses during December and January from 1992 to 2008. Previous smaller studies have provided conflicting evidence, likely due to lower power or to the use of less advanced statistical approaches.
 

Seasonal factors involved?

Demonstration of seasonal variation in the occurrence of AML would, firstly, provide supportive evidence of etiology by seasonal factors, such as infectious agents or environmental factors, and, secondly, focus research onto the etiologic role of such factors.

The current study used population-based data on cases of AML occurring in Spain from a nationwide hospital discharge registry for the years 2004 to 2015. “This is, to our knowledge, the largest study aimed at investigating the potential seasonal and long-term trends in AML incidence in an overall population and in subgroups according to sex and age while employing novel statistical models with serial dependence for discrete-valued time series,” wrote the researchers.

They extracted information from the register of each case about the date of admission, discharge date, the anonymous identifier for each patient, International Classification of Diseases (ICD)–9 codes, sex, and date of birth, from which they derived age groups as described for the at-risk population. For patients hospitalized on more than one occasion, only the record corresponding to their first diagnosis of AML was selected.

AML cases per month were standardized to months of equal length.

Age/sex-standardized monthly incidence rates of AML were calculated using the census of Spanish population in 2010 as a “standard” population. Age-standardized and sex-standardized monthly incidence rates of AML were calculated.

Nine separate time-series decompositions were performed as an initial exploratory analysis on the monthly incidence rates of AML using data for all cases and data for each sex and age group. Nine separate Poisson generalized linear autoregressive moving average (GLARMA) models were fitted to evaluate the temporal dynamics in AML incidence using data for all cases, and data for each sex and age group.
 

Long-term trend

A total of 26,472 patients with a first diagnosis of active AML were hospitalized in Spain and registered at the country’s Minimum Basic Data Set (CMBD) during 2004-2015. In the end, there were 26,475 patients in the study population; a greater proportion of cases were male (56.0%), and the median age at diagnosis was 67 years.

Seasonal and trend decomposition using Loess decomposition of the incidence rates observed in the overall population exhibited seasonal fluctuation with a peak in January. A slight upward trend was apparent from visual inspection with an upturn in early 2005 and a downturn at the end of 2013. As for the differences by sex groups and age groups, Dr. Alonso said, “For both sexes and in age groups 5-19, 20-49, and 50-64 years, we found that the results were identical to those found in the overall population.”

The final model included an upward linear long-term trend, as well as the variables monthly seasonality and December 2015. The estimated monthly long-term trend implies that the monthly incidence rates of AML diagnoses annually increased by 0.4% (95% confidence interval [CI], 0.2%-0.6%; P = .0011), given that the other covariates are held constant.

January displayed the highest incidence rate of AML, with a minimum average difference of 7%, when compared with February (95% CI, 2%-12%; P = .0143) and a maximum average difference of 16%, compared with November (95% CI, 11%-21%; P < .0001) and August (95% CI, 10%-21%; P < .0001).

The incidence rate of AML for December 2015 was 0.43 (95% CI, 0.34-0.54; P < .0001) times the average incidence rate for the rest of the study period.
 

Potential role of viruses

“We have to keep in mind that infectious agents (viral infections) and environmental factors (allergens) don’t disappear in the warmer months,” Dr. Martínez added. “There are just other viruses and different factors. We don’t know the role or the weight that each one of the factors has, either individually or specifically, in the development of AML. In addition, we know that AML is a very heterogeneous disease and that various factors, including genetic ones, can be involved in its etiopathogenesis.”

With respect to the stem cell theory in this leukemia, Dr. Alonso emphasized that, “in theory, the virus could fit into it with no problem. That said, any other environmental agent could also produce the described phenomenon where the rapid proliferation of quiescent leukemic stem cells is stimulated, thereby hastening the diagnosis.”

“Should the etiological factor be found,” Dr. Martínez noted, “we can try to reduce exposure and thereby decrease the incidence of AML. On the other hand, discovering how the environmental factor stimulates the proliferation of quiescent leukemic [stem] cells could enhance our knowledge about the regulation of that.”

As to whether there is evidence for the involvement of infections in other hematologic malignancies, Dr. Martínez reported, “This has already been seen. And this study shows other examples (Epstein-Barr virus and human T-cell lymphotropic virus type 1 with lymphomas), and there could also be Helicobacter pylori  and lymphomas.”

Outside of hematology, human papillomavirus has been associated with cervical cancer, tobacco with lung cancer, sun with skin cancer, and diet with the development of some solid neoplasms.

