SAN FRANCISCO – Adding stereotactic body radiation therapy (SBRT) to sorafenib produced better outcomes among patients with hepatocellular carcinoma (HCC) than sorafenib alone, according to new findings.

The use of SBRT in this setting improved both overall survival and progression-free survival (PFS). There was no increase in adverse events with the addition of SBRT, and results trended toward a quality-of-life benefit at 6 months.

“This adds to the body of evidence for the role of external-beam radiation, bringing SBRT to the armamentarium of treatment options for patients – particularly those with locally advanced HCC and macrovascular invasion, especially if they are treated with tyrosine kinase inhibitors [TKIs],” said lead study author Laura A. Dawson, MD, a clinician scientist at the Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto.

Dr. Dawson presented the findings at the ASCO Gastrointestinal Cancers Symposium 2023.

Approached for an outside comment, Mary Feng, MD, professor of radiation oncology at the University of California, San Francisco, said, “This study is really groundbreaking.”

She added that the investigators should be congratulated for executing this ambitious study with worldwide enrollment for a serious disease.

“There are very few studies demonstrating an overall survival benefit from radiation or any local control modality,” she told this news organization. She suggested that the survival benefit seen in this trial was “likely due to the high percentage of patients (74%) with macrovascular invasion, who stand to benefit the most from treatment.

“This study has established the standard of adding SBRT to patients who are treated with TKIs and raises the question of whether adding SBRT to immunotherapy would also result in a survival benefit. This next question must also be tested in a prospective clinical trial,” she said.
 

Study details

At the study’s inception, sorafenib was the standard of care for patients who were unable to undergo surgery, ablation, and/or transarterial chemoembolization (TACE). Dr. Dawson explained that sorafenib had been shown to improve median overall survival, although there was less benefit if macrovascular invasion was present.

“Integrating radiation strategies in HCC management has been a key question over the past few decades,” she said.

In the current study, Dr. Dawson and colleagues added SBRT to sorafenib. The cohort included 177 patients with new or recurrent HCC who were not candidates for surgery, ablation, or TACE. They were randomly assigned to receive either sorafenib 400 mg twice daily or to SBRT (27.5-50 Gy in five fractions) followed by sorafenib 200 mg twice daily; the dosage was then increased to 400 mg twice daily after 28 days.
 

SBRT improves outcomes

The original plan was to enroll 292 participants, but accrual closed early when the standard of care for systemic treatment of HCC changed following the results of the phase 3 IMbrave150 trial, which showed the superiority of atezolizumab plus bevacizumab as frontline therapy for locally advanced or metastatic HCC. The closure of accrual was agreed upon by the investigators and the data safety monitoring committee, and their statistical analysis plan was revised accordingly. The study became time driven rather than event driven, she noted. This resulted in a decrease from 80% power to 65% power.

The median age of participants was 66 years (range, 27-84 years); 41% had hepatitis C, and 19% had hepatitis B or B/C. Additionally, 82% had Barcelona Clinic Liver Cancer stage C disease, and 74% had macrovascular invasion.

The median follow-up was 13.2 months overall and 33.7 months for living patients.

Median overall survival improved from 12.3 months with sorafenib alone to 15.8 months with the addition of SBRT to the regimen (hazard ratio [HR] = 0.77; one-sided P = .0554). A prespecified multivariable analysis showed that the combination therapy resulted in a statistically significant improvement in overall survival after adjustment for confounders (HR, 0.72; P = .042).

Similarly, median PFS also improved from 5.5 months with sorafenib alone to 9.2 months with SBRT and sorafenib (HR = 0.55; two-sided P = .0001).

With regard to safety, gastrointestinal bleeds occurred in 4% of patients in the combination arm, vs. 6% of those in the monotherapy arm. Overall, rates of treatment-related grade 3+ adverse events did not significantly differ between study arms (42% vs. 47%; P = .52). There were three grade 5 events; two in the sorafenib-only group and one in the SBRT/sorafenib group.

The researchers also evaluated quality of life (QoL). “Our hypothesis was that patients treated with SBRT and sorafenib would have improved quality of life 6 months after the start of treatment compared to sorafenib alone,” said Dr. Dawson.

About half (47%) of participants agreed to fill out QoL assessments, but baseline and 6-month data were available for only about 21% of participants. Although the numbers were considered too small to analyze statistically, substantial improvement was seen in the group that received combination therapy. A total of 10% of patients who received sorafenib reported improvement on the FACT-Hep score, vs. 35% of patients who received SBRT/sorafenib.

“As compared to sorafenib, SBRT improved overall survival and progression-free survival, with no observed increase in adverse events in patients with advanced HCC,” concluded Dr. Dawson.
 

Where does radiation fit?

Invited discussant Laura Goff, MD, associate professor of medicine, Vanderbilt Ingram Cancer Center, Nashville, Tenn., reiterated that SBRT given prior to sorafenib improved outcomes compared to sorafenib alone, and while not definitive, Quality and Outcomes Framework scores appeared to improve at 6 months for the combination arm. “This reassures our concerns about toxicity,” she said.

Dr. Goff pointed out that since the study closed early, owing to changes in standard of care for HCC, the question arises – where does radiation fit in the array of options now available for HCC?

“For one, sorafenib plus SBRT represents an intriguing first-line option for patients who cannot be treated with immunotherapy, such as those who experience a posttransplant recurrence,” Dr. Goff said. “There is also renewed interest in radiation therapy in liver-dominant HCC, and there is active investigation ongoing for a variety of combinations.”

Dr. Dawson reported relationships with Merck and Raysearch. Dr. Goff reported relationships with Agios, ASLAN, AstraZeneca, Basilea, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Exelixis, Genentech, Merck, and QED Therapeutics.

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

SAN FRANCISCO – Adding stereotactic body radiation therapy (SBRT) to sorafenib produced better outcomes among patients with hepatocellular carcinoma (HCC) than sorafenib alone, according to new findings.

The use of SBRT in this setting improved both overall survival and progression-free survival (PFS). There was no increase in adverse events with the addition of SBRT, and results trended toward a quality-of-life benefit at 6 months.

“This adds to the body of evidence for the role of external-beam radiation, bringing SBRT to the armamentarium of treatment options for patients – particularly those with locally advanced HCC and macrovascular invasion, especially if they are treated with tyrosine kinase inhibitors [TKIs],” said lead study author Laura A. Dawson, MD, a clinician scientist at the Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto.

Dr. Dawson presented the findings at the ASCO Gastrointestinal Cancers Symposium 2023.

Approached for an outside comment, Mary Feng, MD, professor of radiation oncology at the University of California, San Francisco, said, “This study is really groundbreaking.”

She added that the investigators should be congratulated for executing this ambitious study with worldwide enrollment for a serious disease.

“There are very few studies demonstrating an overall survival benefit from radiation or any local control modality,” she told this news organization. She suggested that the survival benefit seen in this trial was “likely due to the high percentage of patients (74%) with macrovascular invasion, who stand to benefit the most from treatment.

“This study has established the standard of adding SBRT to patients who are treated with TKIs and raises the question of whether adding SBRT to immunotherapy would also result in a survival benefit. This next question must also be tested in a prospective clinical trial,” she said.
 

Study details

At the study’s inception, sorafenib was the standard of care for patients who were unable to undergo surgery, ablation, and/or transarterial chemoembolization (TACE). Dr. Dawson explained that sorafenib had been shown to improve median overall survival, although there was less benefit if macrovascular invasion was present.

“Integrating radiation strategies in HCC management has been a key question over the past few decades,” she said.

In the current study, Dr. Dawson and colleagues added SBRT to sorafenib. The cohort included 177 patients with new or recurrent HCC who were not candidates for surgery, ablation, or TACE. They were randomly assigned to receive either sorafenib 400 mg twice daily or to SBRT (27.5-50 Gy in five fractions) followed by sorafenib 200 mg twice daily; the dosage was then increased to 400 mg twice daily after 28 days.
 

SBRT improves outcomes

The original plan was to enroll 292 participants, but accrual closed early when the standard of care for systemic treatment of HCC changed following the results of the phase 3 IMbrave150 trial, which showed the superiority of atezolizumab plus bevacizumab as frontline therapy for locally advanced or metastatic HCC. The closure of accrual was agreed upon by the investigators and the data safety monitoring committee, and their statistical analysis plan was revised accordingly. The study became time driven rather than event driven, she noted. This resulted in a decrease from 80% power to 65% power.

The median age of participants was 66 years (range, 27-84 years); 41% had hepatitis C, and 19% had hepatitis B or B/C. Additionally, 82% had Barcelona Clinic Liver Cancer stage C disease, and 74% had macrovascular invasion.

The median follow-up was 13.2 months overall and 33.7 months for living patients.

Median overall survival improved from 12.3 months with sorafenib alone to 15.8 months with the addition of SBRT to the regimen (hazard ratio [HR] = 0.77; one-sided P = .0554). A prespecified multivariable analysis showed that the combination therapy resulted in a statistically significant improvement in overall survival after adjustment for confounders (HR, 0.72; P = .042).

Similarly, median PFS also improved from 5.5 months with sorafenib alone to 9.2 months with SBRT and sorafenib (HR = 0.55; two-sided P = .0001).

With regard to safety, gastrointestinal bleeds occurred in 4% of patients in the combination arm, vs. 6% of those in the monotherapy arm. Overall, rates of treatment-related grade 3+ adverse events did not significantly differ between study arms (42% vs. 47%; P = .52). There were three grade 5 events; two in the sorafenib-only group and one in the SBRT/sorafenib group.

The researchers also evaluated quality of life (QoL). “Our hypothesis was that patients treated with SBRT and sorafenib would have improved quality of life 6 months after the start of treatment compared to sorafenib alone,” said Dr. Dawson.

About half (47%) of participants agreed to fill out QoL assessments, but baseline and 6-month data were available for only about 21% of participants. Although the numbers were considered too small to analyze statistically, substantial improvement was seen in the group that received combination therapy. A total of 10% of patients who received sorafenib reported improvement on the FACT-Hep score, vs. 35% of patients who received SBRT/sorafenib.

“As compared to sorafenib, SBRT improved overall survival and progression-free survival, with no observed increase in adverse events in patients with advanced HCC,” concluded Dr. Dawson.
 

Where does radiation fit?

Invited discussant Laura Goff, MD, associate professor of medicine, Vanderbilt Ingram Cancer Center, Nashville, Tenn., reiterated that SBRT given prior to sorafenib improved outcomes compared to sorafenib alone, and while not definitive, Quality and Outcomes Framework scores appeared to improve at 6 months for the combination arm. “This reassures our concerns about toxicity,” she said.

Dr. Goff pointed out that since the study closed early, owing to changes in standard of care for HCC, the question arises – where does radiation fit in the array of options now available for HCC?

“For one, sorafenib plus SBRT represents an intriguing first-line option for patients who cannot be treated with immunotherapy, such as those who experience a posttransplant recurrence,” Dr. Goff said. “There is also renewed interest in radiation therapy in liver-dominant HCC, and there is active investigation ongoing for a variety of combinations.”

Dr. Dawson reported relationships with Merck and Raysearch. Dr. Goff reported relationships with Agios, ASLAN, AstraZeneca, Basilea, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Exelixis, Genentech, Merck, and QED Therapeutics.

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

SAN FRANCISCO – Adding stereotactic body radiation therapy (SBRT) to sorafenib produced better outcomes among patients with hepatocellular carcinoma (HCC) than sorafenib alone, according to new findings.

The use of SBRT in this setting improved both overall survival and progression-free survival (PFS). There was no increase in adverse events with the addition of SBRT, and results trended toward a quality-of-life benefit at 6 months.

“This adds to the body of evidence for the role of external-beam radiation, bringing SBRT to the armamentarium of treatment options for patients – particularly those with locally advanced HCC and macrovascular invasion, especially if they are treated with tyrosine kinase inhibitors [TKIs],” said lead study author Laura A. Dawson, MD, a clinician scientist at the Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto.

Dr. Dawson presented the findings at the ASCO Gastrointestinal Cancers Symposium 2023.

Approached for an outside comment, Mary Feng, MD, professor of radiation oncology at the University of California, San Francisco, said, “This study is really groundbreaking.”

She added that the investigators should be congratulated for executing this ambitious study with worldwide enrollment for a serious disease.

“There are very few studies demonstrating an overall survival benefit from radiation or any local control modality,” she told this news organization. She suggested that the survival benefit seen in this trial was “likely due to the high percentage of patients (74%) with macrovascular invasion, who stand to benefit the most from treatment.

“This study has established the standard of adding SBRT to patients who are treated with TKIs and raises the question of whether adding SBRT to immunotherapy would also result in a survival benefit. This next question must also be tested in a prospective clinical trial,” she said.
 

Study details

At the study’s inception, sorafenib was the standard of care for patients who were unable to undergo surgery, ablation, and/or transarterial chemoembolization (TACE). Dr. Dawson explained that sorafenib had been shown to improve median overall survival, although there was less benefit if macrovascular invasion was present.

“Integrating radiation strategies in HCC management has been a key question over the past few decades,” she said.

In the current study, Dr. Dawson and colleagues added SBRT to sorafenib. The cohort included 177 patients with new or recurrent HCC who were not candidates for surgery, ablation, or TACE. They were randomly assigned to receive either sorafenib 400 mg twice daily or to SBRT (27.5-50 Gy in five fractions) followed by sorafenib 200 mg twice daily; the dosage was then increased to 400 mg twice daily after 28 days.
 

SBRT improves outcomes

The original plan was to enroll 292 participants, but accrual closed early when the standard of care for systemic treatment of HCC changed following the results of the phase 3 IMbrave150 trial, which showed the superiority of atezolizumab plus bevacizumab as frontline therapy for locally advanced or metastatic HCC. The closure of accrual was agreed upon by the investigators and the data safety monitoring committee, and their statistical analysis plan was revised accordingly. The study became time driven rather than event driven, she noted. This resulted in a decrease from 80% power to 65% power.

The median age of participants was 66 years (range, 27-84 years); 41% had hepatitis C, and 19% had hepatitis B or B/C. Additionally, 82% had Barcelona Clinic Liver Cancer stage C disease, and 74% had macrovascular invasion.

The median follow-up was 13.2 months overall and 33.7 months for living patients.

Median overall survival improved from 12.3 months with sorafenib alone to 15.8 months with the addition of SBRT to the regimen (hazard ratio [HR] = 0.77; one-sided P = .0554). A prespecified multivariable analysis showed that the combination therapy resulted in a statistically significant improvement in overall survival after adjustment for confounders (HR, 0.72; P = .042).

Similarly, median PFS also improved from 5.5 months with sorafenib alone to 9.2 months with SBRT and sorafenib (HR = 0.55; two-sided P = .0001).

With regard to safety, gastrointestinal bleeds occurred in 4% of patients in the combination arm, vs. 6% of those in the monotherapy arm. Overall, rates of treatment-related grade 3+ adverse events did not significantly differ between study arms (42% vs. 47%; P = .52). There were three grade 5 events; two in the sorafenib-only group and one in the SBRT/sorafenib group.

The researchers also evaluated quality of life (QoL). “Our hypothesis was that patients treated with SBRT and sorafenib would have improved quality of life 6 months after the start of treatment compared to sorafenib alone,” said Dr. Dawson.

About half (47%) of participants agreed to fill out QoL assessments, but baseline and 6-month data were available for only about 21% of participants. Although the numbers were considered too small to analyze statistically, substantial improvement was seen in the group that received combination therapy. A total of 10% of patients who received sorafenib reported improvement on the FACT-Hep score, vs. 35% of patients who received SBRT/sorafenib.

“As compared to sorafenib, SBRT improved overall survival and progression-free survival, with no observed increase in adverse events in patients with advanced HCC,” concluded Dr. Dawson.
 

Where does radiation fit?

Invited discussant Laura Goff, MD, associate professor of medicine, Vanderbilt Ingram Cancer Center, Nashville, Tenn., reiterated that SBRT given prior to sorafenib improved outcomes compared to sorafenib alone, and while not definitive, Quality and Outcomes Framework scores appeared to improve at 6 months for the combination arm. “This reassures our concerns about toxicity,” she said.

Dr. Goff pointed out that since the study closed early, owing to changes in standard of care for HCC, the question arises – where does radiation fit in the array of options now available for HCC?

“For one, sorafenib plus SBRT represents an intriguing first-line option for patients who cannot be treated with immunotherapy, such as those who experience a posttransplant recurrence,” Dr. Goff said. “There is also renewed interest in radiation therapy in liver-dominant HCC, and there is active investigation ongoing for a variety of combinations.”

Dr. Dawson reported relationships with Merck and Raysearch. Dr. Goff reported relationships with Agios, ASLAN, AstraZeneca, Basilea, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Exelixis, Genentech, Merck, and QED Therapeutics.

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

THE CASE

James B* is a 7-year-old Black child who presented to his primary care physician (PCP) for a well-child visit. During preventive health screening, James’ mother expressed concerns about his behavior, characterizing him as immature, aggressive, destructive, and occasionally self-loathing. She described him as physically uncoordinated, struggling to keep up with his peers in sports, and tiring after 20 minutes of activity. James slept 10 hours nightly but was often restless and snored intermittently. As a second grader, his academic achievement was not progressing, and he had become increasingly inattentive at home and at school. James’ mother offered several examples of his fighting with his siblings, noncompliance with morning routines, and avoidance of learning activities. Additionally, his mother expressed concern that James, as a Black child, might eventually be unfairly labeled as a problem child by his teachers or held back a grade level in school.

Although James did not have a family history of developmental delays or learning disorders, he had not met any milestones on time for gross or fine motor, language, cognitive, and social-emotional skills. James had a history of chronic otitis media, for which pressure equalizer tubes were inserted at age 2 years. He had not had any major physical injuries, psychological trauma, recent life transitions, or adverse childhood events. When asked, James’ mother acknowledged symptoms of maternal depression but alluded to faith-based reasons for not seeking treatment for herself.

James’ physical examination was unremarkable. His height, weight, and vitals were all within normal limits. However, he had some difficulty with verbal articulation and expression and showed signs of a possible vocal tic. Based on James’ presentation, his PCP suspected attention-deficit/hyperactivity disorder (ADHD), as well as neurodevelopmental delays.

The PCP gave James’ mother the Strengths and Difficulties Questionnaire to complete and the Vanderbilt Assessment Scales for her and James’ teacher to fill out independently and return to the clinic. The PCP also instructed James’ mother on how to use a sleep diary to maintain a 1-month log of his sleep patterns and habits. The PCP consulted the integrated behavioral health clinician (IBHC; a clinical social worker embedded in the primary care clinic) and made a warm handoff for the IBHC to further assess James’ maladaptive behaviors and interactions.

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

James is one of more than 6 million children, ages 3 to 17 years, in the United States who live with ADHD.^1,2 ADHD is the most common neurodevelopmental disorder among children, and it affects multiple cognitive and behavioral domains throughout the lifespan.³ Children with ADHD often initially present in primary care settings; thus, PCPs are well positioned to diagnose the disorder and provide longitudinal treatment. This Behavioral Health Consult reviews clinical assessment and practice guidelines, as well as treatment recommendations applicable across different areas of influence—individual, family, community, and systems—for PCPs and IBHCs to use in managing ADHD in children.

ADHD features can vary by age and sex

ADHD is a persistent pattern of inattention or hyperactivity and impulsivity interfering with functioning or development in childhood and functioning later in adulthood. ADHD symptoms manifest prior to age 12 years and must occur in 2 or more settings.⁴ Symptoms should not be better explained by another psychiatric disorder or occur exclusively during the course of another disorder (TABLE 1).⁴

Psychostimulants are preferred for ADHD. However, a variety of medications are available and may prove efficacious as children grow and their symptoms and the capacity to manage them change.

The rate of heritability is high, with significant incidence among first-degree relatives.⁴ Children with ADHD show executive functioning deficits in 1 or more cognitive domains (eg, visuospatial, memory, inhibitions, decision making, and reward regulation).^4,5 The prevalence of ADHD nationally is approximately 9.8% (2.2%, ages 3-5 years; 10%, ages 6-11 years; 13.2%, ages 12-17 years) in children and adolescents; worldwide prevalence is 7.2%.^1,6 It persists among 2.6% to 6.8% of adults worldwide.⁷

Research has shown that boys ages 6 to 11 years are significantly more likely than girls to exhibit attention-getting, externalizing behaviors or conduct problems (eg, hyperactivity, impulsivity, disruption, aggression).^1,6 On the other hand, girls ages 12 to 17 years tend to display internalized (eg, depressed mood, anxiety, low self-esteem) or inattentive behaviors, which clinicians and educators may assess as less severe and warranting fewer supportive measures.¹

The prevalence of ADHD and its associated factors, which evolve through maturation, underscore the importance of persistent, patient-centered, and collaborative PCP and IBHC clinical management.

Continue to: Begin with a screening tool, move to a clinical interview

When caregivers express concerns about their child’s behavior, focus, mood, learning, and socialization, consider initiating a multimodal evaluation for ADHD.^5,8 Embarking on an ADHD assessment can require extended or multiple visits to arrive at the diagnosis, followed by still more visits to confirm a course of care and adjust medications. The integrative care approach described in the patient case and elaborated on later in this article can help facilitate assessment and treatment of ADHD.⁹

Signs of ADHD may be observed at initial screening using a tool such as the Ages & Stages Questionnaire (https://agesandstages.com/products-pricing/asq3/) to reveal indications of norm deviations or delays commensurate with ADHD.¹⁰ However, to substantiate the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision criteria for an accurate diagnosis,⁴ the American Academy of Pediatrics (AAP) clinical practice guidelines require a thorough clinical interview, administration of a standardized assessment tool, and review of objective reports in conjunction with a physical examination and psychosocial evaluation.⁶ Standardized meas­ures of psychological, neurocognitive, and academic achievement reported by caregivers and collateral contacts (eg, teachers, counselors, coaches, care providers) are needed to maximize data objectivity and symptom accuracy across settings (TABLE 2^10-17). Additionally, periodic reassessment is recommended to validate changes in diagnostic subtype and treatment plans due to the chronic and dynamic nature of ADHD.

Consider comorbidities and alternate diagnoses

The diagnostic possibility of ADHD should also prompt consideration of other childhood disorders due to the high potential for comorbidities.^4,6 In a 2016 study, approximately 64% of children with ADHD exhibited another developmental or psychiatric disorder at some point. These disorders included oppositional defiant or conduct disorders (52%), anxiety (33%), depression (17%), and autism spectrum disorder (14%), as well as Tourette syndrome, learning or language disorders, motor delays, substance use disorders, sleep-wake disorders, personality disorders, and ­suicidality.¹⁸

Various medical disorders may manifest with similar signs or symptoms to ADHD, such as thyroid disorders, seizure disorders, adverse drug effects, anemia, genetic anomalies, and others.^6,19Although further research is needed to ascertain potential associations between recurrent otitis media and language delay and later social, cognitive, or attention challenges, early consultation with an otolaryngologist is warranted if such concerns arise in a child’s early years.²⁰ Following the initial assessment, conduct a targeted examination and lab testing to rule out co-occurring conditions or comorbidities.