“The study speaks about the concept of a latency period. To accept the idea that a factor or virus that’s more prevalent in winter produces, on its own, AML in a few weeks or months means accepting the idea of a very short latency period – something that’s not usually the case. For that, another explanation is given: An abnormal immune response or that a seasonal infectious agent can be capable of promoting leukemogenesis. These are also hypotheses to be explored in the future,” suggested Dr. Martínez.
 

New research network

Several potential limitations of this study should be considered. One limitation is that AML cases were obtained from the CMBD registry as defined by ICD-9, and no other AML classifications were available. Another limitation is that information on the date of onset of clinical symptoms was not available for analysis. In addition, a further limitation related to the source of their data may have led the researchers to underestimate the incidence rates of AML in older patients, as only hospitalized patients were captured in their study.

As for continuing the research, the results make it necessary to carry out complementary epidemiologic studies that will examine the association between seasonal risk factors and the increased diagnosis of AML during winter months.

To go forward, the first step would be to secure funding. For this purpose, a network is being put together featuring collaborators from other world-renowned research groups that are at the top of their respective disciplines. Through this network, they hope to be able to apply together for public research grants from countries in Europe and elsewhere as well as to establish collaborations with various companies in the private sector.

“This could open up new therapeutic avenues in the future, as we could try to force leukemic stem cells to divide, thereby reducing the resistance that the standard treatments usually demonstrate,” Dr. Alonso concluded.

Dr. Alonso received research funding from Incyte, Pfizer International, and Astellas Pharma outside the present work. Dr. Martínez disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish edition. A version of the article appeared on Medscape.com.

Most diagnoses of acute myeloid leukemia (AML) are made during January. This finding strongly implies that seasonal factors, such as infectious agents or environmental triggers, influence the development or proliferation of the disease, which points to prevention opportunities. This was the conclusion of an international study led by a team from the Jiménez Díaz Foundation University Hospital Health Research Institute (IIS-FJD) in Madrid, in collaboration with colleagues from the University of Bristol, England. Their work was published in the British Journal of Haematology.

The study’s aim was to investigate the potential seasonal and long-term trends in AML diagnosis in an overall population and in subgroups according to sex and age. To do so, the researchers examined 26,472 cases of AML diagnosed in Spain between 2004 and 2015. They found seasonality in the diagnosis of this type of leukemia. This “could point to there being an underlying seasonal etiology at play,” noted one of the main authors of the study, Juan Manuel Alonso, MD, a physician in the IIS-FJD’s department of hematology and hemotherapy.

“The environmental triggers involved could be radiation, pollution, allergens, or infectious agents like viruses. We’re leaning toward viruses, because there are already distinct solid tumor and hematologic cancers that are caused by them and because, in the winter months, there’s an increased incidence of cancers due to viral infections,” Dr. Alonso said in an interview. “The etiological mechanism should be different from that exerted by chronic viral pressure, because here we’re dealing with an acute and aggressive disease that probably needs a short incubation period.”
 

Various hypotheses

In an interview, David Martínez, MD, a hematologist at La Fe University Hospital in Valencia, Spain, described the research as “an extremely well done and much-discussed study on AML, a disease that appears to be diagnosed more frequently at a certain time of year – namely, January.

“There’s no clear explanation for this finding,” Dr. Martínez said. “Several possible reasons have been put forward and are being talked about. The one that seems to hold the most water is the hypothesis that infectious agents and environmental factors may have a greater influence. This is because the idea that they’re involved in neoplastic diseases is nothing new. In fact, there are a lot of publications and a good amount of scientific evidence that link viral infections and environmental factors with the development of oncologic diseases.”

AML is a rare disease yet is responsible for many cancer-related deaths. Mutations that cause AML can occur due to an inherited mutant gene or exposure to certain carcinogens, such as chemotherapy, radiotherapy, ionizing radiation, tobacco, and benzene. These findings are broadly similar to those of a large U.S.-based study by Calip et al., who found a peak of adult AML diagnoses during December and January from 1992 to 2008. Previous smaller studies have provided conflicting evidence, likely due to lower power or to the use of less advanced statistical approaches.
 

Seasonal factors involved?

Demonstration of seasonal variation in the occurrence of AML would, firstly, provide supportive evidence of etiology by seasonal factors, such as infectious agents or environmental factors, and, secondly, focus research onto the etiologic role of such factors.

The current study used population-based data on cases of AML occurring in Spain from a nationwide hospital discharge registry for the years 2004 to 2015. “This is, to our knowledge, the largest study aimed at investigating the potential seasonal and long-term trends in AML incidence in an overall population and in subgroups according to sex and age while employing novel statistical models with serial dependence for discrete-valued time series,” wrote the researchers.