If there are behavioral concerns or developmental delays associated with tall stature for age or pubertal or testicular development anomalies, consult a geneticist and a developmental pediatrician for targeted testing and neurodevelopmental assessment, respectively. For example, ADHD is a common comorbidity among boys who also have XYY syndrome (Jacobs syndrome). However, due to the variability of symptoms and severity, XYY syndrome often goes undiagnosed, leaving a host of compounding pervasive and developmental problems untreated. Overall, more than two-thirds of patients with ADHD and a co-occurring condition are either inaccurately diagnosed or not referred for additional assessment and adjunct treatment.²¹

Continue to: Risks that arise over time

Risks that arise over time. As ADHD persists, adolescents are at greater risk for psychiatric comorbidities, suicidality, and functional impairments (eg, risky behaviors, occupational problems, truancy, delinquency, and poor self-esteem).^4,8 Adolescents with internalized behaviors are more likely to experience comorbid depressive disorders with increased risk for self-harm.^4,5,8 As adolescents age and their sense of autonomy increases, there is a tendency among those who have received a diagnosis of ADHD to minimize symptoms and decrease the frequency of routine clinic visits along with medication use and treatment compliance.³ Additionally, abuse, misuse, and misappropriation of stimulants among teens and young adults are commonplace.

Wide-scope, multidisciplinary evaluation and close clinical management reduce the potential for imprecise diagnoses, particularly at critical developmental junctures. AAP suggests that PCPs can treat mild and moderate cases of ADHD, but if the treating clinician does not have adequate training, experience, time, or clinical support to manage this condition, early referral is warranted.⁶

A guide to pharmacotherapy

Approximately 77% of children ages 2 to 17 years with a diagnosis of ADHD receive any form of treatment.² Treatment for ADHD can include behavioral therapy and medication.² AAP clinical practice guidelines caution against prescribing medications for children younger than 6 years, relying instead on ­caregiver-, teacher-, or clinician-­administered behavioral strategies and parental training in behavioral modification. For children and adolescents between ages 6 and 18 years, first-line ­treatment includes pharmacotherapy balanced with behavioral therapy, academic modifications, and educational supports (eg, 504 Plan, individualized education plan [IEP]).⁶

Psychostimulants are preferred. These agents (eg, methylphenidate, amphetamine) remain the most efficacious class of medications to reduce hyperactivity and inattentiveness and to improve function. While long-acting psychostimulants are associated with better medication adherence and ­adverse-effect tolerance than are short-acting forms, the latter offer more flexibility in dosing. Start by titrating any stimulant to the lowest effective dose; reassess monthly until potential rebound effects stabilize.

More than twothirds of ADHD patients with a co-occurring condition are either inaccurately diagnosed or not referred for additional assessment and adjunct treatment.

Due to potential adverse effects of this class of medication, screen for any family history or personal risk for structural or electrical cardiac anomalies before starting pharmacotherapy. If any such risks exist, arrange for further cardiac evaluation before initiating medication.⁶ Adverse effects of stimulants include reduced appetite, gastrointestinal symptoms, headaches, anxiousness, parasomnia, tachycardia, and hypertension.

Continue to: Once medication is stabilized...

Once medication is stabilized, monitor treatment 2 to 3 times per year thereafter; watch for longer-term adverse effects such as weight loss, decreased growth rate, and psychiatric comorbidities including the Food and Drug Administration (FDA)’s black box warning of increased risk for suicidality.^5,6,22

Other options. The optimal duration of psychostimulant use remains debatable, as existing evidence does not support its long-term use (10 years) over other interventions, such as nonstimulants and nonmedicinal therapies.²² Although backed by less evidence, additional medications indicated for the treatment of ADHD include: (1) atomoxetine, a selective norepinephrine reuptake inhibitor, and (2) the selective alpha-2 adrenergic agonists, extended-release guanfacine and extended-release clonidine (third-line agent).²²

Adverse effects of these FDA-approved medications are similar to those observed in stimulant medications. Evaluation of cardiac risks is recommended before starting nonstimulant medications. The alpha-2 adrenergic agonists may also be used as adjunct therapies to stimulants. Before stopping an alpha-2 adrenergic agonist, taper the dosage slowly to avoid the risk for rebound hypertension.^6,23 Given the wide variety of medication options and variability of effects, it may be necessary to try different medications as children grow and their symptoms and capacity to manage them change. Additional guidance on FDA-approved medications is available at www.ADHDMedicationGuide.com.

How multilevel care coordination can work

As with other chronic or developmental conditions, the treatment of ADHD requires an interdisciplinary perspective. Continuous, comprehensive case management can help patients overcome obstacles to wellness by balancing the resolution of problems with the development of resilience. Well-documented collaboration of subspecialists, educators, and other stakeholders engaged in ADHD care at multiple levels (individual, family, community, and health care system) increases the likelihood of meaningful, sustainable gains. Using a patient-centered medical home framework, IBHCs or other allied health professionals embedded in, or co-located with, primary care settings can be key to accessing evidence-based treatments that include: psycho-­education and mindfulness-based stress reduction training for caregivers^24,25; occupational,²⁶ cognitive behavioral,²⁷ or family therapies^28,29; neuro-feedback; computer-based attention training; group- or community-based interventions; and academic and social supports.^5,8

Evidence shows that recognition and diagnostic specificity of ADHD and comorbidities— not true prevalence—vary more widely among minority than among nonminority populations.

Treatment approaches that capitalize on children’s neurologic and psychological plasticity and fortify self-efficacy with developmentally appropriate tools empower them to surmount ADHD symptoms over time.²³ Facilitating children’s resilience within a developmental framework and health system’s capacities with socio-culturally relevant approaches, consultation, and research can optimize outcomes and mitigate pervasiveness into adulthood. While the patient is at the center of treatment, it is important to consider the family, school, and communities in which the child lives, learns, and plays. PCPs and IBHCs together can consider a “try and track” method to follow progress, changes, and outcomes over time. With this method, the physician can employ approaches that focus on the patient, caregiver, or the caregiver–child interaction (TABLE 3).

Continue to: Assess patients' needs and the resources available

Assess patients’ needs and the resources available throughout the system of care beyond the primary care setting. Stay abreast of hospital policies, health care insurance coverage, and community- and school-based health programs, and any gaps in adequate and equitable assessment and treatment. For example, while clinical recommendations include psychiatric care, health insurance availability or limits in coverage may dissuade caregivers from seeking help or limit initial or long-term access to resources for help.³⁰ Integrating or advocating for clinic support resources or staffing to assist patients in navigating and mitigating challenges may lessen the management burden and increase the likelihood and longevity of favorable health outcomes.

Steps to ensuring health care equity

Among children of historically marginalized and racial and ethnic minority groups or those of populations affected by health disparities, ADHD symptoms and needs are often masked by structural biases that lead to inequitable care and outcomes, as well as treatment misprioritization or delays.³¹ In particular, evidence has shown that recognition and diagnostic specificity of ADHD and comorbidities, not prevalence, vary more widely among minority than among nonminority populations,³² contributing to the 23% of children with ADHD who receive no treatment at all.²

Understand caregiver concerns. This diagnosis discrepancy is correlated with symptom rating sensitivities (eg, reliability, perception, accuracy) among informants and how caregivers observe, perceive, appreciate, understand, and report behaviors. This discrepancy is also related to cultural belief differences, physician–patient communication variants, and a litany of other socioeconomic determinants.^2,4,31 Caregivers from some cultural, ethnic, or socioeconomic backgrounds may be doubtful of psychiatric assessment, diagnoses, treatment, or medication, and that can impact how children are engaged in clinical and educational settings from the outset.³¹ In the case we described, James’ mother was initially hesitant to explore psychotropic medications and was concerned about stigmatization within the school system. She also seemed to avoid psychiatric treatment for her own depressive symptoms due to cultural and religious beliefs.

Health care provider concerns. Some PCPs may hesitate to explore medications due to limited knowledge and skill in dosing and titrating based on a child’s age, stage, and symptoms, and a perceived lack of competence in managing ADHD. This, too, can indirectly perpetuate existing health disparities. Furthermore, ADHD symptoms may be deemed a secondary or tertiary concern if other complex or urgent medical or undifferentiated developmental problems manifest.

Compounding matters is the limited dissemination of empiric research articles (including randomized controlled trials with representative samples) and limited education on the effectiveness and safety of psychopharmacologic interventions across the lifespan and different cultural and ethnic groups.⁴ Consequently, patients who struggle with unmanaged ADHD symptoms are more likely to have chronic mental health disorders, maladaptive behaviors, and other co-occurring conditions contributing to the complexity of individual needs, health care burdens, or justice system involvement; this is particularly true for those of racial and ethnic minorities.³³

Continue to: Impact of the COVID-19 pandemic

Impact of the COVID-19 pandemic. Patients—particularly those in minority or health disparity populations—who under normal circumstances might have been hesitant to seek help may have felt even more reluctant to do so during the COVID-19 pandemic. We have not yet learned the degree to which limited availability of preventive health care services, decreased routine visits, and fluctuating insurance coverage has impacted the diagnosis, management, or severity of childhood disorders during the past 2 years. Reports of national findings indicate that prolonged periods out of school and reduced daily structure were associated with increased disruptions in mood, sleep, and appetite, particularly among children with pre-existing pathologies. Evidence suggests that school-aged children experienced more anxiety, regressive behaviors, and parasomnias than they did before the pandemic, while adolescents experienced more isolation and depressive symptoms.^34,35

However, there remains a paucity of large-scale or representative studies that use an intersectional lens to examine the influence of COVID-19 on children with ADHD. Therefore, PCPs and IBHCs should refocus attention on possibly undiagnosed, stagnated, or regressed ADHD cases, as well as the adults who care for them. (See “5 ways to overcome Tx barriers and promote health equity.”)

THE CASE

During a follow-up visit 1 month later, the PCP confirmed the clinical impression of ADHD combined presentation with a clinical interview and review of the Strengths and Difficulties Questionnaire completed by James’ mother and the Vanderbilt Assessment Scales completed by James’ mother and teacher. The sleep diary indicated potential problems and apneas worthy of consults for pulmonary function testing, a sleep study, and otolaryngology examination. The PCP informed James’ mother on sleep hygiene strategies and ADHD medication options. She indicated that she wanted to pursue the referrals and behavioral modifications before starting any medication trial.

The PCP referred James to a developmental pediatrician for in-depth assessment of his overall development, learning, and functioning. The developmental pediatrician ultimately confirmed the diagnosis of ADHD, as well as motor and speech delays warranting physical, occupational, and speech therapies. The developmental pediatrician also referred James for targeted genetic testing because she suspected a genetic disorder (eg, XYY syndrome).

The PCP reconnected James and his mother to the IBHC to facilitate subspecialty and school-based care coordination and to provide in-office and home-based interventions. The IBHC assessed James’ emotional dysregulation and impulsivity as adversely impacting his interpersonal relationships and planned to address these issues with behavioral and ­parent–child interaction therapies and skills training during the course of 6 to 12 visits. James’ mother was encouraged to engage his teacher on his academic performance and to initiate a 504 Plan or IEP for in-school accommodations and support. The IBHC aided in tracking his assessments, referrals, follow-ups, access barriers, and treatment goals.

After 6 months, James had made only modest progress, and his mother requested that he begin a trial of medication. Based on his weight, symptoms, behavior patterns, and sleep habits, the PCP prescribed ­extended-release dexmethylphenidate 10 mg each morning, then extended-release clonidine 0.1 mg nightly. With team-based clinical management of pharmacologic, behavioral, physical, speech, and occupational therapies, James’ behavior and sleep improved, and the signs of a vocal tic diminished.

By the next school year, James demonstrated a marked improvement in impulse control, attention, and academic functioning. He followed up with the PCP at least quarterly for reassessment of his symptoms, growth, and experience of adverse effects, and to titrate medications accordingly. James and his mother continued to work closely with the IBHC monthly to engage interventions and to monitor his progress at home and school.

CORRESPONDENCE
Sundania J. W. Wonnum, PhD, LCSW, National Institute on Minority Health and Health Disparities, 6707 Democracy Boulevard, Suite 800, Bethesda, MD 20892; [email protected]

THE CASE

James B* is a 7-year-old Black child who presented to his primary care physician (PCP) for a well-child visit. During preventive health screening, James’ mother expressed concerns about his behavior, characterizing him as immature, aggressive, destructive, and occasionally self-loathing. She described him as physically uncoordinated, struggling to keep up with his peers in sports, and tiring after 20 minutes of activity. James slept 10 hours nightly but was often restless and snored intermittently. As a second grader, his academic achievement was not progressing, and he had become increasingly inattentive at home and at school. James’ mother offered several examples of his fighting with his siblings, noncompliance with morning routines, and avoidance of learning activities. Additionally, his mother expressed concern that James, as a Black child, might eventually be unfairly labeled as a problem child by his teachers or held back a grade level in school.

Although James did not have a family history of developmental delays or learning disorders, he had not met any milestones on time for gross or fine motor, language, cognitive, and social-emotional skills. James had a history of chronic otitis media, for which pressure equalizer tubes were inserted at age 2 years. He had not had any major physical injuries, psychological trauma, recent life transitions, or adverse childhood events. When asked, James’ mother acknowledged symptoms of maternal depression but alluded to faith-based reasons for not seeking treatment for herself.

James’ physical examination was unremarkable. His height, weight, and vitals were all within normal limits. However, he had some difficulty with verbal articulation and expression and showed signs of a possible vocal tic. Based on James’ presentation, his PCP suspected attention-deficit/hyperactivity disorder (ADHD), as well as neurodevelopmental delays.

The PCP gave James’ mother the Strengths and Difficulties Questionnaire to complete and the Vanderbilt Assessment Scales for her and James’ teacher to fill out independently and return to the clinic. The PCP also instructed James’ mother on how to use a sleep diary to maintain a 1-month log of his sleep patterns and habits. The PCP consulted the integrated behavioral health clinician (IBHC; a clinical social worker embedded in the primary care clinic) and made a warm handoff for the IBHC to further assess James’ maladaptive behaviors and interactions.

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

James is one of more than 6 million children, ages 3 to 17 years, in the United States who live with ADHD.^1,2 ADHD is the most common neurodevelopmental disorder among children, and it affects multiple cognitive and behavioral domains throughout the lifespan.³ Children with ADHD often initially present in primary care settings; thus, PCPs are well positioned to diagnose the disorder and provide longitudinal treatment. This Behavioral Health Consult reviews clinical assessment and practice guidelines, as well as treatment recommendations applicable across different areas of influence—individual, family, community, and systems—for PCPs and IBHCs to use in managing ADHD in children.

ADHD features can vary by age and sex

ADHD is a persistent pattern of inattention or hyperactivity and impulsivity interfering with functioning or development in childhood and functioning later in adulthood. ADHD symptoms manifest prior to age 12 years and must occur in 2 or more settings.⁴ Symptoms should not be better explained by another psychiatric disorder or occur exclusively during the course of another disorder (TABLE 1).⁴

Psychostimulants are preferred for ADHD. However, a variety of medications are available and may prove efficacious as children grow and their symptoms and the capacity to manage them change.

The rate of heritability is high, with significant incidence among first-degree relatives.⁴ Children with ADHD show executive functioning deficits in 1 or more cognitive domains (eg, visuospatial, memory, inhibitions, decision making, and reward regulation).^4,5 The prevalence of ADHD nationally is approximately 9.8% (2.2%, ages 3-5 years; 10%, ages 6-11 years; 13.2%, ages 12-17 years) in children and adolescents; worldwide prevalence is 7.2%.^1,6 It persists among 2.6% to 6.8% of adults worldwide.⁷

Research has shown that boys ages 6 to 11 years are significantly more likely than girls to exhibit attention-getting, externalizing behaviors or conduct problems (eg, hyperactivity, impulsivity, disruption, aggression).^1,6 On the other hand, girls ages 12 to 17 years tend to display internalized (eg, depressed mood, anxiety, low self-esteem) or inattentive behaviors, which clinicians and educators may assess as less severe and warranting fewer supportive measures.¹

The prevalence of ADHD and its associated factors, which evolve through maturation, underscore the importance of persistent, patient-centered, and collaborative PCP and IBHC clinical management.

Continue to: Begin with a screening tool, move to a clinical interview

When caregivers express concerns about their child’s behavior, focus, mood, learning, and socialization, consider initiating a multimodal evaluation for ADHD.^5,8 Embarking on an ADHD assessment can require extended or multiple visits to arrive at the diagnosis, followed by still more visits to confirm a course of care and adjust medications. The integrative care approach described in the patient case and elaborated on later in this article can help facilitate assessment and treatment of ADHD.⁹

Signs of ADHD may be observed at initial screening using a tool such as the Ages & Stages Questionnaire (https://agesandstages.com/products-pricing/asq3/) to reveal indications of norm deviations or delays commensurate with ADHD.¹⁰ However, to substantiate the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision criteria for an accurate diagnosis,⁴ the American Academy of Pediatrics (AAP) clinical practice guidelines require a thorough clinical interview, administration of a standardized assessment tool, and review of objective reports in conjunction with a physical examination and psychosocial evaluation.⁶ Standardized meas­ures of psychological, neurocognitive, and academic achievement reported by caregivers and collateral contacts (eg, teachers, counselors, coaches, care providers) are needed to maximize data objectivity and symptom accuracy across settings (TABLE 2^10-17). Additionally, periodic reassessment is recommended to validate changes in diagnostic subtype and treatment plans due to the chronic and dynamic nature of ADHD.

Consider comorbidities and alternate diagnoses

The diagnostic possibility of ADHD should also prompt consideration of other childhood disorders due to the high potential for comorbidities.^4,6 In a 2016 study, approximately 64% of children with ADHD exhibited another developmental or psychiatric disorder at some point. These disorders included oppositional defiant or conduct disorders (52%), anxiety (33%), depression (17%), and autism spectrum disorder (14%), as well as Tourette syndrome, learning or language disorders, motor delays, substance use disorders, sleep-wake disorders, personality disorders, and ­suicidality.¹⁸

Various medical disorders may manifest with similar signs or symptoms to ADHD, such as thyroid disorders, seizure disorders, adverse drug effects, anemia, genetic anomalies, and others.^6,19Although further research is needed to ascertain potential associations between recurrent otitis media and language delay and later social, cognitive, or attention challenges, early consultation with an otolaryngologist is warranted if such concerns arise in a child’s early years.²⁰ Following the initial assessment, conduct a targeted examination and lab testing to rule out co-occurring conditions or comorbidities.

If there are behavioral concerns or developmental delays associated with tall stature for age or pubertal or testicular development anomalies, consult a geneticist and a developmental pediatrician for targeted testing and neurodevelopmental assessment, respectively. For example, ADHD is a common comorbidity among boys who also have XYY syndrome (Jacobs syndrome). However, due to the variability of symptoms and severity, XYY syndrome often goes undiagnosed, leaving a host of compounding pervasive and developmental problems untreated. Overall, more than two-thirds of patients with ADHD and a co-occurring condition are either inaccurately diagnosed or not referred for additional assessment and adjunct treatment.²¹

Continue to: Risks that arise over time

Risks that arise over time. As ADHD persists, adolescents are at greater risk for psychiatric comorbidities, suicidality, and functional impairments (eg, risky behaviors, occupational problems, truancy, delinquency, and poor self-esteem).^4,8 Adolescents with internalized behaviors are more likely to experience comorbid depressive disorders with increased risk for self-harm.^4,5,8 As adolescents age and their sense of autonomy increases, there is a tendency among those who have received a diagnosis of ADHD to minimize symptoms and decrease the frequency of routine clinic visits along with medication use and treatment compliance.³ Additionally, abuse, misuse, and misappropriation of stimulants among teens and young adults are commonplace.

Wide-scope, multidisciplinary evaluation and close clinical management reduce the potential for imprecise diagnoses, particularly at critical developmental junctures. AAP suggests that PCPs can treat mild and moderate cases of ADHD, but if the treating clinician does not have adequate training, experience, time, or clinical support to manage this condition, early referral is warranted.⁶

A guide to pharmacotherapy

Approximately 77% of children ages 2 to 17 years with a diagnosis of ADHD receive any form of treatment.² Treatment for ADHD can include behavioral therapy and medication.² AAP clinical practice guidelines caution against prescribing medications for children younger than 6 years, relying instead on ­caregiver-, teacher-, or clinician-­administered behavioral strategies and parental training in behavioral modification. For children and adolescents between ages 6 and 18 years, first-line ­treatment includes pharmacotherapy balanced with behavioral therapy, academic modifications, and educational supports (eg, 504 Plan, individualized education plan [IEP]).⁶

Psychostimulants are preferred. These agents (eg, methylphenidate, amphetamine) remain the most efficacious class of medications to reduce hyperactivity and inattentiveness and to improve function. While long-acting psychostimulants are associated with better medication adherence and ­adverse-effect tolerance than are short-acting forms, the latter offer more flexibility in dosing. Start by titrating any stimulant to the lowest effective dose; reassess monthly until potential rebound effects stabilize.

More than twothirds of ADHD patients with a co-occurring condition are either inaccurately diagnosed or not referred for additional assessment and adjunct treatment.

Due to potential adverse effects of this class of medication, screen for any family history or personal risk for structural or electrical cardiac anomalies before starting pharmacotherapy. If any such risks exist, arrange for further cardiac evaluation before initiating medication.⁶ Adverse effects of stimulants include reduced appetite, gastrointestinal symptoms, headaches, anxiousness, parasomnia, tachycardia, and hypertension.

Continue to: Once medication is stabilized...

Once medication is stabilized, monitor treatment 2 to 3 times per year thereafter; watch for longer-term adverse effects such as weight loss, decreased growth rate, and psychiatric comorbidities including the Food and Drug Administration (FDA)’s black box warning of increased risk for suicidality.^5,6,22

Other options. The optimal duration of psychostimulant use remains debatable, as existing evidence does not support its long-term use (10 years) over other interventions, such as nonstimulants and nonmedicinal therapies.²² Although backed by less evidence, additional medications indicated for the treatment of ADHD include: (1) atomoxetine, a selective norepinephrine reuptake inhibitor, and (2) the selective alpha-2 adrenergic agonists, extended-release guanfacine and extended-release clonidine (third-line agent).²²

Adverse effects of these FDA-approved medications are similar to those observed in stimulant medications. Evaluation of cardiac risks is recommended before starting nonstimulant medications. The alpha-2 adrenergic agonists may also be used as adjunct therapies to stimulants. Before stopping an alpha-2 adrenergic agonist, taper the dosage slowly to avoid the risk for rebound hypertension.^6,23 Given the wide variety of medication options and variability of effects, it may be necessary to try different medications as children grow and their symptoms and capacity to manage them change. Additional guidance on FDA-approved medications is available at www.ADHDMedicationGuide.com.

How multilevel care coordination can work

As with other chronic or developmental conditions, the treatment of ADHD requires an interdisciplinary perspective. Continuous, comprehensive case management can help patients overcome obstacles to wellness by balancing the resolution of problems with the development of resilience. Well-documented collaboration of subspecialists, educators, and other stakeholders engaged in ADHD care at multiple levels (individual, family, community, and health care system) increases the likelihood of meaningful, sustainable gains. Using a patient-centered medical home framework, IBHCs or other allied health professionals embedded in, or co-located with, primary care settings can be key to accessing evidence-based treatments that include: psycho-­education and mindfulness-based stress reduction training for caregivers^24,25; occupational,²⁶ cognitive behavioral,²⁷ or family therapies^28,29; neuro-feedback; computer-based attention training; group- or community-based interventions; and academic and social supports.^5,8

Evidence shows that recognition and diagnostic specificity of ADHD and comorbidities— not true prevalence—vary more widely among minority than among nonminority populations.

Treatment approaches that capitalize on children’s neurologic and psychological plasticity and fortify self-efficacy with developmentally appropriate tools empower them to surmount ADHD symptoms over time.²³ Facilitating children’s resilience within a developmental framework and health system’s capacities with socio-culturally relevant approaches, consultation, and research can optimize outcomes and mitigate pervasiveness into adulthood. While the patient is at the center of treatment, it is important to consider the family, school, and communities in which the child lives, learns, and plays. PCPs and IBHCs together can consider a “try and track” method to follow progress, changes, and outcomes over time. With this method, the physician can employ approaches that focus on the patient, caregiver, or the caregiver–child interaction (TABLE 3).

Continue to: Assess patients' needs and the resources available

Assess patients’ needs and the resources available throughout the system of care beyond the primary care setting. Stay abreast of hospital policies, health care insurance coverage, and community- and school-based health programs, and any gaps in adequate and equitable assessment and treatment. For example, while clinical recommendations include psychiatric care, health insurance availability or limits in coverage may dissuade caregivers from seeking help or limit initial or long-term access to resources for help.³⁰ Integrating or advocating for clinic support resources or staffing to assist patients in navigating and mitigating challenges may lessen the management burden and increase the likelihood and longevity of favorable health outcomes.

Steps to ensuring health care equity

Among children of historically marginalized and racial and ethnic minority groups or those of populations affected by health disparities, ADHD symptoms and needs are often masked by structural biases that lead to inequitable care and outcomes, as well as treatment misprioritization or delays.³¹ In particular, evidence has shown that recognition and diagnostic specificity of ADHD and comorbidities, not prevalence, vary more widely among minority than among nonminority populations,³² contributing to the 23% of children with ADHD who receive no treatment at all.²

Understand caregiver concerns. This diagnosis discrepancy is correlated with symptom rating sensitivities (eg, reliability, perception, accuracy) among informants and how caregivers observe, perceive, appreciate, understand, and report behaviors. This discrepancy is also related to cultural belief differences, physician–patient communication variants, and a litany of other socioeconomic determinants.^2,4,31 Caregivers from some cultural, ethnic, or socioeconomic backgrounds may be doubtful of psychiatric assessment, diagnoses, treatment, or medication, and that can impact how children are engaged in clinical and educational settings from the outset.³¹ In the case we described, James’ mother was initially hesitant to explore psychotropic medications and was concerned about stigmatization within the school system. She also seemed to avoid psychiatric treatment for her own depressive symptoms due to cultural and religious beliefs.

Health care provider concerns. Some PCPs may hesitate to explore medications due to limited knowledge and skill in dosing and titrating based on a child’s age, stage, and symptoms, and a perceived lack of competence in managing ADHD. This, too, can indirectly perpetuate existing health disparities. Furthermore, ADHD symptoms may be deemed a secondary or tertiary concern if other complex or urgent medical or undifferentiated developmental problems manifest.

Compounding matters is the limited dissemination of empiric research articles (including randomized controlled trials with representative samples) and limited education on the effectiveness and safety of psychopharmacologic interventions across the lifespan and different cultural and ethnic groups.⁴ Consequently, patients who struggle with unmanaged ADHD symptoms are more likely to have chronic mental health disorders, maladaptive behaviors, and other co-occurring conditions contributing to the complexity of individual needs, health care burdens, or justice system involvement; this is particularly true for those of racial and ethnic minorities.³³

Continue to: Impact of the COVID-19 pandemic

Impact of the COVID-19 pandemic. Patients—particularly those in minority or health disparity populations—who under normal circumstances might have been hesitant to seek help may have felt even more reluctant to do so during the COVID-19 pandemic. We have not yet learned the degree to which limited availability of preventive health care services, decreased routine visits, and fluctuating insurance coverage has impacted the diagnosis, management, or severity of childhood disorders during the past 2 years. Reports of national findings indicate that prolonged periods out of school and reduced daily structure were associated with increased disruptions in mood, sleep, and appetite, particularly among children with pre-existing pathologies. Evidence suggests that school-aged children experienced more anxiety, regressive behaviors, and parasomnias than they did before the pandemic, while adolescents experienced more isolation and depressive symptoms.^34,35

However, there remains a paucity of large-scale or representative studies that use an intersectional lens to examine the influence of COVID-19 on children with ADHD. Therefore, PCPs and IBHCs should refocus attention on possibly undiagnosed, stagnated, or regressed ADHD cases, as well as the adults who care for them. (See “5 ways to overcome Tx barriers and promote health equity.”)

THE CASE

During a follow-up visit 1 month later, the PCP confirmed the clinical impression of ADHD combined presentation with a clinical interview and review of the Strengths and Difficulties Questionnaire completed by James’ mother and the Vanderbilt Assessment Scales completed by James’ mother and teacher. The sleep diary indicated potential problems and apneas worthy of consults for pulmonary function testing, a sleep study, and otolaryngology examination. The PCP informed James’ mother on sleep hygiene strategies and ADHD medication options. She indicated that she wanted to pursue the referrals and behavioral modifications before starting any medication trial.

The PCP referred James to a developmental pediatrician for in-depth assessment of his overall development, learning, and functioning. The developmental pediatrician ultimately confirmed the diagnosis of ADHD, as well as motor and speech delays warranting physical, occupational, and speech therapies. The developmental pediatrician also referred James for targeted genetic testing because she suspected a genetic disorder (eg, XYY syndrome).

The PCP reconnected James and his mother to the IBHC to facilitate subspecialty and school-based care coordination and to provide in-office and home-based interventions. The IBHC assessed James’ emotional dysregulation and impulsivity as adversely impacting his interpersonal relationships and planned to address these issues with behavioral and ­parent–child interaction therapies and skills training during the course of 6 to 12 visits. James’ mother was encouraged to engage his teacher on his academic performance and to initiate a 504 Plan or IEP for in-school accommodations and support. The IBHC aided in tracking his assessments, referrals, follow-ups, access barriers, and treatment goals.

After 6 months, James had made only modest progress, and his mother requested that he begin a trial of medication. Based on his weight, symptoms, behavior patterns, and sleep habits, the PCP prescribed ­extended-release dexmethylphenidate 10 mg each morning, then extended-release clonidine 0.1 mg nightly. With team-based clinical management of pharmacologic, behavioral, physical, speech, and occupational therapies, James’ behavior and sleep improved, and the signs of a vocal tic diminished.

By the next school year, James demonstrated a marked improvement in impulse control, attention, and academic functioning. He followed up with the PCP at least quarterly for reassessment of his symptoms, growth, and experience of adverse effects, and to titrate medications accordingly. James and his mother continued to work closely with the IBHC monthly to engage interventions and to monitor his progress at home and school.

CORRESPONDENCE
Sundania J. W. Wonnum, PhD, LCSW, National Institute on Minority Health and Health Disparities, 6707 Democracy Boulevard, Suite 800, Bethesda, MD 20892; [email protected]

THE CASE

James B* is a 7-year-old Black child who presented to his primary care physician (PCP) for a well-child visit. During preventive health screening, James’ mother expressed concerns about his behavior, characterizing him as immature, aggressive, destructive, and occasionally self-loathing. She described him as physically uncoordinated, struggling to keep up with his peers in sports, and tiring after 20 minutes of activity. James slept 10 hours nightly but was often restless and snored intermittently. As a second grader, his academic achievement was not progressing, and he had become increasingly inattentive at home and at school. James’ mother offered several examples of his fighting with his siblings, noncompliance with morning routines, and avoidance of learning activities. Additionally, his mother expressed concern that James, as a Black child, might eventually be unfairly labeled as a problem child by his teachers or held back a grade level in school.

Although James did not have a family history of developmental delays or learning disorders, he had not met any milestones on time for gross or fine motor, language, cognitive, and social-emotional skills. James had a history of chronic otitis media, for which pressure equalizer tubes were inserted at age 2 years. He had not had any major physical injuries, psychological trauma, recent life transitions, or adverse childhood events. When asked, James’ mother acknowledged symptoms of maternal depression but alluded to faith-based reasons for not seeking treatment for herself.

James’ physical examination was unremarkable. His height, weight, and vitals were all within normal limits. However, he had some difficulty with verbal articulation and expression and showed signs of a possible vocal tic. Based on James’ presentation, his PCP suspected attention-deficit/hyperactivity disorder (ADHD), as well as neurodevelopmental delays.

The PCP gave James’ mother the Strengths and Difficulties Questionnaire to complete and the Vanderbilt Assessment Scales for her and James’ teacher to fill out independently and return to the clinic. The PCP also instructed James’ mother on how to use a sleep diary to maintain a 1-month log of his sleep patterns and habits. The PCP consulted the integrated behavioral health clinician (IBHC; a clinical social worker embedded in the primary care clinic) and made a warm handoff for the IBHC to further assess James’ maladaptive behaviors and interactions.

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

James is one of more than 6 million children, ages 3 to 17 years, in the United States who live with ADHD.^1,2 ADHD is the most common neurodevelopmental disorder among children, and it affects multiple cognitive and behavioral domains throughout the lifespan.³ Children with ADHD often initially present in primary care settings; thus, PCPs are well positioned to diagnose the disorder and provide longitudinal treatment. This Behavioral Health Consult reviews clinical assessment and practice guidelines, as well as treatment recommendations applicable across different areas of influence—individual, family, community, and systems—for PCPs and IBHCs to use in managing ADHD in children.

ADHD features can vary by age and sex

ADHD is a persistent pattern of inattention or hyperactivity and impulsivity interfering with functioning or development in childhood and functioning later in adulthood. ADHD symptoms manifest prior to age 12 years and must occur in 2 or more settings.⁴ Symptoms should not be better explained by another psychiatric disorder or occur exclusively during the course of another disorder (TABLE 1).⁴

Psychostimulants are preferred for ADHD. However, a variety of medications are available and may prove efficacious as children grow and their symptoms and the capacity to manage them change.

The rate of heritability is high, with significant incidence among first-degree relatives.⁴ Children with ADHD show executive functioning deficits in 1 or more cognitive domains (eg, visuospatial, memory, inhibitions, decision making, and reward regulation).^4,5 The prevalence of ADHD nationally is approximately 9.8% (2.2%, ages 3-5 years; 10%, ages 6-11 years; 13.2%, ages 12-17 years) in children and adolescents; worldwide prevalence is 7.2%.^1,6 It persists among 2.6% to 6.8% of adults worldwide.⁷

Research has shown that boys ages 6 to 11 years are significantly more likely than girls to exhibit attention-getting, externalizing behaviors or conduct problems (eg, hyperactivity, impulsivity, disruption, aggression).^1,6 On the other hand, girls ages 12 to 17 years tend to display internalized (eg, depressed mood, anxiety, low self-esteem) or inattentive behaviors, which clinicians and educators may assess as less severe and warranting fewer supportive measures.¹

The prevalence of ADHD and its associated factors, which evolve through maturation, underscore the importance of persistent, patient-centered, and collaborative PCP and IBHC clinical management.

Continue to: Begin with a screening tool, move to a clinical interview

When caregivers express concerns about their child’s behavior, focus, mood, learning, and socialization, consider initiating a multimodal evaluation for ADHD.^5,8 Embarking on an ADHD assessment can require extended or multiple visits to arrive at the diagnosis, followed by still more visits to confirm a course of care and adjust medications. The integrative care approach described in the patient case and elaborated on later in this article can help facilitate assessment and treatment of ADHD.⁹

Signs of ADHD may be observed at initial screening using a tool such as the Ages & Stages Questionnaire (https://agesandstages.com/products-pricing/asq3/) to reveal indications of norm deviations or delays commensurate with ADHD.¹⁰ However, to substantiate the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision criteria for an accurate diagnosis,⁴ the American Academy of Pediatrics (AAP) clinical practice guidelines require a thorough clinical interview, administration of a standardized assessment tool, and review of objective reports in conjunction with a physical examination and psychosocial evaluation.⁶ Standardized meas­ures of psychological, neurocognitive, and academic achievement reported by caregivers and collateral contacts (eg, teachers, counselors, coaches, care providers) are needed to maximize data objectivity and symptom accuracy across settings (TABLE 2^10-17). Additionally, periodic reassessment is recommended to validate changes in diagnostic subtype and treatment plans due to the chronic and dynamic nature of ADHD.

Consider comorbidities and alternate diagnoses

The diagnostic possibility of ADHD should also prompt consideration of other childhood disorders due to the high potential for comorbidities.^4,6 In a 2016 study, approximately 64% of children with ADHD exhibited another developmental or psychiatric disorder at some point. These disorders included oppositional defiant or conduct disorders (52%), anxiety (33%), depression (17%), and autism spectrum disorder (14%), as well as Tourette syndrome, learning or language disorders, motor delays, substance use disorders, sleep-wake disorders, personality disorders, and ­suicidality.¹⁸

Various medical disorders may manifest with similar signs or symptoms to ADHD, such as thyroid disorders, seizure disorders, adverse drug effects, anemia, genetic anomalies, and others.^6,19Although further research is needed to ascertain potential associations between recurrent otitis media and language delay and later social, cognitive, or attention challenges, early consultation with an otolaryngologist is warranted if such concerns arise in a child’s early years.²⁰ Following the initial assessment, conduct a targeted examination and lab testing to rule out co-occurring conditions or comorbidities.

If there are behavioral concerns or developmental delays associated with tall stature for age or pubertal or testicular development anomalies, consult a geneticist and a developmental pediatrician for targeted testing and neurodevelopmental assessment, respectively. For example, ADHD is a common comorbidity among boys who also have XYY syndrome (Jacobs syndrome). However, due to the variability of symptoms and severity, XYY syndrome often goes undiagnosed, leaving a host of compounding pervasive and developmental problems untreated. Overall, more than two-thirds of patients with ADHD and a co-occurring condition are either inaccurately diagnosed or not referred for additional assessment and adjunct treatment.²¹

Continue to: Risks that arise over time

Risks that arise over time. As ADHD persists, adolescents are at greater risk for psychiatric comorbidities, suicidality, and functional impairments (eg, risky behaviors, occupational problems, truancy, delinquency, and poor self-esteem).^4,8 Adolescents with internalized behaviors are more likely to experience comorbid depressive disorders with increased risk for self-harm.^4,5,8 As adolescents age and their sense of autonomy increases, there is a tendency among those who have received a diagnosis of ADHD to minimize symptoms and decrease the frequency of routine clinic visits along with medication use and treatment compliance.³ Additionally, abuse, misuse, and misappropriation of stimulants among teens and young adults are commonplace.

Wide-scope, multidisciplinary evaluation and close clinical management reduce the potential for imprecise diagnoses, particularly at critical developmental junctures. AAP suggests that PCPs can treat mild and moderate cases of ADHD, but if the treating clinician does not have adequate training, experience, time, or clinical support to manage this condition, early referral is warranted.⁶

A guide to pharmacotherapy

Approximately 77% of children ages 2 to 17 years with a diagnosis of ADHD receive any form of treatment.² Treatment for ADHD can include behavioral therapy and medication.² AAP clinical practice guidelines caution against prescribing medications for children younger than 6 years, relying instead on ­caregiver-, teacher-, or clinician-­administered behavioral strategies and parental training in behavioral modification. For children and adolescents between ages 6 and 18 years, first-line ­treatment includes pharmacotherapy balanced with behavioral therapy, academic modifications, and educational supports (eg, 504 Plan, individualized education plan [IEP]).⁶

Psychostimulants are preferred. These agents (eg, methylphenidate, amphetamine) remain the most efficacious class of medications to reduce hyperactivity and inattentiveness and to improve function. While long-acting psychostimulants are associated with better medication adherence and ­adverse-effect tolerance than are short-acting forms, the latter offer more flexibility in dosing. Start by titrating any stimulant to the lowest effective dose; reassess monthly until potential rebound effects stabilize.

More than twothirds of ADHD patients with a co-occurring condition are either inaccurately diagnosed or not referred for additional assessment and adjunct treatment.

Due to potential adverse effects of this class of medication, screen for any family history or personal risk for structural or electrical cardiac anomalies before starting pharmacotherapy. If any such risks exist, arrange for further cardiac evaluation before initiating medication.⁶ Adverse effects of stimulants include reduced appetite, gastrointestinal symptoms, headaches, anxiousness, parasomnia, tachycardia, and hypertension.

Continue to: Once medication is stabilized...

Once medication is stabilized, monitor treatment 2 to 3 times per year thereafter; watch for longer-term adverse effects such as weight loss, decreased growth rate, and psychiatric comorbidities including the Food and Drug Administration (FDA)’s black box warning of increased risk for suicidality.^5,6,22

Other options. The optimal duration of psychostimulant use remains debatable, as existing evidence does not support its long-term use (10 years) over other interventions, such as nonstimulants and nonmedicinal therapies.²² Although backed by less evidence, additional medications indicated for the treatment of ADHD include: (1) atomoxetine, a selective norepinephrine reuptake inhibitor, and (2) the selective alpha-2 adrenergic agonists, extended-release guanfacine and extended-release clonidine (third-line agent).²²

Adverse effects of these FDA-approved medications are similar to those observed in stimulant medications. Evaluation of cardiac risks is recommended before starting nonstimulant medications. The alpha-2 adrenergic agonists may also be used as adjunct therapies to stimulants. Before stopping an alpha-2 adrenergic agonist, taper the dosage slowly to avoid the risk for rebound hypertension.^6,23 Given the wide variety of medication options and variability of effects, it may be necessary to try different medications as children grow and their symptoms and capacity to manage them change. Additional guidance on FDA-approved medications is available at www.ADHDMedicationGuide.com.

How multilevel care coordination can work

As with other chronic or developmental conditions, the treatment of ADHD requires an interdisciplinary perspective. Continuous, comprehensive case management can help patients overcome obstacles to wellness by balancing the resolution of problems with the development of resilience. Well-documented collaboration of subspecialists, educators, and other stakeholders engaged in ADHD care at multiple levels (individual, family, community, and health care system) increases the likelihood of meaningful, sustainable gains. Using a patient-centered medical home framework, IBHCs or other allied health professionals embedded in, or co-located with, primary care settings can be key to accessing evidence-based treatments that include: psycho-­education and mindfulness-based stress reduction training for caregivers^24,25; occupational,²⁶ cognitive behavioral,²⁷ or family therapies^28,29; neuro-feedback; computer-based attention training; group- or community-based interventions; and academic and social supports.^5,8

Evidence shows that recognition and diagnostic specificity of ADHD and comorbidities— not true prevalence—vary more widely among minority than among nonminority populations.

Treatment approaches that capitalize on children’s neurologic and psychological plasticity and fortify self-efficacy with developmentally appropriate tools empower them to surmount ADHD symptoms over time.²³ Facilitating children’s resilience within a developmental framework and health system’s capacities with socio-culturally relevant approaches, consultation, and research can optimize outcomes and mitigate pervasiveness into adulthood. While the patient is at the center of treatment, it is important to consider the family, school, and communities in which the child lives, learns, and plays. PCPs and IBHCs together can consider a “try and track” method to follow progress, changes, and outcomes over time. With this method, the physician can employ approaches that focus on the patient, caregiver, or the caregiver–child interaction (TABLE 3).

Continue to: Assess patients' needs and the resources available

Assess patients’ needs and the resources available throughout the system of care beyond the primary care setting. Stay abreast of hospital policies, health care insurance coverage, and community- and school-based health programs, and any gaps in adequate and equitable assessment and treatment. For example, while clinical recommendations include psychiatric care, health insurance availability or limits in coverage may dissuade caregivers from seeking help or limit initial or long-term access to resources for help.³⁰ Integrating or advocating for clinic support resources or staffing to assist patients in navigating and mitigating challenges may lessen the management burden and increase the likelihood and longevity of favorable health outcomes.

Steps to ensuring health care equity

Among children of historically marginalized and racial and ethnic minority groups or those of populations affected by health disparities, ADHD symptoms and needs are often masked by structural biases that lead to inequitable care and outcomes, as well as treatment misprioritization or delays.³¹ In particular, evidence has shown that recognition and diagnostic specificity of ADHD and comorbidities, not prevalence, vary more widely among minority than among nonminority populations,³² contributing to the 23% of children with ADHD who receive no treatment at all.²

Understand caregiver concerns. This diagnosis discrepancy is correlated with symptom rating sensitivities (eg, reliability, perception, accuracy) among informants and how caregivers observe, perceive, appreciate, understand, and report behaviors. This discrepancy is also related to cultural belief differences, physician–patient communication variants, and a litany of other socioeconomic determinants.^2,4,31 Caregivers from some cultural, ethnic, or socioeconomic backgrounds may be doubtful of psychiatric assessment, diagnoses, treatment, or medication, and that can impact how children are engaged in clinical and educational settings from the outset.³¹ In the case we described, James’ mother was initially hesitant to explore psychotropic medications and was concerned about stigmatization within the school system. She also seemed to avoid psychiatric treatment for her own depressive symptoms due to cultural and religious beliefs.

Health care provider concerns. Some PCPs may hesitate to explore medications due to limited knowledge and skill in dosing and titrating based on a child’s age, stage, and symptoms, and a perceived lack of competence in managing ADHD. This, too, can indirectly perpetuate existing health disparities. Furthermore, ADHD symptoms may be deemed a secondary or tertiary concern if other complex or urgent medical or undifferentiated developmental problems manifest.

Compounding matters is the limited dissemination of empiric research articles (including randomized controlled trials with representative samples) and limited education on the effectiveness and safety of psychopharmacologic interventions across the lifespan and different cultural and ethnic groups.⁴ Consequently, patients who struggle with unmanaged ADHD symptoms are more likely to have chronic mental health disorders, maladaptive behaviors, and other co-occurring conditions contributing to the complexity of individual needs, health care burdens, or justice system involvement; this is particularly true for those of racial and ethnic minorities.³³

Continue to: Impact of the COVID-19 pandemic

Impact of the COVID-19 pandemic. Patients—particularly those in minority or health disparity populations—who under normal circumstances might have been hesitant to seek help may have felt even more reluctant to do so during the COVID-19 pandemic. We have not yet learned the degree to which limited availability of preventive health care services, decreased routine visits, and fluctuating insurance coverage has impacted the diagnosis, management, or severity of childhood disorders during the past 2 years. Reports of national findings indicate that prolonged periods out of school and reduced daily structure were associated with increased disruptions in mood, sleep, and appetite, particularly among children with pre-existing pathologies. Evidence suggests that school-aged children experienced more anxiety, regressive behaviors, and parasomnias than they did before the pandemic, while adolescents experienced more isolation and depressive symptoms.^34,35

However, there remains a paucity of large-scale or representative studies that use an intersectional lens to examine the influence of COVID-19 on children with ADHD. Therefore, PCPs and IBHCs should refocus attention on possibly undiagnosed, stagnated, or regressed ADHD cases, as well as the adults who care for them. (See “5 ways to overcome Tx barriers and promote health equity.”)