They extracted information from the register of each case about the date of admission, discharge date, the anonymous identifier for each patient, International Classification of Diseases (ICD)–9 codes, sex, and date of birth, from which they derived age groups as described for the at-risk population. For patients hospitalized on more than one occasion, only the record corresponding to their first diagnosis of AML was selected.

AML cases per month were standardized to months of equal length.

Age/sex-standardized monthly incidence rates of AML were calculated using the census of Spanish population in 2010 as a “standard” population. Age-standardized and sex-standardized monthly incidence rates of AML were calculated.

Nine separate time-series decompositions were performed as an initial exploratory analysis on the monthly incidence rates of AML using data for all cases and data for each sex and age group. Nine separate Poisson generalized linear autoregressive moving average (GLARMA) models were fitted to evaluate the temporal dynamics in AML incidence using data for all cases, and data for each sex and age group.
 

Long-term trend

A total of 26,472 patients with a first diagnosis of active AML were hospitalized in Spain and registered at the country’s Minimum Basic Data Set (CMBD) during 2004-2015. In the end, there were 26,475 patients in the study population; a greater proportion of cases were male (56.0%), and the median age at diagnosis was 67 years.

Seasonal and trend decomposition using Loess decomposition of the incidence rates observed in the overall population exhibited seasonal fluctuation with a peak in January. A slight upward trend was apparent from visual inspection with an upturn in early 2005 and a downturn at the end of 2013. As for the differences by sex groups and age groups, Dr. Alonso said, “For both sexes and in age groups 5-19, 20-49, and 50-64 years, we found that the results were identical to those found in the overall population.”

The final model included an upward linear long-term trend, as well as the variables monthly seasonality and December 2015. The estimated monthly long-term trend implies that the monthly incidence rates of AML diagnoses annually increased by 0.4% (95% confidence interval [CI], 0.2%-0.6%; P = .0011), given that the other covariates are held constant.

January displayed the highest incidence rate of AML, with a minimum average difference of 7%, when compared with February (95% CI, 2%-12%; P = .0143) and a maximum average difference of 16%, compared with November (95% CI, 11%-21%; P < .0001) and August (95% CI, 10%-21%; P < .0001).

The incidence rate of AML for December 2015 was 0.43 (95% CI, 0.34-0.54; P < .0001) times the average incidence rate for the rest of the study period.
 

Potential role of viruses

“We have to keep in mind that infectious agents (viral infections) and environmental factors (allergens) don’t disappear in the warmer months,” Dr. Martínez added. “There are just other viruses and different factors. We don’t know the role or the weight that each one of the factors has, either individually or specifically, in the development of AML. In addition, we know that AML is a very heterogeneous disease and that various factors, including genetic ones, can be involved in its etiopathogenesis.”

With respect to the stem cell theory in this leukemia, Dr. Alonso emphasized that, “in theory, the virus could fit into it with no problem. That said, any other environmental agent could also produce the described phenomenon where the rapid proliferation of quiescent leukemic stem cells is stimulated, thereby hastening the diagnosis.”

“Should the etiological factor be found,” Dr. Martínez noted, “we can try to reduce exposure and thereby decrease the incidence of AML. On the other hand, discovering how the environmental factor stimulates the proliferation of quiescent leukemic [stem] cells could enhance our knowledge about the regulation of that.”

As to whether there is evidence for the involvement of infections in other hematologic malignancies, Dr. Martínez reported, “This has already been seen. And this study shows other examples (Epstein-Barr virus and human T-cell lymphotropic virus type 1 with lymphomas), and there could also be Helicobacter pylori  and lymphomas.”

Outside of hematology, human papillomavirus has been associated with cervical cancer, tobacco with lung cancer, sun with skin cancer, and diet with the development of some solid neoplasms.

“The study speaks about the concept of a latency period. To accept the idea that a factor or virus that’s more prevalent in winter produces, on its own, AML in a few weeks or months means accepting the idea of a very short latency period – something that’s not usually the case. For that, another explanation is given: An abnormal immune response or that a seasonal infectious agent can be capable of promoting leukemogenesis. These are also hypotheses to be explored in the future,” suggested Dr. Martínez.
 

New research network

Several potential limitations of this study should be considered. One limitation is that AML cases were obtained from the CMBD registry as defined by ICD-9, and no other AML classifications were available. Another limitation is that information on the date of onset of clinical symptoms was not available for analysis. In addition, a further limitation related to the source of their data may have led the researchers to underestimate the incidence rates of AML in older patients, as only hospitalized patients were captured in their study.