THE CASE

During a follow-up visit 1 month later, the PCP confirmed the clinical impression of ADHD combined presentation with a clinical interview and review of the Strengths and Difficulties Questionnaire completed by James’ mother and the Vanderbilt Assessment Scales completed by James’ mother and teacher. The sleep diary indicated potential problems and apneas worthy of consults for pulmonary function testing, a sleep study, and otolaryngology examination. The PCP informed James’ mother on sleep hygiene strategies and ADHD medication options. She indicated that she wanted to pursue the referrals and behavioral modifications before starting any medication trial.

The PCP referred James to a developmental pediatrician for in-depth assessment of his overall development, learning, and functioning. The developmental pediatrician ultimately confirmed the diagnosis of ADHD, as well as motor and speech delays warranting physical, occupational, and speech therapies. The developmental pediatrician also referred James for targeted genetic testing because she suspected a genetic disorder (eg, XYY syndrome).

The PCP reconnected James and his mother to the IBHC to facilitate subspecialty and school-based care coordination and to provide in-office and home-based interventions. The IBHC assessed James’ emotional dysregulation and impulsivity as adversely impacting his interpersonal relationships and planned to address these issues with behavioral and ­parent–child interaction therapies and skills training during the course of 6 to 12 visits. James’ mother was encouraged to engage his teacher on his academic performance and to initiate a 504 Plan or IEP for in-school accommodations and support. The IBHC aided in tracking his assessments, referrals, follow-ups, access barriers, and treatment goals.

After 6 months, James had made only modest progress, and his mother requested that he begin a trial of medication. Based on his weight, symptoms, behavior patterns, and sleep habits, the PCP prescribed ­extended-release dexmethylphenidate 10 mg each morning, then extended-release clonidine 0.1 mg nightly. With team-based clinical management of pharmacologic, behavioral, physical, speech, and occupational therapies, James’ behavior and sleep improved, and the signs of a vocal tic diminished.

By the next school year, James demonstrated a marked improvement in impulse control, attention, and academic functioning. He followed up with the PCP at least quarterly for reassessment of his symptoms, growth, and experience of adverse effects, and to titrate medications accordingly. James and his mother continued to work closely with the IBHC monthly to engage interventions and to monitor his progress at home and school.

CORRESPONDENCE
Sundania J. W. Wonnum, PhD, LCSW, National Institute on Minority Health and Health Disparities, 6707 Democracy Boulevard, Suite 800, Bethesda, MD 20892; [email protected]

Evidence summary

Mixed results on exercise’s effect on neuropsychiatric symptoms

A 2020 systematic review and meta-analysis of 18 RCTs investigated the effect of home-based physical activity on several markers of behavioral and psychological symptoms of dementia (BPSD). These symptoms were measured using the caregiver-completed neuropsychiatric inventory (NPI), which in­cludes agitation. There was substantial heterogeneity between trials; however, 4 RCTs (472 patients) were included in a meta-­analysis of the NPI. These RCTs were nonblinded, given the nature of the intervention.¹

Interventions to enhance physical activity ranged from 12 weeks to 2 years in duration, with 2 to 8 contacts from the study team per week. The type of physical activity varied and included cardiorespiratory endurance, balance training, resistance training, and activities of daily living training.¹

Exercise was associated with significantly fewer symptoms on the NPI, although the effect size was small (standard mean difference [SMD] = –0.37; 95% CI, –0.57 to –0.17). Heterogeneity in the interventions and assessments were limitations to this meta-analysis.¹

A 2015 systematic review and meta-­analysis of 18 RCTs compared the effect of exercise interventions against a control group for the treatment of BPSD, utilizing 10 behavioral and 2 neurovegetative components of the NPI (each scored from 0 to 5) in patients with dementia. Studies were included if they used ≥ 1 exercise intervention compared to a control or usual care group without additional exercise recommendations. Thirteen studies had a multicomponent training intervention (≥ 2 exercise types grouped together in the same training session), 2 used tai chi, 4 used walking, and 1 used dance and movement therapy. These RCTs were conducted in a variety of settings, including community-dwelling and long-term care facilities (n = 6427 patients).²

Exercise did not reduce global BPSD (N = 4441 patients), with a weighted mean difference (WMD) of −3.9 (95% CI, −9.0 to 1.2; P = .13). Exploratory analysis did not show improvement in aberrant motor behavior with exercise (WMD = –0.55; 95% CI, –1.10 to 0.001; P = .05). Limitations of this review included the small number of studies, heterogeneity of the population, and limitations in data accessibility.²

A 2017 hospital-based RCT evaluated the effects of a short-term exercise program on neuropsychiatric signs and symptoms in patients with dementia in 3 specialized dementia care wards (N = 85). Patients had a diagnosis of dementia, minimum length of stay of 1 week, no delirium, and the ability to perform the Timed Up and Go Test. The intervention group included a 2-week exercise program of four 20-minute exercise sessions per day on 3 days per week, involving strengthening or endurance exercises, in addition to treatment as usual. The control group included a 2-week period of social-stimulation programs consisting of table games for 120 minutes per week, in addition to treatment as usual.³

Exercise remains a small tool to address a big problem.

Of 85 patients randomized, 15 (18%) were lost to follow-up (14 of whom were discharged early from the hospital). Among the 70 patients included in the final analysis, the mean age was 80 years; 47% were female and 53% male; and the mean Mini-Mental Status Examination score was 18.3 (≤ 23 indicates dementia). In both groups, most patients had moderate dementia, moderate neuropsychiatric signs and symptoms, and a low level of psychotic symptoms. Patients in the intervention group had a higher adherence rate compared with those in the control group.³

Continue to: The primary outcome...

The primary outcome was neuropsychiatric signs and symptoms as measured by the Alzheimer’s Disease Cooperative Study–­Clinical Global Impression of Change (ADCS-CGIC). Compared to the control group, the intervention group experienced greater improvement on the ADCS-CGIC dimensions of emotional agitation (SMD = –0.9; P < .001), lability (SMD = –1.1; P < .001), psychomotor agitation (SMD = –0.7; P = .01), and verbal aggression (SMD = –0.5; P = .04). However, there were no differences between groups in the physical aggression dimension. Trial limitations included potential impact of the drop-out rate and possible blinding issues, as nursing staff performing assessments could have seen to which group a patient was allocated.³

A 2016 factorial cluster RCT of 16 nursing homes (with at least 60% of the population having dementia) compared the use of ­person-centered care vs person-centered care plus at least 1 randomly assigned additional intervention (eg, antipsychotic medication use review, social interaction interventions, and exercise over a period of 9 months) (n = 277, with 193 analyzed per protocol). Exercise was implemented at 1 hour per week or at an increase of 20% above baseline and compared with a control group with no change in exercise.⁴

Exercise significantly improved neuropsychiatric symptoms. The baseline NPI score of 14.54 improved by –3.59 (95% CI, –7.08 to –0.09; P < .05). However, none of the study interventions significantly improved the agitation-specific scores. The primary limitation of this study was that antipsychotic prescribing was at the discretion of the provider and not according to a protocol. In addition, the authors noted that the trial was inadequately powered to correct for testing 3 primary outcomes.⁴

Editor’s takeaway

Dementia and dementia with agitation are challenging conditions to treat. Disappointingly, physical exercise had inconsistent and generally minimal effect on agitation in dementia. Nevertheless, exercise had other positive effects. So, considering the benefits that exercise does provide, its low cost, and its limited adverse effects, exercise remains a small tool to address a big problem.

Evidence summary

Mixed results on exercise’s effect on neuropsychiatric symptoms

A 2020 systematic review and meta-analysis of 18 RCTs investigated the effect of home-based physical activity on several markers of behavioral and psychological symptoms of dementia (BPSD). These symptoms were measured using the caregiver-completed neuropsychiatric inventory (NPI), which in­cludes agitation. There was substantial heterogeneity between trials; however, 4 RCTs (472 patients) were included in a meta-­analysis of the NPI. These RCTs were nonblinded, given the nature of the intervention.¹

Interventions to enhance physical activity ranged from 12 weeks to 2 years in duration, with 2 to 8 contacts from the study team per week. The type of physical activity varied and included cardiorespiratory endurance, balance training, resistance training, and activities of daily living training.¹

Exercise was associated with significantly fewer symptoms on the NPI, although the effect size was small (standard mean difference [SMD] = –0.37; 95% CI, –0.57 to –0.17). Heterogeneity in the interventions and assessments were limitations to this meta-analysis.¹

A 2015 systematic review and meta-­analysis of 18 RCTs compared the effect of exercise interventions against a control group for the treatment of BPSD, utilizing 10 behavioral and 2 neurovegetative components of the NPI (each scored from 0 to 5) in patients with dementia. Studies were included if they used ≥ 1 exercise intervention compared to a control or usual care group without additional exercise recommendations. Thirteen studies had a multicomponent training intervention (≥ 2 exercise types grouped together in the same training session), 2 used tai chi, 4 used walking, and 1 used dance and movement therapy. These RCTs were conducted in a variety of settings, including community-dwelling and long-term care facilities (n = 6427 patients).²

Exercise did not reduce global BPSD (N = 4441 patients), with a weighted mean difference (WMD) of −3.9 (95% CI, −9.0 to 1.2; P = .13). Exploratory analysis did not show improvement in aberrant motor behavior with exercise (WMD = –0.55; 95% CI, –1.10 to 0.001; P = .05). Limitations of this review included the small number of studies, heterogeneity of the population, and limitations in data accessibility.²

A 2017 hospital-based RCT evaluated the effects of a short-term exercise program on neuropsychiatric signs and symptoms in patients with dementia in 3 specialized dementia care wards (N = 85). Patients had a diagnosis of dementia, minimum length of stay of 1 week, no delirium, and the ability to perform the Timed Up and Go Test. The intervention group included a 2-week exercise program of four 20-minute exercise sessions per day on 3 days per week, involving strengthening or endurance exercises, in addition to treatment as usual. The control group included a 2-week period of social-stimulation programs consisting of table games for 120 minutes per week, in addition to treatment as usual.³

Exercise remains a small tool to address a big problem.

Of 85 patients randomized, 15 (18%) were lost to follow-up (14 of whom were discharged early from the hospital). Among the 70 patients included in the final analysis, the mean age was 80 years; 47% were female and 53% male; and the mean Mini-Mental Status Examination score was 18.3 (≤ 23 indicates dementia). In both groups, most patients had moderate dementia, moderate neuropsychiatric signs and symptoms, and a low level of psychotic symptoms. Patients in the intervention group had a higher adherence rate compared with those in the control group.³

Continue to: The primary outcome...

The primary outcome was neuropsychiatric signs and symptoms as measured by the Alzheimer’s Disease Cooperative Study–­Clinical Global Impression of Change (ADCS-CGIC). Compared to the control group, the intervention group experienced greater improvement on the ADCS-CGIC dimensions of emotional agitation (SMD = –0.9; P < .001), lability (SMD = –1.1; P < .001), psychomotor agitation (SMD = –0.7; P = .01), and verbal aggression (SMD = –0.5; P = .04). However, there were no differences between groups in the physical aggression dimension. Trial limitations included potential impact of the drop-out rate and possible blinding issues, as nursing staff performing assessments could have seen to which group a patient was allocated.³

A 2016 factorial cluster RCT of 16 nursing homes (with at least 60% of the population having dementia) compared the use of ­person-centered care vs person-centered care plus at least 1 randomly assigned additional intervention (eg, antipsychotic medication use review, social interaction interventions, and exercise over a period of 9 months) (n = 277, with 193 analyzed per protocol). Exercise was implemented at 1 hour per week or at an increase of 20% above baseline and compared with a control group with no change in exercise.⁴

Exercise significantly improved neuropsychiatric symptoms. The baseline NPI score of 14.54 improved by –3.59 (95% CI, –7.08 to –0.09; P < .05). However, none of the study interventions significantly improved the agitation-specific scores. The primary limitation of this study was that antipsychotic prescribing was at the discretion of the provider and not according to a protocol. In addition, the authors noted that the trial was inadequately powered to correct for testing 3 primary outcomes.⁴

Editor’s takeaway

Dementia and dementia with agitation are challenging conditions to treat. Disappointingly, physical exercise had inconsistent and generally minimal effect on agitation in dementia. Nevertheless, exercise had other positive effects. So, considering the benefits that exercise does provide, its low cost, and its limited adverse effects, exercise remains a small tool to address a big problem.

Evidence summary

Mixed results on exercise’s effect on neuropsychiatric symptoms

A 2020 systematic review and meta-analysis of 18 RCTs investigated the effect of home-based physical activity on several markers of behavioral and psychological symptoms of dementia (BPSD). These symptoms were measured using the caregiver-completed neuropsychiatric inventory (NPI), which in­cludes agitation. There was substantial heterogeneity between trials; however, 4 RCTs (472 patients) were included in a meta-­analysis of the NPI. These RCTs were nonblinded, given the nature of the intervention.¹

Interventions to enhance physical activity ranged from 12 weeks to 2 years in duration, with 2 to 8 contacts from the study team per week. The type of physical activity varied and included cardiorespiratory endurance, balance training, resistance training, and activities of daily living training.¹

Exercise was associated with significantly fewer symptoms on the NPI, although the effect size was small (standard mean difference [SMD] = –0.37; 95% CI, –0.57 to –0.17). Heterogeneity in the interventions and assessments were limitations to this meta-analysis.¹

A 2015 systematic review and meta-­analysis of 18 RCTs compared the effect of exercise interventions against a control group for the treatment of BPSD, utilizing 10 behavioral and 2 neurovegetative components of the NPI (each scored from 0 to 5) in patients with dementia. Studies were included if they used ≥ 1 exercise intervention compared to a control or usual care group without additional exercise recommendations. Thirteen studies had a multicomponent training intervention (≥ 2 exercise types grouped together in the same training session), 2 used tai chi, 4 used walking, and 1 used dance and movement therapy. These RCTs were conducted in a variety of settings, including community-dwelling and long-term care facilities (n = 6427 patients).²

Exercise did not reduce global BPSD (N = 4441 patients), with a weighted mean difference (WMD) of −3.9 (95% CI, −9.0 to 1.2; P = .13). Exploratory analysis did not show improvement in aberrant motor behavior with exercise (WMD = –0.55; 95% CI, –1.10 to 0.001; P = .05). Limitations of this review included the small number of studies, heterogeneity of the population, and limitations in data accessibility.²

A 2017 hospital-based RCT evaluated the effects of a short-term exercise program on neuropsychiatric signs and symptoms in patients with dementia in 3 specialized dementia care wards (N = 85). Patients had a diagnosis of dementia, minimum length of stay of 1 week, no delirium, and the ability to perform the Timed Up and Go Test. The intervention group included a 2-week exercise program of four 20-minute exercise sessions per day on 3 days per week, involving strengthening or endurance exercises, in addition to treatment as usual. The control group included a 2-week period of social-stimulation programs consisting of table games for 120 minutes per week, in addition to treatment as usual.³

Exercise remains a small tool to address a big problem.

Of 85 patients randomized, 15 (18%) were lost to follow-up (14 of whom were discharged early from the hospital). Among the 70 patients included in the final analysis, the mean age was 80 years; 47% were female and 53% male; and the mean Mini-Mental Status Examination score was 18.3 (≤ 23 indicates dementia). In both groups, most patients had moderate dementia, moderate neuropsychiatric signs and symptoms, and a low level of psychotic symptoms. Patients in the intervention group had a higher adherence rate compared with those in the control group.³

Continue to: The primary outcome...

The primary outcome was neuropsychiatric signs and symptoms as measured by the Alzheimer’s Disease Cooperative Study–­Clinical Global Impression of Change (ADCS-CGIC). Compared to the control group, the intervention group experienced greater improvement on the ADCS-CGIC dimensions of emotional agitation (SMD = –0.9; P < .001), lability (SMD = –1.1; P < .001), psychomotor agitation (SMD = –0.7; P = .01), and verbal aggression (SMD = –0.5; P = .04). However, there were no differences between groups in the physical aggression dimension. Trial limitations included potential impact of the drop-out rate and possible blinding issues, as nursing staff performing assessments could have seen to which group a patient was allocated.³

A 2016 factorial cluster RCT of 16 nursing homes (with at least 60% of the population having dementia) compared the use of ­person-centered care vs person-centered care plus at least 1 randomly assigned additional intervention (eg, antipsychotic medication use review, social interaction interventions, and exercise over a period of 9 months) (n = 277, with 193 analyzed per protocol). Exercise was implemented at 1 hour per week or at an increase of 20% above baseline and compared with a control group with no change in exercise.⁴

Exercise significantly improved neuropsychiatric symptoms. The baseline NPI score of 14.54 improved by –3.59 (95% CI, –7.08 to –0.09; P < .05). However, none of the study interventions significantly improved the agitation-specific scores. The primary limitation of this study was that antipsychotic prescribing was at the discretion of the provider and not according to a protocol. In addition, the authors noted that the trial was inadequately powered to correct for testing 3 primary outcomes.⁴

Editor’s takeaway

Dementia and dementia with agitation are challenging conditions to treat. Disappointingly, physical exercise had inconsistent and generally minimal effect on agitation in dementia. Nevertheless, exercise had other positive effects. So, considering the benefits that exercise does provide, its low cost, and its limited adverse effects, exercise remains a small tool to address a big problem.

Key clinical point: In patients with germline BRCA1/2-wildtype metastatic triple-negative breast cancer (TNBC) with a BRCA-like phenotype, cisplatin plus veliparib significantly improved progression-free survival (PFS) without causing any unprecedented adverse events.

Major finding: PFS was significantly improved with cisplatin+veliparib vs cisplatin+placebo (hazard ratio 0.57; log-rank P  =  .01) in patients with BRCA-like TNBC, but not in germline BRCA1/2-mutated (P  =  .54) and non-BRCA-like (P  =  .57) groups. No new toxicity signals were observed.

Study details: Findings are from the phase 2 S1416 study including 320 patients with metastatic TNBC (n = 305) or estrogen receptor (ER)-positive/progesterone receptor (PR)-positive/both ER and PR positive, human epidermal growth factor receptor 2-negative BC (n = 15) who were randomly assigned to receive cisplatin with either veliparib or placebo.

Disclosures: This study was funded by the US National Cancer Institute and other sources. Some authors declared receiving grants, payments, or honoraria from; serving on advisory boards for; or having other financial or non-financial ties with several sources.

Source: Rodler E et al. Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2023 (Jan 6). Doi: 10.1016/S1470-2045(22)00739-2

Key clinical point: In patients with germline BRCA1/2-wildtype metastatic triple-negative breast cancer (TNBC) with a BRCA-like phenotype, cisplatin plus veliparib significantly improved progression-free survival (PFS) without causing any unprecedented adverse events.

Major finding: PFS was significantly improved with cisplatin+veliparib vs cisplatin+placebo (hazard ratio 0.57; log-rank P  =  .01) in patients with BRCA-like TNBC, but not in germline BRCA1/2-mutated (P  =  .54) and non-BRCA-like (P  =  .57) groups. No new toxicity signals were observed.

Study details: Findings are from the phase 2 S1416 study including 320 patients with metastatic TNBC (n = 305) or estrogen receptor (ER)-positive/progesterone receptor (PR)-positive/both ER and PR positive, human epidermal growth factor receptor 2-negative BC (n = 15) who were randomly assigned to receive cisplatin with either veliparib or placebo.

Disclosures: This study was funded by the US National Cancer Institute and other sources. Some authors declared receiving grants, payments, or honoraria from; serving on advisory boards for; or having other financial or non-financial ties with several sources.

Source: Rodler E et al. Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2023 (Jan 6). Doi: 10.1016/S1470-2045(22)00739-2

Key clinical point: In patients with germline BRCA1/2-wildtype metastatic triple-negative breast cancer (TNBC) with a BRCA-like phenotype, cisplatin plus veliparib significantly improved progression-free survival (PFS) without causing any unprecedented adverse events.

Major finding: PFS was significantly improved with cisplatin+veliparib vs cisplatin+placebo (hazard ratio 0.57; log-rank P  =  .01) in patients with BRCA-like TNBC, but not in germline BRCA1/2-mutated (P  =  .54) and non-BRCA-like (P  =  .57) groups. No new toxicity signals were observed.

Study details: Findings are from the phase 2 S1416 study including 320 patients with metastatic TNBC (n = 305) or estrogen receptor (ER)-positive/progesterone receptor (PR)-positive/both ER and PR positive, human epidermal growth factor receptor 2-negative BC (n = 15) who were randomly assigned to receive cisplatin with either veliparib or placebo.

Disclosures: This study was funded by the US National Cancer Institute and other sources. Some authors declared receiving grants, payments, or honoraria from; serving on advisory boards for; or having other financial or non-financial ties with several sources.

Source: Rodler E et al. Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2023 (Jan 6). Doi: 10.1016/S1470-2045(22)00739-2

Key clinical point: Women with invasive breast cancer (BC) who have germline pathogenic variants (PV) in BRCA1, BRCA2, CHEK2, or PALB2 have 2-3 times higher risk for contralateral BC than those without these PVs.

Major finding: The overall risk for contralateral BC was significantly elevated in all women with germline PV in BRCA1 (hazard ratio [HR] 2.7; P < .001), BRCA2 (HR 3.0; P < .001), and CHEK2 (HR 1.9; P  =  .03), and in the subset of women with estrogen receptor-negative BC and germline PV in PALB2 (HR 2.9; P  =  .006).

Study details: Findings are from an analysis of the CARRIERS study including 15,104 women with invasive BC who underwent ipsilateral surgery.

Disclosures: This study was supported by US National Institutes of Health grants and other sources. The authors declared serving as consultants or advisors and on speakers’ bureaus; receiving research funding, travel, accommodation expenses, or honoraria; and having other ties with several sources.

Source: Yadav S, Boddicker NJ, et al. Contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2. J Clin Oncol. 2023 (Jan 9). Doi: 10.1200/JCO.22.01239

Key clinical point: Women with invasive breast cancer (BC) who have germline pathogenic variants (PV) in BRCA1, BRCA2, CHEK2, or PALB2 have 2-3 times higher risk for contralateral BC than those without these PVs.

Major finding: The overall risk for contralateral BC was significantly elevated in all women with germline PV in BRCA1 (hazard ratio [HR] 2.7; P < .001), BRCA2 (HR 3.0; P < .001), and CHEK2 (HR 1.9; P  =  .03), and in the subset of women with estrogen receptor-negative BC and germline PV in PALB2 (HR 2.9; P  =  .006).

Study details: Findings are from an analysis of the CARRIERS study including 15,104 women with invasive BC who underwent ipsilateral surgery.

Disclosures: This study was supported by US National Institutes of Health grants and other sources. The authors declared serving as consultants or advisors and on speakers’ bureaus; receiving research funding, travel, accommodation expenses, or honoraria; and having other ties with several sources.

Source: Yadav S, Boddicker NJ, et al. Contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2. J Clin Oncol. 2023 (Jan 9). Doi: 10.1200/JCO.22.01239

Key clinical point: Women with invasive breast cancer (BC) who have germline pathogenic variants (PV) in BRCA1, BRCA2, CHEK2, or PALB2 have 2-3 times higher risk for contralateral BC than those without these PVs.

Major finding: The overall risk for contralateral BC was significantly elevated in all women with germline PV in BRCA1 (hazard ratio [HR] 2.7; P < .001), BRCA2 (HR 3.0; P < .001), and CHEK2 (HR 1.9; P  =  .03), and in the subset of women with estrogen receptor-negative BC and germline PV in PALB2 (HR 2.9; P  =  .006).

Study details: Findings are from an analysis of the CARRIERS study including 15,104 women with invasive BC who underwent ipsilateral surgery.

Disclosures: This study was supported by US National Institutes of Health grants and other sources. The authors declared serving as consultants or advisors and on speakers’ bureaus; receiving research funding, travel, accommodation expenses, or honoraria; and having other ties with several sources.

Source: Yadav S, Boddicker NJ, et al. Contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2. J Clin Oncol. 2023 (Jan 9). Doi: 10.1200/JCO.22.01239

SAN FRANCISCO – Patients with refractory advanced gastroesophageal cancer (AGOC) have a poor prognosis, with limited options following failure of second-line therapy. New data showing improved survival suggest that regorafenib (Stivarga) may offer a new treatment option in these patients.

“Regorafenib significantly improves survival compared with placebo in patients with refractory AGOC, delaying deterioration in global quality of life,” said lead author Nick Pavlakis, PhD, MBBS, Royal North Shore Hospital, St. Leonards, Australia. “There were also no new toxicity signals.”

He emphasized that benefit was consistent in all preplanned subgroups. “This offers a new treatment option in this setting,” Dr. Pavlakis said.

He presented the findings at the ASCO Gastrointestinal Cancers Symposium 2023.

Regorafenib is an oral multikinase inhibitor targeting kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-beta, FGFR), and oncogenesis (RAF, RET, and KIT). It is already approved for several indications including metastatic colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma. 

AGOC could be a new indication for the drug. Use in this patient population was explored in an earlier trial, Dr. Pavlakis commented.

“We previously demonstrated the regorafenib prolonged progression-free survival in the INTEGRATE phase 2 trial,” he said. “Based on those results, we undertook the phase 3 INTEGRATE II study. The goal was to examine if regorafenib improves overall survival after failure of at least two lines of treatment.”

However, Dr. Pavlakis noted that during the conduct of this study, there was a change of practice in gastric cancer. “There was an evolution of new evidence in support of additional chemotherapy and immune checkpoint inhibitors such as nivolumab, and very interesting data on the combination of nivolumab and regorafenib from a study being conducted in Japan. So we amended the protocol and evolved the INTEGRATE II to INTEGRATE IIa, to continue evaluating regorafenib versus placebo, and then to evolve to the INTEGRATE IIb study to evaluate regorafenib plus nivolumab versus chemotherapy,” he explained.

The results he presented at the meeting came from the phase 3 INTEGRATE II part of this trial. The other part of the trial, INTEGRATE IIb, is still accruing.

A total of 251 patients were enrolled from five countries and stratified by tumor location, geographic location (Asia vs. “rest of the world”), and prior treatment with VEGF inhibitors.

The cohort was randomly assigned to receive 160 mg regorafenib and best supportive care or placebo plus BSC.

After 238 events, the overall survival hazard ratio was 0.68. “The survival benefit of regorafenib was best observed in the 12-month survival of 19% versus 6%,” said Pavlakis.

The median overall survival for regorafenib versus placebo was 4.5 versus 4.0 months (HR, 0.70; P = .011).

After preplanned adjustment for multiplicity, there were no statistically significant differences across regions (Asia vs. non-Asia) or other prespecified subgroups.

In the pooled analysis, which included study populations from both the INTEGRATE and INTEGRATE IIa populations, the median overall survival was 5.0 versus 4.1 (HR, 0.70; P = .001).  

Regorafenib also improved progression-free survival (median PFS, 1.8 vs. 1.6 months; HR, 0.52; P < .0001) and it delayed deterioration in global quality of life as compared with placebo (P = .0043).

Toxicity was similar to that previously reported in other studies, and adverse events were mostly grade 1 and 2.
 

A building block?

In a comment, Pamela Kunz, MD, director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center, New Haven, Conn., said that she would consider the results with regorafenib in this setting as statistically significant, but with questionable clinical significance.

“The median overall survival difference 0.5 months or about 2 weeks is very modest, especially when taking into consideration the side effect profile,” she said. “I think that regorafenib as a building block for the additional phase 3 study is more interesting.”

“There is data that suggests synergy between VEGF inhibitors and immune checkpoint inhibitors, so I am eager to see the results of INEGRATE IIb [exploring regorafenib use with nivolumab],” Dr. Kunz added.

The study is sponsored by the Australasian Gastro-Intestinal Trials Group. Dr. Pavlakis reported relationships with Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda. Dr. Kunz reported relationships with Ipsen, Novartis (Advanced Accelerator Applications), Genentech/Roche, Amgen, Crinetics Pharmaceuticals, Natera, HUTCHMED, and Isotope Technologies Munich.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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

SAN FRANCISCO – Patients with refractory advanced gastroesophageal cancer (AGOC) have a poor prognosis, with limited options following failure of second-line therapy. New data showing improved survival suggest that regorafenib (Stivarga) may offer a new treatment option in these patients.

“Regorafenib significantly improves survival compared with placebo in patients with refractory AGOC, delaying deterioration in global quality of life,” said lead author Nick Pavlakis, PhD, MBBS, Royal North Shore Hospital, St. Leonards, Australia. “There were also no new toxicity signals.”

He emphasized that benefit was consistent in all preplanned subgroups. “This offers a new treatment option in this setting,” Dr. Pavlakis said.

He presented the findings at the ASCO Gastrointestinal Cancers Symposium 2023.

Regorafenib is an oral multikinase inhibitor targeting kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-beta, FGFR), and oncogenesis (RAF, RET, and KIT). It is already approved for several indications including metastatic colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma. 

AGOC could be a new indication for the drug. Use in this patient population was explored in an earlier trial, Dr. Pavlakis commented.

“We previously demonstrated the regorafenib prolonged progression-free survival in the INTEGRATE phase 2 trial,” he said. “Based on those results, we undertook the phase 3 INTEGRATE II study. The goal was to examine if regorafenib improves overall survival after failure of at least two lines of treatment.”

However, Dr. Pavlakis noted that during the conduct of this study, there was a change of practice in gastric cancer. “There was an evolution of new evidence in support of additional chemotherapy and immune checkpoint inhibitors such as nivolumab, and very interesting data on the combination of nivolumab and regorafenib from a study being conducted in Japan. So we amended the protocol and evolved the INTEGRATE II to INTEGRATE IIa, to continue evaluating regorafenib versus placebo, and then to evolve to the INTEGRATE IIb study to evaluate regorafenib plus nivolumab versus chemotherapy,” he explained.

The results he presented at the meeting came from the phase 3 INTEGRATE II part of this trial. The other part of the trial, INTEGRATE IIb, is still accruing.

A total of 251 patients were enrolled from five countries and stratified by tumor location, geographic location (Asia vs. “rest of the world”), and prior treatment with VEGF inhibitors.

The cohort was randomly assigned to receive 160 mg regorafenib and best supportive care or placebo plus BSC.

After 238 events, the overall survival hazard ratio was 0.68. “The survival benefit of regorafenib was best observed in the 12-month survival of 19% versus 6%,” said Pavlakis.

The median overall survival for regorafenib versus placebo was 4.5 versus 4.0 months (HR, 0.70; P = .011).

After preplanned adjustment for multiplicity, there were no statistically significant differences across regions (Asia vs. non-Asia) or other prespecified subgroups.

In the pooled analysis, which included study populations from both the INTEGRATE and INTEGRATE IIa populations, the median overall survival was 5.0 versus 4.1 (HR, 0.70; P = .001).  

Regorafenib also improved progression-free survival (median PFS, 1.8 vs. 1.6 months; HR, 0.52; P < .0001) and it delayed deterioration in global quality of life as compared with placebo (P = .0043).

Toxicity was similar to that previously reported in other studies, and adverse events were mostly grade 1 and 2.
 

A building block?

In a comment, Pamela Kunz, MD, director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center, New Haven, Conn., said that she would consider the results with regorafenib in this setting as statistically significant, but with questionable clinical significance.

“The median overall survival difference 0.5 months or about 2 weeks is very modest, especially when taking into consideration the side effect profile,” she said. “I think that regorafenib as a building block for the additional phase 3 study is more interesting.”

“There is data that suggests synergy between VEGF inhibitors and immune checkpoint inhibitors, so I am eager to see the results of INEGRATE IIb [exploring regorafenib use with nivolumab],” Dr. Kunz added.

The study is sponsored by the Australasian Gastro-Intestinal Trials Group. Dr. Pavlakis reported relationships with Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda. Dr. Kunz reported relationships with Ipsen, Novartis (Advanced Accelerator Applications), Genentech/Roche, Amgen, Crinetics Pharmaceuticals, Natera, HUTCHMED, and Isotope Technologies Munich.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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

SAN FRANCISCO – Patients with refractory advanced gastroesophageal cancer (AGOC) have a poor prognosis, with limited options following failure of second-line therapy. New data showing improved survival suggest that regorafenib (Stivarga) may offer a new treatment option in these patients.

“Regorafenib significantly improves survival compared with placebo in patients with refractory AGOC, delaying deterioration in global quality of life,” said lead author Nick Pavlakis, PhD, MBBS, Royal North Shore Hospital, St. Leonards, Australia. “There were also no new toxicity signals.”

He emphasized that benefit was consistent in all preplanned subgroups. “This offers a new treatment option in this setting,” Dr. Pavlakis said.

He presented the findings at the ASCO Gastrointestinal Cancers Symposium 2023.

Regorafenib is an oral multikinase inhibitor targeting kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-beta, FGFR), and oncogenesis (RAF, RET, and KIT). It is already approved for several indications including metastatic colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma. 

AGOC could be a new indication for the drug. Use in this patient population was explored in an earlier trial, Dr. Pavlakis commented.

“We previously demonstrated the regorafenib prolonged progression-free survival in the INTEGRATE phase 2 trial,” he said. “Based on those results, we undertook the phase 3 INTEGRATE II study. The goal was to examine if regorafenib improves overall survival after failure of at least two lines of treatment.”

However, Dr. Pavlakis noted that during the conduct of this study, there was a change of practice in gastric cancer. “There was an evolution of new evidence in support of additional chemotherapy and immune checkpoint inhibitors such as nivolumab, and very interesting data on the combination of nivolumab and regorafenib from a study being conducted in Japan. So we amended the protocol and evolved the INTEGRATE II to INTEGRATE IIa, to continue evaluating regorafenib versus placebo, and then to evolve to the INTEGRATE IIb study to evaluate regorafenib plus nivolumab versus chemotherapy,” he explained.

The results he presented at the meeting came from the phase 3 INTEGRATE II part of this trial. The other part of the trial, INTEGRATE IIb, is still accruing.

A total of 251 patients were enrolled from five countries and stratified by tumor location, geographic location (Asia vs. “rest of the world”), and prior treatment with VEGF inhibitors.

The cohort was randomly assigned to receive 160 mg regorafenib and best supportive care or placebo plus BSC.

After 238 events, the overall survival hazard ratio was 0.68. “The survival benefit of regorafenib was best observed in the 12-month survival of 19% versus 6%,” said Pavlakis.

The median overall survival for regorafenib versus placebo was 4.5 versus 4.0 months (HR, 0.70; P = .011).

After preplanned adjustment for multiplicity, there were no statistically significant differences across regions (Asia vs. non-Asia) or other prespecified subgroups.

In the pooled analysis, which included study populations from both the INTEGRATE and INTEGRATE IIa populations, the median overall survival was 5.0 versus 4.1 (HR, 0.70; P = .001).  

Regorafenib also improved progression-free survival (median PFS, 1.8 vs. 1.6 months; HR, 0.52; P < .0001) and it delayed deterioration in global quality of life as compared with placebo (P = .0043).

Toxicity was similar to that previously reported in other studies, and adverse events were mostly grade 1 and 2.
 

A building block?

In a comment, Pamela Kunz, MD, director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center, New Haven, Conn., said that she would consider the results with regorafenib in this setting as statistically significant, but with questionable clinical significance.

“The median overall survival difference 0.5 months or about 2 weeks is very modest, especially when taking into consideration the side effect profile,” she said. “I think that regorafenib as a building block for the additional phase 3 study is more interesting.”

“There is data that suggests synergy between VEGF inhibitors and immune checkpoint inhibitors, so I am eager to see the results of INEGRATE IIb [exploring regorafenib use with nivolumab],” Dr. Kunz added.

The study is sponsored by the Australasian Gastro-Intestinal Trials Group. Dr. Pavlakis reported relationships with Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda. Dr. Kunz reported relationships with Ipsen, Novartis (Advanced Accelerator Applications), Genentech/Roche, Amgen, Crinetics Pharmaceuticals, Natera, HUTCHMED, and Isotope Technologies Munich.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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

This transcript has been edited for clarity.

Robert D. Glatter, MD: Welcome. I’m Dr Robert Glatter, medical adviser for Medscape Emergency Medicine. Today, we have Dr. Paul Pepe, an emergency physician and highly recognized expert in EMS, critical care, and resuscitation, along with Ryan Quinn, EMS chief for Edina Fire Department in Edina, Minn., joining us to discuss a significant advance in resuscitation for patients with nonshockable rhythms in cardiac arrest with a remarkable increase in neurologically intact survival. Welcome, gentlemen.

Dr. Pepe, I’d like to start off by thanking you for taking time to join us to discuss this novel concept of head-up or what you now refer to as a neuroprotective cardiopulmonary resuscitation (CPR) bundle. Can you define what this entails and why it is referred to as a neuroprotective CPR bundle?

Paul E. Pepe, MD, MPH: CPR has been life saving for 60 years the way we’ve performed it, but probably only in a very small percentage of cases. That’s one of the problems. We have almost a thousand people a day who have sudden cardiac arrest out in the community alone and more in the hospital.

We know that early defibrillation and early CPR can contribute, but it’s still a small percentage of those. About 75%-85% of the cases that we go out to see will have nonshockable rhythms and flatlines. Some cases are what we call “pulseless electrical activity,” meaning that it looks like there is some kind of organized complex, but there is no pulse associated with it.

That’s why it’s a problem, because they don’t come back. Part of the reason why we see poor outcomes is not only that these cases tend to be people who, say, were in ventricular fibrillation and then just went on over time and were not witnessed or resuscitated or had a long response time. They basically either go into flatline or autoconvert into these bizarre rhythms.

The other issue is the way we perform CPR. CPR has been lifesaving, but it only generates about 20% and maybe 15% in some cases of normal blood flow, and particularly, cerebral perfusion pressure. We’ve looked at this nicely in the laboratory.

For example, during chest compressions, we’re hoping during the recoil phase to pull blood down and back into the right heart. The problem is that you’re not only setting a pressure rate up here to the arterial side but also, you’re setting back pressure wave on the venous side. Obviously, the arterial side always wins out, but it’s just not as efficient as it could be, at 20% or 30%.

What does this entail? It entails several independent mechanisms in terms of how they work, but they all do the same thing, which is they help to pull blood out of the brain and back into the right heart by basically manipulating intrathoracic pressure and creating more of a vacuum to get blood back there.

It’s so important that people do quality CPR. You have to have a good release and that helps us suck a little bit of blood and sucks the air in. As soon as the air rushes in, it neutralizes the pressure and there’s no more vacuum and nothing else is happening until the next squeeze.

What we have found is that we can cap the airway just for a second with a little pop-up valve. It acts like when you’re sucking a milkshake through a straw and it creates more of a vacuum in the chest. Just a little pop-up valve that pulls a little bit more blood out of the brain and the rest of the body and into the right heart.

We’ve shown in a human study that, for example, the systolic blood pressure almost doubles. It really goes from 40 mm Hg during standard CPR up to 80 mm Hg, and that would be sustained for 14-15 minutes. That was a nice little study that was done in Milwaukee a few years ago.

The other thing that happens is, if you add on something else, it’s like a toilet plunger. I think many people have seen it; it’s called “active compression-decompression.” It not only compresses, but it decompresses. Where it becomes even more effective is that if you had broken bones or stiff bones as you get older or whatever it may be, as you do the CPR, you’re still getting the push down and then you’re getting the pull out. It helps on several levels. More importantly, when you put the two together, they’re very synergistic.

We, have already done the clinical trial that is the proof of concept, and that was published in The Lancet about 10 years ago. In that study, we found that the combination of those two dramatically improved survival rates by 50%, with 1-year survival neurologically intact. That got us on the right track.

The interesting thing is that someone said, “Can we lift the head up a little bit?” We did a large amount of work in the laboratory over 10 years, fine tuning it. When do you first lift the head? How soon is too soon? It’s probably bad if you just go right to it.

We had to get the pump primed a little bit with these other things to get the flow going better, not only pulling blood out of the brain but now, you have a better flow this way. You have to prime at first for a couple of minutes, and we worked out the timing: Is it 3 or 4 minutes? It seems the timing is right at about 2 minutes, then you gradually elevate the head over about 2 minutes. We’re finding that seems to be the optimal way to do it. About 2 minutes of priming with those other two devices, the adjuncts, and then gradually elevate the head over 2 minutes.

When we do that in the laboratory, we’re getting normalized cerebral perfusion pressures. You’re normalizing the flow back again with that. We’re seeing profound differences in outcome as a result, even in these cases of the nonshockables.
 

Dr. Glatter: What you’re doing basically is resulting in an increase in cardiac output, essentially. That really is important, especially in these nonshockable rhythms, correct?

Dr. Pepe: Absolutely. As you’re doing this compression and you’re getting these intracranial pulse waves that are going up because they’re colliding up there. It could be even damaging in itself, but we’re seeing these intracranial raises. The intracranial pressure starts going up more and more over time. Also, peripherally in most people, you’re not getting good flow out there; then, your vasculature starts to relax. The arterials are starting to not get oxygen, so they don’t go out.

With this technique where we’re returning the pressure, we’re getting to 40% of normal now with the active compression-decompression CPR plus an impedance threshold device (ACD+ITD CPR) approach. Now, you add this, and you’re almost normalizing. In humans, even in these asystole patients, we’re seeing end-title CO₂s which are generally in the 15-20 range with standard CPR are now up with ACD+ITD CPR in the 30%-40% range, where we’re getting through 30 or 40 end-tidal CO₂s. Now, we’re seeing even the end-tidal CO₂s moving up into the 40s and 50s. We know there’s a surrogate marker telling us that we are generating much better flows not only to the rest of the body, but most importantly, to the brain.
 

Dr. Glatter: Ryan, could you tell us about the approach in terms of on scene, what you’re doing and how you use the device itself? Maybe you could talk about the backpack that you developed with your fire department?

Ryan P. Quinn, BS, EMS: Our approach has always been to get to the patient quickly, like everybody’s approach on a cardiac arrest when you’re responding. We are an advanced life-support paramedic ambulance service through the fire department – we’re all cross-trained firefighter paramedics. Our first vehicle from the fire department is typically the ambulance. It’s smaller and a little quicker than the fire engine. Two paramedics are going to jump out with two backpacks. One has the automated compressive device (we use the Lucas), and the other one is the sequential patient lifting device, the EleGARD.

Our two paramedics are quick to the patient’s side, and once they make contact with the patient to verify pulseless cardiac arrest, they will unpack. One person will go right to compressions if there’s nobody on compressions already. Sometimes we have a first responder police officer with an automated external defibrillator (AED). We go right to the patient’s side, concentrate on compressions, and within 90 seconds to 2 minutes, we have our bags unpacked, we’ve got the devices turned on, patient lifted up, slid under the device, and we have a supraglottic airway that is placed within 15 seconds already premade with the ITD on top. We have a sealed airway that we can continue to compress with Dr. Pepe’s original discussion of building on what’s previously been shown to work.

Dr. Pepe: Let me make a comment about this. This is so important, what Ryan is saying, because it’s something we found during the study. It’s really a true pit-crew approach. You’re not only getting these materials, which you think you need a medical Sherpa for, but you don’t. They set it up and then when they open it up, it’s all laid out just exactly as you need it. It’s not just how fast you get there; it’s how fast you get this done.

When we look at all cases combined against high-performance systems that had some of the highest survival rates around, when we compare it to those, we found that overall, even if you looked at the ones that had over 20-minute responses, the odds ratios were still three to four times higher. It was impressive.

If you looked at it under 15 minutes, which is really reasonable for most systems that get there by the way, the average time that people start CPR in any system in these studies has been about 8 minutes if you actually start this thing, which takes about 2 minutes more for this new bundle of care with this triad, it’s almost 12-14 times higher in terms of the odds ratio. I’ve never seen anything like that where the higher end is over 100 in terms of your confidence intervals.

Ryan’s system did really well and is one of those with even higher levels of outcomes, mostly because they got it on quickly. It’s like the AED for nonshockables but better because you have a wider range of efficacy where it will work.
 

Dr. Glatter: When the elapsed time was less than 11 minutes, that seemed to be an inflection point in the study, is that correct? You saw that 11-fold higher incidence in terms of neurologically intact survival, is that correct?

Dr. Pepe: We picked that number because that was the median time to get it on board. Half the people were getting it within that time period. The fact that you have a larger window, we’re talking about 13- almost 14-fold improvements in outcome if it was under 15 minutes. It doesn’t matter about the 11 or the 12. It’s the faster you get it on board, the better off you are.

Dr. Glatter: What’s the next step in the process of doing trials and having implementation on a larger scale based on your Annals of Emergency Medicine study? Where do you go from here?

Dr. Pepe: I’ve come to find out there are many confounding variables. What was the quality of CPR? How did people ventilate? Did they give the breath and hold it? Did they give a large enough breath so that blood can go across the transpulmonary system? There are many confounding variables. That’s why I think, in the future, it’s going to be more of looking at things like propensity score matching because we know all the variables that change outcomes. I think that’s going to be a way for me.

The other thing is that we were looking at only 380 cases here. When this doubles up in numbers, as we accrue more cases around the country of people who are implementing this, these numbers I just quoted are going to go up much higher. Unwitnessed asystole is considered futile, and you just don’t get them back. To be able to get these folks back now, even if it’s a small percentage, and the fact that we know that we’re producing this better flow, is pretty striking.

I’m really impressed, and the main thing is to make sure people are educated about it. Number two is that they understand that it has to be done right. It cannot be done wrong or you’re not going to see the differences. Getting it done right is not only following the procedures, the sequence, and how you do it, but it also has to do with getting there quickly, including assigning the right people to put it on and having well-trained people who know what they’re doing.
 

Dr. Glatter: In general, the lay public obviously should not attempt this in the field lifting someone’s head up in the sense of trying to do chest compressions. I think that message is important that you just said. It’s not ready for prime time yet in any way. It has to be done right.

Dr. Pepe: Bystanders have to learn CPR – they will buy us time and we’ll have better outcomes when they do that. That’s number one. Number two is that as more and more systems adopt this, you’re going to see more people coming back. If you think about what we’re doing now, if we only get back 5% of these nonshockable vs. less than 1%, it’s 5% of 800 people a day because a thousand people a day die. Several dozens of lives can be saved on a daily basis, coming back neurologically intact. That’s the key thing.

Dr. Glatter: Ryan, can you comment about your experience in the field? Is there anything in terms of your current approach that you think would be ideal to change at this point?

Mr. Quinn: We’ve established that this is the approach that we want to take and we’re just fine tuning it to be more efficient. Using the choreography of which person is going to do which role, we have clearly defined roles and clearly defined command of the scene so we’re not missing anything. Training is extremely important.