As for continuing the research, the results make it necessary to carry out complementary epidemiologic studies that will examine the association between seasonal risk factors and the increased diagnosis of AML during winter months.

To go forward, the first step would be to secure funding. For this purpose, a network is being put together featuring collaborators from other world-renowned research groups that are at the top of their respective disciplines. Through this network, they hope to be able to apply together for public research grants from countries in Europe and elsewhere as well as to establish collaborations with various companies in the private sector.

“This could open up new therapeutic avenues in the future, as we could try to force leukemic stem cells to divide, thereby reducing the resistance that the standard treatments usually demonstrate,” Dr. Alonso concluded.

Dr. Alonso received research funding from Incyte, Pfizer International, and Astellas Pharma outside the present work. Dr. Martínez disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish edition. A version of the article appeared on Medscape.com.

Most diagnoses of acute myeloid leukemia (AML) are made during January. This finding strongly implies that seasonal factors, such as infectious agents or environmental triggers, influence the development or proliferation of the disease, which points to prevention opportunities. This was the conclusion of an international study led by a team from the Jiménez Díaz Foundation University Hospital Health Research Institute (IIS-FJD) in Madrid, in collaboration with colleagues from the University of Bristol, England. Their work was published in the British Journal of Haematology.

The study’s aim was to investigate the potential seasonal and long-term trends in AML diagnosis in an overall population and in subgroups according to sex and age. To do so, the researchers examined 26,472 cases of AML diagnosed in Spain between 2004 and 2015. They found seasonality in the diagnosis of this type of leukemia. This “could point to there being an underlying seasonal etiology at play,” noted one of the main authors of the study, Juan Manuel Alonso, MD, a physician in the IIS-FJD’s department of hematology and hemotherapy.

“The environmental triggers involved could be radiation, pollution, allergens, or infectious agents like viruses. We’re leaning toward viruses, because there are already distinct solid tumor and hematologic cancers that are caused by them and because, in the winter months, there’s an increased incidence of cancers due to viral infections,” Dr. Alonso said in an interview. “The etiological mechanism should be different from that exerted by chronic viral pressure, because here we’re dealing with an acute and aggressive disease that probably needs a short incubation period.”
 

Various hypotheses

In an interview, David Martínez, MD, a hematologist at La Fe University Hospital in Valencia, Spain, described the research as “an extremely well done and much-discussed study on AML, a disease that appears to be diagnosed more frequently at a certain time of year – namely, January.

“There’s no clear explanation for this finding,” Dr. Martínez said. “Several possible reasons have been put forward and are being talked about. The one that seems to hold the most water is the hypothesis that infectious agents and environmental factors may have a greater influence. This is because the idea that they’re involved in neoplastic diseases is nothing new. In fact, there are a lot of publications and a good amount of scientific evidence that link viral infections and environmental factors with the development of oncologic diseases.”

AML is a rare disease yet is responsible for many cancer-related deaths. Mutations that cause AML can occur due to an inherited mutant gene or exposure to certain carcinogens, such as chemotherapy, radiotherapy, ionizing radiation, tobacco, and benzene. These findings are broadly similar to those of a large U.S.-based study by Calip et al., who found a peak of adult AML diagnoses during December and January from 1992 to 2008. Previous smaller studies have provided conflicting evidence, likely due to lower power or to the use of less advanced statistical approaches.
 

Seasonal factors involved?

Demonstration of seasonal variation in the occurrence of AML would, firstly, provide supportive evidence of etiology by seasonal factors, such as infectious agents or environmental factors, and, secondly, focus research onto the etiologic role of such factors.

The current study used population-based data on cases of AML occurring in Spain from a nationwide hospital discharge registry for the years 2004 to 2015. “This is, to our knowledge, the largest study aimed at investigating the potential seasonal and long-term trends in AML incidence in an overall population and in subgroups according to sex and age while employing novel statistical models with serial dependence for discrete-valued time series,” wrote the researchers.

They extracted information from the register of each case about the date of admission, discharge date, the anonymous identifier for each patient, International Classification of Diseases (ICD)–9 codes, sex, and date of birth, from which they derived age groups as described for the at-risk population. For patients hospitalized on more than one occasion, only the record corresponding to their first diagnosis of AML was selected.

AML cases per month were standardized to months of equal length.

Age/sex-standardized monthly incidence rates of AML were calculated using the census of Spanish population in 2010 as a “standard” population. Age-standardized and sex-standardized monthly incidence rates of AML were calculated.

Nine separate time-series decompositions were performed as an initial exploratory analysis on the monthly incidence rates of AML using data for all cases and data for each sex and age group. Nine separate Poisson generalized linear autoregressive moving average (GLARMA) models were fitted to evaluate the temporal dynamics in AML incidence using data for all cases, and data for each sex and age group.
 