Dr. Glatter: Paul, I want to ask you about your anecdotal experience of people waking up quickly and talking after elevating their heads and going through this process. Having people talk about it and waking up is really fascinating. Maybe you can comment further on this.

Dr. Pepe: That’s a great point that you bring up because a 40- to 50-year-old guy who got saved with this approach, when he came around, he said he was hearing what people were saying. When he came out of it, he found out he had been getting CPR for about 25 minutes because he had persistent recurring ventricular fibrillation. He said, “How could I have survived that that long?”

When we told him about the new approach, he added, “Well, that’s like neuroprotective.” He’s right, because in the laboratory, we showed it was neuroprotective and we’re also getting better flows back there. It goes along with everything else, and so we’ve adopted the name because it is.

These are really high-powered systems we are comparing against, and we have the same level of return of spontaneous circulation. The major difference was when you started talking about the neurointact survival. We don’t have enough numbers yet, but next go around, we’re going to look at cerebral performance category (CPC) – CPC1 vs. the CPC2 – which were both considered intact, but CPC1 is actually better. We’re seeing many more of those, anecdotally.

I also wanted to mention that people do bring this up and say, “Well, let’s do a trial.” As far as we’re concerned, the trial’s been done in terms of The Lancet study 10 years ago that showed that the active compression-decompression had tremendously better outcomes. We show in the laboratories that you augment that a little bit. These are all [Food and Drug Administration] approved. You can go out and buy it tomorrow and get it done. I have no conflicts of interest, by the way, with any of this.

To have this device that’s going to have the potential of saving so many more lives is really an exciting breakthrough. More importantly, we’re understanding more now about the physiology of CPR and why it works. It could work much better with the approaches that we’ve been developing over the last 20 years or so.

Dr. Glatter: Absolutely. I want to thank both of you gentlemen. It’s been really an incredible experience to learn more about an advance in resuscitation that could truly be lifesaving. Thank you again for taking time to join us.

Dr. Glatter is an attending physician in the department of emergency medicine, Lenox Hill Hospital, New York. Dr. Pepe is professor, department of management, policy, and community health, University of Texas Health Sciences Center, Houston. Mr. Quinn is EMS Chief, Edina (Minn.) Fire Department. No conflicts of interest were reported.

A version of this article first appeared Jan. 26 on Medscape.com.

This transcript has been edited for clarity.

Robert D. Glatter, MD: Welcome. I’m Dr Robert Glatter, medical adviser for Medscape Emergency Medicine. Today, we have Dr. Paul Pepe, an emergency physician and highly recognized expert in EMS, critical care, and resuscitation, along with Ryan Quinn, EMS chief for Edina Fire Department in Edina, Minn., joining us to discuss a significant advance in resuscitation for patients with nonshockable rhythms in cardiac arrest with a remarkable increase in neurologically intact survival. Welcome, gentlemen.

Dr. Pepe, I’d like to start off by thanking you for taking time to join us to discuss this novel concept of head-up or what you now refer to as a neuroprotective cardiopulmonary resuscitation (CPR) bundle. Can you define what this entails and why it is referred to as a neuroprotective CPR bundle?

Paul E. Pepe, MD, MPH: CPR has been life saving for 60 years the way we’ve performed it, but probably only in a very small percentage of cases. That’s one of the problems. We have almost a thousand people a day who have sudden cardiac arrest out in the community alone and more in the hospital.

We know that early defibrillation and early CPR can contribute, but it’s still a small percentage of those. About 75%-85% of the cases that we go out to see will have nonshockable rhythms and flatlines. Some cases are what we call “pulseless electrical activity,” meaning that it looks like there is some kind of organized complex, but there is no pulse associated with it.

That’s why it’s a problem, because they don’t come back. Part of the reason why we see poor outcomes is not only that these cases tend to be people who, say, were in ventricular fibrillation and then just went on over time and were not witnessed or resuscitated or had a long response time. They basically either go into flatline or autoconvert into these bizarre rhythms.

The other issue is the way we perform CPR. CPR has been lifesaving, but it only generates about 20% and maybe 15% in some cases of normal blood flow, and particularly, cerebral perfusion pressure. We’ve looked at this nicely in the laboratory.

For example, during chest compressions, we’re hoping during the recoil phase to pull blood down and back into the right heart. The problem is that you’re not only setting a pressure rate up here to the arterial side but also, you’re setting back pressure wave on the venous side. Obviously, the arterial side always wins out, but it’s just not as efficient as it could be, at 20% or 30%.

What does this entail? It entails several independent mechanisms in terms of how they work, but they all do the same thing, which is they help to pull blood out of the brain and back into the right heart by basically manipulating intrathoracic pressure and creating more of a vacuum to get blood back there.

It’s so important that people do quality CPR. You have to have a good release and that helps us suck a little bit of blood and sucks the air in. As soon as the air rushes in, it neutralizes the pressure and there’s no more vacuum and nothing else is happening until the next squeeze.

What we have found is that we can cap the airway just for a second with a little pop-up valve. It acts like when you’re sucking a milkshake through a straw and it creates more of a vacuum in the chest. Just a little pop-up valve that pulls a little bit more blood out of the brain and the rest of the body and into the right heart.

We’ve shown in a human study that, for example, the systolic blood pressure almost doubles. It really goes from 40 mm Hg during standard CPR up to 80 mm Hg, and that would be sustained for 14-15 minutes. That was a nice little study that was done in Milwaukee a few years ago.

The other thing that happens is, if you add on something else, it’s like a toilet plunger. I think many people have seen it; it’s called “active compression-decompression.” It not only compresses, but it decompresses. Where it becomes even more effective is that if you had broken bones or stiff bones as you get older or whatever it may be, as you do the CPR, you’re still getting the push down and then you’re getting the pull out. It helps on several levels. More importantly, when you put the two together, they’re very synergistic.

We, have already done the clinical trial that is the proof of concept, and that was published in The Lancet about 10 years ago. In that study, we found that the combination of those two dramatically improved survival rates by 50%, with 1-year survival neurologically intact. That got us on the right track.

The interesting thing is that someone said, “Can we lift the head up a little bit?” We did a large amount of work in the laboratory over 10 years, fine tuning it. When do you first lift the head? How soon is too soon? It’s probably bad if you just go right to it.

We had to get the pump primed a little bit with these other things to get the flow going better, not only pulling blood out of the brain but now, you have a better flow this way. You have to prime at first for a couple of minutes, and we worked out the timing: Is it 3 or 4 minutes? It seems the timing is right at about 2 minutes, then you gradually elevate the head over about 2 minutes. We’re finding that seems to be the optimal way to do it. About 2 minutes of priming with those other two devices, the adjuncts, and then gradually elevate the head over 2 minutes.

When we do that in the laboratory, we’re getting normalized cerebral perfusion pressures. You’re normalizing the flow back again with that. We’re seeing profound differences in outcome as a result, even in these cases of the nonshockables.
 

Dr. Glatter: What you’re doing basically is resulting in an increase in cardiac output, essentially. That really is important, especially in these nonshockable rhythms, correct?

Dr. Pepe: Absolutely. As you’re doing this compression and you’re getting these intracranial pulse waves that are going up because they’re colliding up there. It could be even damaging in itself, but we’re seeing these intracranial raises. The intracranial pressure starts going up more and more over time. Also, peripherally in most people, you’re not getting good flow out there; then, your vasculature starts to relax. The arterials are starting to not get oxygen, so they don’t go out.

With this technique where we’re returning the pressure, we’re getting to 40% of normal now with the active compression-decompression CPR plus an impedance threshold device (ACD+ITD CPR) approach. Now, you add this, and you’re almost normalizing. In humans, even in these asystole patients, we’re seeing end-title CO₂s which are generally in the 15-20 range with standard CPR are now up with ACD+ITD CPR in the 30%-40% range, where we’re getting through 30 or 40 end-tidal CO₂s. Now, we’re seeing even the end-tidal CO₂s moving up into the 40s and 50s. We know there’s a surrogate marker telling us that we are generating much better flows not only to the rest of the body, but most importantly, to the brain.
 

Dr. Glatter: Ryan, could you tell us about the approach in terms of on scene, what you’re doing and how you use the device itself? Maybe you could talk about the backpack that you developed with your fire department?

Ryan P. Quinn, BS, EMS: Our approach has always been to get to the patient quickly, like everybody’s approach on a cardiac arrest when you’re responding. We are an advanced life-support paramedic ambulance service through the fire department – we’re all cross-trained firefighter paramedics. Our first vehicle from the fire department is typically the ambulance. It’s smaller and a little quicker than the fire engine. Two paramedics are going to jump out with two backpacks. One has the automated compressive device (we use the Lucas), and the other one is the sequential patient lifting device, the EleGARD.

Our two paramedics are quick to the patient’s side, and once they make contact with the patient to verify pulseless cardiac arrest, they will unpack. One person will go right to compressions if there’s nobody on compressions already. Sometimes we have a first responder police officer with an automated external defibrillator (AED). We go right to the patient’s side, concentrate on compressions, and within 90 seconds to 2 minutes, we have our bags unpacked, we’ve got the devices turned on, patient lifted up, slid under the device, and we have a supraglottic airway that is placed within 15 seconds already premade with the ITD on top. We have a sealed airway that we can continue to compress with Dr. Pepe’s original discussion of building on what’s previously been shown to work.

Dr. Pepe: Let me make a comment about this. This is so important, what Ryan is saying, because it’s something we found during the study. It’s really a true pit-crew approach. You’re not only getting these materials, which you think you need a medical Sherpa for, but you don’t. They set it up and then when they open it up, it’s all laid out just exactly as you need it. It’s not just how fast you get there; it’s how fast you get this done.

When we look at all cases combined against high-performance systems that had some of the highest survival rates around, when we compare it to those, we found that overall, even if you looked at the ones that had over 20-minute responses, the odds ratios were still three to four times higher. It was impressive.

If you looked at it under 15 minutes, which is really reasonable for most systems that get there by the way, the average time that people start CPR in any system in these studies has been about 8 minutes if you actually start this thing, which takes about 2 minutes more for this new bundle of care with this triad, it’s almost 12-14 times higher in terms of the odds ratio. I’ve never seen anything like that where the higher end is over 100 in terms of your confidence intervals.

Ryan’s system did really well and is one of those with even higher levels of outcomes, mostly because they got it on quickly. It’s like the AED for nonshockables but better because you have a wider range of efficacy where it will work.
 

Dr. Glatter: When the elapsed time was less than 11 minutes, that seemed to be an inflection point in the study, is that correct? You saw that 11-fold higher incidence in terms of neurologically intact survival, is that correct?

Dr. Pepe: We picked that number because that was the median time to get it on board. Half the people were getting it within that time period. The fact that you have a larger window, we’re talking about 13- almost 14-fold improvements in outcome if it was under 15 minutes. It doesn’t matter about the 11 or the 12. It’s the faster you get it on board, the better off you are.

Dr. Glatter: What’s the next step in the process of doing trials and having implementation on a larger scale based on your Annals of Emergency Medicine study? Where do you go from here?

Dr. Pepe: I’ve come to find out there are many confounding variables. What was the quality of CPR? How did people ventilate? Did they give the breath and hold it? Did they give a large enough breath so that blood can go across the transpulmonary system? There are many confounding variables. That’s why I think, in the future, it’s going to be more of looking at things like propensity score matching because we know all the variables that change outcomes. I think that’s going to be a way for me.

The other thing is that we were looking at only 380 cases here. When this doubles up in numbers, as we accrue more cases around the country of people who are implementing this, these numbers I just quoted are going to go up much higher. Unwitnessed asystole is considered futile, and you just don’t get them back. To be able to get these folks back now, even if it’s a small percentage, and the fact that we know that we’re producing this better flow, is pretty striking.

I’m really impressed, and the main thing is to make sure people are educated about it. Number two is that they understand that it has to be done right. It cannot be done wrong or you’re not going to see the differences. Getting it done right is not only following the procedures, the sequence, and how you do it, but it also has to do with getting there quickly, including assigning the right people to put it on and having well-trained people who know what they’re doing.
 

Dr. Glatter: In general, the lay public obviously should not attempt this in the field lifting someone’s head up in the sense of trying to do chest compressions. I think that message is important that you just said. It’s not ready for prime time yet in any way. It has to be done right.

Dr. Pepe: Bystanders have to learn CPR – they will buy us time and we’ll have better outcomes when they do that. That’s number one. Number two is that as more and more systems adopt this, you’re going to see more people coming back. If you think about what we’re doing now, if we only get back 5% of these nonshockable vs. less than 1%, it’s 5% of 800 people a day because a thousand people a day die. Several dozens of lives can be saved on a daily basis, coming back neurologically intact. That’s the key thing.

Dr. Glatter: Ryan, can you comment about your experience in the field? Is there anything in terms of your current approach that you think would be ideal to change at this point?

Mr. Quinn: We’ve established that this is the approach that we want to take and we’re just fine tuning it to be more efficient. Using the choreography of which person is going to do which role, we have clearly defined roles and clearly defined command of the scene so we’re not missing anything. Training is extremely important.

Dr. Glatter: Paul, I want to ask you about your anecdotal experience of people waking up quickly and talking after elevating their heads and going through this process. Having people talk about it and waking up is really fascinating. Maybe you can comment further on this.

Dr. Pepe: That’s a great point that you bring up because a 40- to 50-year-old guy who got saved with this approach, when he came around, he said he was hearing what people were saying. When he came out of it, he found out he had been getting CPR for about 25 minutes because he had persistent recurring ventricular fibrillation. He said, “How could I have survived that that long?”

When we told him about the new approach, he added, “Well, that’s like neuroprotective.” He’s right, because in the laboratory, we showed it was neuroprotective and we’re also getting better flows back there. It goes along with everything else, and so we’ve adopted the name because it is.

These are really high-powered systems we are comparing against, and we have the same level of return of spontaneous circulation. The major difference was when you started talking about the neurointact survival. We don’t have enough numbers yet, but next go around, we’re going to look at cerebral performance category (CPC) – CPC1 vs. the CPC2 – which were both considered intact, but CPC1 is actually better. We’re seeing many more of those, anecdotally.

I also wanted to mention that people do bring this up and say, “Well, let’s do a trial.” As far as we’re concerned, the trial’s been done in terms of The Lancet study 10 years ago that showed that the active compression-decompression had tremendously better outcomes. We show in the laboratories that you augment that a little bit. These are all [Food and Drug Administration] approved. You can go out and buy it tomorrow and get it done. I have no conflicts of interest, by the way, with any of this.

To have this device that’s going to have the potential of saving so many more lives is really an exciting breakthrough. More importantly, we’re understanding more now about the physiology of CPR and why it works. It could work much better with the approaches that we’ve been developing over the last 20 years or so.

Dr. Glatter: Absolutely. I want to thank both of you gentlemen. It’s been really an incredible experience to learn more about an advance in resuscitation that could truly be lifesaving. Thank you again for taking time to join us.

Dr. Glatter is an attending physician in the department of emergency medicine, Lenox Hill Hospital, New York. Dr. Pepe is professor, department of management, policy, and community health, University of Texas Health Sciences Center, Houston. Mr. Quinn is EMS Chief, Edina (Minn.) Fire Department. No conflicts of interest were reported.

A version of this article first appeared Jan. 26 on Medscape.com.

This transcript has been edited for clarity.

Robert D. Glatter, MD: Welcome. I’m Dr Robert Glatter, medical adviser for Medscape Emergency Medicine. Today, we have Dr. Paul Pepe, an emergency physician and highly recognized expert in EMS, critical care, and resuscitation, along with Ryan Quinn, EMS chief for Edina Fire Department in Edina, Minn., joining us to discuss a significant advance in resuscitation for patients with nonshockable rhythms in cardiac arrest with a remarkable increase in neurologically intact survival. Welcome, gentlemen.

Dr. Pepe, I’d like to start off by thanking you for taking time to join us to discuss this novel concept of head-up or what you now refer to as a neuroprotective cardiopulmonary resuscitation (CPR) bundle. Can you define what this entails and why it is referred to as a neuroprotective CPR bundle?

Paul E. Pepe, MD, MPH: CPR has been life saving for 60 years the way we’ve performed it, but probably only in a very small percentage of cases. That’s one of the problems. We have almost a thousand people a day who have sudden cardiac arrest out in the community alone and more in the hospital.

We know that early defibrillation and early CPR can contribute, but it’s still a small percentage of those. About 75%-85% of the cases that we go out to see will have nonshockable rhythms and flatlines. Some cases are what we call “pulseless electrical activity,” meaning that it looks like there is some kind of organized complex, but there is no pulse associated with it.

That’s why it’s a problem, because they don’t come back. Part of the reason why we see poor outcomes is not only that these cases tend to be people who, say, were in ventricular fibrillation and then just went on over time and were not witnessed or resuscitated or had a long response time. They basically either go into flatline or autoconvert into these bizarre rhythms.

The other issue is the way we perform CPR. CPR has been lifesaving, but it only generates about 20% and maybe 15% in some cases of normal blood flow, and particularly, cerebral perfusion pressure. We’ve looked at this nicely in the laboratory.

For example, during chest compressions, we’re hoping during the recoil phase to pull blood down and back into the right heart. The problem is that you’re not only setting a pressure rate up here to the arterial side but also, you’re setting back pressure wave on the venous side. Obviously, the arterial side always wins out, but it’s just not as efficient as it could be, at 20% or 30%.

What does this entail? It entails several independent mechanisms in terms of how they work, but they all do the same thing, which is they help to pull blood out of the brain and back into the right heart by basically manipulating intrathoracic pressure and creating more of a vacuum to get blood back there.

It’s so important that people do quality CPR. You have to have a good release and that helps us suck a little bit of blood and sucks the air in. As soon as the air rushes in, it neutralizes the pressure and there’s no more vacuum and nothing else is happening until the next squeeze.

What we have found is that we can cap the airway just for a second with a little pop-up valve. It acts like when you’re sucking a milkshake through a straw and it creates more of a vacuum in the chest. Just a little pop-up valve that pulls a little bit more blood out of the brain and the rest of the body and into the right heart.

We’ve shown in a human study that, for example, the systolic blood pressure almost doubles. It really goes from 40 mm Hg during standard CPR up to 80 mm Hg, and that would be sustained for 14-15 minutes. That was a nice little study that was done in Milwaukee a few years ago.

The other thing that happens is, if you add on something else, it’s like a toilet plunger. I think many people have seen it; it’s called “active compression-decompression.” It not only compresses, but it decompresses. Where it becomes even more effective is that if you had broken bones or stiff bones as you get older or whatever it may be, as you do the CPR, you’re still getting the push down and then you’re getting the pull out. It helps on several levels. More importantly, when you put the two together, they’re very synergistic.

We, have already done the clinical trial that is the proof of concept, and that was published in The Lancet about 10 years ago. In that study, we found that the combination of those two dramatically improved survival rates by 50%, with 1-year survival neurologically intact. That got us on the right track.

The interesting thing is that someone said, “Can we lift the head up a little bit?” We did a large amount of work in the laboratory over 10 years, fine tuning it. When do you first lift the head? How soon is too soon? It’s probably bad if you just go right to it.

We had to get the pump primed a little bit with these other things to get the flow going better, not only pulling blood out of the brain but now, you have a better flow this way. You have to prime at first for a couple of minutes, and we worked out the timing: Is it 3 or 4 minutes? It seems the timing is right at about 2 minutes, then you gradually elevate the head over about 2 minutes. We’re finding that seems to be the optimal way to do it. About 2 minutes of priming with those other two devices, the adjuncts, and then gradually elevate the head over 2 minutes.

When we do that in the laboratory, we’re getting normalized cerebral perfusion pressures. You’re normalizing the flow back again with that. We’re seeing profound differences in outcome as a result, even in these cases of the nonshockables.
 

Dr. Glatter: What you’re doing basically is resulting in an increase in cardiac output, essentially. That really is important, especially in these nonshockable rhythms, correct?

Dr. Pepe: Absolutely. As you’re doing this compression and you’re getting these intracranial pulse waves that are going up because they’re colliding up there. It could be even damaging in itself, but we’re seeing these intracranial raises. The intracranial pressure starts going up more and more over time. Also, peripherally in most people, you’re not getting good flow out there; then, your vasculature starts to relax. The arterials are starting to not get oxygen, so they don’t go out.

With this technique where we’re returning the pressure, we’re getting to 40% of normal now with the active compression-decompression CPR plus an impedance threshold device (ACD+ITD CPR) approach. Now, you add this, and you’re almost normalizing. In humans, even in these asystole patients, we’re seeing end-title CO₂s which are generally in the 15-20 range with standard CPR are now up with ACD+ITD CPR in the 30%-40% range, where we’re getting through 30 or 40 end-tidal CO₂s. Now, we’re seeing even the end-tidal CO₂s moving up into the 40s and 50s. We know there’s a surrogate marker telling us that we are generating much better flows not only to the rest of the body, but most importantly, to the brain.
 

Dr. Glatter: Ryan, could you tell us about the approach in terms of on scene, what you’re doing and how you use the device itself? Maybe you could talk about the backpack that you developed with your fire department?

Ryan P. Quinn, BS, EMS: Our approach has always been to get to the patient quickly, like everybody’s approach on a cardiac arrest when you’re responding. We are an advanced life-support paramedic ambulance service through the fire department – we’re all cross-trained firefighter paramedics. Our first vehicle from the fire department is typically the ambulance. It’s smaller and a little quicker than the fire engine. Two paramedics are going to jump out with two backpacks. One has the automated compressive device (we use the Lucas), and the other one is the sequential patient lifting device, the EleGARD.

Our two paramedics are quick to the patient’s side, and once they make contact with the patient to verify pulseless cardiac arrest, they will unpack. One person will go right to compressions if there’s nobody on compressions already. Sometimes we have a first responder police officer with an automated external defibrillator (AED). We go right to the patient’s side, concentrate on compressions, and within 90 seconds to 2 minutes, we have our bags unpacked, we’ve got the devices turned on, patient lifted up, slid under the device, and we have a supraglottic airway that is placed within 15 seconds already premade with the ITD on top. We have a sealed airway that we can continue to compress with Dr. Pepe’s original discussion of building on what’s previously been shown to work.

Dr. Pepe: Let me make a comment about this. This is so important, what Ryan is saying, because it’s something we found during the study. It’s really a true pit-crew approach. You’re not only getting these materials, which you think you need a medical Sherpa for, but you don’t. They set it up and then when they open it up, it’s all laid out just exactly as you need it. It’s not just how fast you get there; it’s how fast you get this done.

When we look at all cases combined against high-performance systems that had some of the highest survival rates around, when we compare it to those, we found that overall, even if you looked at the ones that had over 20-minute responses, the odds ratios were still three to four times higher. It was impressive.

If you looked at it under 15 minutes, which is really reasonable for most systems that get there by the way, the average time that people start CPR in any system in these studies has been about 8 minutes if you actually start this thing, which takes about 2 minutes more for this new bundle of care with this triad, it’s almost 12-14 times higher in terms of the odds ratio. I’ve never seen anything like that where the higher end is over 100 in terms of your confidence intervals.