Long-term trend

A total of 26,472 patients with a first diagnosis of active AML were hospitalized in Spain and registered at the country’s Minimum Basic Data Set (CMBD) during 2004-2015. In the end, there were 26,475 patients in the study population; a greater proportion of cases were male (56.0%), and the median age at diagnosis was 67 years.

Seasonal and trend decomposition using Loess decomposition of the incidence rates observed in the overall population exhibited seasonal fluctuation with a peak in January. A slight upward trend was apparent from visual inspection with an upturn in early 2005 and a downturn at the end of 2013. As for the differences by sex groups and age groups, Dr. Alonso said, “For both sexes and in age groups 5-19, 20-49, and 50-64 years, we found that the results were identical to those found in the overall population.”

The final model included an upward linear long-term trend, as well as the variables monthly seasonality and December 2015. The estimated monthly long-term trend implies that the monthly incidence rates of AML diagnoses annually increased by 0.4% (95% confidence interval [CI], 0.2%-0.6%; P = .0011), given that the other covariates are held constant.

January displayed the highest incidence rate of AML, with a minimum average difference of 7%, when compared with February (95% CI, 2%-12%; P = .0143) and a maximum average difference of 16%, compared with November (95% CI, 11%-21%; P < .0001) and August (95% CI, 10%-21%; P < .0001).

The incidence rate of AML for December 2015 was 0.43 (95% CI, 0.34-0.54; P < .0001) times the average incidence rate for the rest of the study period.
 

Potential role of viruses

“We have to keep in mind that infectious agents (viral infections) and environmental factors (allergens) don’t disappear in the warmer months,” Dr. Martínez added. “There are just other viruses and different factors. We don’t know the role or the weight that each one of the factors has, either individually or specifically, in the development of AML. In addition, we know that AML is a very heterogeneous disease and that various factors, including genetic ones, can be involved in its etiopathogenesis.”

With respect to the stem cell theory in this leukemia, Dr. Alonso emphasized that, “in theory, the virus could fit into it with no problem. That said, any other environmental agent could also produce the described phenomenon where the rapid proliferation of quiescent leukemic stem cells is stimulated, thereby hastening the diagnosis.”

“Should the etiological factor be found,” Dr. Martínez noted, “we can try to reduce exposure and thereby decrease the incidence of AML. On the other hand, discovering how the environmental factor stimulates the proliferation of quiescent leukemic [stem] cells could enhance our knowledge about the regulation of that.”

As to whether there is evidence for the involvement of infections in other hematologic malignancies, Dr. Martínez reported, “This has already been seen. And this study shows other examples (Epstein-Barr virus and human T-cell lymphotropic virus type 1 with lymphomas), and there could also be Helicobacter pylori  and lymphomas.”

Outside of hematology, human papillomavirus has been associated with cervical cancer, tobacco with lung cancer, sun with skin cancer, and diet with the development of some solid neoplasms.

“The study speaks about the concept of a latency period. To accept the idea that a factor or virus that’s more prevalent in winter produces, on its own, AML in a few weeks or months means accepting the idea of a very short latency period – something that’s not usually the case. For that, another explanation is given: An abnormal immune response or that a seasonal infectious agent can be capable of promoting leukemogenesis. These are also hypotheses to be explored in the future,” suggested Dr. Martínez.
 

New research network

Several potential limitations of this study should be considered. One limitation is that AML cases were obtained from the CMBD registry as defined by ICD-9, and no other AML classifications were available. Another limitation is that information on the date of onset of clinical symptoms was not available for analysis. In addition, a further limitation related to the source of their data may have led the researchers to underestimate the incidence rates of AML in older patients, as only hospitalized patients were captured in their study.

As for continuing the research, the results make it necessary to carry out complementary epidemiologic studies that will examine the association between seasonal risk factors and the increased diagnosis of AML during winter months.

To go forward, the first step would be to secure funding. For this purpose, a network is being put together featuring collaborators from other world-renowned research groups that are at the top of their respective disciplines. Through this network, they hope to be able to apply together for public research grants from countries in Europe and elsewhere as well as to establish collaborations with various companies in the private sector.

“This could open up new therapeutic avenues in the future, as we could try to force leukemic stem cells to divide, thereby reducing the resistance that the standard treatments usually demonstrate,” Dr. Alonso concluded.

Dr. Alonso received research funding from Incyte, Pfizer International, and Astellas Pharma outside the present work. Dr. Martínez disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish edition. A version of the article appeared on Medscape.com.