Ryan’s system did really well and is one of those with even higher levels of outcomes, mostly because they got it on quickly. It’s like the AED for nonshockables but better because you have a wider range of efficacy where it will work.
 

Dr. Glatter: When the elapsed time was less than 11 minutes, that seemed to be an inflection point in the study, is that correct? You saw that 11-fold higher incidence in terms of neurologically intact survival, is that correct?

Dr. Pepe: We picked that number because that was the median time to get it on board. Half the people were getting it within that time period. The fact that you have a larger window, we’re talking about 13- almost 14-fold improvements in outcome if it was under 15 minutes. It doesn’t matter about the 11 or the 12. It’s the faster you get it on board, the better off you are.

Dr. Glatter: What’s the next step in the process of doing trials and having implementation on a larger scale based on your Annals of Emergency Medicine study? Where do you go from here?

Dr. Pepe: I’ve come to find out there are many confounding variables. What was the quality of CPR? How did people ventilate? Did they give the breath and hold it? Did they give a large enough breath so that blood can go across the transpulmonary system? There are many confounding variables. That’s why I think, in the future, it’s going to be more of looking at things like propensity score matching because we know all the variables that change outcomes. I think that’s going to be a way for me.

The other thing is that we were looking at only 380 cases here. When this doubles up in numbers, as we accrue more cases around the country of people who are implementing this, these numbers I just quoted are going to go up much higher. Unwitnessed asystole is considered futile, and you just don’t get them back. To be able to get these folks back now, even if it’s a small percentage, and the fact that we know that we’re producing this better flow, is pretty striking.

I’m really impressed, and the main thing is to make sure people are educated about it. Number two is that they understand that it has to be done right. It cannot be done wrong or you’re not going to see the differences. Getting it done right is not only following the procedures, the sequence, and how you do it, but it also has to do with getting there quickly, including assigning the right people to put it on and having well-trained people who know what they’re doing.
 

Dr. Glatter: In general, the lay public obviously should not attempt this in the field lifting someone’s head up in the sense of trying to do chest compressions. I think that message is important that you just said. It’s not ready for prime time yet in any way. It has to be done right.

Dr. Pepe: Bystanders have to learn CPR – they will buy us time and we’ll have better outcomes when they do that. That’s number one. Number two is that as more and more systems adopt this, you’re going to see more people coming back. If you think about what we’re doing now, if we only get back 5% of these nonshockable vs. less than 1%, it’s 5% of 800 people a day because a thousand people a day die. Several dozens of lives can be saved on a daily basis, coming back neurologically intact. That’s the key thing.

Dr. Glatter: Ryan, can you comment about your experience in the field? Is there anything in terms of your current approach that you think would be ideal to change at this point?

Mr. Quinn: We’ve established that this is the approach that we want to take and we’re just fine tuning it to be more efficient. Using the choreography of which person is going to do which role, we have clearly defined roles and clearly defined command of the scene so we’re not missing anything. Training is extremely important.

Dr. Glatter: Paul, I want to ask you about your anecdotal experience of people waking up quickly and talking after elevating their heads and going through this process. Having people talk about it and waking up is really fascinating. Maybe you can comment further on this.

Dr. Pepe: That’s a great point that you bring up because a 40- to 50-year-old guy who got saved with this approach, when he came around, he said he was hearing what people were saying. When he came out of it, he found out he had been getting CPR for about 25 minutes because he had persistent recurring ventricular fibrillation. He said, “How could I have survived that that long?”

When we told him about the new approach, he added, “Well, that’s like neuroprotective.” He’s right, because in the laboratory, we showed it was neuroprotective and we’re also getting better flows back there. It goes along with everything else, and so we’ve adopted the name because it is.

These are really high-powered systems we are comparing against, and we have the same level of return of spontaneous circulation. The major difference was when you started talking about the neurointact survival. We don’t have enough numbers yet, but next go around, we’re going to look at cerebral performance category (CPC) – CPC1 vs. the CPC2 – which were both considered intact, but CPC1 is actually better. We’re seeing many more of those, anecdotally.

I also wanted to mention that people do bring this up and say, “Well, let’s do a trial.” As far as we’re concerned, the trial’s been done in terms of The Lancet study 10 years ago that showed that the active compression-decompression had tremendously better outcomes. We show in the laboratories that you augment that a little bit. These are all [Food and Drug Administration] approved. You can go out and buy it tomorrow and get it done. I have no conflicts of interest, by the way, with any of this.

To have this device that’s going to have the potential of saving so many more lives is really an exciting breakthrough. More importantly, we’re understanding more now about the physiology of CPR and why it works. It could work much better with the approaches that we’ve been developing over the last 20 years or so.

Dr. Glatter: Absolutely. I want to thank both of you gentlemen. It’s been really an incredible experience to learn more about an advance in resuscitation that could truly be lifesaving. Thank you again for taking time to join us.

Dr. Glatter is an attending physician in the department of emergency medicine, Lenox Hill Hospital, New York. Dr. Pepe is professor, department of management, policy, and community health, University of Texas Health Sciences Center, Houston. Mr. Quinn is EMS Chief, Edina (Minn.) Fire Department. No conflicts of interest were reported.

A version of this article first appeared Jan. 26 on Medscape.com.

When you became a doctor, you may have moved to one city for med school, another for residency, and a third to be an attending. All that moving can make it hard to maintain friendships. Factor in the challenges from the pandemic, and a physician’s life can be lonely. So, when a patient invites you for coffee or a game of pickleball, do you accept? For almost one-third of the physicians who responded to the Medscape Physician Friendships: The Joys and Challenges 2022, the answer might be yes.

About 29% said they develop friendships with patients. However, a lot depends on the circumstances. As one physician in the report said: “I have been a pediatrician for 35 years, and my patients have grown up and become productive adults in our small, rural, isolated area. You can’t help but know almost everyone.”

As the daughter of a cardiologist, Nishi Mehta, MD, a radiologist and founder of the largest physician-only Facebook group in the country, grew up with that small-town-everyone-knows-the-doctor model.

“When I was a kid, I’d go to the mall, and my friends and I would play a game: How long before a patient [of my dad’s] comes up to me?” she said. At the time, Dr. Mehta was embarrassed, but now she marvels that her dad knew his patients so well that they would recognize his daughter in crowded suburban mall.

In other instances, a physician may develop a friendly relationship after a patient leaves their care. For example, Leo Nissola, MD, now a full-time researcher and immunotherapy scientist in San Francisco, has stayed in touch with some of the patients he treated while at the University of Texas MD Anderson Cancer Center, Houston.

Dr. Nissola said it was important to stay connected with the patients he had meaningful relationships with. “It becomes challenging, though, when a former patient asks for medical advice.” At that moment, “you have to be explicitly clear that the relationship has changed.”
 

A hard line in the sand

The blurring of lines is one reason many doctors refuse to befriend patients, even after they are no longer treating them. The American College of Physicians Ethics Manual advises against treating anyone with whom you have a close relationship, including family and friends.

“Friendships can get in the way of patients being honest with you, which can interfere with medical care,” Dr. Mehta said. “If a patient has a concern related to something they wouldn’t want you to know as friends, it can get awkward. They may elect not to tell you.”

And on the flip side, friendship can provide a view into your private life that you may not welcome in the exam room.

“Let’s say you go out for drinks [with a patient], and you’re up late, but you have surgery the next day,” said Brandi Ring, MD, an ob.gyn. and the associate medical director at the Center for Children and Women in Houston. Now, one of your patients knows you were out until midnight when you had to be in the OR at 5:00 a.m.

Worse still, your relationship could color your decisions about a patient’s care, even unconsciously. It can be hard to maintain objectivity when you have an emotional investment in someone’s well-being.

“We don’t necessarily treat family and friends to the standards of medical care,” said Dr. Ring. “We go above and beyond. We might order more tests and more scans. We don’t always follow the guidelines, especially in critical illness.”

For all these reasons and more, the ACP advises against treating friends.
 

Put physician before friend

But adhering to those guidelines can lead physicians to make some painful decisions. Cutting yourself off from the possibility of friendship is never easy, and the Medscape report found that physicians tend to have fewer friends than the average American.

“Especially earlier in my practice, when I was a young parent, and I would see a lot of other young parents in the same stage in life, I’d think, ‘In other circumstances, I would be hanging out at the park with this person,’ “ said Kathleen Rowland, MD, a family medicine physician and vice chair of education in the department of family medicine at Rush University, Chicago. “But the hard part is, the doctor-patient relationship always comes first.”

To a certain extent, one’s specialty may determine the feasibility of becoming friends with a patient. While Dr. Mehta has never done so, as a radiologist, she doesn’t usually see patients repeatedly. Likewise, a young gerontologist may have little in common with his octogenarian patients. And an older pediatrician is not in the same life stage as his patients’ sleep-deprived new parents, possibly making them less attractive friends.

However, practicing family medicine is all about long-term physician-patient relationships. Getting to know patients and their families over many years can lead to a certain intimacy. Dr. Rowland said that, while a wonderful part of being a physician is getting that unique trust whereby patients tell you all sorts of things about their lives, she’s never gone down the friendship path.

“There’s the assumption I’ll take care of someone for a long period of time, and their partner and their kids, maybe another generation or two,” Dr. Rowland said. “People really do rely on that relationship to contribute to their health.”

Worse, nowadays, when people may be starved for connection, many patients want to feel emotionally close and cared for by their doctor, so it’d be easy to cross the line. While patients deserve a compassionate, caring doctor, the physician is left to walk the line between those boundaries. Dr. Rowland said, “It’s up to the clinician to say: ‘My role is as a doctor. You deserve caring friends, but I have to order your mammogram and your blood counts. My role is different.’ ”
 

Friendly but not friends

It can be tricky to navigate the boundary between a cordial, warm relationship with a patient and that patient inviting you to their daughter’s wedding.

“People may mistake being pleasant and friendly for being friends,” said Larry Blosser, MD, chief medical officer at Central Ohio Primary Care, Westerville. In his position, he sometimes hears from patients who have misunderstood their relationship with a doctor in the practice. When that happens, he advises the physician to consider the persona they’re presenting to the patient. If you’re overly friendly, there’s the potential for confusion, but you can’t be aloof and cold, he said.

Maintaining that awareness helps to prevent a patient’s offhand invitation to catch a movie or go on a hike. And verbalizing it to your patients can make your relationship clear from the get-go.

“I tell patients we’re a team. I’m the captain, and they’re my MVP. When the match is over, whatever the results, we’re done,” said Karenne Fru, MD, PhD, a fertility specialist at Oma Fertility Atlanta. Making deep connections is essential to her practice, so Dr. Fru structures her patient interactions carefully. “Infertility is such an isolating experience. While you’re with us, we care about what’s going on in your life, your pets, and your mom’s chemo. We need mutual trust for you to be compliant with the care.”

However, that approach won’t work when you see patients regularly, as with family practice or specialties that see the same patients repeatedly throughout the year. In those circumstances, the match is never over but one in which the onus is on the physician to establish a friendly yet professional rapport without letting your self-interest, loneliness, or lack of friends interfere.

“It’s been a very difficult couple of years for a lot of us. Depending on what kind of clinical work we do, some of us took care of healthy people that got very sick or passed away,” Dr. Rowland said. “Having the chance to reconnect with people and reestablish some of that closeness, both physical and emotional, is going to be good for us.”

Just continue conveying warm, trusting compassion for your patients without blurring the friend lines.

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

When you became a doctor, you may have moved to one city for med school, another for residency, and a third to be an attending. All that moving can make it hard to maintain friendships. Factor in the challenges from the pandemic, and a physician’s life can be lonely. So, when a patient invites you for coffee or a game of pickleball, do you accept? For almost one-third of the physicians who responded to the Medscape Physician Friendships: The Joys and Challenges 2022, the answer might be yes.

About 29% said they develop friendships with patients. However, a lot depends on the circumstances. As one physician in the report said: “I have been a pediatrician for 35 years, and my patients have grown up and become productive adults in our small, rural, isolated area. You can’t help but know almost everyone.”

As the daughter of a cardiologist, Nishi Mehta, MD, a radiologist and founder of the largest physician-only Facebook group in the country, grew up with that small-town-everyone-knows-the-doctor model.

“When I was a kid, I’d go to the mall, and my friends and I would play a game: How long before a patient [of my dad’s] comes up to me?” she said. At the time, Dr. Mehta was embarrassed, but now she marvels that her dad knew his patients so well that they would recognize his daughter in crowded suburban mall.

In other instances, a physician may develop a friendly relationship after a patient leaves their care. For example, Leo Nissola, MD, now a full-time researcher and immunotherapy scientist in San Francisco, has stayed in touch with some of the patients he treated while at the University of Texas MD Anderson Cancer Center, Houston.

Dr. Nissola said it was important to stay connected with the patients he had meaningful relationships with. “It becomes challenging, though, when a former patient asks for medical advice.” At that moment, “you have to be explicitly clear that the relationship has changed.”
 

A hard line in the sand

The blurring of lines is one reason many doctors refuse to befriend patients, even after they are no longer treating them. The American College of Physicians Ethics Manual advises against treating anyone with whom you have a close relationship, including family and friends.

“Friendships can get in the way of patients being honest with you, which can interfere with medical care,” Dr. Mehta said. “If a patient has a concern related to something they wouldn’t want you to know as friends, it can get awkward. They may elect not to tell you.”

And on the flip side, friendship can provide a view into your private life that you may not welcome in the exam room.

“Let’s say you go out for drinks [with a patient], and you’re up late, but you have surgery the next day,” said Brandi Ring, MD, an ob.gyn. and the associate medical director at the Center for Children and Women in Houston. Now, one of your patients knows you were out until midnight when you had to be in the OR at 5:00 a.m.

Worse still, your relationship could color your decisions about a patient’s care, even unconsciously. It can be hard to maintain objectivity when you have an emotional investment in someone’s well-being.

“We don’t necessarily treat family and friends to the standards of medical care,” said Dr. Ring. “We go above and beyond. We might order more tests and more scans. We don’t always follow the guidelines, especially in critical illness.”

For all these reasons and more, the ACP advises against treating friends.
 

Put physician before friend

But adhering to those guidelines can lead physicians to make some painful decisions. Cutting yourself off from the possibility of friendship is never easy, and the Medscape report found that physicians tend to have fewer friends than the average American.

“Especially earlier in my practice, when I was a young parent, and I would see a lot of other young parents in the same stage in life, I’d think, ‘In other circumstances, I would be hanging out at the park with this person,’ “ said Kathleen Rowland, MD, a family medicine physician and vice chair of education in the department of family medicine at Rush University, Chicago. “But the hard part is, the doctor-patient relationship always comes first.”

To a certain extent, one’s specialty may determine the feasibility of becoming friends with a patient. While Dr. Mehta has never done so, as a radiologist, she doesn’t usually see patients repeatedly. Likewise, a young gerontologist may have little in common with his octogenarian patients. And an older pediatrician is not in the same life stage as his patients’ sleep-deprived new parents, possibly making them less attractive friends.

However, practicing family medicine is all about long-term physician-patient relationships. Getting to know patients and their families over many years can lead to a certain intimacy. Dr. Rowland said that, while a wonderful part of being a physician is getting that unique trust whereby patients tell you all sorts of things about their lives, she’s never gone down the friendship path.

“There’s the assumption I’ll take care of someone for a long period of time, and their partner and their kids, maybe another generation or two,” Dr. Rowland said. “People really do rely on that relationship to contribute to their health.”

Worse, nowadays, when people may be starved for connection, many patients want to feel emotionally close and cared for by their doctor, so it’d be easy to cross the line. While patients deserve a compassionate, caring doctor, the physician is left to walk the line between those boundaries. Dr. Rowland said, “It’s up to the clinician to say: ‘My role is as a doctor. You deserve caring friends, but I have to order your mammogram and your blood counts. My role is different.’ ”
 

Friendly but not friends

It can be tricky to navigate the boundary between a cordial, warm relationship with a patient and that patient inviting you to their daughter’s wedding.

“People may mistake being pleasant and friendly for being friends,” said Larry Blosser, MD, chief medical officer at Central Ohio Primary Care, Westerville. In his position, he sometimes hears from patients who have misunderstood their relationship with a doctor in the practice. When that happens, he advises the physician to consider the persona they’re presenting to the patient. If you’re overly friendly, there’s the potential for confusion, but you can’t be aloof and cold, he said.

Maintaining that awareness helps to prevent a patient’s offhand invitation to catch a movie or go on a hike. And verbalizing it to your patients can make your relationship clear from the get-go.

“I tell patients we’re a team. I’m the captain, and they’re my MVP. When the match is over, whatever the results, we’re done,” said Karenne Fru, MD, PhD, a fertility specialist at Oma Fertility Atlanta. Making deep connections is essential to her practice, so Dr. Fru structures her patient interactions carefully. “Infertility is such an isolating experience. While you’re with us, we care about what’s going on in your life, your pets, and your mom’s chemo. We need mutual trust for you to be compliant with the care.”

However, that approach won’t work when you see patients regularly, as with family practice or specialties that see the same patients repeatedly throughout the year. In those circumstances, the match is never over but one in which the onus is on the physician to establish a friendly yet professional rapport without letting your self-interest, loneliness, or lack of friends interfere.

“It’s been a very difficult couple of years for a lot of us. Depending on what kind of clinical work we do, some of us took care of healthy people that got very sick or passed away,” Dr. Rowland said. “Having the chance to reconnect with people and reestablish some of that closeness, both physical and emotional, is going to be good for us.”

Just continue conveying warm, trusting compassion for your patients without blurring the friend lines.

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

When you became a doctor, you may have moved to one city for med school, another for residency, and a third to be an attending. All that moving can make it hard to maintain friendships. Factor in the challenges from the pandemic, and a physician’s life can be lonely. So, when a patient invites you for coffee or a game of pickleball, do you accept? For almost one-third of the physicians who responded to the Medscape Physician Friendships: The Joys and Challenges 2022, the answer might be yes.

About 29% said they develop friendships with patients. However, a lot depends on the circumstances. As one physician in the report said: “I have been a pediatrician for 35 years, and my patients have grown up and become productive adults in our small, rural, isolated area. You can’t help but know almost everyone.”

As the daughter of a cardiologist, Nishi Mehta, MD, a radiologist and founder of the largest physician-only Facebook group in the country, grew up with that small-town-everyone-knows-the-doctor model.

“When I was a kid, I’d go to the mall, and my friends and I would play a game: How long before a patient [of my dad’s] comes up to me?” she said. At the time, Dr. Mehta was embarrassed, but now she marvels that her dad knew his patients so well that they would recognize his daughter in crowded suburban mall.

In other instances, a physician may develop a friendly relationship after a patient leaves their care. For example, Leo Nissola, MD, now a full-time researcher and immunotherapy scientist in San Francisco, has stayed in touch with some of the patients he treated while at the University of Texas MD Anderson Cancer Center, Houston.

Dr. Nissola said it was important to stay connected with the patients he had meaningful relationships with. “It becomes challenging, though, when a former patient asks for medical advice.” At that moment, “you have to be explicitly clear that the relationship has changed.”
 

A hard line in the sand

The blurring of lines is one reason many doctors refuse to befriend patients, even after they are no longer treating them. The American College of Physicians Ethics Manual advises against treating anyone with whom you have a close relationship, including family and friends.

“Friendships can get in the way of patients being honest with you, which can interfere with medical care,” Dr. Mehta said. “If a patient has a concern related to something they wouldn’t want you to know as friends, it can get awkward. They may elect not to tell you.”

And on the flip side, friendship can provide a view into your private life that you may not welcome in the exam room.

“Let’s say you go out for drinks [with a patient], and you’re up late, but you have surgery the next day,” said Brandi Ring, MD, an ob.gyn. and the associate medical director at the Center for Children and Women in Houston. Now, one of your patients knows you were out until midnight when you had to be in the OR at 5:00 a.m.

Worse still, your relationship could color your decisions about a patient’s care, even unconsciously. It can be hard to maintain objectivity when you have an emotional investment in someone’s well-being.

“We don’t necessarily treat family and friends to the standards of medical care,” said Dr. Ring. “We go above and beyond. We might order more tests and more scans. We don’t always follow the guidelines, especially in critical illness.”

For all these reasons and more, the ACP advises against treating friends.
 

Put physician before friend

But adhering to those guidelines can lead physicians to make some painful decisions. Cutting yourself off from the possibility of friendship is never easy, and the Medscape report found that physicians tend to have fewer friends than the average American.

“Especially earlier in my practice, when I was a young parent, and I would see a lot of other young parents in the same stage in life, I’d think, ‘In other circumstances, I would be hanging out at the park with this person,’ “ said Kathleen Rowland, MD, a family medicine physician and vice chair of education in the department of family medicine at Rush University, Chicago. “But the hard part is, the doctor-patient relationship always comes first.”

To a certain extent, one’s specialty may determine the feasibility of becoming friends with a patient. While Dr. Mehta has never done so, as a radiologist, she doesn’t usually see patients repeatedly. Likewise, a young gerontologist may have little in common with his octogenarian patients. And an older pediatrician is not in the same life stage as his patients’ sleep-deprived new parents, possibly making them less attractive friends.

However, practicing family medicine is all about long-term physician-patient relationships. Getting to know patients and their families over many years can lead to a certain intimacy. Dr. Rowland said that, while a wonderful part of being a physician is getting that unique trust whereby patients tell you all sorts of things about their lives, she’s never gone down the friendship path.

“There’s the assumption I’ll take care of someone for a long period of time, and their partner and their kids, maybe another generation or two,” Dr. Rowland said. “People really do rely on that relationship to contribute to their health.”

Worse, nowadays, when people may be starved for connection, many patients want to feel emotionally close and cared for by their doctor, so it’d be easy to cross the line. While patients deserve a compassionate, caring doctor, the physician is left to walk the line between those boundaries. Dr. Rowland said, “It’s up to the clinician to say: ‘My role is as a doctor. You deserve caring friends, but I have to order your mammogram and your blood counts. My role is different.’ ”
 

Friendly but not friends

It can be tricky to navigate the boundary between a cordial, warm relationship with a patient and that patient inviting you to their daughter’s wedding.

“People may mistake being pleasant and friendly for being friends,” said Larry Blosser, MD, chief medical officer at Central Ohio Primary Care, Westerville. In his position, he sometimes hears from patients who have misunderstood their relationship with a doctor in the practice. When that happens, he advises the physician to consider the persona they’re presenting to the patient. If you’re overly friendly, there’s the potential for confusion, but you can’t be aloof and cold, he said.

Maintaining that awareness helps to prevent a patient’s offhand invitation to catch a movie or go on a hike. And verbalizing it to your patients can make your relationship clear from the get-go.

“I tell patients we’re a team. I’m the captain, and they’re my MVP. When the match is over, whatever the results, we’re done,” said Karenne Fru, MD, PhD, a fertility specialist at Oma Fertility Atlanta. Making deep connections is essential to her practice, so Dr. Fru structures her patient interactions carefully. “Infertility is such an isolating experience. While you’re with us, we care about what’s going on in your life, your pets, and your mom’s chemo. We need mutual trust for you to be compliant with the care.”

However, that approach won’t work when you see patients regularly, as with family practice or specialties that see the same patients repeatedly throughout the year. In those circumstances, the match is never over but one in which the onus is on the physician to establish a friendly yet professional rapport without letting your self-interest, loneliness, or lack of friends interfere.

“It’s been a very difficult couple of years for a lot of us. Depending on what kind of clinical work we do, some of us took care of healthy people that got very sick or passed away,” Dr. Rowland said. “Having the chance to reconnect with people and reestablish some of that closeness, both physical and emotional, is going to be good for us.”

Just continue conveying warm, trusting compassion for your patients without blurring the friend lines.

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

SAN DIEGO – As with many markers for the evaluation of challenging melanocytic lesions, preferentially expressed antigen in melanoma (PRAME) has its benefits and drawbacks, according to Cora Humberson, MD.

“I’m a fan, but there are issues with it,” Dr. Humberson, dermatopathology coordinator in the department of pathology at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “It’s all in how you use it.”

PRAME is part of the cancer/testis (CT) antigens, of which more than 40 have now been identified. They are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumor types, including melanoma and carcinomas of the bladder, lung, and liver. “The biological function of these antigens is not fully understood, but they may act as a repressor of retinoic acid, potentially inhibiting differentiation, inhibiting proliferation arrest – things that we associate with malignancy,” she said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “These immunogenic proteins are being pursued as targets for therapeutic cancer vaccines,” she noted.

CT antigens are also being evaluated for their role in oncogenesis, she added. Recapitulation of portions of the germline gene-expression might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, and metastatic capacity.

According to Dr. Humberson, PRAME can be used to differentiate comingled nevus and melanoma, to distinguish between nevoid melanoma and nevus, and for melanoma margin assessment in sun-damaged skin. One potential pitfall is that sun-damaged melanocytes may express PRAME. “The older the person and the more sun damage [they have], the more likely you are to see this, but the melanocytes won’t be grouped, they’ll be scattered,” she said.

Another pitfall is that less than 15% of nevi may express PRAME. “PRAME can be expressed in scars, so if you’re looking at a spindle cell lesion, be aware that you might be looking at a scar if you’re seeing PRAME expression,” she added. She also noted that PRAME immunohistochemistry (IHC) expression is not a prognostic biomarker in thin melanomas.

If fewer than 25% of cells in a melanocytic lesion express PRAME, most published assessments of PRAME IHC favor nevi as the diagnosis. “If more than 75% are expressing it, it favors melanoma,” Dr. Humberson said. “There’s a big category in between. It’s not that 30% is more likely benign or that 60% is more likely malignant; you can’t really depend upon [PRAME] if you’re in this range.”

A diagnostic accuracy study found that when more than 75% of cells express PRAME, the marker has a sensitivity of 0.63 and a specificity of 0.97.

Selected PRAME-related published references she recommended include: J Cutan Pathol. 2021;48(9):1115-23; Diagnostics. 2022 Sep 9; 12(9):2197, and J Cutan Pathol. 2022;49(9):829-32.

Dr. Humberson reported having no relevant disclosures.

SAN DIEGO – As with many markers for the evaluation of challenging melanocytic lesions, preferentially expressed antigen in melanoma (PRAME) has its benefits and drawbacks, according to Cora Humberson, MD.

“I’m a fan, but there are issues with it,” Dr. Humberson, dermatopathology coordinator in the department of pathology at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “It’s all in how you use it.”

PRAME is part of the cancer/testis (CT) antigens, of which more than 40 have now been identified. They are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumor types, including melanoma and carcinomas of the bladder, lung, and liver. “The biological function of these antigens is not fully understood, but they may act as a repressor of retinoic acid, potentially inhibiting differentiation, inhibiting proliferation arrest – things that we associate with malignancy,” she said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “These immunogenic proteins are being pursued as targets for therapeutic cancer vaccines,” she noted.

CT antigens are also being evaluated for their role in oncogenesis, she added. Recapitulation of portions of the germline gene-expression might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, and metastatic capacity.

According to Dr. Humberson, PRAME can be used to differentiate comingled nevus and melanoma, to distinguish between nevoid melanoma and nevus, and for melanoma margin assessment in sun-damaged skin. One potential pitfall is that sun-damaged melanocytes may express PRAME. “The older the person and the more sun damage [they have], the more likely you are to see this, but the melanocytes won’t be grouped, they’ll be scattered,” she said.

Another pitfall is that less than 15% of nevi may express PRAME. “PRAME can be expressed in scars, so if you’re looking at a spindle cell lesion, be aware that you might be looking at a scar if you’re seeing PRAME expression,” she added. She also noted that PRAME immunohistochemistry (IHC) expression is not a prognostic biomarker in thin melanomas.

If fewer than 25% of cells in a melanocytic lesion express PRAME, most published assessments of PRAME IHC favor nevi as the diagnosis. “If more than 75% are expressing it, it favors melanoma,” Dr. Humberson said. “There’s a big category in between. It’s not that 30% is more likely benign or that 60% is more likely malignant; you can’t really depend upon [PRAME] if you’re in this range.”

A diagnostic accuracy study found that when more than 75% of cells express PRAME, the marker has a sensitivity of 0.63 and a specificity of 0.97.

Selected PRAME-related published references she recommended include: J Cutan Pathol. 2021;48(9):1115-23; Diagnostics. 2022 Sep 9; 12(9):2197, and J Cutan Pathol. 2022;49(9):829-32.

Dr. Humberson reported having no relevant disclosures.

SAN DIEGO – As with many markers for the evaluation of challenging melanocytic lesions, preferentially expressed antigen in melanoma (PRAME) has its benefits and drawbacks, according to Cora Humberson, MD.

“I’m a fan, but there are issues with it,” Dr. Humberson, dermatopathology coordinator in the department of pathology at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “It’s all in how you use it.”

PRAME is part of the cancer/testis (CT) antigens, of which more than 40 have now been identified. They are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumor types, including melanoma and carcinomas of the bladder, lung, and liver. “The biological function of these antigens is not fully understood, but they may act as a repressor of retinoic acid, potentially inhibiting differentiation, inhibiting proliferation arrest – things that we associate with malignancy,” she said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “These immunogenic proteins are being pursued as targets for therapeutic cancer vaccines,” she noted.

CT antigens are also being evaluated for their role in oncogenesis, she added. Recapitulation of portions of the germline gene-expression might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, and metastatic capacity.

According to Dr. Humberson, PRAME can be used to differentiate comingled nevus and melanoma, to distinguish between nevoid melanoma and nevus, and for melanoma margin assessment in sun-damaged skin. One potential pitfall is that sun-damaged melanocytes may express PRAME. “The older the person and the more sun damage [they have], the more likely you are to see this, but the melanocytes won’t be grouped, they’ll be scattered,” she said.

Another pitfall is that less than 15% of nevi may express PRAME. “PRAME can be expressed in scars, so if you’re looking at a spindle cell lesion, be aware that you might be looking at a scar if you’re seeing PRAME expression,” she added. She also noted that PRAME immunohistochemistry (IHC) expression is not a prognostic biomarker in thin melanomas.

If fewer than 25% of cells in a melanocytic lesion express PRAME, most published assessments of PRAME IHC favor nevi as the diagnosis. “If more than 75% are expressing it, it favors melanoma,” Dr. Humberson said. “There’s a big category in between. It’s not that 30% is more likely benign or that 60% is more likely malignant; you can’t really depend upon [PRAME] if you’re in this range.”

A diagnostic accuracy study found that when more than 75% of cells express PRAME, the marker has a sensitivity of 0.63 and a specificity of 0.97.

Selected PRAME-related published references she recommended include: J Cutan Pathol. 2021;48(9):1115-23; Diagnostics. 2022 Sep 9; 12(9):2197, and J Cutan Pathol. 2022;49(9):829-32.

Dr. Humberson reported having no relevant disclosures.

Cancer appears to have overtaken cardiovascular disease (CVD) as a leading cause of death in adults with type 2 diabetes, a 20-year population study in England suggests.

The researchers found that, from 1998 to 2018, in more than 130,000 adults aged 35 and older with type 2 diabetes, all-cause mortality declined for all ages, but cancer mortality increased for those aged 75 and older; people with type 2 diabetes who were smokers had higher and steadily increasing cancer mortality rates; and people with type 2 diabetes had more than twice the rate of colorectal, pancreatic, liver, and endometrial cancer mortality than age- and sex-matched individuals in the general population.

The findings suggest that “cancer prevention strategies therefore deserve at least a similar level of attention as cardiovascular disease prevention, particularly in older people and for some cancers such as liver, colorectal, and pancreatic cancer,” the researchers wrote.

Tailored cancer prevention and early-detection strategies are needed to address persistent inequalities in the older population, the most deprived, and smokers, they added.
 

Breast cancer rates in younger women with type 2 diabetes rising

According to the researchers, “early cancer detection through changes to existing screening [programs], or more in-depth investigations for suspected/nonspecific symptoms, may reduce the number of avoidable cancer deaths in people with type 2 diabetes.”

Moreover, breast cancer rates in younger women with type 2 diabetes are rising by 4.1% per year, they wrote, which suggests such women are high risk and should be screened at a younger age, but screening age would need to be determined in cost-effectiveness analyses.

The study by Suping Ling, PhD, and colleagues was published online in Diabetologia.
 

Results challenge belief that preventing CVD is priority in type 2 diabetes

“The prevention of cardiovascular disease has been, and is still considered, a priority in people with diabetes,” the researchers wrote.

“Our results challenge this view by showing that cancer may have overtaken cardiovascular disease as a leading cause of death in people with type 2 diabetes.”

“The proportion of cancer deaths out of all-cause deaths remains high (> 30%) in young ages, and it was steadily increasing in older ages,” Dr. Ling, from the department of noncommunicable disease epidemiology, London School of Hygiene & Tropical Medicine, said in a comment.

“Combined with previous studies reporting decreasing CVD mortality rates,” she said, “we concluded that cancer might have overtaken CVD as the leading cause of death in people with type 2 diabetes.”

Many evidence-based cancer-prevention strategies related to lifestyle (such as being physically active, being a healthy weight, eating a better diet, stopping smoking, as summarized by the World Cancer Research Fund), are helpful for preventing both cancer and CVD, Ling observed.

However, in the medical community, many additional efforts were made for monitoring, early detection, and innovating medications for CVD, she noted. “Therefore, we would like to propose a similar level of attention and effort for cancer in people with type 2 diabetes.”
 

Deaths from cancer vs. all causes in patients with diabetes

The researchers identified 137,804 patients aged 35 and older who were newly diagnosed with type 2 diabetes from 1998 to 2018 in general practices in the UK that were part of the Clinical Practice Research Datalink.

Patients were a median age of 64 years and 45% were women. Most (83%) were White, followed by South Asian (3.5%), Black (2.0%), and other (3%); 8.4% had missing information for race. Patients had a median body mass index (BMI) of 30.6 kg/m².

Researchers divided patients into socioeconomic quintiles of most to least deprived based on income, employment, education, and other factors. During a median follow-up of 8.4 years, there were 39,212 deaths (28.5%).
 

Cancer mortality in subgroups of patients with type 2 diabetes

Researchers analyzed annual deaths from cancer and from all causes over 20 years in subgroups of patients with type 2 diabetes.

In adults with type 2 diabetes, the average percentage change in cancer mortality per year, from 1998 to 2018 decreased in people aged 55 and 65 (–1.4% and –0.2%, respectively), but increased in people aged 75 and 85 (1.2% and 1.6%, respectively); increased more in women than in men (1.5% vs 1.0%), although women had lower cancer mortality than men; and increased more in the least deprived (wealthiest) individuals than in the most deprived (1.5% vs 1.0%). Cancer mortality rates were consistently higher in the most deprived individuals, Dr. Ling noted.

Cancer mortality also increased more in people with class III obesity (BMI ≥ 35) versus normal weight (5.8% vs 0.7%) and versus other weights. In addition, there was an upward trend in cancer mortality in people who were White or former/current smokers.
 

Deaths from specific cancers in diabetes vs. general population

Next, researchers determined cancer mortality ratios – the cancer mortality of the patients with diabetes divided by the cancer mortality of the general population.

They determined this for all cancers, the four most common cancers in the United Kingdom (lung, colorectal, breast, and prostate), and cancers caused by type 2 diabetes (pancreatic, liver, gallbladder, and endometrial cancer), standardized by sex and age.

Mortality from all cancer was 18% higher in patients with type 2 diabetes, compared with the general population.

Overall, mortality from colorectal cancer, pancreatic cancer, and liver cancer was 2.4 times, 2.12 times, and 2.13 times higher, respectively, in patients with type 2 diabetes than in the general population.

Mortality from breast cancer was 9% higher and mortality from endometrial cancer was 2.08 times higher in women with type 2 diabetes than in women in the general population.

There was a constant upward trend for mortality rates for pancreatic, liver, and lung cancer at all ages, colorectal cancer at most ages, breast cancer at younger ages, and prostate and endometrial cancer at older ages.

The study was funded by Hope Against Cancer. Dr. Ling reported no relevant financial relationships.

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

Cancer appears to have overtaken cardiovascular disease (CVD) as a leading cause of death in adults with type 2 diabetes, a 20-year population study in England suggests.

The researchers found that, from 1998 to 2018, in more than 130,000 adults aged 35 and older with type 2 diabetes, all-cause mortality declined for all ages, but cancer mortality increased for those aged 75 and older; people with type 2 diabetes who were smokers had higher and steadily increasing cancer mortality rates; and people with type 2 diabetes had more than twice the rate of colorectal, pancreatic, liver, and endometrial cancer mortality than age- and sex-matched individuals in the general population.

The findings suggest that “cancer prevention strategies therefore deserve at least a similar level of attention as cardiovascular disease prevention, particularly in older people and for some cancers such as liver, colorectal, and pancreatic cancer,” the researchers wrote.

Tailored cancer prevention and early-detection strategies are needed to address persistent inequalities in the older population, the most deprived, and smokers, they added.
 

Breast cancer rates in younger women with type 2 diabetes rising

According to the researchers, “early cancer detection through changes to existing screening [programs], or more in-depth investigations for suspected/nonspecific symptoms, may reduce the number of avoidable cancer deaths in people with type 2 diabetes.”

Moreover, breast cancer rates in younger women with type 2 diabetes are rising by 4.1% per year, they wrote, which suggests such women are high risk and should be screened at a younger age, but screening age would need to be determined in cost-effectiveness analyses.

The study by Suping Ling, PhD, and colleagues was published online in Diabetologia.
 

Results challenge belief that preventing CVD is priority in type 2 diabetes

“The prevention of cardiovascular disease has been, and is still considered, a priority in people with diabetes,” the researchers wrote.

“Our results challenge this view by showing that cancer may have overtaken cardiovascular disease as a leading cause of death in people with type 2 diabetes.”

“The proportion of cancer deaths out of all-cause deaths remains high (> 30%) in young ages, and it was steadily increasing in older ages,” Dr. Ling, from the department of noncommunicable disease epidemiology, London School of Hygiene & Tropical Medicine, said in a comment.

“Combined with previous studies reporting decreasing CVD mortality rates,” she said, “we concluded that cancer might have overtaken CVD as the leading cause of death in people with type 2 diabetes.”

Many evidence-based cancer-prevention strategies related to lifestyle (such as being physically active, being a healthy weight, eating a better diet, stopping smoking, as summarized by the World Cancer Research Fund), are helpful for preventing both cancer and CVD, Ling observed.

However, in the medical community, many additional efforts were made for monitoring, early detection, and innovating medications for CVD, she noted. “Therefore, we would like to propose a similar level of attention and effort for cancer in people with type 2 diabetes.”
 

Deaths from cancer vs. all causes in patients with diabetes

The researchers identified 137,804 patients aged 35 and older who were newly diagnosed with type 2 diabetes from 1998 to 2018 in general practices in the UK that were part of the Clinical Practice Research Datalink.

Patients were a median age of 64 years and 45% were women. Most (83%) were White, followed by South Asian (3.5%), Black (2.0%), and other (3%); 8.4% had missing information for race. Patients had a median body mass index (BMI) of 30.6 kg/m².

Researchers divided patients into socioeconomic quintiles of most to least deprived based on income, employment, education, and other factors. During a median follow-up of 8.4 years, there were 39,212 deaths (28.5%).
 

Cancer mortality in subgroups of patients with type 2 diabetes

Researchers analyzed annual deaths from cancer and from all causes over 20 years in subgroups of patients with type 2 diabetes.

In adults with type 2 diabetes, the average percentage change in cancer mortality per year, from 1998 to 2018 decreased in people aged 55 and 65 (–1.4% and –0.2%, respectively), but increased in people aged 75 and 85 (1.2% and 1.6%, respectively); increased more in women than in men (1.5% vs 1.0%), although women had lower cancer mortality than men; and increased more in the least deprived (wealthiest) individuals than in the most deprived (1.5% vs 1.0%). Cancer mortality rates were consistently higher in the most deprived individuals, Dr. Ling noted.

Cancer mortality also increased more in people with class III obesity (BMI ≥ 35) versus normal weight (5.8% vs 0.7%) and versus other weights. In addition, there was an upward trend in cancer mortality in people who were White or former/current smokers.
 

Deaths from specific cancers in diabetes vs. general population

Next, researchers determined cancer mortality ratios – the cancer mortality of the patients with diabetes divided by the cancer mortality of the general population.

They determined this for all cancers, the four most common cancers in the United Kingdom (lung, colorectal, breast, and prostate), and cancers caused by type 2 diabetes (pancreatic, liver, gallbladder, and endometrial cancer), standardized by sex and age.

Mortality from all cancer was 18% higher in patients with type 2 diabetes, compared with the general population.

Overall, mortality from colorectal cancer, pancreatic cancer, and liver cancer was 2.4 times, 2.12 times, and 2.13 times higher, respectively, in patients with type 2 diabetes than in the general population.

Mortality from breast cancer was 9% higher and mortality from endometrial cancer was 2.08 times higher in women with type 2 diabetes than in women in the general population.

There was a constant upward trend for mortality rates for pancreatic, liver, and lung cancer at all ages, colorectal cancer at most ages, breast cancer at younger ages, and prostate and endometrial cancer at older ages.

The study was funded by Hope Against Cancer. Dr. Ling reported no relevant financial relationships.

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

Cancer appears to have overtaken cardiovascular disease (CVD) as a leading cause of death in adults with type 2 diabetes, a 20-year population study in England suggests.

The researchers found that, from 1998 to 2018, in more than 130,000 adults aged 35 and older with type 2 diabetes, all-cause mortality declined for all ages, but cancer mortality increased for those aged 75 and older; people with type 2 diabetes who were smokers had higher and steadily increasing cancer mortality rates; and people with type 2 diabetes had more than twice the rate of colorectal, pancreatic, liver, and endometrial cancer mortality than age- and sex-matched individuals in the general population.

The findings suggest that “cancer prevention strategies therefore deserve at least a similar level of attention as cardiovascular disease prevention, particularly in older people and for some cancers such as liver, colorectal, and pancreatic cancer,” the researchers wrote.

Tailored cancer prevention and early-detection strategies are needed to address persistent inequalities in the older population, the most deprived, and smokers, they added.
 

Breast cancer rates in younger women with type 2 diabetes rising

According to the researchers, “early cancer detection through changes to existing screening [programs], or more in-depth investigations for suspected/nonspecific symptoms, may reduce the number of avoidable cancer deaths in people with type 2 diabetes.”

Moreover, breast cancer rates in younger women with type 2 diabetes are rising by 4.1% per year, they wrote, which suggests such women are high risk and should be screened at a younger age, but screening age would need to be determined in cost-effectiveness analyses.

The study by Suping Ling, PhD, and colleagues was published online in Diabetologia.
 

Results challenge belief that preventing CVD is priority in type 2 diabetes

“The prevention of cardiovascular disease has been, and is still considered, a priority in people with diabetes,” the researchers wrote.

“Our results challenge this view by showing that cancer may have overtaken cardiovascular disease as a leading cause of death in people with type 2 diabetes.”

“The proportion of cancer deaths out of all-cause deaths remains high (> 30%) in young ages, and it was steadily increasing in older ages,” Dr. Ling, from the department of noncommunicable disease epidemiology, London School of Hygiene & Tropical Medicine, said in a comment.

“Combined with previous studies reporting decreasing CVD mortality rates,” she said, “we concluded that cancer might have overtaken CVD as the leading cause of death in people with type 2 diabetes.”

Many evidence-based cancer-prevention strategies related to lifestyle (such as being physically active, being a healthy weight, eating a better diet, stopping smoking, as summarized by the World Cancer Research Fund), are helpful for preventing both cancer and CVD, Ling observed.

However, in the medical community, many additional efforts were made for monitoring, early detection, and innovating medications for CVD, she noted. “Therefore, we would like to propose a similar level of attention and effort for cancer in people with type 2 diabetes.”
 

Deaths from cancer vs. all causes in patients with diabetes

The researchers identified 137,804 patients aged 35 and older who were newly diagnosed with type 2 diabetes from 1998 to 2018 in general practices in the UK that were part of the Clinical Practice Research Datalink.

Patients were a median age of 64 years and 45% were women. Most (83%) were White, followed by South Asian (3.5%), Black (2.0%), and other (3%); 8.4% had missing information for race. Patients had a median body mass index (BMI) of 30.6 kg/m².

Researchers divided patients into socioeconomic quintiles of most to least deprived based on income, employment, education, and other factors. During a median follow-up of 8.4 years, there were 39,212 deaths (28.5%).
 

Cancer mortality in subgroups of patients with type 2 diabetes

Researchers analyzed annual deaths from cancer and from all causes over 20 years in subgroups of patients with type 2 diabetes.

In adults with type 2 diabetes, the average percentage change in cancer mortality per year, from 1998 to 2018 decreased in people aged 55 and 65 (–1.4% and –0.2%, respectively), but increased in people aged 75 and 85 (1.2% and 1.6%, respectively); increased more in women than in men (1.5% vs 1.0%), although women had lower cancer mortality than men; and increased more in the least deprived (wealthiest) individuals than in the most deprived (1.5% vs 1.0%). Cancer mortality rates were consistently higher in the most deprived individuals, Dr. Ling noted.

Cancer mortality also increased more in people with class III obesity (BMI ≥ 35) versus normal weight (5.8% vs 0.7%) and versus other weights. In addition, there was an upward trend in cancer mortality in people who were White or former/current smokers.
 

Deaths from specific cancers in diabetes vs. general population

Next, researchers determined cancer mortality ratios – the cancer mortality of the patients with diabetes divided by the cancer mortality of the general population.

They determined this for all cancers, the four most common cancers in the United Kingdom (lung, colorectal, breast, and prostate), and cancers caused by type 2 diabetes (pancreatic, liver, gallbladder, and endometrial cancer), standardized by sex and age.

Mortality from all cancer was 18% higher in patients with type 2 diabetes, compared with the general population.

Overall, mortality from colorectal cancer, pancreatic cancer, and liver cancer was 2.4 times, 2.12 times, and 2.13 times higher, respectively, in patients with type 2 diabetes than in the general population.

Mortality from breast cancer was 9% higher and mortality from endometrial cancer was 2.08 times higher in women with type 2 diabetes than in women in the general population.

There was a constant upward trend for mortality rates for pancreatic, liver, and lung cancer at all ages, colorectal cancer at most ages, breast cancer at younger ages, and prostate and endometrial cancer at older ages.

The study was funded by Hope Against Cancer. Dr. Ling reported no relevant financial relationships.

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